Alireza Moafi

Bio: Alireza Moafi is an academic researcher from Isfahan University of Medical Sciences. The author has contributed to research in topics: Minimal residual disease & Childhood Acute Lymphoblastic Leukemia. The author has an hindex of 10, co-authored 43 publications receiving 287 citations.

mRNA expression profile of multidrug-resistant genes in acute lymphoblastic leukemia of children, a prognostic value for ABCA3 and ABCA2.

Abstract: Multidrug resistance (MDR) is an important cause of treatment failure in acute lymphoblastic leukemia (ALL). The ABC family of membrane transporters is proposed, albeit with controversy, to be involved in this process. The present study aims to investigate the mRNA expression profile of several genes of this family, including ABCA2, ABCA3, ABCB1/MDR1, MRP1/ABCC1, MRP3/ABCC3, ABCG2/BCRP, and the intracellular transporter MVP/LRP, in childhood ALL, and to evaluate their association with response to therapy. Some genes in the present research are being studied for the first time in Iran. Using quantitative real-time PCR, we evaluated 27 children with ALL at diagnosis and 15 children with normal bone marrow. The status of response to therapy was assessed one year after the onset of therapy through investigating the IgH/TCRγ gene rearrangements. Our findings indicate a considerable and direct relationship between mRNA expression levels of ABCA2, ABCA3, MDR1, and MRP1 genes and positive minimal residual disease (MRD) measured after one year of treatment. Statistical analysis revealed that expression of these genes higher than the cutoff point will raise the risk of MRD by 15-, 6.25-, 12-, and 9-fold, respectively. No relationship was found between of MVP/LRP, MRP3 and ABCG2 genes expression and ALL prognoses. Considering the direct and significant relationship between the increased expression of ABCA2, ABCA3, MDR1, and MRP1 genes and positive risk of MRD in children with ALL, evaluating the expression profile of these genes on diagnosis may identify high risk individuals and help plan a more efficient treatment strategy.

Integrative computational in-depth analysis of dysregulated miRNA-mRNA interactions in drug-resistant pediatric acute lymphoblastic leukemia cells: an attempt to obtain new potential gene-miRNA pathways involved in response to treatment.

Abstract: Acute lymphoblastic leukemia (ALL) is the major neoplasia type among children. Despite the tremendous success of current treatment strategies, drug resistance still remains a major cause of chemotherapy failure and relapse in pediatric patients. Overwhelming evidence illustrates that microRNAs (miRNAs) act as post-transcriptional regulators of drug-resistance-related genes. The current study was aimed at how dysregulated miRNA-mRNA-signaling pathway interaction networks mediate resistance to four commonly used chemotherapy agents in pediatric ALL, including asparaginase, daunorubicin, prednisolone, and vincristine. Using public expression microarray datasets, a holistic in silico approach was utilized to investigate candidate drug resistance miRNA-mRNA-signaling pathway interaction networks in pediatric ALL. Our systems biology approach nominated significant drug resistance and cross-resistance miRNAs, mRNAs, and cell signaling pathways based on anti-correlative relationship between miRNA and mRNA expression pattern. To sum up, our systemic analysis disclosed either a new potential role of miRNAs, or a possible mechanism of cellular drug resistance, in chemotherapy resistance of pediatric ALL. The current study may shed light on predicting drug response and overcoming drug resistance in childhood ALL for subsequent generations of chemotherapies.

The translational expression of ABCA2 and ABCA3 is a strong prognostic biomarker for multidrug resistance in pediatric acute lymphoblastic leukemia.

