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Senior managers play an essential role in organizations. They shape organizational strategy and culture, define missions including opportunities for new markets, and business models. Their commitment to the organization is critical to organizational performance, but research on the personality traits of top managers and their commitment to organizations is limited.Therefore, this research has been conducted with the aim of the role and position of multiple personality components in fulfilling the organizational obligations of senior financial managers in companies listed on the Tehran Stock Exchange. Where relying on self-affirmation theory, the implications of the "dark triad traits" of top managers (narcissism, psychopathy, and Machiavellianism) for their organizational commitment and the mediating role of role clarity and the moderating role of resource availability are examined. In this regard, In this research, the three-component conceptual model developed by Allen and Mayer (1990) has been used to distinguish affective, continuance and normative commitment. A research model was developed from the literature review and the three-component model developed by Allen and Mayer, and then it was developed using the structural equation method on a sample of 384 respondents from all activists, brokers, investors, experts. Seniors and specialists of the companies admitted to the Tehran Stock Exchange were evaluated. The results of this study show that psychosis has a significant effect on organizational normative commitment, narcissism an organizational normative commitment, and Machiavellian personality approach on emotional organizational commitment in companies listed to the Tehran Stock Exchange. Also, the availability of resources as a moderating variable has a significant effect on the relationship between multiple personality components of senior financial managers and organizational commitments in companies listed on the stock exchange. Finally, the results showed that the multiple personality components of senior financial managers have a significant effect on the transparency of the role in the companies.

Objective: Kienböck disease is a rare condition characterized by severe pain and restricted wrist movement. Variouspalliative methods have been proposed as therapeutic strategies for alleviating symptoms. Mesenchymal stromal cell transplantationhas been suggested as an innovative and promising approach due to its potential for inducing regeneration andimmunomodulation in the necrotic tissue. This study aims to evaluate the safety of autologous bone marrow derivedmesenchymal stromal cells (BM-MSCs) transplantation after core decompression in Kienböck disease.Materials and Methods: In this phase I of an open-label clinical trial, three patients (one female and two males) withstage 2 Kienböck disease underwent autologous BM-MSCs transplantation following lunate core decompression. Thepatients were followed up for six months to assess safety as well as secondary clinical outcomes, including pain level,range of motion (ROM), and functional disability.Results: Safety of BM-MSCs injection following the core decompression was evaluated by recording post-treatmentcomplications during the six-month follow-up. No adverse events (AEs) or severe AEs (SAEs) were reported, indicatingthat BM-MSCs injection after core decompression is a safe intervention. All patients showed a remarkable reductionin visual analog scale (VAS) scores and "Disabilities of the Arm, Shoulder, and Hand" (DASH) questionnaire scores,suggesting the therapeutic potential of this intervention. Moreover, an increase in the ROM indicated that BM-MSCstransplantation can improve wrist functionality. Additionally, radiographic assessments before and after cell infusiondemonstrated a reduction in lunate sclerosis after six months of follow-up.Conclusion: The transplantation of autologous BM-MSCs following lunate core decompression seems to be a safeclinical intervention and may lead to pain relief in patients with Kienböck disease. Furthermore, this procedure may helpprevent disease progression during the follow-up period (registration number: NCT02646007).

Abstract Gelatin-methacryloyl (GelMA) is a highly adaptable biomaterial extensively utilized in skin regeneration applications. However, it is frequently imperative to enhance its physical and biological qualities by including supplementary substances in its composition. The purpose of this study was to fabricate and characterize a bi-layered GelMA-gelatin scaffold using 3D bioprinting. The upper section of the scaffold was encompassed with keratinocytes to simulate the epidermis, while the lower section included fibroblasts and HUVEC cells to mimic the dermis. A further step involved the addition of amniotic membrane extract (AME) to the scaffold in order to promote angiogenesis. The incorporation of gelatin into GelMA was found to enhance its stability and mechanical qualities. While the Alamar blue test demonstrated that a high concentration of GelMA (20%) resulted in a decrease in cell viability, the live/dead cell staining revealed that incorporation of AME increased the quantity of viable HUVECs. Further, gelatin upregulated the expression of KRT10 in keratinocytes and VIM in fibroblasts. Additionally, the histological staining results demonstrated the formation of well-defined skin layers and the creation of extracellular matrix (ECM) in GelMA/gelatin hydrogels during a 14-day culture period. Our study showed that a 3D-bioprinted composite scaffold comprising GelMA, gelatin, and AME can be used to regenerate skin tissues.

Objective: There is interest in using cytotoxic T lymphocyte antigen-4 (CTLA-4) immunotherapy to treat blood cancers.Unfortunately, patients with acute lymphoblastic leukaemia (ALL) frequently exhibit resistance to treatment and naturalkiller (NK) cell exhaustion. This study aims to increase the cytotoxic potency of natural killer cells by using CTLA-4 toblock the Nalm-6 leukaemia cell line.Materials and Methods: In this experimental study, NK cells were purified from the peripheral blood mononuclear cells(PBMCs) of 10 healthy people and assessed by flow cytometry for purity and viability. The purified cells were activatedovernight at 37°C and 5% CO2 with interleukin-15 (IL-15, 10 ng/ml) followed by evaluation of expressions of CTLA-4,activating and inhibitory receptors, and the release of interferon gamma (IFN-γ) and granzyme B (GZM B). CTLA-4expression on NK cells from recurrent ALL patients was also evaluated. Finally, the cytotoxic activity of NK cells wasassessed after the CTLA-4 blockade.Results: The purity of the isolated cells was 96.58 ± 2.57%. Isolated NK cells activated with IL-15 resulted in significantlyhigher CTLA-4 expression (8.75%, P

