Publications by authors named "Ahmad Monabati"

102 Publications

Generalized exfoliative skin rash as an early predictor of supratherapeutic voriconazole trough levels in a leukemic child: A case report.

Curr Med Mycol 2020 Sep;6(3):73-78

Department of Clinical Pharmacy, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.

Background And Purpose: Skin rashes, mostly seen in children and adolescents, are considered among the most common side effects of azole antifungals. Although therapeutic concentrations of voriconazole (VCZ) have been documented for infected skin, there is no evidence specifying whether specific dermatologic side effects could predict high VCZ serum concentration, especially in high-risk leukemic children.

Case Report: Herein, we report a unique skin side effect of VCZ in a 5-year-old boy with T-cell acute lymphoblastic leukemia (ALL) referred to Amir Medical Oncology Center in Shiraz, Iran. The patient experienced erythroderma and macular rashes shortly after VCZ consumption, leading to generalized exfoliative skin rashes. Concurrent to these skin manifestations, VCZ serum concentration reached the supratherapeutic levels despite the recommended VCZ doses. As a result, VCZ was withheld, and the patient was treated with caspofungin. The lesions were resolved gradually within 2 weeks, and the patient successfully completed his treatment course with caspofungin.

Conclusion: The unique case presented in this study emphasizes the need for a high index of suspicion for VCZ toxicity in any patient with atypical dermatologic manifestations, especially generalized exfoliative skin rashes. Based on this report, VCZ supratherapeutic concentration could be predicted early in the course of treatment. Additional therapeutic dose monitoring should be considered to establish a confirmatory diagnosis. It is required to further investigate the toxic effect of high VCZ concentration on the skin epithelium.
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http://dx.doi.org/10.18502/cmm.6.3.4500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018824PMC
September 2020

Immune Checkpoint Molecules in Primary Diffuse Large B-Cell Lymphoma of the Central Nervous System.

Basic Clin Neurosci 2020 Jul-Aug;11(4):491-498. Epub 2020 Jul 1.

Department of Pathology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.

Introduction: Primary Diffuse Large B Cell Lymphoma of CNS (PCNSL) is a rare variant of Diffuse Large B Cell Lymphoma (DLBCL) and presents with an aggressive clinical course and usually resistant to commonly used therapy regimens. Recently, role of immune checkpoint molecules including PD-1 and PD-L1 confirmed in some solid tumors and lymphoma resulting tumor cells escape the immune system and help to survive and to spread. Inhibitors of PD-1 and PD-L1 have shown lasting responses in several solid and some hematological tumors, while limited studies evaluate checkpoint molecules on PCNSL.

Method: In this study, we investigated PD-1 and PD-L1 expression by immunostaining on 71 patients with PCNSL and correlation with demographic data, location of the tumor, proliferation rate, cell of origin, and CD8 positive T cell infiltration in tumor microenvironment.

Results: 16 from71 showed PD-1 expression, while PD-L1 expression were 42/71. No association was determined between PD-1/PD-L1 expression and gender, cell of origin, and proliferation rate, but a highly significant difference was determined between the infiltration of CD8 positive T cells in two groups of PD-1/PD-L1 positive and negative.

Conclusion: This study revealed expression of check point molecules in remarkable number of PCNSL which may open new therapeutic recommendations in this aggressive lymphoma type.
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http://dx.doi.org/10.32598/bcn.11.4.2542.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878047PMC
July 2020

PD-L1 expression in tumor lesions and soluble PD-L1 serum levels in patients with breast cancer: TNBC versus TPBC.

Breast Dis 2021 Jan 25. Epub 2021 Jan 25.

Department of Immunology, Shiraz University of Medical Sciences, Shiraz, Iran.

Background: Block of programmed cell death protein 1 (PD-1) interaction with its ligand, PD-L1, enhances anti-tumor activity.

Objectives: We aimed to assess the association between PD-L1 expression in tumor cells and CD8+ tumor infiltrating T cells (TILs) as well as soluble (s)PD-L1 serum levels in patients with triple negative breast cancer (TNBC) compared to triple positive (TPBC).

Methods: A total of 113 tumor sections and 133 serum samples were available from 144 patients with breast cancer (72 TNBC and 72 TPBC). Dual immunohistochemistry staining was applied to determine differential PD-L1 expression in tumor cells and CD8+ TILs. Soluble PD-L1 serum levels were also evaluated in patients compared to 40 healthy women by ELISA method.

Results: Despite TPBC patients which were mostly grades 1/2, TNBC patients were grade 3 (72% versus 66.7%, P < 0.001). Most of the TNBC patients were stages I/II, whereas most of the TPBC patients were stages III/IV (57.3% versus 68.3%,P = 0.005). There was no difference in tumor size and metastasis between TNBC and TPBC patients, although the number of involved lymph nodes was significantly more in TPBC patients (P = 0.0012). PD-L1 expression was detected in 11.5% of samples mostly in TNBC subtype and was associated with advanced grades (P = 0.039). There was no relationship between PD-L1 expression and tumor stage. PD-L1 expression in CD8+ TILs was nonsignificantly higher than tumor cells. Serum levels of sPD-L1 showed no difference between patients and healthy women. We found no correlation between PD-L1 expression in tumor lesions and serum levels of sPD-L1 in patients.

Conclusion: PD-L1 expression was more detected in our patients with TNBC. It seems that, these patients who are resistant to standard chemotherapy regimens may get benefit from PD-L1 inhibition therapy and because of its low serum levels, sPD-L1 cannot interfere with this therapy.
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http://dx.doi.org/10.3233/BD-201049DOI Listing
January 2021

Metformin-Loaded PCL/PVA Fibrous Scaffold Preseeded with Human Endometrial Stem Cells for Effective Guided Bone Regeneration Membranes.