Abstract: PURPOSE The aim of this work was to study the correlation between the expressions of the ABCA2 and ABCA3 genes at the mRNA and protein levels in children with acute lymphoblastic leukemia (ALL) and the effects of this association on multidrug resistance (MDR). MATERIALS AND METHODS Sixty-nine children with de novo ALL and 25 controls were enrolled in the study. Mononuclear cells were isolated from the bone marrow. The mRNA levels of ABCA2 and ABCA3 were measured by real-time polymerase chain reaction (PCR). Samples with high mRNA levels were assessed for respective protein levels by Western blotting. Following the first year of treatment, persistent monoclonality of T-cell gamma receptors or immunoglobulin H (IgH) gene rearrangement was assessed and considered as the MDR. The tertiary structure of ABCA2 was predicted using Phyre2 and I-TASSER web systems and compared to that of ABCA3, which has been previously reported. Molecular docking was performed using DOCK 6.7. RESULTS Real-time quantitative PCR (qRT-PCR) showed high levels of ABCA2 and ABCA3 mRNAs in 13 and 17 samples, respectively. Among them, five and eight individuals demonstrated high levels of ABCA2 and ABCA3, respectively. Response to chemotherapy was significantly decreased (P=0.001) when the mRNA and protein of both genes were overexpressed compared to individuals with high transcriptional levels of either ABCA2 or ABCA3 alone. Close similarity between ABCA2 and ABCA3 structures was revealed by protein tertiary structure prediction, whereas molecular docking analysis suggested similar binding of chemotherapy drugs and therefore a potentially similar role in determining the MDR. CONCLUSION Our findings suggested, for the first time, that quantification of the protein level of ABCA2 and ABCA3 transporters had a prognostic impact on pediatric ALL MDR. Furthermore, the tertiary structure of ABCA2 was predicted for the first time, and docking analysis revealed a possible compensatory effect between ABCA2 and ABCA3 transporters, which may contribute to the efflux of cytotoxic drugs and, ultimately, to chemoresistance.

Unusual sites of bone involvement in Langerhans cell histiocytosis: a systematic review of the literature

Abstract: Langerhans cell histiocytosis (LCH) is a rare disease that originates from the uncontrolled proliferation and accumulation of bone marrow-derived immature myeloid dendritic cells. Dendritic cells are a type of histiocyte that play an important role in the human immune system and are found in the bone, skin, stomach, eyes, intestines, and lungs. This systematic review aimed to collect and report published case reports of rare bone disease caused by LCH to avoid misdiagnoses or delays in diagnosis. We systematically searched Scopus, PubMed, Embase, and Web of Sciences from August 1, 2000 to December 31, 2019. Studies reporting cases of LCH with rare bone involvement were included. We identified 60 articles including 64 cases. Of the identified cases, 31 (48.4%) involved children, and 33 (51.6%) involved adults. Additionally, 46.9% (30 individuals) were from Asian countries. The mean age of the children was 7.6 ± 4.3 years and that of the adults was 36 ± 12 years. The findings indicated that unifocal bone involvements were the most prevalent form of the disease (68.7%), and, overall, the skull and chest wall were the most commonly affected bones in both adults and children. The spine and long bones were the second most commonly affected bones in children, and the spine and jaw were the second most commonly affected bones in adults. Pain and swelling were the most frequent presenting signs among the investigated cases, and loss of consciousness, myelopathy, nerve palsy, visual loss, torticollis and clicking sounds were rare signs. Osteolytic lesions were the most frequent radiologic feature (62.5%), and intracranial hemorrhage, fluid–fluid level, dura and intracranial extension and pathologic fractures were rare radiological features. Total excision, curettage and observation in the unifocal group of patients and systemic chemotherapy in the other groups (i.e., multifocal and multisystem) were the most frequent management approaches. The recovery rates of the unifocal and multifocal groups were 77.3% and 81.8%, respectively, while that of the multisystem group was 55.5%. The rates of recurrence and mortality in the multisystem group were 11% and were higher than those in the other groups. LCH is a rare disease that can affect any organ in the human body. However, bone is the most commonly involved organ, and rare bone involvements may be the first or only symptom of the disease due to the rarity of such lesions; a lack of familiarity with them may result in misdiagnosis or delayed diagnosis.

Two decades of pre-marital screening for beta-thalassemia in central Iran.