Introduction: For cell-based therapies of lung injury, several cell sources have been extensively studied. However, the potential of human fetal respiratory cells has not been systematically explored for this purpose. Here, we hypothesize that these cells could be one of the top sources and hence, we extensively updated the definition of their phenotype. Methods: Human fetal lower respiratory tissues from pseudoglandular and canalicular stages and their isolated epithelial cells were evaluated by immunostaining, electron microscopy, flow cytometry, organoid assay, and gene expression studies. The regenerative potential of the isolated cells has been evaluated in a rat model of bleomycin-induced pulmonary injury by tracheal instillation on days 0 and 14 after injury and harvest of the lungs on day 28. Results: We determined the relative and temporal, and spatial pattern of expression of markers of basal (KRT5, KRT14, TRP63), non-basal (AQP3 and pro-SFTPC), and early progenitor (NKX2.1, SOX2, SOX9) cells. Also, we showed the potential of respiratory-derived cells to contribute to in vitro formation of alveolar and airway-like structures in organoids. Cell therapy decreased fibrosis formation in rat lungs and improved the alveolar structures. It also upregulated the expression of IL-10 (up to 17.22 folds) and surfactant protein C (up to 2.71 folds) and downregulated the expression of TGF-β (up to 5.89 folds) and AQP5 (up to 3.28 folds). Conclusion: We provide substantial evidence that human fetal respiratory tract cells can improve the regenerative process after lung injury. Also, our extensive characterization provides an updated phenotypic profile of these cells.

This study investigates the groundbreaking and significant integration of plurilingualism and multilingualism within the context of teaching English as a Foreign Language (EFL). The incorporation of this approach presents a potential for redefining educational paradigms to promote inclusivity and equality. However, it also presents other issues that necessitate careful examination, including theoretical uncertainties, practical challenges, and constraints associated with critical pedagogy. The subject matter beyond the boundaries of academic discussion, exerting influence on the educational experiences of individuals globally, and necessitates an approach that is attuned to the specific situation. It is imperative to recognize the inherent complexities of languages, as they serve not only as means of communication, but also as cultural, authoritative, and individual manifestations. To address this intricate task in an effective manner, it is imperative for future scholars to embrace a dual approach characterized by boldness and humility, while acknowledging the extensive global ramifications involved. The achievement that could be attained in this domain requires a denial of overly simplistic resolutions and demands an active, intricate comprehension of the intricate aspects of language and education.

The mechanical performance and corrosion behavior are crucial factors for additively manufactured Ti–6Al–4V porous implants, which are influenced by implant design, fabrication method, and post-processing. In the present study, effects of geometrical parameters and heat treatment on the compression and corrosion behaviors of Ti–6Al–4V sheet-based gyroid implants fabricated by laser powder-bed fusion (LPBF) process are investigated. The results showed that an increase in the pore size (ranging from 600 to 1200 μm) did not alter the microstructure, while decreased the Young's modulus and strength of the implants. The post-processing heat treatment resulted in the α' → α + β phase transformation which influenced mechanical properties. The mechanical properties of all scaffolds were found to be comparable to those of human bone. The heat-treated implants showed superior corrosion resistance than the as-built ones. Furthermore, the corrosion resistance of both as-built and heat-treated implants improved with increasing the pore size. The LPBFed Ti–6Al–4V implants with gyroid-sheet structure can be a promising candidate for biomedical implants from both compressive and corrosion behaviors points of view.

Abstract Accumulating data reveals that tumors possess a specialized subset of cancer cells named cancer stem cells (CSCs), responsible for metastasis and recurrence of malignancies, with various properties such as self‐renewal, heterogenicity, and capacity for drug resistance. Some signaling pathways or processes like Notch, epithelial to mesenchymal transition (EMT), Hedgehog (Hh), and Wnt, as well as CSCs' surface markers such as CD44, CD123, CD133, and epithelial cell adhesion molecule (EpCAM) have pivotal roles in acquiring CSCs properties. Therefore, targeting CSC‐related signaling pathways and surface markers might effectively eradicate tumors and pave the way for cancer survival. Since current treatments such as chemotherapy and radiation therapy cannot eradicate all of the CSCs and tumor relapse may happen following temporary recovery, improving novel and more efficient therapeutic options to combine with current treatments is required. Immunotherapy strategies are the new therapeutic modalities with promising results in targeting CSCs. Here, we review the targeting of CSCs by immunotherapy strategies such as dendritic cell (DC) vaccines, chimeric antigen receptors (CAR)‐engineered immune cells, natural killer‐cell (NK‐cell) therapy, monoclonal antibodies (mAbs), checkpoint inhibitors, and the use of oncolytic viruses (OVs) in pre‐clinical and clinical studies. This review will mainly focus on blood malignancies but also describe solid cancers.

Abstract In recent years, the anticancer properties of metabolites from halophilic microorganisms have received a lot of attention. Twenty-nine halophilic bacterial strains were selected from a culture collection to test the effects of their supernatant metabolites on stem cell-like properties of six human cancer cell lines. Human fibroblasts were used as normal control. Sphere and colony formation assay were done to assess the stem cell-like properties. invasion and migration assay, and tumor development in mice model were done to assess the anti-tumorigenesis effect in vitro and in vivo. The metabolites from Salinivenus iranica demonstrated the most potent cytotoxic effect on breast cancer cell lines (IC50 = 100 µg/mL) among all strains, with no effect on normal cells. In MDA-MB-231 cells, the supernatant metabolites enhanced both early and late apoptosis (approximately 9.5% and 48.8%, respectively) and decreased the sphere and colony formation ability of breast cancer cells. Furthermore, after intratumor injection of metabolites, tumors developed in the mice models reduced dramatically, associated with increased pro-apoptotic caspase-3 expression. The purified cytotoxic molecule, a phenol amine with a molecular weight of 1961.73 Dalton (IC50 = 1 µg/mL), downregulated pluripotency gene SRY-Box Transcription Factor 2 (SOX-2) expression in breast cancer cells which is associated with resistance to conventional anticancer treatment. In conclusion, we suggested that the phenol amine molecule from Salinivenus iranica could be a potential anti-breast cancer component.

