Yazar "Ganjalikhani Hakemi, Mazdak" seçeneğine göre listele

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    An in silico investigation on the binding site preference of PD-1 and PD-L1 for designing antibodies for targeted cancer therapy
    (2024) Abdolmaleki, Sarah; Ganjalikhani Hakemi, Mazdak; Ganjalikhany, Mohamad Reza
    Cancer control and treatment remain a significant challenge in cancer therapy and recently immune checkpoints has considered as a novel treatment strategy to develop anti-cancer drugs. Many cancer types use the immune checkpoints and its ligand, PD-1/PD-L1 pathway, to evade detection and destruction by the immune system, which is associated with altered effector function of PD-1 and PD-L1 overexpression on cancer cells to deactivate T cells. In recent years, mAbs have been employed to block immune checkpoints, therefore normalization of the anti-tumor response has enabled the scientists to develop novel biopharmaceuticals. In vivo affinity maturation of antibodies in targeted therapy has sometimes failed, and current experimental methods cannot accommodate the accurate structural details of protein-protein interactions. Therefore, determining favorable binding sites on the protein surface for modulator design of these interactions is a major challenge. In this study, we used the in silico methods to identify favorable binding sites on the PD-1 and PD-L1 and to optimize mAb variants on a large scale. At first, all the binding areas on PD-1 and PD-L1 have been identified. Then, using the RosettaDesign protocol, thousands of antibodies have been generated for 11 different regions on PD-1 and PD-L1 and then the designs with higher stability, affinity, and shape complementarity were selected. Next, molecular dynamics simulations and MM-PBSA analysis were employed to understand the dynamic, structural features of the complexes and measure the binding affinity of the final designs. Our results suggest that binding sites 1, 3 and 6 on PD-1 and binding sites 9 and 11 on PD-L1 can be regarded as the most appropriate sites for the inhibition of PD-1-PD-L1 interaction by the designed antibodies. This study provides comprehensive information regarding the potential binding epitopes on PD-1 which could be considered as hotspots for designing potential biopharmaceuticals. We also showed that mutations in the CDRs regions will rearrange the interaction pattern between the designed antibodies and targets (PD-1 and PD-L1) with improved affinity to effectively inhibit protein-protein interaction and block the immune checkpoint.
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    Immune-dysregulation harnessing in myeloid neoplasms
    (2024) Sharifi, Mohammad Jafar; Xu, Ling; Nasiri, Nahid; Ashja Arvan, Mehnoosh; Soleimanzadeh, Hadis; Ganjalikhani Hakemi, Mazdak
    Myeloid malignancies arise in bone marrow microenvironments and shape these microenvironments in favor of malignant development. Immune suppression is one of the most important stages in myeloid leukemia progression. Leukemic clone expansion and immune dysregulation occur simultaneously in bone marrow microenvironments. Complex interactions emerge between normal immune system elements and leukemic clones in the bone marrow. In recent years, researchers have identified several of these pathological interactions. For instance, recent works shows that the secretion of inflammatory cytokines such as tumor necrosis factor-α (TNF-α), from bone marrow stromal cells contributes to immune dysregulation and the selective proliferation of JAK2V617F+ clones in myeloproliferative neoplasms. Moreover, inflammasome activation and sterile inflammation result in inflamed microenvironments and the development of myelodysplastic syndromes. Additional immune dysregulations, such as exhaustion of T and NK cells, an increase in regulatory T cells, and impairments in antigen presentation are common findings in myeloid malignancies. In this review, we discuss the role of altered bone marrow microenvironments in the induction of immune dysregulations that accompany myeloid malignancies. We also consider both current and novel therapeutic strategies to restore normal immune system function in the context of myeloid malignancies.
