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Mojdeh Akbari,1 Fakhrolmolouk Yassaee,2 Mona Aminbeidokhti,1 Atieh Abedin-Do,1,3 Reza Mirfakhraie1,41Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; 2Department of Obstetrics and Gynecology, Taleghani Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran; 3GREB, Dental Faculty, Department of Regenerative Medicine, Faculty of Medicine, Laval University, Quebec, Canada; 4Department of Molecular Genetics, Genomic Research Center, Shahid Beheshti University of Medical Sciences, Tehran, IranCorrespondence: Reza MirfakhraieDepartment of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Koodakyar St, Velenjak Ave, Chamran highway, Tehran 19395-4719, IranTel/Fax +98 212 387 2572Email reza_mirfakhraie@yahoo.comFakhrolmolouk YassaeeDepartment of Obstetrics and Gynecology, Taleghani Hospital, Shahid Beheshti University of Medical Sciences, PO Box 1985717413, Tehran, IranEmail Dr_fyass@yahoo.comBackground: Uterine leiomyomas (ULMs) are benign uterine tumors that are estrogen-dependent. Recent studies suggest that the abnormal expression of the steroid receptor RNA activator 1 (SRA1) long non-coding RNA (lncRNA) might participate in the mechanisms of tumorigenesis of some hormone-dependent tumors including breast cancer. SRA1 is known to enhance the transcriptional activity of steroid receptors and also promotes steroidogenesis. The level of steroid hormones, such as estrogen and the progesterone, and their receptors play an important role in the development and growth of leiomyoma. The aim of the present study was to determine the expression level of lncRNA SRA1 in ULM tissues considering the MED12 mutation pattern.Methods: Mutation screening was performed for MED12 exons 1 and 2 and the intronic flanking regions using Sanger sequencing in 60 ULM tissues. Quantitative real-time polymerase chain reaction (qRT-PCRs) was performed in order to estimate the expression of lncRNA SRA1 in leiomyoma samples with and without MED12 gene mutations. The expression results were analyzed by using LinReg and REST software.Results: Mutations were detected in exon 2 of the MED12 in 28 (46.67%) ULM samples; including, 21 (75%) missense mutations and 7 (25%) in-frame deletions. No mutation was detected in the MED12 exon 1. LncRNA SRA1 was over-expressed in ULM samples without MED12 mutation compared with ULM samples harboring MED12 mutation (Expression ratio=2.5, P-value=0.004).Conclusion: Present results suggest that lncRNA SRA1 may explain the phenotypic difference observed in the tumor size of ULM samples considering MED12 mutation pattern. Therefore, it serves as a good therapeutic target and provides new insight into understanding the disease molecular mechanism.Keywords: MED12, mutation, SRA1, lncRNA, uterine leiomyoma

Maryam Khani,1 Jalil Hosseini,2 Reza Mirfakhraie,1 Mohsen Habibi,3 Eznollah Azargashb,4 Farkhondeh Pouresmaeili1,21Medical Genetics Department, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; 2Infertility and Reproductive Health Research Center (IRHRC), Shahid Beheshti University of Medical Sciences, Tehran, Iran; 3Central laboratory, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; 4Department of Community Medicine, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, IranIntroduction: Prostate cancer (PCa) is the most common cancer among men and the second cause of cancer death among men. For early detection and differentiating PCa from benign prostate hyperplasia (BPH) tissue biopsy has been used for decades. However, circulating cell-free DNA (ccfDNA) testing is a noninvasive, fast, easily repeatable, and sensitive liquid biopsy for cancer detection. Hence, we aimed to investigate the value of the ccfDNA concentration and integrity index in peripheral blood of a population of Iranian prostatic patients for early diagnosis of the disease.Materials and methods: 100 subjects including 30 PCa, 40 BPH, and 30 healthy individuals were selected. ccfDNA was extracted from fresh blood plasma, and its total concentration and the integrity index were estimated by amplification of ALU115 and ALU247 repeat elements using quantitative real-time PCR.Results: In the PCa group, the ccfDNA concentration and its integrity were significantly higher than that of the BPH and healthy groups (P-value

Mahnaz Seifi-Alan,1 Roshanak Shams,1 Mojgan Bandehpour,2 Reza Mirfakhraie,1 Soudeh Ghafouri-Fard1 1Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran; 2Department of Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran Purpose: Neuropilin-1 (NRP1) as an isoform-specific receptor for vascular endothelial growth factor and placenta growth factor in endothelial cells has been demonstrated to be expressed in breast cancer cells where it plays functional roles in cell survival, invasion, and migration. We hypothesized that an expression of NRP1 in breast cancer tissues is associated with clinicopathological data of patients and expression of the tumor suppressor miR-206. Patients and methods: We evaluated the expression of NRP1 in 48 invasive ductal carcinomas of the breast and their corresponding adjacent noncancerous tissues (ANCTs) by means of real-time polymerase chain reaction. We also extracted data on miR-206 gene expression from the same cohort of patients to evaluate the correlation between expression levels of miR-206 and NRP1. In addition, we quantified NRP1 protein levels using the enzyme-linked immunosorbent assay technique. Results: No significant difference was found in NRP1 expression between tumoral tissues and ANCTs. We also assessed the associations between expression levels of NRP1 and clinicopathological data of patients and found no significant associations between NRP1 transcript levels and any characteristic. However, NRP1 protein concentrations were significantly higher in patients with lymph node involvement compared with those without lymph node involvement. No correlation was found between NRP1 and miR-206 expression levels. Conclusion: NRP1 protein levels might be an indicator of metastasis potential in breast cancer. Future studies are needed to confirm these results in larger cohorts of patients. Keywords: NRP1, neuropilin-1, breast cancer

Mohaddeseh Salehi,1,* Mona Amin-Beidokhti,2,* Behnam Safarpour Lima,3 Milad Gholami,2 Gholam-Reza Javadi,1 Reza Mirfakhraie2,4 1Department of Biology, Islamic Azad University, Science and Research Branch, 2Department of Medical Genetics, 3Department of Neurology, School of Medicine, 4Genomic Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran *These authors contributed equally to this work Introduction: Migraine is a painful complex neurovascular disease characterized by recurrent moderate-to-severe headaches. Increased level of homocysteine is related to dilation of cerebral vessels and endothelial injury that could trigger migraine attacks. Functional polymorphisms in the MTHFR gene affect homocysteine metabolism and, therefore, play an important role in the etiology of the disease. Objectives: We aimed to investigate the possible association between MTHFR gene rs4846049, C677T, and A1298C polymorphisms and the risk of migraine in Iranian population. Methods: In this genetic association study, 498 individuals were enrolled, including 223 migraine patients and 275 healthy controls. Genotyping was performed using tetra-primer ARMS-PCR for rs4846049 and PCR-restriction fragment length polymorphism for C677T and A1298C polymorphisms. Results: The association between rs4846049 and C677T polymorphisms and migraine was observed. For the rs4846049 polymorphism, the association was detected under a dominant model (P=0.007; odds ratio [OR] =0.60; 95% confidence interval [CI], 0.41–0.87), and for the C677T polymorphism, the TT genotype frequency was significantly different in the studied groups (P=0.009; OR =2.48; 95% CI, 1.25–4.92). No significant differences in the genotype or allele frequencies were found for the A1298C polymorphism between the migraineurs and controls. Conclusion: Present data provide evidence for the association of rs4846049 and C677T polymorphisms in the MTHFR gene and migraine. Further studies are required to validate the significance of the studied genetic variations in diverse ethnic populations. Keywords: migraine, genetic association study, MTHFR, single nucleotide polymorphism