Objective: The biological factors secreted from cells and cell-based products stimulate growth, proliferation, andmigration of the cells in their microenvironment, and play vital roles in promoting wound healing. The amniotic membraneextract (AME), which is rich in growth factors (GFs), can be loaded into a cell-laden hydrogel and released to a woundsite to promote the healing of the wound. The present study was conducted to optimize the concentration of theloaded AME that induces secretion of GFs and structural collagen protein from cell-laden AME-loaded collagen-basedhydrogels, to promote wound healing in vitro.Materials and Methods: In this experimental study, fibroblast-laden collagen-based hydrogel loaded with differentconcentrations of AME (0.1, 0.5, 1, and 1.5 mg/mL, as test groups) and without AME (as control group), were incubatedfor 7 days. The total proteins secreted by the cells from the cell-laden hydrogel loaded with different concentrations ofAME were collected and the levels of GFs and type I collagen were assessed using ELISA method. Cell proliferationand scratch assay were done to evaluate the function of the construct.Results: The results of ELISA showed that the concentrations of GFs in the conditioned medium (CM) secreted from thecell-laden AME-loaded hydrogel were significantly higher than those secreted by only the fibroblast group. Interestingly,the metabolic activity of fibroblasts and the ability of the cells to migrate in scratch assay significantly increased in theCM3-treated fibroblast culture compared to other groups. The concentrations of the cells and the AME for preparationof CM3 group were 106 cell/mL and 1 mg/mL, respectively.Conclusion: We showed that 1 mg/ml of AME loaded in fibroblast-laden collagen hydrogel significantly enhanced thesecretion of EGF, KGF, VEGF, HGF, and type I collagen. The CM3 secreted from the cell-laden AME-loaded hydrogelpromoted proliferation and scratch area reduction in vitro.

Objectives: Sexual harassment is one of the most common workplace issues that female employees may experience. The issue is especially severe for women working in a healthcare setting due to factors, such as unequal hierarchical power, night shifts, and a significant volume of visitors, etc. This study sought to characterize and categorize responses to and causes of acute sexual harassment. Methods: Thirty-nine hospital employees who had experienced sexual harassment were selected for in-depth interviews as part of a qualitative study designed to collect data. Results: The responses were categorized chronologically as pre-, during-, and post-harassment. Preventive strategies were the most notable pre-harassment responses, whereas, during harassment, diffusion, denial, avoidance, and behavioral changes were the most significant responses. Nonetheless, since diffusion, avoidance, non-disclosure, and non-reporting could result in the persistence of the harassment, the post-harassment strategies shed light on the factors that determined the victims' failure to disclose sexual harassment. Discussion: Although women experience sexual harassment in healthcare settings, they typically refrain from reporting it and respond passively to such situations. Formal and informal organizational support for the harassed women can empower them to resist harassers and report their conduct in hospital settings.

Objective: Natural killer (NK) cells are critical immune cells for acute myeloid leukemia (AML) targeting. However,little is known about the relationship between using checkpoint inhibitors and heat shock protein 70 (Hsp70) as NK cellactivators to control AML. Therefore, the study aims to find the best formulation of Hsp70, human PD-1 (Programmedcell death protein 1) blocker, and interleukin 15 (IL-15) to activate NK cells against AML.Materials and Methods: In this experimental study, the NK cells were isolated from mononuclear cells (MNCs) byusing magnetic activation cell sorting (MACS) and were activated using the different combinations of Hsp70, PD-1blocker, and IL-15 and then followed by immunophenotyping, functional assays to estimate their killing potential, andevaluation of expression pattern of PRF1, PIK3CB, PD-1, AKT-1, FAS-L, TRAIL, and GER A and B.Results: The expression of PD-1 was significantly (P

Background and purpose: Human pluripotent stem cells (hPSCs) with the ability to differentiate into adult cells have provided a new perspective for treatment of some diseases. But, the efficiency of differentiation methods to generate hematopoietic progenitor cells (HPCs) is faced with multiple challenges. In the present study, we investigated the formation of hemato-endothelial-like structures and HPCs from hPSCs. Materials and methods: To generate hemato-endothelial structures and HPCs, in first method, three-dimensional aggregations of hPSCs were co-cultured on OP9 cells. In second and third methods, embryoid bodies (EBs) were differentiated spontaneously or directly in the culture medium containing BMP4, bFGF, SCF, and VEGF. In differentiation process, cell morphology was evaluated by microscopic observation and the expression of CD34 and CD45 markers were analyzed by flow cytometry. In addition, the ability of HPCs to differentiate into various types of blood cells was evaluated using colony formation assay, Wright-Giemsa staining, and CD86 immunofluorescence staining. Results: Findings showed that all three methods generated cells with endothelial-like morphology and HPCs. These cells were able to proliferate, form cell clusters with different efficiency and differentiate into erythroid cells, macrophages, and dendritic cells. Conclusion: The use of cultured cells in defined conditions without a feeder layer is preferred in cell therapy. Therefore, despite the ability of all these methods to generate HPCs, direct differentiation of EBs under defined conditions is a better option for generatingHPCs from hPSCs.