ACS Biomater Sci Eng 2021 01 21;7(1):222-231. Epub 2020 Dec 21.

Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran 5546914177, Iran.

Many studies have been devoted to investigating the potential of guided bone regeneration (GBR) membranes for bone defect reconstruction. Regardless of approaches for treating damaged bone tissues, a beneficial therapeutic strategy has remained a challenge. In this study, a novel GBR membrane with polycaprolactone (PCL) and poly(vinyl alcohol) (PVA) containing different concentrations of metformin (Met) for improving osteogenic properties was developed. The membranes were evaluated for their hydrophilicity, degradation rate, swelling ratio, drug release, mechanical properties, and biological responses. The results showed a significant increase in hydrophilicity, swelling ratio, and degradation rate and no significant changes in mechanical properties of PCL/PVA membranes with Met concentration enhancement. A decrease in cell viability cultured on the surface of the PCL/PVA membrane was seen when the amount of Met was changed from 10 to 15 wt %. The results of the quantitative real-time polymerase chain reaction (qRT-PCR) also confirmed the higher secretion of osteogenic-related genes in a PCL/PVA/Cell/10 wt % Met scaffold than in the PCL/PVA/Cell sample. Therefore, further studies were conducted using the electrospun PCL/PVA membrane containing human endometrial stem cells (hEnSCs) and 10% Met. Histopathological and histomorphometric results confirmed that PCL/PVA/hEnSCs/10 wt % Met has excellent potential to differentiate hEnSCs into osteogenic lineages and bone regeneration in calvarial defects of rats. The results of this study confirm the high potential of the PCL/PVA/10 wt % Met fibrous membrane preseeded with hEnSCs in GBR applications.
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http://dx.doi.org/10.1021/acsbiomaterials.0c00958DOI Listing
January 2021

A Depressed Hyperpigmented Nodule on Back of a Middle Aged Man.

Indian J Dermatol 2020 Jul-Aug;65(4):313-314

Molecular Dermatology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.

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http://dx.doi.org/10.4103/ijd.IJD_603_18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7423225PMC
August 2020

Association of killer-cell immunoglobulin-like receptor genes with acute myelogenous leukaemia.

Int J Immunogenet 2020 Dec 6;47(6):512-521. Epub 2020 Aug 6.

Department of Immunology, Shiraz University of Medical Sciences, Shiraz, Iran.

Killer-cell immunoglobulin-like receptors (KIRs) are important because of their key roles in NK cell development and function. Some KIR genes have been associated with the incidence of haematological malignancies. This study was designed to determine whether the inheritance of specific KIR genes is associated with susceptibility to acute myelogenous leukaemia (AML) in Persians living in south-western Iran. KIR genes and KIR2DS4 variants were typed by polymerase chain reaction-sequence-specific primer (PCR-SSP) in 167 patients with AML and 169 healthy controls. Our results showed 10% of patients-mostly females-were classified as M3. Flt3 mutations were detected in 26% of patients, most of whom had internal tandem duplication (ITD). The frequency of activating KIRs (aKIRs)-mainly KIR3DS1-was higher in patients, whereas inhibitory KIRs (iKIRs)-particularly KIR3DL1 and KIR2DL1-were more common among controls. The incidence of the KIR2DS4fl allele was higher among patients with non-M3 AML than controls. We also found a higher frequency of 4 or more iKIR genes in the controls and a higher frequency of 4 or more aKIR genes in the patients. Individuals with more iKIR than aKIR belonged predominantly to the control group. Individuals with the telomeric AA genotype who had inherited the KIR2DS4fl allele were more frequent in the patient group. According to our results, increased frequency of aKIRs in patients with AML may lead to the hyperactivation of NK cells against malignant cells with reduced or lack of HLA class I molecules followed by NK cell exhaustion which allow malignant cells to progress.
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http://dx.doi.org/10.1111/iji.12509DOI Listing
December 2020

Expression Pattern of Telomerase Reverse Transcriptase (hTERT) Variants and Bcl-2 in Peripheral Lymphocytes of Systemic Lupus Erythematosus Patients.

Iran J Pathol 2020 21;15(3):225-231. Epub 2020 Apr 21.

Department of Immunology, Shiraz University of Medical Sciences, Shiraz, Iran.

Background & Objective: It is not clear whether activated lymphocytes of patients with systemic lupus erythematosus (SLE) are more proliferative or less apoptotic. We aimed to delineate potential differences between B and T cells of SLE patients compared to healthy controls regarding the telomerase activity and apoptosis status.

Methods: In this cross-sectional case control study, Blood samples were taken from 10 SLE patients and 10 healthy controls. B and T cells were separated using magnetic cell sorting system. Telomeric repeat amplification protocol (TRAP) assay and real-time PCR were used to determine the telomerase activity and the expression of alternatively spliced variants.

Results: Four patients under treatment showed significant telomerase activity in their T cells. Four of the newly diagnosed patients showed telomerase activity in their B cells (20% of all patients and 40% of new onset patients). There was no specific pattern of human telomerase reverse transcriptase variant expression within the patients' lymphocytes. A significantly reduced expression of was detected in B cells (=0.018) and a trend toward lower expression in T cells was seen in SLE patients compared to healthy controls.