In brief, we report an Iranian family with a history of both azoospermia and premature ovarian insufficiency with the same heterozygote mutation in the NR5A1 gene that can be transmitted. As far as we know, this is the first observation that a common mutation in NR5A1 can cause these above-mentioned phenotypes in a family. [ABSTRACT FROM AUTHOR]

Introduction: Genetic factors cause about 10% of male infertility. However, the etiology of the majority of male infertility cases including non-obstructive azoospermia or severe oligospermia remains idiopathic. Defects in DNA repair during spermatogenesis are thought to underlie some types of testicular failure. Evidence is accumulating to demonstrate the importance of DNA repair defects in human non-obstructive azoospermia. In eukaryotes, homologs of the bacterial MutL proteins, including MLH3, function in DNA mismatch repair and recombination pathway and therefore may play a crucial role in spermatogenesis. Materials and Methods: In the present study, we investigated the association between C2531T polymorphism in the MLH3 gene non-obstructive azoospermia using the tetra-amplification refractory mutation system-PCR (4P-ARMS-PCR) method in 94 non-obstructive azoospermia patients and 80 fertile controls. The amplified DNA was visualized on 2.0% agarose gel containing DNA safe viewer. Results: We observed an increased risk of male infertility associated with the MLH3 (CT+TT) (OR, 2.34; 95% CI, 1.19-4.62; p=0.012) genotype, compared to the MLH3 CC genotype. Conclusion: Our results show an association between C2531T polymorphism in MLH3 with non-obstructive azoospermia. Therefore, the MLH3 polymorphism may be genetic determinants for human spermatogenesis impairment. [ABSTRACT FROM AUTHOR]

Introduction: The Wnt/β-catenin signaling pathway controls many developmental processes during the entire lifetime where its disorders can cause a wide range of pathologic defects including cancer in both animals and humans. It has some key roles in reproductive processes. The aim of this study was to compare expression of FZD10 gene (the main receptor) and GSK3-β gene (the key regulator) of this signaling pathway in obstructive and non-obstructive azoospermic men. Materials and Methods: WNT3a protein concentration, expression level of FZD10 and GSK3-β genes were measured and compared between two groups of infertile men (with obstructive and nonobstructive azoospermia). Samples were obtained by testicular biopsy and screened for the most common mutations (84, 86 and 255) in the SRY region and CFTR before analyzing. FZD10 and GSK3-β gene expression was assessed quantitatively by real time-PCR. Results: The WNT3a protein concentration had no significant difference between the two test groups and controls. Expression level of FZD10 gene had no significant difference between two patient groups and control, however was slightly less in non-obstructive azoospermic men. Expression of GSK3-β was down-regulated in non-obstructive azoospermia compared with normal and obstructive azoospermia groups (p<0.05). Conclusion: Down-regulation of GSK3-β may cause to non-obstructive azoospermia in which the spermatogenesis is impalanced. Regulation and modification of GSK3-β gene expression by drugs could be used as a therapeutic solution. [ABSTRACT FROM AUTHOR]

Background and Objective: Autosomal recessive genetic disorders pose significant health challenges in regions where consanguineous marriages are prevalent. The utilization of exome sequencing as a frequently employed methodology has enabled a clear delineation of diagnostic efficacy and mode of inheritance within multiplex consanguineous families. However, these aspects remain less elucidated within simplex families., Methods: In this study involving 12 unrelated simplex Iranian families presenting syndromic autism, we conducted singleton exome sequencing. The identified genetic variants were validated using Sanger sequencing, and for the missense variants in FOXG1 and DMD, 3D protein structure modeling was carried out to substantiate their pathogenicity. To examine the expression patterns of the candidate genes in the fetal brain, adult brain, and muscle, RT-qPCR was employed., Results: In four families, we detected an autosomal dominant gene (FOXG1), an autosomal recessive gene (CHKB), and two X-linked autism genes (IQSEC2 and DMD), indicating diverse inheritance patterns. In the remaining eight families, we were unable to identify any disease-associated genes. As a result, our variant detection rate stood at 33.3% (4/12), surpassing rates reported in similar studies of smaller cohorts. Among the four newly identified coding variants, three are de novo (heterozygous variant p.Trp546Ter in IQSEC2, heterozygous variant p.Ala188Glu in FOXG1, and hemizygous variant p.Leu211Met in DMD), while the homozygous variant p.Glu128Ter in CHKB was inherited from both healthy heterozygous parents. 3D protein structure modeling was carried out for the missense variants in FOXG1 and DMD, which predicted steric hindrance and spatial inhibition, respectively, supporting the pathogenicity of these human mutants. Additionally, the nonsense variant in CHKB is anticipated to influence its dimerization - crucial for choline kinase function - and the nonsense variant in IQSEC2 is predicted to eliminate three functional domains. Consequently, these distinct variants found in four unrelated individuals with autism are likely indicative of loss-of-function mutations., Conclusions: In our two syndromic autism families, we discovered variants in two muscular dystrophy genes, DMD and CHKB. Given that DMD and CHKB are recognized for their participation in the non-cognitive manifestations of muscular dystrophy, it indicates that some genes transcend the boundary of apparently unrelated clinical categories, thereby establishing a novel connection between ASD and muscular dystrophy. Our findings also shed light on the complex inheritance patterns observed in Iranian consanguineous simplex families and emphasize the connection between autism spectrum disorder and muscular dystrophy. This underscores a likely genetic convergence between neurodevelopmental and neuromuscular disorders., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: The ultra-rare autosomal recessive genetic disorder, You-Hoover-Fong Syndrome (YHFS), is caused by defects in the TELO2 gene and is characterized by intellectual disability, developmental delay, and ocular impairments. This study aims to contribute to a better understanding of YHFS by reviewing previous cases and introducing a novel variant in a new case., Methods: Whole exome sequencing (WES) was conducted on the proband to identify genetic variants, and Sanger sequencing was used to confirm variants within the family. This article presents a comprehensive collection of reported cases of YHFS, incorporating both molecular and clinical data, through an extensive literature search and analysis of English-language studies published until June 2023., Results: Using WES, a novel homozygous missense variant, c.1799A > G (p. Tyr600Cys), was identified in the TELO2 gene in a 4-year-old Iranian male patient. Novel clinical features, including choanal atresia and clubfoot, were also identified. A comprehensive literature review identified 27 patients with YHFS, with 20 variants in the TELO2 gene. Missense pathogenic variants were the most common type of pathogenic variant, and the most common features were microcephaly and intellectual impairment., Conclusion: This study presents the first case of pathogenic variants in TELO2 gene in Iran, expands the genotypic and phenotypic spectrum of YHFS and contributes to the growing body of literature pertaining to YHFS. Furthermore, our findings highlight the importance of genetic testing for non-consanguineous carrier screening, as compound heterozygosity may be a significant factor in the development of YHFS. Further research is needed to clarify the molecular mechanisms underlying YHFS pathogenesis., (© 2024. Fondazione Società Italiana di Neurologia.)