As climate change exacerbates drought conditions, global crop production faces an escalating threat. Fortunately, an eco-friendly solution lies in harnessing the potential of plant-associated plant growth-promoting bacteria. However, it's crucial to recognize that drought's impact extends beyond plants; it also influences the composition, abundance, and activity of bacterial communities. Amongst these root-associated bacterial communities, Actinobacteria are key players in preserving the well-being of plant hosts during drought stress, with research demonstrating minimal disruption to these communities under drought conditions. Actinobacteria, found ubiquitously, are exceptional candidates for promoting plant growth due to their prevalence in soil and the rhizosphere, their adeptness at colonizing plant roots and surfaces, and their capability to produce diverse secondary metabolites under drought stress. With these attributes, members of the Actinobacteria phylum present themselves as the most promising candidates for microbial inoculation of plants. They are enriched in the rhizosphere and endosphere microbiomes of crops enduring water deficit stress conditions. Notably, Actinobacteria, particularly the Streptomyces genus, employ various mechanisms, such as the modulation of phytohormone levels, reinforcement of antioxidant enzymes, enhanced water and nutrient uptake, and more, to alleviate water deficit stress in crops. This comprehensive review explores actinobacterial diversity associated with plants and delves into the impact of drought stress on the diversity of the Actinobacteria. It also examines the mechanisms through which Actinobacteria mitigate drought stress in plants. Emphasizing the role of multi-omics techniques in broadening our understanding of plant-Actinobacteria interactions, this review aims to inspire further exploration in this relatively uncharted research territory. Furthermore, it discusses future research directions for the application of Actinobacteria with plant growth-promoting traits, underlining their potential for sustainable agricultural practices.

Background: The World Health Organization has mentioned infertility as a public health problem that can lead to depression, anxiety, social exclusion, and sexual disorders. This biological, psychological, and social crisis creates a defective cycle that weakens fertility and causes dysfunction in sexual performance and satisfaction. But do infertile couples in Tehran also experience such quality experiences in life? Aims: The aim of this study was to investigate the phenomenon of infertility experience and the impact of this event on the marital quality of life in couples. Methods: The research method was qualitative and phenomenological. It tried to examine and discover the lived experience of infertile couples by entering the phenomenological world. The population of the present study consisted of all couples with infertility experience who were referred to Royan Research Institute in 1400. The sampling method was purposeful according to most qualitative schemes in order to have phenomenological information, and the researcher based the obtained data on 15 Analyzed the Colaizzi method. The validity of the findings was confirmed by the re-coding method by expert professors. Results: Analyzing and coding the cognitive phenomenon by Colaizzi method, identified 36 sub-categories and according to their similarity and semantic similarity, in 7 main concepts including the couple and social suffering from child-free life, intellectual and emotional issues in the treatment path, suggestion of Divorce or polygamy, lack of empathy and compatibility of those around the couple, isolation and apathy of the couple, increase in anxiety and stress of the couple, decrease in the quality of the marital relationship, decrease in the financial security of the couple are categorized. Conclusion: The results showed that the phenomenon of infertility, in line with previous research, is associated with a noticeable decrease in the marital quality of life in couples in Tehran city and has created important issues, including the possibility of separation and divorce, coldness of relationships, decreased motivation, intellectual, emotional and social challenges, which are necessarily paying attention to the reduction of these cases is felt in order to increase the marital quality of life in these couples.

Abstract Bone scan is highly sensitive whole‐body imaging with relative low radiation in patients with non‐localized skeletal symptoms. Patient is 12‐year‐old boy with Down syndrome, suffering recent claudication and exacerbated left knee pain unable to walk even with crutches. Three‐dimensional Single photon emission computed tomography/Computed tomography (SPECT/CT) detected left slipped capital femoral epiphysis (SCFE) and secondary Avascular necrosis (AVN).

Introduction: Malignant breast cancer (BC) frequently contains a rare population of cells called cancer stem cells which underlie tumor relapse and metastasis, and targeting these cells may improve treatment options and outcomes for patients with BC. The aim of the present study was to determine the effect of silibinin on the self-renewal capacity, tumorgenicity, and metastatic potential of mammospheres. Methods: The effect of silibinin on viability and proliferation of MCF-7, MDA-MB-231 mammospheres, and MDA-MB-468 cell aggregation was determined after 72-120 hours of treatment. Colony and sphere formation ability, and the expression of stemness, differentiation, and epithelial-mesenchymal-transition (EMT)-associated genes were assessed by reverse transcription-quantitative polymerase chain reaction (qRT-PCR) in mammospheres treated with an IC50 dose of silibinin. Additionally, the antitumor capacity of silibinin was assessed in vivo, in mice. Results: The results of the present study showed that silibinin decreased the viability of all mammospheres derived from MCF-7, MDA-MB-231, and MDA-MB-468 cell aggregation in a dose-dependent manner. Colony and sphere-forming ability, as well as the expression of genes associated with EMT were reduced in mammospheres treated with silibinin. Additionally, the expression of genes associated with stemness and metastasis was also decreased and the expression of genes associated with differentiation were increased. Intra-tumoral injection of 2 mg/kg silibinin decreased tumor volumes in mice by 2.8 fold. Conclusion: The present study demonstrated that silibinin may have exerted its anti-tumor effects in BC by targeting the BC stem cells, reducing the tumorgenicity and metastasis. Therefore, silibinin may be a potential adjuvant for treatment of BC.