Conclusion: Although not definitive, our results may suggest that B cells may have more active roles during the earlier phases of the disease attack, while T cells take over when the disease reaches its chronic stages.
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http://dx.doi.org/10.30699/ijp.2020.110994.2187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354072PMC
April 2020

A comparison of the effects of Stevia extract and metformin on metabolic syndrome indices in rats fed with a high-fat, high-sucrose diet.

J Food Biochem 2020 08 1;44(8):e13242. Epub 2020 Jun 1.

Department of Pathology and Hematology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.

The beneficial effects of Stevia on metabolic indices have been studied in recent years. However, controversial results emphasize the need for further investigation. We aimed to examine and compare the effects of Stevia's hydroalcoholic extract with two dosages (200, 400 mg/kg) with those of metformin (100 mg/kg) on metabolic syndrome (MetS) indices of rats fed with a high-fat, high-sucrose diet (HFHS). It was found that both Stevia extract and metformin could prevent the adverse effects of a HFHS on lipid profile, liver enzymes, total antioxidant capacity (TAC), and histopathologic factors. Except for the finding that metformin showed a greater potential to alleviate insulin resistance than did Stevia extract, no significant difference was observed between the rats receiving metformin or Stevia extract. In addition, using a high treatment dosage of Stevia extract did not lead to better results than a low dosage. Collectively, the efficacy of Stevia extracts to modify metabolic, oxidative, and histopathological indices in a MetS model was comparable to that of the metformin. PRACTICAL APPLICATIONS: This study was aimed to compare the efficiency of Stevia hydroalcoholic extract with metformin in attenuating MetS abnormalities of rats induced by a high-fat, high-sucrose diet. The results showed the beneficial changes caused due to the administration of Stevia extract on lipid profile, antioxidant capacity, liver enzyme, and liver histopathological indices. The changes were comparable with the results of metformin group. Despite some promising results, further investigation is suggested to evaluate the effectiveness of Stevia extract on human subjects.
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http://dx.doi.org/10.1111/jfbc.13242DOI Listing
August 2020

Differential expression of drug resistance genes in CD146 positive dental pulp derived stem cells and CD146 negative fibroblasts.

Clin Exp Dent Res 2020 08 7;6(4):448-456. Epub 2020 May 7.

Oral and Dental Disease Research Center, Department of Operative Dentistry, School of Dentistry, Shiraz Universityof Medical Sciences, Shiraz, Iran.

Introduction: The stem cell portion of the dental pulp derived cultures (DPSCs) showed a higher resistance to cytotoxic effect of restorative dental materials compared to pulpal fibroblasts (DPFs). Here, we aimed to compare the expression of some drug resistant genes between these cells.

Methods And Materials: To separate DPSCs from DPFs, we used magnetic cell sorting technique based on CD146 expression. To assess the stem cell properties, the positive and negative portions underwent colony forming assays and were induced to be differentiated into the adipocytes, osteoblasts, hepatocytes, and neural cells. Cell surface antigen panels were checked using immune fluorescence and flow-cytometry techniques. The mRNA expression of 14 ABC transporters including ABCA2, ABCB1, ABCB11, ABCC1, ABCC2, ABCC3, ABCC4, ABCC5-2, ABCC5-4,ABCC5-13, ABCC6, ABCC10, ABCC11, and ABCG2 genes was assessed, using quantitative RT-PCR technique.

Results: Only the CD146 positive portion could be differentiated into the desired fates, and they formed higher colonies (16.7 ± 3.32 vs. 1.7 ± 1.67, p < .001). The cell surface antigen panels were the same, except for CD146 and STRO-1 markers which were expressed only in the positive portion. Among the ABC transporter genes studied, the positive portion showed a higher expression (approximately two-fold) of ABCA2, ABCC5-13, and ABCC5-2 genes.

Conclusion: Dental pulp stem cells which can be separated from dental pulp fibroblasts based on CD146 expression, express higher levels of some drug resistance genes which probably accounts for their features of more resistance to cytotoxic effects of some dental materials. This needs to be more validated in future.
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http://dx.doi.org/10.1002/cre2.297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7453779PMC
August 2020

AICAR and nicotinamide treatment synergistically augment the proliferation and attenuate senescence-associated changes in mesenchymal stromal cells.

Stem Cell Res Ther 2020 02 3;11(1):45. Epub 2020 Feb 3.

Department of Cardiovascular Medicine, Shiraz University of Medical Sciences, PO Box 71344-1864, Shiraz, Iran.

Background: Mesenchymal stromal cell (MSC) stemness capacity diminishes over prolonged in vitro culture, which negatively affects their application in regenerative medicine. To slow down the senescence of MSCs, here, we have evaluated the in vitro effects of 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), an AMPK activator, and nicotinamide (NAM), an activator of sirtuin1 (SIRT1).

Methods: Human adipose-derived MSCs were cultured to passage (P) 5. Subsequently, the cells were grown in either normal medium alone (control group), the medium supplemented with AICAR (1 mM) and NAM (5 mM), or in the presence of both for 5 weeks to P10. Cell proliferation, differentiation capacity, level of apoptosis and autophagy, morphological changes, total cellular reactive oxygen species (ROS), and activity of mTORC1 and AMPK were compared among different treatment groups.

Results: MSCs treated with AICAR, NAM, or both displayed an increase in proliferation and osteogenic differentiation, which was augmented in the group receiving both. Treatment with AICAR or NAM led to decreased expression of β-galactosidase, reduced accumulation of dysfunctional lysosomes, and characteristic morphologic features of young MSCs. Furthermore, while NAM administration could significantly reduce the total cellular ROS in aged MSCs, AICAR treatment did not. Moreover, AICAR-treated cells possess a high proliferation capacity; however, they also show the highest level of cellular apoptosis. The observed effects of AICAR and NAM were in light of the attenuated mTORC1 activity and increased AMPK activity and autophagy.