Glycogen storage diseases (GSDs) are a group of rare inherited metabolic disorders characterized by clinical, locus, and allele heterogeneity. This study aims to investigate the phenotype and genotype spectrum of GSDs in a cohort of 14 families from Iran using whole-exome sequencing (WES) and variant analysis. WES was performed on 14 patients clinically suspected of GSDs. Variant analysis was performed to identify genetic variants associated with GSDs. A total of 13 variants were identified, including six novel variants, and seven previously reported pathogenic variants in genes such as AGL, G6PC, GAA, PYGL, PYGM, GBE1, SLC37A4, and PHKA2. Most types of GSDs observed in the cohort were associated with hepatomegaly, which was the most common clinical presentation. This study provides valuable insights into the phenotype and genotype spectrum of GSDs in a cohort of Iranian patients. The identification of novel variants adds to the growing body of knowledge regarding the genetic landscape of GSDs and has implications for genetic counseling and future therapeutic interventions. The diverse nature of GSDs underscores the need for comprehensive genetic testing methods to improve diagnostic accuracy. Continued research in this field will enhance our understanding of GSDs, ultimately leading to improved management and outcomes for individuals affected by these rare metabolic disorders., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: B cell acute lymphoblastic leukemia-lymphoma (B-ALL) accounts for approximately 75% of ALL cases and is observed in children and adults. Recent advances in disease diagnosis, stratification and prognostication have led to a better characterization of different subgroups of ALL. Notwithstanding the significant improvement in the complete remission rate of B-ALL, patients with minimal residual disease (MRD) and relapsed/refractory (R/R) settings suffer from poor outcomes., Hypothesis: However, novel therapies, such as agents targeting tyrosine kinases or the CD20 molecule, combination therapies and improved supportive care, have changed the treatment landscape of B-ALL., Method and Results: Meanwhile, blinatumomab has been FDA-approved for MRD-positive or R/R B-ALL patients. Blinatumomab is a bispecific T cell engager containing the CD3 and CD19 that recognize domains redirecting cytotoxic T cells to lyse B cells. Promising outcomes, including long-term overall survival and improved MRD-negative response rates, have been reported in patients who received this drug. Adding blinatumomab to new ALL regimens seems promising for achieving better outcomes in poor prognosis B-ALL patients. Nevertheless, the neurotoxicity and cytokine release syndrome are the two major adverse events following the blinatumomab therapy., Conclusion: This review summarizes the function and effectiveness of blinatumomab in R/R and MRD positive B-ALL patients. Furthermore, blinatumomab's positive and negative aspects as a novel therapy for B-ALL patients have been briefly discussed., Competing Interests: Conflicts of interest The authors have no conflicts of interest to declare., (Copyright © 2023. Published by Elsevier España, S.L.U.)

Background and Aims: The occurrence of thiamine metabolism dysfunction syndrome (THMD), a rare autosomal recessive condition, may be linked to various mutations found in the TPK1 and SLC19A3 genes. The disease chiefly manifests through ataxia, muscle hypotonia, abrupt or subacute onset encephalopathy, and a decline in developmental milestones achieved during the early stages of infancy. We present findings from an investigation that involved two individuals from Iran, both of whom experienced seizures along with ataxia and hypotonia. The underlying genetic causes were found with the use of next-generation sequencing (NGS) technology, which has facilitated the detection of causal changes in a variety of genetic disorders., Material and Methods: The selection of cases for this study was based on the phenotypic and genetic information that was obtainable from the Center for Comprehensive Genetic Services. The genetic basis for the problems observed among the participants was determined through the application of whole-exome sequencing (WES). Subsequently, sanger sequencing was employed as a means of validating any identified variations suspected to be causative., Results: The first patient exhibited a homozygous mutation in the TPK1 gene, NM&#95;022445.4:c.224 T > A:p.I75 N, resulting in the substitution of isoleucine for asparagine at position 75 (p.I75 N). In our investigation, patient 2 exhibited a homozygous variant, NM&#95;025243.4:c.1385dupA:pY462X, within the SLC19A3 gene., Conclusions: Collectively, when presented with patients showcasing ataxia, encephalopathy, and basal ganglia necrosis, it is essential to account for thiamine deficiency in light of the potential advantages of prompt intervention. At times, it may be feasible to rectify this deficiency through the timely administration of thiamine dosages. Accordingly, based on the results of the current investigation, these variations may be useful for the diagnosis and management of patients with THMD., Competing Interests: The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication., (© 2024 The Authors.)

Background: Pontocerebellar hypoplasia is an umbrella term describing a heterogeneous group of prenatal neurodegenerative disorders mostly affecting the pons and cerebellum, with 17 types associated with 25 genes. However, some types of PCH lack sufficient information, which highlights the importance of investigating and introducing more cases to further elucidate the clinical, radiological, and biochemical features of these disorders. The aim of this study is to provide an in-depth review of PCH and to identify disease genes and their inheritance patterns in 12 distinct Iranian families with clinically confirmed PCH., Methods: Cases included in this study were selected based on their phenotypic and genetic information available at the Center for Comprehensive Genetic Services. Whole-exome sequencing (WES) was used to discover the underlying genetic etiology of participants' problems, and Sanger sequencing was utilized to confirm any suspected alterations. We also conducted a comprehensive molecular literature review to outline the genetic features of the various subtypes of PCH., Results: This study classified and described the underlying etiology of PCH into three categories based on the genes involved. Twelve patients also were included, eleven of whom were from consanguineous parents. Ten different variations in 8 genes were found, all of which related to different types of PCH. Six novel variations were reported, including SEPSECS, TSEN2, TSEN54, AMPD2, TOE1, and CLP1. Almost all patients presented with developmental delay, hypotonia, seizure, and microcephaly being common features. Strabismus and elevation in lactate levels in MR spectroscopy were novel phenotypes for the first time in PCH types 7 and 9., Conclusions: This study merges previously documented phenotypes and genotypes with unique novel ones. Due to the diversity in PCH, we provided guidance for detecting and diagnosing these heterogeneous groups of disorders. Moreover, since certain critical conditions, such as spinal muscular atrophy, can be a differential diagnosis, providing cases with novel variations and clinical findings could further expand the genetic and clinical spectrum of these diseases and help in better diagnosis. Therefore, six novel genetic variants and novel clinical and paraclinical findings have been reported for the first time. Further studies are needed to elucidate the underlying mechanisms and potential therapeutic targets for PCH., (© 2024. The Author(s).)