BACKGROUND: Restless legs syndrome (RLS) has been associated with a variety of diseases, including chronic obstructive pulmonary disease (COPD), which can worsen the symptoms of underlying disease and correlates with co-morbidities. We aimed to investigate RLS in patients with chemical warfare-induced lung diseases. METHODS: This cross-sectional study recruited patients with sulfur mustard (SM) lung injury, their healthy family members, and patients with COPD from August 2018 to August 2019. COPD was confirmed by medical history, physical examination, and spirometry according to GOLD COPD guidelines. RLS diagnosis was recognized by the International Restless Legs Syndrome Study Group (IRLSSG) and severity was assessed using the International Restless Legs Scale (IRLS) rating scale. Other research measures were COPD Assessment Test (CAT), modified Medical Research Council (mMRC) scale for dyspnoea severity, and Epworth Sleepiness Scale (ESS) for daytime somnolence. Laboratory values included hemoglobin, ferritin, creatinine, and fibrinogen. RESULTS: This study was conducted on 143 men in three groups: 40 (30.0%) SM-exposed veterans, 73 (55.3%) patients with COPD, and 30 (20.9%) healthy cases. Due to the high prevalence of COPD and better comparison with the control group, more patients with COPD were selected. 20 cases (50%) of the veterans group had RLS, while 25 (32.9%) cases of COPD were affected by this disorder. One normal case (3.33%) suffered from RLS. The chemical veterans who suffered from cough, sputum production, chest pain, and hemoptysis had a higher incidence in proportion to patients with COPD (P < 0.001). The CAT score was significantly higher in SM-exposed veterans with RLS (P = 0.004). CONCLUSION: RLS is more common in SM lung injuries with higher CAT scores; therefore, evaluation and treatment of RLS are recommended in mustard lung victims.

Introduction: B lymphocyte-induced maturation protein 1 (BLIMP1) encoded by the positive regulatory domain 1 gene (PRDM1), is a key regulator in T cell differentiation in mouse models. BLIMP1-deficiency results in a lower effector phenotype and a higher memory phenotype. Methods: In this study, we aimed to determine the role of transcription factor BLIMP1 in human T cell differentiation. Specifically, we investigated the role of BLIMP1 in memory differentiation and exhaustion of human T cells. We used CRISPR interference (CRISPRi) to knock-down BLIMP1 and investigated the differential expressions of T cell memory and exhaustion markers in BLIMP1-deficient T cells in comparison with BLIMP1-sufficient ex vivo expanded human T cells. Results: BLIMP1-deficiency caused an increase in central memory (CM) T cells and a decrease in effector memory (EM) T cells. There was a decrease in the amount of TIM3 exhaustion marker expression in BLIMP1-deficient T cells; however, there was an increase in PD1 exhaustion marker expression in BLIMP1-deficient T cells compared with BLIMP1-sufficient T cells. Conclusion: Our study provides the first functional evidence of the impact of BLIMP1 on the regulation of human T cell memory and exhaustion phenotype. These findings suggest that BLIMP1 may be a promising target to improve the immune response in adoptive T cell therapy settings.

This research has been investigated, economy and balance-sheet effects of the money growth rate targeting. According to financial statements of the banking network and national accounts, using dynamic stochastic general equilibrium New Keynesian and statistical data for the period 1991-2019.For estimating parameters, is used New Keynesian DSGE model and Bayesian method. This paper verify the validity of the model by analyzing the impulse response functions and Brooks and Goleman test. The results of the model indicate that the effect of negative the money growth rate targeting, reduce deposits, reduce loans interest rates, lead to reducing banks' resources, bank lending and then the health of the banks would compromise. In this way, investment and production will be reduced. Also, the effect of stock prices increasing, deposit, loan decrease and investment and production increase. Therefore, this research suggests the policy of negative the money growth rate targeting coincide with the policy of raising interest rates and stock price rising.

Objective: Acute myeloid leukemia (AML) is characterized by abnormalities of differentiation and growth of primary hematopoietic stem cells (HSCs) in the blood and bone marrow. In many studies, miR-625-5p has been shown to inhibit downstream pathways from affecting the metastasis and invasion of the integrin-linked kinase (ILK) signaling pathway. It has been proved that the expression of miR-625-5p decreases in AML cell lines. This study aimed to investigate the effect of miR-625-5p upregulation on the invasion of KG1 ell line in vitro. Materials and Methods: In this experimental study, we investigated the impact of upregulation of miR-625-5p on invasion via the ILK/AKT pathway in the KG1 cell line. After transfection using the viral method, the cellular invasion was assessed by invasion assay and the levels of miR-625-5p genes and protein were evaluated by quantitative polymerase chain reaction (qPCR) and western blotting. Moreover, CXCR4 level was assessed by flow cytometry. Results: The invasion significantly reduced in MiR-625-5p-transfected KG1 cells (P

Gastric cancer (GC) is one of the leading causes of cancer-related deaths worldwide. The major problems of patients with GC are the lack of proper response to the treatment, drug resistance and metastasis attributed to the presence of a subpopulation of cells inside the tumour that are called cancer stem cells (CSCs). In addition, deregulation of microRNAs (miRNAs) has been reported in different stages of GC. The aim of the present study is to determine and introduce miRNAs that contribute to regulation of stemness, metastasis and drug resistance in GC. A systematic review, we conducted data mining of available datasets and a review of previous studies to select miRNAs that target stemness, epithelial-mesenchymal transition (EMT) and drug resistance. All selected miRNAs were analysed by R software to find a common miRNA target for all three processes. Then, the target prediction of miRNAs and their related signalling pathways were obtained by using bioinformatics tools, ONCO.IO and KEGG databases, respectively. We identified seven miRNAs (miR-34a, miR-23a, miR-27a, miR-30a, miR-19b, miR-107, miR-100) from our searching approach. These miRNAs regulate pathways that contribute to stemness, EMT and drug resistance in GC. Four (miR- 34a, miR-23a, miR-30a, and miR-100) had significant interactions with each other and 52 target genes among them, from which MYC, CDK6, NOTCH1, NOTCH2, SIRT1, CD44, CD24, and AXL were involved in the regulation of several biological processes. These data suggest that the three significant properties can be regulated by common miRNAs (hsa-miR-34a, hsa-miR-23a, hsa-miR-30a and hsa-miR-100). Hence, targeting selected miRNAs or their targets might be helpful to stop tumour growth and metastasis development, and increase tumour sensitivity to chemotherapy agents. This signature can also be assumed for early detection of metastasis or drug resistance. However, there should be additional experimentation to validate these results.