Conclusions: Selective inhibition of mTORC1 by AICAR and NAM boosts autophagy, retains MSCs' self-renewal and multi-lineage differentiation capacity, and postpones senescence-associated changes after prolonged in vitro culture. Additionally, co-administration of AICAR and NAM shows an additive or probably a synergistic effect on cellular senescence.
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http://dx.doi.org/10.1186/s13287-020-1565-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6998366PMC
February 2020

Cytoplasmic Her2/neu Immunohistochemical Staining in Breast Cancer; From a Molecular Point of View.

Iran J Pathol 2019 1;14(3):270-271. Epub 2019 Jul 1.

Department of Hematopathology, Molecular Pathology and Cytogenetics, Shiraz University of Medical Sciences, Shiraz, Iran.

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http://dx.doi.org/10.30699/ijp.2019.76630.1732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6742732PMC
July 2019

Awareness of Hemophagocytic Lymphohistiocytosis as an Unusual Cause of Liver Failure in the Neonatal Period.

J Pediatr Hematol Oncol 2020 08;42(6):e479-e482

Department of Pathology, Shiraz University of Medical Sciences, Shiraz, Iran.

Background: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome that predominantly affects infants from birth to 18 months of age, characterized by fever and multiorgan failure. Liver injury has been rarely reported as a presenting sign in the neonatal period. This study reports a case with HLH in the neonatal period who presented with acute liver failure.

Case Presentation: Herein, a 3-day-old female newborn was admitted with cytopenia, increased liver enzymes, hypofibrinogenemia, and markedly elevated serum ferritin. Hemophagocytosis of bone marrow biopsy confirmed the diagnosis of HLH. The newborn was treated with HLH-2004 protocol, but she finally died from multiorgan failure.

Conclusion: Growing awareness of HLH as a cause of liver failure in the neonatal period can be associated with early treatment and reduces mortality in this group of patients.
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http://dx.doi.org/10.1097/MPH.0000000000001600DOI Listing
August 2020

Lymphoepithelial - Like Carcinoma with Papillary Transitional Cell Carcinoma of the Urinary Bladder Associated with Carcinoma in situ Changes of the Urothelium; A Case Report and Review of Literature.

Iran J Pathol 2019 10;14(2):156-164. Epub 2019 Jun 10.

M.D, Pasteur Pathobiology Laboratory, Shiraz, Iran.

Lymphoepithelial - like carcinoma, is rarely recognized in the urinary bladder and less commonly occurs with papillary transitional cell carcinoma i.e. mixed pattern. Also, less uncommon is the occurrence of carcinoma in situ changes in the adjacent urothelium of these tumors. Here, a case of lymphoepithelial - like carcinoma and papillary transitional cell carcinoma associated with carcinoma in situ changes of urothelium of the urinary bladder has been reported the prognosis of this type of malignancy as well as its management will be discussed. Meanwhile, immunohistochemical stains have been carried out to differentiate it from lymphoma of the urinary bladder and the findings will be discussed.
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http://dx.doi.org/10.30699/IJP.14.2.156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6679663PMC
June 2019

Overexpression of Semaphorin-3A and Semaphorin-4D in the Peripheral Blood from Newly Diagnosed Patients with Chronic Lymphocytic Leukemia.

Int J Hematol Oncol Stem Cell Res 2019 Jan;13(1):25-34

Molecular Medicine Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.

Semaphorins play prominent roles in physiological and pathological processes such as vascular development, tumor growth and immune responses. Semaphorins have different roles in various kinds of cancers, but there is no study concerning their expression in the chronic lymphocytic leukemia (CLL). This study aimed to assess the SEMA3A, SEMA4A and SEMA4D expression in patients with CLL. Peripheral blood specimens were collected from 30 newly-diagnosed untreated patients with CLL and 30 healthy subjects as a control group. The SEMA3A, SEMA4A and SEMA4D expression was determined by real-time PCR method. The fold change expression of SEMA3A and SEMA4D was 7.58 ± 2.66 and 3.20 ± 0.99 in patients with CLL, and was 1.01 ± 0.31 and 1.00 ± 0.27 in healthy subjects, respectively. The CLL patients expressed higher amounts of SEMA3A and SEMA4D in comparison with healthy subjects (P<0.02 and P<0.03, respectively). The fold change expression of SEMA3A in patients with stage II (11.12 ± 5.35) was also higher than patients with stage I (4.49 ± 1.61, P<0.05). No significant difference was also observed in the expression of SEMA4A and SEMA4D between patients with stage I and stage II CLL. In both CLL and control groups, the fold change expression of SEMA3A was higher in men than in women (P<0.03 and P<0.02, respectively). The results of the study indicated elevated expression of the SEMA3A and SEMA4D in patients with CLL. The SEMA3A expression was influenced by tumor stage and gender of participants.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6557972PMC
January 2019

A Rare Chromosomal Abnormality in Chronic Lymphocytic Leukemia: t(13;13)

Turk J Haematol 2020 05 14;37(2):121-122. Epub 2019 Jun 14.

Shiraz University of Medical Sciences Molecular Pathology and Cytogenetic Section, Medical Faculty, Department of Pathology, Shiraz, Iran

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http://dx.doi.org/10.4274/tjh.galenos.2019.2019.0134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236408PMC
May 2020

Evaluation of the CD123 Expression and FLT3 Gene Mutations in Patients with Acute Myeloid Leukemia.