Abstract: Thalassemia is the most widespread recessive disease worldwide (Ryan et al. 2010; Weatherall and Clegg 2001). Beta-thalassemia is characterized by the deficiency or absence of beta globin production. The condition is clinically mild in the healthy carrier that can be easily detected through routine blood testing, but intermediate or severe in the patients who are born with 25 % chance at each pregnancy from parents who are both healthy carriers. Thalassemia carriers are today present worldwide with high frequencies mainly in the endemic countries of Africa, the Middle East, the Indian subcontinent, Southeast Asia, and the Mediterranean region (Fucharoen and Winichagoon 2007; AlHamdan et al. 2007; Sarper et al. 2009). Thalassemia is a common disease in Iran with higher frequencies in the north and south parts of the country (Haddow 2005; Samavat and Modell 2004; Moafi et al. 2010). Thalassemia major leads to serious medical, social, and economic problems for patients and their families, and patient’s care represents a considerable financial burden for the public health budget (Verma et al. 2011; Langlois et al. 2008). After a 5-year pilot screening, the Iranian Ministry of Health approved in 1996 a mandatory national screening protocol for premarital testing. This program included a laboratory strategy to identify and counsel couples at risk providing support and care (Samavat and Modell 2004; Iranian Health 2004). Although compared to other regions, the Isfahan province can be considered an area at moderate prevalence; premarital screening was locally started in 1992 and gradually extended to the entire province by 1997 (Zeinalian et al. 2009). This report presents the results of the premarital screening program applied in the Isfahan province during the last two decades (1992–2010).

ABC Family Transporters.

Abstract: The transport of specific molecules across lipid membranes is an essential function of all living organisms. The processes are usually mediated by specific transporters. One of the largest transporter families is the ATP-binding cassette (ABC) family. More than 40 ABC transporters have been identified in human, which are divided into 7 subfamilies (ABCA to ABCG) based on their gene structure, amino acid sequence, domain organization, and phylogenetic analysis. Of them, at least 11 ABC transporters including P-glycoprotein (P-GP/ABCB1), multidrug resistance-associated proteins (MRPs/ABCCs), and breast cancer resistance protein (BCRP/ABCG2) are involved in multidrug resistance (MDR) development. These ABC transporters are expressed in various tissues such as the liver, intestine, kidney, and brain, playing important roles in absorption, distribution, and excretion of drugs. Some ABC transporters are also involved in diverse cellular processes such as maintenance of osmotic homeostasis, antigen processing, cell division, immunity, cholesterol, and lipid trafficking. Several human diseases such as cystic fibrosis, sitosterolemia, Tangier disease, intrahepatic cholestasis, and retinal degeneration are associated with mutations in corresponding transporters. This chapter will describe function and expression of several ABC transporters (such as P-GP, BCRP, and MRPs), their substrates and inhibitors, as well as their clinical significance.

The role of ABC transporters in ovarian cancer progression and chemoresistance.

Abstract: Over 80% of ovarian cancer patients develop chemoresistance which results in a lethal course of the disease. A well-established cause of chemoresistance involves the family of ATP-binding cassette transporters, or ABC transporters that transport a wide range of substrates including metabolic products, nutrients, lipids, and drugs across extra- and intra-cellular membranes. Expressions of various ABC transporters, shown to reduce the intracellular accumulation of chemotherapy drugs, are increased following chemotherapy and impact on ovarian cancer survival. Although clinical trials to date using ABC transporter inhibitors have been disappointing, ABC transporter inhibition remains an attractive potential adjuvant to chemotherapy. A greater understanding of their physiological functions and role in ovarian cancer chemoresistance will be important for the development of more effective targeted therapies. This article will review the role of the ABC transporter family in ovarian cancer progression and chemoresistance as well as the clinical attempts used to date to reverse chemoresistance.

Neuroblastoma Origin and Therapeutic Targets for Immunotherapy

Abstract: Neuroblastoma is a pediatric solid cancer of heterogeneous clinical behavior. The unique features of this type of cancer frequently hamper the process of determining clinical presentation and predicting therapy effectiveness. The tumor can spontaneously regress without treatment or actively develop and give rise to metastases despite aggressive multimodal therapy. In recent years, immunotherapy has become one of the most promising approaches to the treatment of neuroblastoma. Still, only one drug for targeted immunotherapy of neuroblastoma, chimeric monoclonal GD2-specific antibodies, is used in the clinic today, and its application has significant limitations. In this regard, the development of effective and safe GD2-targeted immunotherapies and analysis of other potential molecular targets for the treatment of neuroblastoma represents an important and topical task. The review summarizes biological characteristics of the origin and development of neuroblastoma and outlines molecular markers of neuroblastoma and modern immunotherapy approaches directed towards these markers.