Background: Cornelia de Lange Syndrome (CdLS) is a rare genetic disorder characterized by a range of physical, cognitive, and behavioral abnormalities. This study aimed to perform a comprehensive review of the literature on CdLS and investigate two cases of CdLS with distinct phenotypes that underwent WES to aid in their diagnosis., Methods: We conducted a comprehensive review of the literature on CdLS along with performing whole-exome sequencing on two CdLS patients with distinct phenotypes, followed by Sanger sequencing validation and in-silico analysis., Results: The first case exhibited a classic CdLS phenotype, but the initial WES analysis of blood-derived DNA failed to identify any mutations in CdLS-related genes. However, a subsequent WES analysis of skin-derived DNA revealed a novel heterozygous mutation in the NIPBL gene (NM&#95;133433.4:c.6534&#95;6535del, p.Met2178Ilefs*8). The second case was presented with a non-classic CdLS phenotype, and WES analysis of blood-derived DNA identified a heterozygous missense variant in the SMC1A gene (NM&#95;006306.4:c.2320G>A, p.Asp774Asn)., Conclusions: The study shows the importance of considering mosaicism in classic CdLS cases and the value of WES for identifying genetic defects. These findings contribute to our understanding of CdLS genetics and underscore the need for comprehensive genetic testing to enhance the diagnosis and management of CdLS patients., (© 2024. The Author(s).)

Aberrant activation of Wnt pathway is linked to dysregulation of several genes. DACT1 and DACT2 are members of the DACT family that participate in antagonizing of the Wnt signaling cascade. Thus in this study, we assessed the mRNA levels of DACT1 , DACT2 , and CYCLIN D1 in 70 pairs of CRC tissues compared to the adjacent tissues. Determination of the mRNA levels of DACT1 , DACT2 , and CYCLIN D1 was done by Quantitative Real-Time PCR (qRT-PCR). The correlation between DACT1 , DACT2 , and CYCLIN D1 genes was also examined. Receiver operating characteristic (ROC) curves was plotted to assess the diagnostic power. The association between histopathological parameters and the DACT1 , DACT2 , and CYCLIN D1 genes was investigated. The expression levels of DACT1 and CYCLIN D1 were remarkably higher in CRC tissues compared to the adjacent tissues ( p  < 0.0001). However, the expression of DACT2 was decreased ( p  < 0.001). Our results showed a significant correlation between the expression of DACT1 and CYCLIN D1 ( p  < 0.0001). DACT1 (AUC = 0.74, p  < 0.0001), DACT2 (AUC = 0.69, p  < 0.0003), and CYCLIN D1 (AUC = 0.75, p  < 0.0001) had good effectiveness in separation between CRC samples and adjacent tissues. We found a significant association between DACT1 expression with tumor site ( p  < 0.01). Also, a significant association was detected between DACT2 and CYCLIN D1 with tumor stage ( p < 0.005 and p  < 0.038, respectively). The findings suggested that DACT1 could function as an oncogene, whereas DACT2 was downregulated and can be considered as a tumor suppressor in CRC.

Background: The Ccr4-Not complex (CNOT complex in mammals) is a unique and highly conserved complex with numerous cellular functions. Until now, there has been relatively little known about the importance of the CNOT complex subunits in the DNA damage response (DDR) in mammalian cells. CNOT4 is a subunit of the complex with E3 ubiquitin ligase activity that interacts transiently with the CNOT1 subunit. Here, we attempt to investigate the role of human CNOT4 subunit in the DDR in human cells., Material and Methods: In this study, cell viability in the absence of CNOT4 was assessed using a Cell Titer-Glo Luminescence assay up to 4 days post siRNA transfection. In a further experiment, CNOT4-depleted HeLa cells were exposed to 3Gy ionizing radiation (IR). Ataxia telangiectasia-mutated (ATM) and ATM Rad3-related (ATR) signaling pathways were then investigated by western blotting for phosphorylated substrates. In addition, foci formation of histone 2A family member X (γH2AX), replication protein A (RPA), TP53 binding protein 1 (53BP1), and DNA repair protein RAD51 homolog 1 was also determined by immunofluorescence microscopy comparing control and CNOT4-depleted HeLa cells 0, 8, and 24 h post IR treatment., Results: Our results from cell viability assays showed a significant reduction of cell growth activity at 24 (P value 0.02) and 48 h (P value 0.002) post siRNA. Western blot analysis showed slightly reduced or slightly delayed DDR signaling in CNOT4-depleted HeLa cells after IR. More significantly, we observed increased formation of γH2AX, RPA, 53BP1, and RAD51 foci after IR in CNOT4-depleted cells compared with the control cells., Conclusion: We conclude that depletion of CNOT4 affects various aspects of the cellular response to DNA damage., (Copyright © 2023 Copyright: © 2023 Journal of Cancer Research and Therapeutics.)

Infantile hypotonia with psychomotor retardation and characteristic facies 1 (IHPRF1) is caused by biallelic mutations in the NALCN gene, the major ion channel responsible for the background Na + conduction in neurons. Through whole-exome sequencing (WES), we report three novel homozygous variants in three families, including c.1434 + 1G > A, c.3269G > A, and c.2648G > T, which are confirmed and segregated by Sanger sequencing. Consequently, intron 12's highly conserved splice donor location is disrupted by the pathogenic c.1434 + 1G > A variation, most likely causing the protein to degrade through nonsense-mediated decay (NMD). Subsequently, a premature stop codon is thus generated at amino acid 1090 of the protein as a result of the pathogenic c.3269G > A; p.W1090* variation, resulting in NMD or truncated protein production. Lastly, the missense mutation c.2648G > T; p.G883V can play a critical role in the interplay of functional domains. This study introduces recurrent urinary tract infections for the first time, broadening the phenotypic range of IHPRF1 syndrome in addition to the genotypic spectrum. This trait may result from insufficient bladder emptying, which may be related to the NALCN channelosome's function in background Na + conduction. This work advances knowledge about the molecular genetic underpinnings of IHPRF1 and introduces a novel phenotype through the widespread use of whole exome sequencing., (© 2023. Fondazione Società Italiana di Neurologia.)

Neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV) is a rare autosomal dominant genetic disorder caused by genetic alterations in the CTNNB1 gene. CTNNB1 is a gene that encodes β-catenin, an effector protein in the canonical Wnt pathway involved in stem cell differentiation and proliferation, synaptogenesis, and a wide range of essential cellular mechanisms. Mutations in this gene are also found in specific malignancies as well as exudative vitreoretinopathy. To date, only a limited number of cases of this disease have been reported, and though they share some phenotypic manifestations such as intellectual disability, developmental delay, microcephaly, behavioral abnormalities, and dystonia, the variety of phenotypic traits of these patients shows extreme heterogeneity. In this study, two cases of NEDSDV with de novo CTNNB1 mutations: c.1420C>T(p.R474X) and c.1377&#95;1378Del(p.Ala460Serfs*29), found with whole exome sequencing (WES) have been reported and the clinical and paraclinical characteristics of these patients have been described. Due to such a wide range of clinical characteristics, the identification of new patients and novel variants is of great importance in order to establish a more complete phenotypic spectrum, as well as to conclude the genotype-phenotype correlations in these cases., (© 2023. Fondazione Società Italiana di Neurologia.)