Iran J Pathol 2018 25;13(4):438-446. Epub 2018 Sep 25.

Dept. of Pathology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.

Background And Objective: Identification of cytogenetic and molecular changes plays an important role in acute myeloid leukemia (AML) patients. Thus, they are used in classification, prognosis and treatment of the disease. The CD123 expression and FLT3 gene mutations are also the variations that may assist in prognosis and treatment of patients with AML.

Methods: This study was performed on 76 patients as new cases of AML. The correlation between CD123 immunohistochemical (IHC) expression and FLT3 gene mutations with each other as well as morphological, immunophenotypical and cytogenetic factors was studied.

Results: The results represented the CD123 IHC expression in 55.3% and FLT3 gene mutations in 28.9% of cases. We found that 81.3% of patients who had FLT3/ITD gene mutations revealed IHC of CD123 expression (=0.019). The CD123 expression against FLT3 was also correlated with monocytic differentiation in bone marrow blasts (=0.031). There were significant correlations between IHC expression of CD123 and FLT3/ITD mutations with a high percentage of aspirated bone marrow blasts (=0.01 and =0.006, respectively) as well as the lack of CD34 expression in bone marrow blasts (=0.007 and =0.021, respectively).

Conclusion: The CD123 IHC positive AMLs were correlated with certain pathologic features, some of which can be similar with correlations of background mutation of FLT3/ITD; According to the negative predictive value (NPV), 88.2% of CD123 IHC showed FLT3 gene mutation. In addition to its use in targeted therapy, it could be a marker to decide what molecular tests to use in the next steps.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6358557PMC
September 2018

Blastic Plasmacytoid Dendritic Cell Neoplasm; A Report of Three Cases.

Iran J Med Sci 2019 Jan;44(1):74-78

Department of Hematopathology, Molecular Pathology and Cytogenetics, Shiraz University of Medical Sciences, Shiraz, Iran.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematodermic myeloid malignancy that is known to be derived from plasmacytoid dendritic cells which are characterized by expression of CD4, CD56, and more specific markers such as CD123. Here, the authors present three cases of BPDCN diagnosed in the past two years and address different available diagnostic modalities such as morphology, immunohistochemistry, flow cytometry, and cytogenetics. Overall, we believe that although BPDCN is a rare diagnosis, it should not be left unchecked. Currently, available immunophenotyping markers are of great help, but the main clue to figure out the problem of BPDCN is clinicopathologic suspicion.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6330528PMC
January 2019

Overexpression of indoleamine 2,3-dioxygenase correlates with regulatory T cell phenotype in acute myeloid leukemia patients with normal karyotype.

Blood Res 2018 Dec 17;53(4):294-298. Epub 2018 Dec 17.

Department of Pathology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.

Background: Production of immunosuppressive enzymes such as indoleamine 2,3-dioxygenase (IDO) is one of the strategies employed by hematologic malignancies, including acute myeloid leukemia (AML), to circumvent immune surveillance. Moreover, IDO has the ability to convert CD4CD25 conventional T cells into regulatory T cells (Tregs). In this study, we evaluated the expression of IDO in cytogenetically normal acute myeloid leukemia (CN-AML) patients and its correlation with the Treg marker, FOXP3, as well as clinical and laboratory parameters.

Methods: Thirty-seven newly diagnosed CN-AML patients were enrolled in our study along with 22 healthy individuals. The expression of the and genes was analyzed by SYBR Green real-time PCR.

Results: Both and were highly upregulated in CN-AML patients compared to control groups (=0.004 and =0.031, respectively). A positive correlation was observed between and expression among AML patients (r=0.512, =0.001). Expression of and showed no significant correlation with laboratory parameters such as white blood cell and platelet counts, hemoglobin levels, bone marrow blast percentage, gender, and mutation status (>0.05).

Conclusion: Higher expression in CN-AML patients may be associated with an increased Treg phenotype which may promote disease progression and lead to poor prognosis of CN-AML patients.
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http://dx.doi.org/10.5045/br.2018.53.4.294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6300669PMC
December 2018

An Unusual Case Report: Occurrence of Renal Cell Carcinoma, Basal Cell Carcinoma and Chronic Lymphocytic Leukemia in a Case of Papillary Thyroid Carcinoma Treated with Radioactive Iodine.

Iran J Med Sci 2018 Nov;43(6):659-663

Department of Hematology and Medical Oncology, Shiraz University of Medical Sciences, Shiraz, Iran.

The standard therapy for thyroid cancer is total or near total thyroidectomy, followed by the administration of radioactive iodine for remnant ablation or residual disease. Patients with radioiodine therapy are predisposed to second malignant neoplasms in organs such as central nervous system (CNS), breast, prostate, kidney, bone marrow, salivary gland, and digestive tract. Exposure to carcinogen including occupational and therapy related hazard, aging and genetic susceptibility are other causes of second primary cancers. The second primary malignancies are not uncommon and, nowadays, the prevalence of it is mildly increasing due to the increasing survival of cancer patients and advances in early diagnosis and therapeutic modalities. Here, we present a fifty-one-year-old man with papillary thyroid carcinoma (PTC), who developed chronic lymphocytic leukemia (CLL), renal cell carcinoma (RCC), and basal cell carcinoma (BCC) in 15-20 years after radioactive iodine therapy. Second primary tumors are increasing and environmental, genetic susceptibility and increase in survival of cancer patients are the major risk factors.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6230934PMC
November 2018

MYC, BCL2, and BCL6 rearrangements in primary central nervous system lymphoma of large B cell type.