Abstract One of the obstacles in treating different cancers, especially solid tumors, is cancer stem cells (CSCs) with their ability in resistance to chemo/radio therapy. The efforts for finding advanced treatments to overcome these cells have led to the emergence of advanced immune cell-based therapy (AICBT). Today, NK cells have become the center of attention since they have been proved to show an appropriate cytotoxicity against different cancer types as well as the capability of detecting and killing CSCs. Attempts for reaching an off-the-shelf source of NK cells have been made and resulted in the emergence of chimeric antigen receptor natural killer cells (CAR-NK cells). The CAR technology has then been used for generating more cytotoxic and efficient NK cells, which has increased the hope for cancer treatment. Since utilizing this advanced technology to target CSCs have been published in few studies, the present study has focused on discussing the characteristics of CSCs, which are detected and targeted by NK cells, the advantages and restrictions of using CAR-NK cells in CSCs treatment and the probable challenges in this process.

Objective: The clinical studies of acute myeloid leukaemia (AML) revealed that antigen escaping variants cause cancer recurrence even after treatment with chimeric antigen receptor (CAR)-T cells that target a single tumour antigen. Due to the heterogeneous expression of antigens on leukaemia blasts, we hypothesized that a novel bispecific CAR, directed to the folate receptor beta (FRβ)-binding single-chain variable fragment (scFv) and an IL3α-binding receptor (CD123) that has more expression in AML blasts, can decrease CAR-T cell exhaustion and increase the efficacy of CAR-T cells to prevent antigen escaping and consequent recurrence of AML. Materials and Methods: In this experimental study, the survival, proliferation, and cytolysis of CAR-T cells remains suboptimal even with a costimulatory endodomain. Hence, we designed and constructed a tandem CAR that joins an FRβ and CD123 in the second generation retroviral vector to generate a bispecific tandem CAR (TanCAR-T cell). Results: TanCAR FRβ-CD123 T cells showed distinct binding to FRβ or CD123 expressing cells. They could lyse the leukaemia cell lines (66.1 ± 11%) comparable to the single CAR-T cells against these determinants. TanCAR FRβ-CD123 T cells simultaneously engaged FRβ and CD123, which promoted T cell activation in targeting and lysis of the examined leukaemia cell lines. TanCAR-T cell significantly induced interferon gamma (IFNγ) and interleukin 2 (IL-2) production more than single CAR-T cells, which produced a synergistic enhancement of TanCAR FRβ-CD123 T cell function when dual antigens faced simultaneously. Conclusion: Dual-specific TanCAR FRβ-CD123 T cells showed therapeutic potential to improve AML control by coengaging FRβ and CD123 molecules in a robust, divalent immune system. This strategy may be a useful therapeutic approach in patients with relapsed B-cell malignancies.

Objective: Epithelial-mesenchymal transition (EMT) and the stemness potency in association with BRAF mutation are in dispensable to the progression of melanoma. Recently, microRNAs (miRNAs) have been introduced as the regulator of a multitude of oncogenic functions in most of tumors. Therefore identifying and interpreting the expression patterns of these miRNAs is essential. The present study sought to find common miRNAs regulating all three important pathways in melanoma development. Materials and Methods: In this experimental study, 18 miRNAs that importantly contribute to EMT and have a role in regulating self-renewal and the BRAF pathway were selected based on current literature and cross-analysis with available databases. Subsequently, their expression patterns were evaluated in 20 melanoma patients, normal tissues, serum from patients and control subjects, and melanospheres. Pattern discovery and integrative regulatory network analysis were used to find the most important miRNAs in melanoma progression. Results: Among 18 selected miRNAs, miR-205, -141, -203, -15b, and -9 were differentially expressed in tumor samples than normal tissues. Among them, miR-205, -15b, and -9 significantly expressed in serum samples and healthy donors. Attribute Weighting and decision trees (DT) analysis presented evidence that the combination of miR-205, -203, -9, and -15b can regulate self-renewal and EMT process, by affecting CDH1, CCND1, and VEGF expression. Conclusion: We suggested here that miR-205, -15b, -203, -9 pattern as the key miRNAs linked to melanoma status, the pluripotency, proliferation, and motility of malignant cells. However, further investigations are required to find the mechanisms underlying the combinatory effects of the above mentioned miRNAs.

Objective: Specific expression of therapeutic genes in cancer therapy has been per used for many years. One of the innovative strategies that have recently been introduced is employing miRNA response elements (MREs) of microRNAs (whose expression are reduced or inhibited in cancerous cells) into the 3´UTR of the therapeutic genes for their specific expression. Accordingly, MREs of anti-metastatic miRNA family have been used in 3´UTR of the metastasis suppressor gene in the corresponding cells to evaluate the level of metastatic behavior. Material and Methods: In this experimental study, 3´UTR of the ZEB1 gene with 592 bp length, encompassing multiple MREs of miR-141, miR-429, miR-200b and miR-200c, was employed to replace BRMS1 3´UTR. The obtained vector was then assessed in the context of MCF-10A, MDA-MB231 and MCF-7 cells. Results: It was shown that the employed MREs are able to up-regulate BRMS expression in the metastatic MDAMB231 cells (almost 3.5-fold increase), while it was significantly reduced within tumorigenic/non-metastatic MCF-7 cells. Specific expression of BRMS1 in metastatic cells led to a significant reduction in their migratory and invasive characteristics (about 65% and 55%, respectively). Two-tailed student’s t test was utilized for statistical analysis. Conclusion: It was demonstrated that a chimeric vector containing BRMS1 which is regulated by miR-200 family response element may represent a promising therapeutic tool. This is due to the capability of the chimeric vector for cell type-specific expression of anti-metastatic genes with lowest side-effects. It consequently prohibits the invasive characteristics of metastatic cells.