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    Morphology-dependent immunomodulatory coating of hydroxyapatite/PEO for magnesium-based bone implants
    (2023) Farshid, Safoura; Kharaziha, Mahshid; Salehi, Hossein; Ganjalikhani Hakemi, Mazdak
    One of the most critical issues concerning orthopedic implants is the risk of chronic inflammation, which poses a threat to the bone healing process. Osteo-immunomodulation plays a pivotal role in implant technology by influencing proinflammatory and anti-inflammatory responses, ultimately promoting bone healing. This study aims to investigate the morphology-dependent osteo-immunomodulatory properties of a hydroxyapatite (HA)/plasma electrolytic oxidation (PEO)-coated WE43 alloy. In this context, following the PEO process with various operational parameters (duty cycles of 50-40, 50-20, 70-40%, and frequencies of 0.5, 0.8, and 1 kHz), a layer of HA was applied as the top coating using a straightforward hot-dip process. The results revealed the formation of the PEO layer with distinct morphologies and pore sizes, depending on the operational parameters. Specifically, a uniform PEO coating with small pore sizes (5.2-5.3 ?m) led to the creation of plate-like HA particles, while a random-like HA structure formed on nonuniform surfaces with large pores (7.0-11.1 ?m) of PEO. Moreover, it was observed that the plate-like HA coating exhibited higher adhesion strength than the random one (classified as class 2 vs class 3 based on cross-cut standards). Furthermore, electrochemical impedance spectroscopy (EIS) and polarization studies confirmed a substantial increase in the polarization resistance (680 k?) and total impedance (48?559.6 ?) for the plate-like HA/PEO as compared to the substrate (an increase of 1511-fold and 311-fold, respectively) and the random HA/PEO samples (an increase of 85-fold and 18-fold, respectively). In addition, compared to random HA coatings, there was a significant enhancement in the viability (150% control vs 96% control), proliferation, and differentiation of MG63 cells when exposed to plate-like HA coatings. Moreover, surface morphology and chemistry pronouncedly impacted macrophages' viability, morphology, and phenotype. Notably, plate-like HA coatings resulted in a higher upregulation of BMP-2 and TGF-? than proinflammatory cytokines (IL-6 and M-CSF), indicating a polarization of macrophage type 1 (M1) toward type 2 (M2). In summary, the bilayer HA/PEO coating exhibited remarkable osteo-immunomodulatory activity, making it highly appealing for use in bone implant applications.
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    Potential diagnostic value of abnormal pyroptosis genes expression in myelodysplastic syndromes (MDS): A primary observational cohort study
    (2024) Soltani, Mohammad; Sharifi, Mohammad Jafar; Khalilian, Parvin; Sharifi, Mehran; Nematollahi, Pardis; Shapourian, Hooriyeh; Ganjalikhani Hakemi, Mazdak
    Background: Myelodysplastic syndromes (MDS) are determined by ineffective hematopoiesis and bone marrow cytological dysplasia with somatic gene mutations and chromosomal abnormalities. Accumulating evidence has revealed the pivotal role of NLRP3 inflammasome activation and pyroptotic cell death in the pathogenesis of MDS. Although MDS can be diagnosed with a variety of morphologic and cytogenetic tests, most of these tests have limitations or problems in practice. Materials and Methods: In the present study, we evaluated the expression of genes that form the inflammasome (NLRP3, ASC, and CASP1) in bone marrow specimens of MDS patients and compared the results with those of other leukemias to evaluate their diagnostic value for MDS. Primary samples of this observational cohort study were collected from aspiration samples of patients with myelodysplastic syndromes (27 cases) and patients with non-myelodysplastic syndrome hematological cancers (45 cases). After RNA extraction and c.DNA synthesis, candidate transcripts and housekeeping transcripts were measured by real-time PCR method (SYBER Green assay). Using Kruskal-Wallis the relative gene expressions were compared and differences with p value less than 0.05 were considered as significant. Discrimination capability, cut-off, and area under curve (AUC) of all markers were analyzed with recessive operation curve (ROC) analysis. Results: We found that Caspase-1 and ASC genes expressed at more levels in MDS specimens compared to non-MDS hematological malignancies. A relative average expression of 10.22 with a p-value of 0.001 and 1.86 with p=0.019 was detected for Caspase-1 and ASC, respectively. ROC curve analysis shows an AUC of 0.739 with p=0.0001 for Caspase-1 and an AUC of 0.665 with p=0.0139 for ASC to MDS discrimination. Conclusion: Our results show that Caspase-1 and ASC gene expression levels can be used as potential biomarkers for MDS diagnosis. Prospective studies with large sample numbers are suggested.