Ann Hematol 2019 Jan 11;98(1):169-173. Epub 2018 Oct 11.

Pathology and Stem Cell Research Center, Afzalipour Medical School, Kerman University of Medical Sciences, Kerman, Iran.

Primary central nervous system lymphoma (PCNSL) is a rare specific subtype of non-Hodgkin lymphoma limited to the brain, leptomeninges, spinal cord, or eyes without any systemic presentation and relapse which mostly takes place in CNS. In more than 95% of patients, it is of diffuse large B cell lymphoma (DLBCL) type. Categorizing PCNSL to germinal center cell like or activated B cell like, as we usually do for DLBCL NOS, may not be applicable for predicting outcome. Possible prognostic significance of MYC, BCL2, and/or BCL6 rearrangements may be important given what we know about their impact in systemic DLBCL, but we have limited knowledge about the status of double or triple hit molecular changes in PCNSL. Here, we have investigated prevalence of these molecular alterations in PCNSL. Two independent tissue microarrays constructed from 78 formalin-fixed paraffin-embedded blocks of confirmed PCNSL were tested for rearrangement of MYC, BCL2, and BCL6 by interphase fluorescent in situ hybridization (FISH) using break apart dual color probes. BCL6 translocation was detected in 15 (12%) cases. Translocation involving MYC and BCL2 was identified in 3 cases (3.8%) and 1 case (1.3%) respectively. One double hit lymphoma was discovered with both MYC/BCL2 translocation (1.3%). To the best of our knowledge, few organized studies have been conducted for MYC, BCL2, and/or BCL6 rearrangement in PCNSL. This study is evaluating large number of PCNSL. Double or triple hit events which are rarely seen in PCNSL.
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http://dx.doi.org/10.1007/s00277-018-3498-zDOI Listing
January 2019

Purification of Stem Cells from Oral Pyogenic Granuloma Tissue.

Open Dent J 2018 29;12:560-566. Epub 2018 Aug 29.

Department of Operative Dentistry, School of Dentistry, Shiraz University of Medical Sciences, Shiraz, Iran.

Introduction: The isolation of stem cells from pathologically damaged dental tissues has been examined only by a few studies. The purpose of this study was to evaluate the possibility of isolation of stem cells from pyogenic granuloma.

Methods: Pyogenic granuloma tissues were enzymatically digested and the resulting single cells were cultured. Then, the cultured cells differentiated into adipocytes and osteoblasts cells. Flow cytometry analyses were performed on markers such as CD 90, CD 73, CD105, CD 45 and CD14. Other features were also analyzed including the effect of colony formation and potentials of differentiation into adipocytes and osteoblasts.

Results: The cells derived from pyogenic granuloma tissue formed higher colonies similar to typical spindle-shaped fibroblasts. The cells were positive for mesenchymal markers such as CD 44, CD 271, CD 90, and CD 73, and negative for surface molecules such as CD 14, CD 34 and CD 45. Moreover, they successfully differentiated into adipocytes and osteoblasts.

Conclusion: The cells isolated from pyogenic granuloma could form CFU fibroblastic units expressing an appropriate marker panel of the cell surface antigen and adequate differentiation potential, all of which met the Cell Therapy International Association criteria for the definition of mesenchymal stromal cells. Pyogenic granuloma contains cells with stem cell properties.
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http://dx.doi.org/10.2174/1874210601812010560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6118039PMC
August 2018

O6-Methyguanine-DNA Methyl Transferase (MGMT) Promoter Methylation in Serum DNA of Iranian Patients with Colorectal Cancer

Asian Pac J Cancer Prev 2018 May 26;19(5):1223-1227. Epub 2018 May 26.

Gastroenterohepatology Research Center, Nemazi Hospital, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.

Introduction: Colorectal cancer (CRC) is a leading cause of cancer deaths worldwide but current molecular targeted therapy is not providing major success in CRC treatment, so early detection by non-invasive methods continues to be vital. Aberrant methylation of CpG islands in promoter regions is associated with inactivation of various tumor suppressor genes. O6-methyguanine-DNA methyltransferase (MGMT) is a DNA repair enzyme that removes mutagenic and cytotoxic adducts from O6-guanine in DNA. Aberrant hypermethylation of the MGMT promoter has been associated with lack of mRNA expression, with concomitant loss of protein content and enzyme activity. AIM: Our aim was to determine whether MGMT promoter methylation might be detectable in circulating free DNA in the serum of CRC patients and normal individuals using a methylation specific (MSP) polymerase chain reaction (PCR) method. Methods: A total of 70 subjects were enrolled in the study. Of these, 30 patients who were diagnosed previously as untreated colon adenocarcinoma by a gastroenterologist and the other 40 were nearly age-matched individuals who had a normal colonoscopic evaluation (except for hemorrhoids or fissures) and normal pathologic reports. After bisulphite modification of DNA, serum samples were examined for MGMT promoter methylation using MSP. Results: Ninety percent of CRC patients had MGMT promoter hypermethylation as compared to no methylation in normal subjects’ serum. Most of the cancers were stage П and moderately differentiated adenocarcinomas; nearly 60% were found in the left colon. No statistically significant correlation was found between the promoter methylation status and gender and age. Discussion and Conclusions: MGMT hypermethylation can be detected in free circulating DNA in serum of CRC patients and can be used “as a clinical biomarker” for early diagnosis and prognostic assessment of the disease. Our data confirm previous studies indicating utility for free circulating DNA as a serum biomarker for early detection, diagnosis and monitoring of CRC patients.
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http://dx.doi.org/10.22034/APJCP.2018.19.5.1223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6031839PMC
May 2018

Additional cytogenetic aberrations in chronic myeloid leukemia: a single-center experience in the Middle East.