Abstract Background The natural killer (NK) cells differentiated from umbilical cord blood (UCB) hematopoietic stem cells (HSCs) may be more suitable for cell-based immunotherapy compared to the NK cells from adult donors. This is due to the possibility to choose alloreactive donors and potentially more robust in vivo expansion. However, the cytotoxicity of UCB-HSC-derived NK cells against cancer cells might be suboptimal. To overcome this obstacle, we attempted to generate NK cells with potent antitumor activity by targeting RAS/MAPK, IGF-1R and TGF-β signaling pathways using IL-15, IGF-1 and SIS3 respectively. Methods The CD34 + cells were isolated from human UCB mononuclear cells through magnetic activation cell sorting (MACS) with purity of (≥ 90%) and were subjected to differentiate into NK cells. After 21 days of induction with SFTG36 (SCF, FLt-3L, TPO, GM-CSF, IL-3 and IL-6), IS721 (IGF-1, SIS3, IL-7 and IL-21) and IL-15/Hsp70 media, NK cells phenotypes were studied and their cytotoxicity against K562 human erythroleukemia cells and SKOV3 ovarian carcinoma cells was analyzed. Results The NK cells induced in SFTG36/IS721 medium were selected for activation due to their higher expression of CD56 + 16 + CD3 − (93.23% ± 0.75) and mean fluorescence intensity (MFI) of NKG2D + (168.66 ± 20.00) and also a higher fold expansion potential (11.893 ± 1.712) compared to the other groups. These cells once activated with IL-15, demonstrated a higher cytotoxicity against K562 (≥ 90%; P ≤ 0.001) and SKOV3 tumor cells (≥ 65%; P ≤ 0.001) compared to IL-15/Hsp70-activated NK cells. Conclusions The differentiation of ex vivo expanded CD34 + cells through manipulation of RAS/MAPK, IGF-1R and TGF-β signaling pathways is an efficient approach for generating functional NK cells that can be used for cancer immunotherapy.

Analysis of circulating tumor DNA (ctDNA) can be used to characterize and monitor cancers. Recently, non-invasive prenatal testing (NIPT) as a new next-generation sequencing (NGS)-based approach has been applied for detecting ctDNA. This study aimed to investigate the copy number variations (CNVs) utilizing the non-invasive prenatal testing in plasma ctDNA from ovarian cancer (OC) patients who were treated with neoadjuvant chemotherapy (NAC). The plasma samples of six patients, including stages II–IV, were collected during the pre- and post-NAC treatment that were divided into NAC-sensitive and NAC-resistant groups during the follow-up time. CNV analysis was performed using the NIPT via two methods “an open-source algorithm WISECONDORX and NextGENe software.” Results of these methods were compared in pre- and post-NAC of OC patients. Finally, bioinformatics tools were used for data mining from The Cancer Genome Atlas (TCGA) to investigate CNVs in OC patients. WISECONDORX analysis indicated fewer CNV changes on chromosomes before treatment in the NAC-sensitive rather than NAC-resistant patients. NextGENe data indicated that CNVs are not only observed in the coding genes but also in non-coding genes. CNVs in six genes were identified, including HSF1, TMEM249, MROH1, GSTT2B, ABR, and NOMO2, only in NAC-resistant patients. The comparison of these six genes in NAC-resistant patients with The Cancer Genome Atlas data illustrated that the total alteration frequency is amplification, and the highest incidence of the CNVs (≥35% based on TCGA data) is found in MROH1, TMEM249, and HSF1 genes on the chromosome (Chr) 8. Based on TCGA data, survival analysis showed a significant reduction in the overall survival among chemotherapy-resistant patients as well as a high expression level of these three genes compared to that of sensitive samples (all, p < 0.0001). The continued Chr8 study using WISECONDORX revealed CNV modifications in NAC-resistant patients prior to NAC therapy, but no CNV changes were observed in NAC-sensitive individuals. Our findings showed that low coverage whole-genome sequencing analysis used for NIPT could identify CNVs in ctDNA of OC patients before and after chemotherapy. These CNVs are different in NAC-sensitive and -resistant patients highlighting the potential application of this approach in cancer patient management.

Abstract Wnt5A signals through various receptors that confer versatile biological functions. Here, we used Wnt5A overexpressing human ovarian SKOV-3 and OVCAR-3 stable clones for assessing integrin expression, cell proliferation, migration, invasion, and the ability of multicellular aggregates (MCAs) formation. We found here, that Wnt5A regulates differently the expression of its receptors in the stable Wnt5A overexpressing clones. The expression levels of Frizzled (FZD)-2 and -5, were increased in different clones. However ROR-1, -2 expression levels were differently regulated in clones. Wnt5A overexpressing clones showed increased cell proliferation, migration, and clonogenicity. Moreover, Wnt5A overexpressing SKOV-3 clone showed increased MCAs formation ability. Cell invasion had been increased in OVCAR-3-derived clones, while this was decreased in SKOV-3-derived clone. Importantly, αv integrin expression levels were increased in all assessed clones, accompanied by increased cell attachment to fibronectin and focal adhesion kinase activity. Moreover, the treatment of clones with Box5 as a Wnt5A/FZD5 antagonist abrogates ITGAV increase, cell proliferation, migration, and their attachment to fibronectin. Accordingly, we observed significantly higher expression levels of ITGAV and ITGB3 in human high-grade serous ovarian cancer specimens and ITGAV correlated positively with Wnt5A in metastatic serous type ovarian cancer. In summary, we hypothesize here, that Wnt5A/FZD-5 signaling modulate αv integrin expression levels that could be associated with ovarian cancer cell proliferation, migration, and fibronectin attachment.