Inflammatory bowel disease (IBD) manifests as chronic inflammation within the gastrointestinal tract. The study focuses on a long noncoding RNA (lncRNA) known as Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1). MALAT1's misregulation has been linked with various autoimmune diseases and regulates proinflammatory cytokines. The role of IL6 in immune-triggered conditions, including IBD, is another focal point. In this research, the expression of MALAT1 and IL6 in IBD patients was meticulously analyzed to uncover potential interactions. The study involved 33 IBD patients (13 with Crohn's disease and 20 with ulcerative colitis) and 20 healthy counterparts. Quantitative real-time polymerase chain reaction determined the MALAT1 and IL6 gene expression levels. The competitive endogenous RNA (ceRNA) regulatory network was constructed using several tools, including LncRRIsearch and Cytoscape. A deep dive into the Inflammatory Bowel Disease database was undertaken to understand IL6's role in IBD. Drugs potentially targeting these genes were also pinpointed using DGIdb. Results indicated a notable elevation in the expression levels of MALAT1 and IL6 in IBD patients versus healthy controls. MALAT1 and IL6 did not show a direct linear correlation, but IL6 could serve as MALAT1's target. Analyses unveiled interactions between MALAT1 and IL6, regulated by hsa-miR-202-3p, hsa-miR-1-3p, and has-miR-9-5p. IL6's pivotal role in IBD-associated inflammation, likely interacting with other cytokines, was accentuated. Moreover, potential drugs like CILOBRADINE for MALAT1 and SILTUXIMAB for IL6 were identified. This research underscored MALAT1 and IL6's potential value as targets in diagnosis and treatment for IBD patients.

Importance: Lip, oral, and pharyngeal cancers are important contributors to cancer burden worldwide, and a comprehensive evaluation of their burden globally, regionally, and nationally is crucial for effective policy planning., Objective: To analyze the total and risk-attributable burden of lip and oral cavity cancer (LOC) and other pharyngeal cancer (OPC) for 204 countries and territories and by Socio-demographic Index (SDI) using 2019 Global Burden of Diseases, Injuries, and Risk Factors (GBD) Study estimates., Evidence Review: The incidence, mortality, and disability-adjusted life years (DALYs) due to LOC and OPC from 1990 to 2019 were estimated using GBD 2019 methods. The GBD 2019 comparative risk assessment framework was used to estimate the proportion of deaths and DALYs for LOC and OPC attributable to smoking, tobacco, and alcohol consumption in 2019., Findings: In 2019, 370 000 (95% uncertainty interval [UI], 338 000-401 000) cases and 199 000 (95% UI, 181 000-217 000) deaths for LOC and 167 000 (95% UI, 153 000-180 000) cases and 114 000 (95% UI, 103 000-126 000) deaths for OPC were estimated to occur globally, contributing 5.5 million (95% UI, 5.0-6.0 million) and 3.2 million (95% UI, 2.9-3.6 million) DALYs, respectively. From 1990 to 2019, low-middle and low SDI regions consistently showed the highest age-standardized mortality rates due to LOC and OPC, while the high SDI strata exhibited age-standardized incidence rates decreasing for LOC and increasing for OPC. Globally in 2019, smoking had the greatest contribution to risk-attributable OPC deaths for both sexes (55.8% [95% UI, 49.2%-62.0%] of all OPC deaths in male individuals and 17.4% [95% UI, 13.8%-21.2%] of all OPC deaths in female individuals). Smoking and alcohol both contributed to substantial LOC deaths globally among male individuals (42.3% [95% UI, 35.2%-48.6%] and 40.2% [95% UI, 33.3%-46.8%] of all risk-attributable cancer deaths, respectively), while chewing tobacco contributed to the greatest attributable LOC deaths among female individuals (27.6% [95% UI, 21.5%-33.8%]), driven by high risk-attributable burden in South and Southeast Asia., Conclusions and Relevance: In this systematic analysis, disparities in LOC and OPC burden existed across the SDI spectrum, and a considerable percentage of burden was attributable to tobacco and alcohol use. These estimates can contribute to an understanding of the distribution and disparities in LOC and OPC burden globally and support cancer control planning efforts.

Background: Compared to other breast cancer subtypes, triple-negative breast cancer (TNBC) has always been challenging for clinicians due to its aggressive behavior and lack of a specific treatment. There is a confirmed association between invasive features of tumors and increased epithelial-mesenchymal transition (EMT) process, which is consistent with a higher rate of EMT in TNBC., Methods and Results: We investigated the expression of EMT-related genes, SNAI1 and MMP7, and EMT-related lncRNAs, treRNA and SBF2-AS1, in 50 TNBC tumors and 50 non-TNBC tumors to reveal more regulators and effectors involved in TNBC malignancy. In the present study, we showed the overexpression of all the studied genes and lncRNAs in TNBC tumors compared to non-TNBC samples. Moreover, a significant association was observed between MMP7 and treRNA expression levels and larger tumor size. A positive correlation between SNAI1 and lncRNA treRNA expression levels was also detected., Conclusions: Due to the differential expression and the potential diagnostic power of the studied genes, SBF2-AS1 and treRNA can be proposed as new probable biomarkers and therapeutic targets in TNBC., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: Despite the fact that numerous studies have investigated the association between genetic polymorphisms and colorectal cancer (CRC), more research is required to comprehend the molecular mechanisms of CRC. In the present study, we investigated the association between lncRNA HOTAIR rs2366152 and rs1899663 polymorphisms with CRC susceptibility in the Iranian population., Methods: This case-control study consisting of 187 CRC patients and 200 healthy samples. The tetra-amplification refractory mutation system-polymerase chain reaction (Tetra-ARMS-PCR) technique was used for the genotyping of rs2366152 and rs1899663 polymorphisms., Results: The findings showed that the AG genotype of the rs2366152 polymorphism has a protective effect on CRC susceptibility (OR = 0.60, 95% CI: 0.38-0.94, p-value = 0.023). Furthermore, rs2366152 polymorphism associated with CRC risk in an over dominant inheritance model (p-value = 0.0089). According to the outcomes of the rs1899663 polymorphism, the GT genotype had protective effects on CRC risk (OR = 0.55, 95% CI: 0.35-0.86, p-value = 0.008). Moreover, statistical analysis has shown that the rs1899663 polymorphism was associated with CRC risk in dominant (p-value = 0.013) and overdominant (p-value = 0.0086) inheritance models in the Iranian population., Conclusion: This study confirmed that HOTAIR rs2366152 and rs1899663 polymorphisms associated with CRC risk in different inheritance models. It is indeed necessary to do additional research to verify our findings., (© 2023 The Authors. Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC.)