Blood Res 2018 Mar 27;53(1):49-52. Epub 2018 Mar 27.

Molecular Pathology and Cytogenetic Ward, Pathology Department, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.

Background: Additional cytogenetic aberrations are associated with disease progression in chronic myeloid leukemia (CML). This study was conducted to determine the type and frequency of these aberrations and their relationship with hematologic and molecular findings in the Middle East.

Methods: In this retrospective study, 134 well-established cases of CML were selected from 2010 to 2016. Their hematologic phase and type of fusion gene were determined. Finally, their karyotypes were analyzed and reported according to ISCN 2013.

Results: Patients had a mean age of 44 years. Twenty-two patients (16.4%) showed additional cytogenetic aberrations. Nine patients (6.7%) harbored a variant Philadelphia chromosome, and most were in the chronic phase. Seventeen patients (12.7%) had major and minor route abnormalities. There was a significant relationship between additional cytogenetic aberrations and major molecular response (=0.032). Patient survival in the group with additional cytogenetic aberrations was significantly lower (49.7±11.1 mo) than that in the group without additional cytogenetic aberrations (77.3±3.1 mo) (=0.031).

Conclusion: This study revealed the same frequency of additional cytogenetic aberrations in CML as found in previous studies. Additional chromosomal aberrations led to shorter survival and lower rates of achievement of a major molecular response.
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http://dx.doi.org/10.5045/br.2018.53.1.49DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5898994PMC
March 2018

8p11 Stem Cell Leukemia/Lymphoma Syndrome without Myeloproliferation: A Rare Clinical Entity.

Indian J Hematol Blood Transfus 2018 Apr 27;34(2):383-384. Epub 2017 Sep 27.

1Molecular Pathology and Cytogenetic Ward, Pathology Department, Medical Faculty, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.

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http://dx.doi.org/10.1007/s12288-017-0884-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5884995PMC
April 2018

The Prevalence of Human Papilloma Virus in Squamous Cell Carcinoma of Oral Tongue.

Iran J Pathol 2017 1;12(2):144-149. Epub 2017 Apr 1.

Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.

Background And Objective: Oral tongue Squamous Cell carcinoma (SCC) commonly involves males between the sixth to eighth decades of life. Major risk factors are tobacco usage and alcohol consumption. The increasing number of patients developing oral tongue cancer without these well-known risk factors suggests that a viral infection, such as Human Papillomavirus (HPV), may be responsible for this increase, by acting as an oncogenic agent. This study investigated the prevalence of HPV infection and its clinicopathologic significance in oral tongue SCCs.

Methods: Tissue blocks from a total of 50 cases (patients with oral tongue SCC) and 50 controls (palatine tonsillar tissues with benign diagnosis) were selected. DNA was extracted from tumoral and non-tumoral tissue blocks. Detection of common HPV DNA by nested Polymerase Chain Reaction (PCR), and high-risk genotypes, HPV 16 and HPV 18, by conventional PCR, was achieved and the results correlated with clinicopathological parameters.

Results: Of the 50 patients (18 males and 32 females with a mean age of 57.36±12.18 years, and age range of 27 to 86 years), 7 (14%) had HPV positive results. None of the control group subjects had HPV DNA positive results (P-value of 0.012). The HPV genotype 16/18 was not detected in positive cases. No statistically significant association was found between HPV status and gender, age, tumor grade, tumor stage or lymph node involvement.

Conclusion: Although there was a significantly higher prevalence of HPV in oral tongue SCC, its association with carcinogenesis in this area requires further studies.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5831070PMC
April 2017

PAX-5 positive anaplastic large cell lymphoma presenting by dysphagia; a case report.

Gastroenterol Hepatol Bed Bench 2017 ;10(4):332-336

Transplant Research Center, Shiraz University of Medical Science, Shiraz, Iran.

Anaplastic large cell lymphoma (ALCL) is a distinct pathologic entity with characteristic morphologic, im¬munophenotypic and cytogenetic features. Obstructive symptoms are rare presentation of ALCL. We report a 16-year-old boy who initially presented with dysphagia. Upper gastrointestinal endoscopy revealed severe stenosis with an infiltrative process starting from 24 cm of incisors in lower esophagus Esophageal mucosal biopsy demonstrated lymphomatous involvement that ancillary tests confirmed the diagnosis of ALCL, ALK (kinase-positive), and PAX5 positive. The patient responded to CHOP-based chemotherapy. This case illustrated an unusual presentation of primary Non Hodgkin lymphoma of esophagus.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5758743PMC
January 2017

Aging and stem cell therapy: AMPK as an applicable pharmacological target for rejuvenation of aged stem cells and achieving higher efficacy in stem cell therapy.

Hematol Oncol Stem Cell Ther 2018 Dec 19;11(4):189-194. Epub 2017 Oct 19.

Department of Pathology, Shiraz University of Medical Sciences, Shiraz, Iran; Hematology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.