Background: The evidence obtained from experimental studies suggests the tumor-suppressive effects of vitamin D by controlling the differentiation, proliferation, and apoptosis in cancerous cells. Furthermore, the deregulation of genes involved in vitamin D metabolism has been reported in several types of cancer., Methods: In the present study, we investigated the expression level of vitamin D metabolic pathway genes, including VDR, CYP3A4, RXRα, and GC, in colorectal cancer (CRC) samples compared with the adjacent tissues by using quantitative RT-PCR., Results: The results indicated significant downregulation of CYP3A4 and VDR genes in CRC tissues compared with the adjacent control tissues (p < 0.01). RXRA and GC expression levels did not show any significant alteration among the studied samples. Moreover, a positive correlation was observed between the expression level of CYP3A4 and VDR genes (p < 0.0001). ROC curve analysis also revealed the potential diagnostic power of CYP3A4 and VDR genes in CRC samples., Conclusion: Reduction in the expression of both CYP3A4 and VDR plays an important role in CRC due to the possible impairment in vitamin D metabolism. Further studies concerning the relationship between the expression of these genes and colorectal cancer pathogenesis and treatment are recommended., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Circular RNAs (circRNAs) are a new class of endogenous non-coding RNAs involved in several cellular and biological processes, including gene expression regulation, microRNA function, transcription regulation, and translation modification. Therefore, these non-coding RNAs have important roles in the pathogenesis of various diseases. Male infertility is mainly due to abnormal sperm parameters such as motility, morphology, and concentration. Recent studies have confirmed the role of circRNAs in spermatogenesis, and the expression of several circRNAs is confirmed in seminal plasma, spermatozoa, and testicular tissue. It is suggested that deregulation of circRNAs is involved in different types of male infertility, including azoospermia, oligozoospermia, and asthenozoospermia. In the present review, we aimed to discuss the potential roles of circRNAs in spermatogenesis failure, sperm defects, and male infertility. Due to their conserved and special structure and tissue-specific expression pattern, circRNAs can be applied as reliable noninvasive molecular biomarkers, therapeutic and pharmaceutical targets in male infertility., (© 2022. Society for Reproductive Investigation.)

Recent advances in adoptive cell therapy have considerably changed the paradigm of cancer immunotherapy. Although current immunotherapies could cure many patients with multiple myeloma (MM), relapsed/refractory MM (RR/MM) is still challenging in some cases. Natural killer (NK) cells are innate immune cells that exert effective cytotoxic activity against malignant cells like myeloma cells. In addition to their antitumor properties, NK cells do not induce graft versus host disease following transplantation. Therefore, they provide a promising approach to treating RR/MM patients. Currently, attempts have been made to produce large-scale and good manufacturing practices (GMP) of NK cells. Ex vivo expanded/activated NK cells derived from the own patient or allogenic donors are potential options for NK cell therapy in MM. Besides, novel cell-based products such as NK cell lines and chimeric antigen receptor (CAR)-NK cells may provide an off-the-shelf source for NK cell therapy. Here, we summarized NK cell activity in the MM microenvironment and focused on different NK cell therapy methods for MM patients., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2022. Published by Elsevier Inc.)

Immune reconstitution after hematopoietic stem cell transplantation (HSCT) with a conditioning regimen has appeared to be a promising treatment for autoimmune diseases and hematologic malignancies. This study aimed to assess the T cell receptor (TCR) repertoire diversity in CD4+ cells of patients with hematological malignancies who received allogeneic or autologous HSCT. The diversity of the TCR repertoire was evaluated in 13 patients with hematologic malignancies before and four months after HSCT. Amino acid changes in the 25 Vβ families were evaluated using Spectratyping and data were presented as Hamming distance (HD). HD more than 20% was considered a change in TCR repertoire after HSCT. The mean HD was significantly changed after transplantation in all Vβ gene families, with most amino acid changes in p4 and p22 families. There was a strong negative correlation between the HD as the index of TCR repertoire and age (r = -0.62,). The results revealed no association between HD mean and parameters such as sex, disease, conditioning regimen, and type of transplantation. Our data revealed that commonly used conditioning regimens in Iran could successfully cause TCR repertoire diversity in patients with hematologic malignancies in the short term. The amount of change in TCR repertoire was inversely correlated with the increasing age of patients.

Background: Breast cancer (BC) is the most prevalent and fatal cancer in women. Given that there are very few studies investigating the overexpression of four members of ERBB genes, we decided to investigate the correlation between these four genes with clinicopathological characteristics in breast cancer cases., Methods: Tumoural tissue of 50 patients with sporadic invasive ductal BC was recruited. Also, control samples were provided from adjacent non-cancerous tissues (ANCTs) of the same patients. The expression of four ERBB genes was evaluated by real-time PCR and its correlation with clinicopathological characteristics was assessed., Results: Only ERBB2 (HER2) was overexpressed in tumoural tissue compared with ANCTs. Our data showed a significant relationship between ERBB1 overexpression with triple-negative tumors, ER, and PR negativity (P < 0.05). Also, ERBB2 overexpression indicated a significant correlation with several pathological characteristics such as age < 50, tumor size larger than 2 cm, early and advanced stages, negative involved lymph nodes, luminal B, triple-negative, ERBB2-enrich, estrogen receptor (ER) and progesterone receptor (PR) negative tumors, Ki-67 mutation more than 15%, and finally HER2/neu immunohistochemistry (IHC) positive and intermediate (P < 0.05). Moreover, this study demonstrated that ERBB4 overexpression had a significant correlation with tumor size smaller than 2 cm, grade I and II tumors (early-stage tumors), luminal A, ER and PR positive tumors, HER-2/neu IHC intermediate, and tumors that had a Ki-67 mutation lower than 15% (P < 0.05). Besides, our analysis showed a significant correlation between the expression of ERBB1 with ERBB2 and ERBB3 with ERBB4 (P < 0.05)., Conclusions: Our findings showed a significant relationship between unfavorable clinicopathological characteristics with ERBB1 and ERBB2 overexpression, but overexpression of ERBB4 was correlated with favorable outcomes., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: Gnathodiaphyseal dysplasia (GDD) is an ultrarare autosomal dominant bone dysplasia characterized by cementoosseous lesions of the jawbones, bone fragility, frequent bone fractures at the young age, bowing of tubular bones, and diaphyseal sclerosis of long bones associated with generalized osteopenia. GDD is caused by point mutations in anoctamin-5 (ANO5) on chromosome 11p14.3. For the past few years, next generation sequencing (NGS) technology has facilitated the discovery of causative variants in genetically heterogeneous diseases., Methods: In this study, exome sequencing (ES) was performed using the DNA sample of the proband. Family histories and clinical information were collected through comprehensive medical examination and genetic counseling., Results: ES results identified a heterozygous variant, NM&#95;213599.3:c.1078T>C(p.Cys360Arg) in the ANO5 gene. Sanger sequencing was performed to confirm the detected pathogenic variant in DNA samples of the entire family (except deceased individuals), which segregated with the disease within the family. Finally, in silico analysis was applied to test the pathogenicity of the variant using various online software., Conclusion: In summary, our investigation identified a novel pathogenic variant in the ANO5, responsible for gnathodiaphyseal dysplasia in a large Iranian family. Therefore, based on the present study, this variant can be helpful for diagnosis and effective management of GDD patients., (© 2022 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Motility and morphology are two important characteristics of a fertile spermatozoon. CFAP44 gene encodes flagellar protein 44 involved in the formation and function of the flagella and cilia. Long non-coding RNAs are regulatory elements involved in several processes, including reproduction. We aimed to study the alterations in the expressions of CFAP44 and CFAP44-AS1 genes in infertile men with asthenozoospermia and terato-asthenozoospermia. In this case-control study, a total of 105 subjects, including 35 TAZ patients, 34 AZ patients and 35 normozoospermic men, were enrolled. After RNA extraction from spermatozoa samples, quantitative real-time PCR was performed to compare the expression of CFAP44 and CFAP44-AS1 between the studied groups. A meaningful reduction in CFAP44 expression and a significant reduction in the expression of CFAP44-AS1 were observed. Moreover, a positive correlation between both genes' expressions and normal sperm morphology was detected in NZ, AZ and TAZ groups. Also, there was a positive relation between CFAP44 gene expression and sperm motility in AZ and TAZ groups. The expression of CFAP44-AS1 was positively correlated with sperm motility and morphology. Present results confirm the role of CFAP44 and CFAP44-AS1 in the motility and morphology of spermatozoon, and deregulation of these genes may contribute to male infertility., (© 2022 Wiley-VCH GmbH.)

MIR4435-2HG (LINC00978) is a long non-coding RNA (lncRNA) that acts as an oncogene in almost all cancers. This lncRNA participates in the molecular cascades involved in other disorders such as coronary artery diseases, osteonecrosis, osteoarthritis, osteoporosis, and periodontitis. MIR4435-2HG exerts its functions via the spectrum of different mechanisms, including inhibition of apoptosis, sponging microRNAs (miRNAs), promoting cell proliferation, increasing cell invasion and migration, and enhancing epithelial to mesenchymal transition (EMT). MIR4435-2HG can regulate several signaling pathways, including Wnt, TGF-β/SMAD, Nrf2/HO-1, PI3K/AKT, MAPK/ERK, and FAK/AKT/β‑catenin signaling pathways; therefore, it can lead to tumor progression. In the present review, we aimed to discuss the potential roles of lncRNA MIR4435-2HG in developing cancerous and non-cancerous conditions. Due to its pivotal role in different disorders, this lncRNA can serve as a potential biomarker in future investigations. Moreover, it may serve as a potential therapeutic target for the treatment of various diseases., (© 2022. The Author(s).)

Background: Triple-negative breast cancer (TNBC) is the most challenging subtype of breast cancer and does not benefit from the existing targeted therapies. In the present study, we used bioinformatics and experimental approaches to assess the genes that are somehow involved in the epithelial-mesenchymal transition (EMT) pathway which may explain the invasive features of TNBC., Method and Results: We analyzed five GEO datasets consisting of 657 breast tumors by GEO2R online software to achieve common differentially expressed genes (DEGs) between TNBC and non-TNBC tumors. The expression of the selected coding and non-coding genes was validated in 100 breast tumors, including fifty TNBC and fifty non-TNBC samples, using quantitative Real-Time PCR (qRT-PCR). The bioinformatics approach resulted in a final DEG list consisting of ten upregulated and seventeen downregulated genes (logFC ≥|1| and P < 0.05). Co-expression network construction indicated the FOXC1 transcription factor as a central hub node. Considering the notable role of FOXC1 in EMT, the expression levels of FOXC1-related lncRNAs, lnc-FOXCUT and lnc-DANCR, were also evaluated in the studied tumors. The results of qRT-PCR confirmed notable upregulation of FOXC1, lnc-FOXCUT, and lnc-DANCR in TNBC tissues compared to non-TNBC samples (P < 0.0001, P = 0.0005, and P = 0.0008, respectively). Moreover, ROC curve analysis revealed the potential biomarker role of FOXC1 in TNBC samples., Conclusion: Present study suggested that the deregulation of FOXC1/lnc-FOXCUT/lnc-DANCR axis may contribute to the aggressive features of triple-negative breast tumors. Therefore, this axis may be considered as a new probable therapeutic target in the treatment of TNBC., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

Uterine leiomyoma (UL), as the most prevalent type of women's health disorders, is a benign tumor that originates from the smooth muscle cell layer of the uterus. A great number of associated complications are observed including infertility, miscarriage, bleeding, pain, dysmenorrhea, menorrhagia, and dyspareunia. Although the etiology of UL is largely undefined, environmental and genetic factors are witnessed to engage in the UL development. As long non-coding RNAs (lncRNAs) are involved in various types of cellular functions, in recent years, a great deal of attention has been drawn to them and their possible roles in UL pathogenesis. Moreover, they have illustrated their potential to be promising candidates for UL treatment. In this review paper, firstly, an overview of UL pathogenesis is presented. Then, the regulation of lncRNAs in UL and their possible mechanisms in cancer development are reviewed. Eventually, therapeutic approaches targeting lncRNAs in various cancers and UL are explored., (© 2021. Society for Reproductive Investigation.)

CTNNB1 encodes for the β-catenin protein, a component of the cadherin adhesion complex, which regulates cell-cell adhesion and gene expression in the canonical Wnt signaling pathway. Mutations in CTNNB1 have been reported to be associated with cancer and mental disorders. Recently, loss-of-function mutations in CTNNB1 have been observed in patients with intellectual disability and some other clinical manifestations including motor and language delays, microcephaly, and mild visual defects. We report an 8-year-old Iranian girl with intellectual disability, hypotonia, impaired vision such as vitreomacular adhesion, motor delay, and speech delay. A novel, de novo nonsense mutation (c.1014G > A; p.Trp338Ter) in exon 7 of the CTNNB1 (NM&#95;001904) gene was detected and confirmed by whole-exome sequencing and Sanger sequencing, respectively. This study helps to expand the growing list of loss-of-function mutations known in the CTNNB1 gene., (© 2022. Fondazione Società Italiana di Neurologia.)