In recent years, tissue regeneration has become a promising field for developing stem cell-based transplantation therapies for human patients. Adult stem cells are affected by the same aging mechanisms that involve somatic cells. One of the mechanisms involved in cellular aging is hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1) and disruption of 5' adenosine monophosphate-activated protein kinase (AMPK). Aging of stem cells results in their impaired regenerative capacity and depletion of stem cell pools in adult tissue, which results in lower efficacy of stem cell therapy. By utilizing an effective therapeutic intervention for aged stem cells, stem cell therapy can become more promising for future application. mTORC1 inhibition is a practical approach to preserve the stem cell pool. In this article, we review the dynamic interaction between sirtuin (silent mating type information regulation 2 homolog) 1, AMPK, and mTORC1. We propose that using AMPK activators such as 5-aminoimidazole-4-carboxamide ribonucleotide, A769662, metformin, and oxidized nicotinamide adenine dinucleotide (NAD) are practical ways to be employed for achieving better optimized results in stem cell-based transplantation therapies.
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http://dx.doi.org/10.1016/j.hemonc.2017.08.001DOI Listing
December 2018

Endothelial progenitor cell subsets and preeclampsia: Findings and controversies.

J Chin Med Assoc 2017 Oct 14;80(10):615-622. Epub 2017 Jul 14.

Infertility and Reproductive Medicine Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.

Vascular remodeling is an essential component of gestation. Endothelial progenitor cells (EPCs) play an important role in the regulation of vascular homeostasis. The results of studies measuring the number of EPCs in normal pregnancies and in preeclampsia have been highly controversial or even contradictory because of some variations in technical issues and different methodologies enumerating three distinct subsets of EPCs: circulating angiogenic cells (CAC), colony forming unit endothelial cells (CFU-ECs), and endothelial colony-forming cells (ECFCs). In general, most studies have shown an increase in the number of CACs in the maternal circulation with a progression in the gestational age in normal pregnancies, while functional capacities measured by CFU-ECs and ECFCs remain intact. In the case of preeclampsia, mobilization of CACs and ECFCs occurs in the peripheral blood of pregnant women, but the functional capacities shown by culture of the derived colony-forming assays (CFU-EC and ECFC assays) are altered. Furthermore, the number of all EPC subsets will be reduced in umbilical cord blood in the case of preeclampsia. As EPCs play an important role in the homeostasis of vascular networks, the difference in their frequency and functionality in normal pregnancies and those with preeclampsia can be expected. In this review, there was an attempt to provide a justification for these controversies.
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http://dx.doi.org/10.1016/j.jcma.2017.06.013DOI Listing
October 2017

Role of CD146 Enrichment in Purification of Stem Cells Derived from Dental Pulp Polyp.

Iran Endod J 2017 ;12(1):92-97

Hematology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; ; Molecular Pathology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.

Introduction: Hyperplastic pulpitis (pulp polyp) tissues contains cells with stem cell properties similar to that of the dental pulp stem cells (DPSCs). It has also been shown that CD146 enrichment can homogenize the cultures of DPSCs and enhance the colony forming potentials of their cultures. This study determines whether CD146 enrichment can help purifying the stem cells from heterogeneous cultures of the pulp polyp derived stem cells (PPSCs).

Methods And Materials: Healthy dental pulps and pulp polyp tissues were enzymatically digested and the harvested single cells were sorted according to the presence of CD146 marker. The sorted cells were seeded directly for colony forming unit (CFU) assays of the negative and positive portions. Flowcytometric antigen panel and differentiation assays were used to see if these cells conform with mesenchymal stems cells (MSCs) definition. Differences between the between groups was assessed using independent t-test. The level of significance was set at 0.05.

Results: Normal pulp tissue derived cells formed higher colonies (42.5±16.8 per 10 cells) than the pulp polyp (17.75±8.9 per 10 cells) (=0.015). The CD146 positive portion of the polyp derived cells formed an average of 91.5±29.7 per 10 cells per CFU. On the other hand, CD146 negative portion did not show any colonies (<0.001). Both resources showed cells with flowcytometric antigen panel and differentiation potentials conforming to MSC definition.

Conclusion: The entire CFU of PPSCs were formed within CD146 enriched portion. It seems that CD146 enrichment may reduce the number of possible fibroblasts of the pulp polyps and may further homogenize the culture of the PPSCs.
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http://dx.doi.org/10.22037/iej.2017.19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5282388PMC
January 2017

A Rare Case of Extramedullary T/Myeloid Mixed Phenotype Acute Leukemia with t(1;5)(q23;q33).

Case Rep Pathol 2016 26;2016:8937940. Epub 2016 Dec 26.

Department of Pathology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.

Mixed phenotype acute leukemia (MPAL) is a rare neoplasm which accounts for 2-5% of all leukemias and it is classified under heading of acute leukemia of ambiguous lineage in 2008 WHO classification. This patient was a 61-year-old man who presented with malaise and weakness. In physical examination there was cervical and axillary lymphadenopathy. Paraclinical evaluation revealed anemia (Hb = 10.3 g/dL, MCV = 108 fl). Histologic sections of the axillary lymph node revealed leukemic involvement with two discrete populations of cells in immunohistochemistry. One population was immunoreactive for MPO and the other showed immunostaining for CD3, CD99, and tdt. Differential count of bone marrow cells in marrow aspirate had 6% blast. Karyotype study on bone marrow culture depicted an interesting finding which was t(1;5)(q23;q33). An extensive search on literature was done for the same genetic change. A similar translocation has been mentioned in literature for other hematologic malignancies but not for same neoplasm; anyhow this translocation was an imbalanced one and led to der(5)t(1;5)(q12-25;q13-q35).
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http://dx.doi.org/10.1155/2016/8937940DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5220414PMC
December 2016