Background Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) has been increasingly used as a therapeutic approach for hematological malignancies. Several potential strategies have been developed for treating or preventing allo-HSCT complications, specifically graft-versus-host disease (GVHD). GVHD could significantly affect the morbidity and mortality of patients after allo-HSCT. Curative treatment and prophylaxis regimens for GVHD could reduce GVHD incidence and improve survival rate. Among these therapeutic strategies, mesenchymal stem cell (MSCs) mediated immunomodulation has been explored widely in clinical trials. MSCs immunomodulation ability in GVHD correlates with the interactions of MSCs with innate and adaptive immune cells. However, signaling pathways responsible for MSCs' impact on GVHD regulation, like JAK/STAT, NOTCH, MAPK/ERK, and NFκβ signaling pathways, have not been clearly described yet. This review aims to illuminate the effect of MSCs-mediated immunomodulation in GVHD management after allo-HSCT representing the role of MSCs therapy on signaling pathways in GVHD. Conclusion MSCs could potentially modulate immune responses, prevent GVHD, and improve survival after allo-HSCT. Previous studies have investigated different signaling pathways' contributions to MSCs immunoregulatory ability. Accordingly, targeting signaling pathways components involved in MSCs related GVHD regulation is proven to be beneficial., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Despite many efforts to discover the important role of the autophagy process in the pathogenesis of colorectal cancer (CRC), the exact involved molecular mechanism still remains to be elucidated. Recently, a limited number of studies have been employed to discover the impact of autophagy genes' variants on the development and progression of CRC. Here, we evaluated the association between two single-nucleotide polymorphisms (SNPs) in the main components of the autophagy genes, ATG16L1 rs2241880, and ATG5 rs1475270, and the CRC risk in an Iranian population., Methods: During this investigation, a total of 369 subjects, including 179 CRC patients and 190 non-cancer controls have been genotyped using Tetra-primer amplification refractory mutation system-polymerase chain reaction (TP-ARMS-PCR) method., Result: The results demonstrated that the T allele of the ATG16L1 rs2241880 was significantly associated with the increased risk of CRC in the studied population (OR 1.64, 95% CI: 1.21-2.22, p = 0.0015). Moreover, ATG16L1 rs2241880 TT genotype increased the susceptibility to CRC (OR 3.31, 95% CI: 1.64-6.69, p = 0.0008). Furthermore, a significant association was observed under the recessive and dominant inheritance models (p = 0.0015 and p = 0.017, respectively). No statistically significant differences were found in the ATG5 rs1475270 alleles and genotypes between the cases and controls., Conclusion: The results of the present study may be helpful concerning the risk stratification in CRC patients based on the genotyping approach of autophagy pathways and emphasize the need for further investigations among different populations and ethnicities to refine our conclusions., (© 2021 The Authors. Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC.)

Acute myeloblastic leukemia (AML) is one of the most common types of blood malignancies that results in an AML-associated high mortality rate each year. Several causes have been reported as prognostic factors for AML in children and adults, the most important of which are cytogenetic abnormalities and environmental risk factors. Following the discovery of numerous drugs for AML treatment, leukemic cells sought a way to escape from the cytotoxic effects of chemotherapy drugs, leading to treatment failure. Nowadays, comprehensive studies have looked at the role of extracellular vesicles (EVs) secreted by AML blasts and how the microenvironment of the tumor changes in favor of cancer progression and survival to discover the mechanisms of treatment failure to choose the well-advised treatment. Reports show that malignant cells secrete EVs that transmit messages to adjacent cells and the tumor's microenvironment. By secreting EVs, containing immune-inhibiting cytokines, AML cells inactivate the immune system against malignant cells, thus ensuring their survival. Also, increased secretion of EVs in various malignancies indicates an unfavorable prognostic factor and the possibility of drug resistance. In this study, we briefly reviewed the challenges of treating AML with a glance at the EVs' role in this process. It is hoped that with a deeper understanding of EVs, new therapies will be developed to eliminate the relapse of leukemic cells., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: Preeclampsia (PE) is a pregnancy hypertensive disorder that affects both maternal and fetal health. Many studies have investigated possible mechanisms in the pathogenesis of PE although the role of the placenta is undeniable. Evaluation of placental-specific microRNAs may provide additional data about the pathogenic mechanism of PE. This study compared the expression levels of Hsa-miR-517a/b in placental tissues obtained from PE patients and healthy controls., Material and Methods: One hundred tissues were obtained from fetal and maternal sides of the placenta of PE patients and healthy controls. Expression analysis was performed using quantitative real-time polymerase chain reaction., Results: Hsa-miR-517a/b level was significantly decreased in PE compared to controls (expression ratio: 0.40; p=0.007). Down-regulation of Hsa-miR-517a/b was also detected in fetal-side placental samples when compared to maternal-side in PE (expression ratio: 0.33; p=0.04). Furthermore, decreased expression of Hsa-miR-517a/b was detected in fetal-side tissue from PE cases compared to fetal-side samples from healthy pregnancies (expression ratio: 0.36; p=0.03). In maternal-side placental samples the expression level did not differ between PE and healthy pregnancies (p=0.1)., Conclusion: These results demonstrate a differential expression of Hsa-miR-517a/b within placentas in pregnancies affected by PE and between placentas from PE and healthy pregnancies. Further studies are required to investigate a possible role for Hsa-miR-517a/b in the pathogenesis of PE.

Background: Hematopoietic stem cell transplantation (HSCT) is one of the treatments for hematologic malignancies. Numerous factors affect the HSCT outcome. The purpose of this study was to investigate the effect of post-HSCT administration of granulocyte colony-stimulating factor (post-G-CSF) on early neutrophil and platelet engraftment in allogeneic HSCT (allo-HSCT)., Material & Methods: The study was performed on 76 patients diagnosed with AML and ALL. All patients underwent allo-HSCT at Taleghani stem cell transplantation center, Tehran, Iran, from February 2016 to December 2018. Chemotherapy regimens based on patients' conditions were selected between myeloablative and reduced-intensity regimens., Results: Statistical analysis revealed that the number of administered G-CSF units after HSCT was a time-dependent variable. Statistical analysis before day +11 reported that patients who received G-CSF <14 units had three times better early neutrophil engraftment than those with G-CSF ≥14 (CI 95%, AHR = 3.03, p:0.002). CD3+ cells count <318.5 × 10 6 /kg was associated with fast platelet engraftment (CI 95%, AHR 2.28, p:0.01)., Conclusion: In this study, post-G-CSF stimulation was associated with early engraftment in a time- and dose-dependent manner. Administration of G-CSF beyond 14 units resulted in adverse effects on neutrophil early engraftment. It also appeared that with a reduction in CD3+ cell counts, the likelihood of GVHD decreases, and platelet engraftment occurs earlier. Further investigations in the future are required to determine the factors affecting the process of early engraftment., (© 2021 The Authors. Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC.)

Colorectal cancer (CRC) as a lethal malignancy has been associated with dysregulation of several genes and pathways. Long noncoding RNAs (lncRNAs) play an important role in gene expression regulation. In the current research, we aim to evaluate the expression of LINC00978 in CRC samples and adjacent tissues. Using Quantitative Real-Time PCR (qRT-PCR) method, we assessed the expression levels of LINC00978 and β-catenin in 70 pairs of CRC and adjacent tissues. Moreover, the association between clinicopathological features and the LINC00978 expression levels was investigated. To assess the diagnostic power of LINC00978 expression in CRC, receiver operating characteristic (ROC) curve was plotted. The relationship between LINC00978 and β-catenin expression levels was evaluated using correlation analysis. A markedly increased level of LINC00978 and β-catenin expression levels was observed in CRC samples compared with adjacent tissues (P < 0.0001). No significant association was detected between LINC00978 expression level and the patient's clinicopathological features. The results of Pearson's correlation coefficient highlighted a positive correlation between LINC00978 and β-catenin expression (r 2  = 0.4695, P < 0.0001). According to the area under curve (AUC) value, LINC00978 expression differentiates CRC samples from the adjacent tissues (AUC = 0.81, P < 0.0001). The present results suggest that LINC00978 may play a critical role in CRC progression via Wnt pathway. The potential role of LINC00978 as a diagnostic biomarker needs to be further investigated in future studies., (Copyright © 2021 Elsevier Inc. All rights reserved.)