Abstract Background Small molecule compounds have been well recognized for their promising power in the generation, expansion, and maintenance of embryonic or adult stem cells. The aim of this study was to identify a novel combination of small molecules in order to optimize the ex vivo expansion of umbilical cord blood-derived CD34+ cells. Methods Considering the most important signaling pathways involved in the self-renewal of hematopoietic stem cells, CB-CD34+ cells were expanded with cytokines in the presence of seven small molecules including SB, PD, Chir, Bpv, Pur, Pμ, and NAM. The eliminativism approach was used to find the best combination of selected small molecules for effective ex vivo expansion of CD34+ cell. In each step, proliferation, self-renewal, and clonogenic potential of the expanded cells as well as expression of some hematopoietic stem cell-related genes were studied. Finally, the engraftment potential of expanded cells was also examined by the mouse intra-uterine transplantation model. Results Our data shows that the simultaneous use of SB431542 (TGF-β inhibitor), Chir9901 (GSK3 inhibitor), and Bpv (PTEN inhibitor) resulted in a 50-fold increase in the number of CD34+CD38− cells. This was further reflected in approximately 3 times the increase in the clonogenic potential of the small molecule cocktail-expanded cells. These cells, also, showed a 1.5-fold higher engraftment potential in the peripheral blood of the NMRI model of in utero transplantation. These results are in total conformity with the upregulation of HOXB4, GATA2, and CD34 marker gene as well as the CXCR4 homing gene. Conclusion Taken together, our findings introduce a novel combination of small molecules to improve the yield of existing protocols used in the expansion of hematopoietic stem cells.

Abstract Background At the present time, colorectal cancer (CRC) is still known as a disease with a high mortality rate. Theranostics are flawless scenarios that link diagnosis with therapy, including precision medicine as a critical platform that relies on the development of biomarkers particularly “liquid biopsy”. Circulating tumor cells (CTCs) and tumor-derived exosomes (TDEs) in a liquid biopsy approach are of substantial importance in comparison with traditional ones, which cannot generally be performed to determine the dynamics of the tumor due to its wide restriction of range. Thus, recent attempts has shifted towards minimally noninvasive methods. Main text CTCs and TDEs, as significant signals emitted from the tumor microenvironment, which are also detectable in the blood, prove themselves to be promising novel biomarkers for cancer diagnosis, prognosis, and treatment response prediction. The therapeutic potential of them is still limited, and studies are at its infancy. One of the major challenges for the implementation of CTCs and TDEs which are new trends in translational medicine is the development of isolation and characterization; a standardizable approach. This review highlights and discusses the current challenges to find the bio fluids application in CRC early detection and clinical management. Conclusion Taken together, CTCs and TDEs as silent drivers of metastasis can serve in the management of cancer patient treatment and it is of the upmost importance to expand our insight into this subject. However, due to the limited data available from clinical trials, further validations are required before addressing their putative application in oncology.

Purpose: To evaluate the role of topical umbilical cord serum (TUCS) therapy in treating corneal epithelial defects (CEDs) after diabetic vitrectomy. Methods: In this double-masked, randomized clinical trial, we included 80 eyes of 80 patients who were candidates for vitrectomy due to proliferative diabetic retinopathy complications. In cases of corneal edema obscuring the fundus view during surgery, the corneal epithelium was removed using a 6-mm trephine and a blade no.15. The day after the surgery, patients were randomly divided into two groups: (1) the TUCS group that received 20% TUCS six times/day in addition to the conventional treatment of CED and (2) the control group, which was prescribed artificial tears as placebo in addition to the conventional treatment of CED. The rate of healing of CEDs was measured via two maximum linear dimensions perpendicular to each other at the start of therapy and on postoperative days 1–5, 7, and 12. Results: Of 80 eyes, 40 were assigned to each treatment group. The mean times to complete CED healing were 2.4 ± 0.7 and 3.8 ± 2.1 days in the TUCS and control groups, respectively (P < 0.001). Persistent CED occurred in two eyes in the control group but in no eyes in the TUCS group. Conclusion: TUCS therapy may be safe and effective in healing CEDs after vitrectomy in patients with diabetes.

BackgroundMicroRNAs (miRNAs) are frequently deregulated in various types of cancer. While antisense oligonucleotides are used to block oncomiRs, delivery of tumour-suppressive miRNAs holds great potential as a potent anti-cancer strategy. Here, we aim to determine, and functionally analyse, miRNAs that are lowly expressed in various types of tumour but abundantly expressed in multiple normal tissues.MethodsThe miRNA sequencing data of 14 cancer types were downloaded from the TCGA dataset. Significant differences in miRNA expression between tumor and normal samples were calculated using limma package (R programming). An adjusted p value < 0.05 was used to compare normal versus tumor miRNA expression profiles. The predicted gene targets were obtained using TargetScan, miRanda, and miRDB and then subjected to gene ontology analysis using Enrichr. Only GO terms with an adjusted p < 0.05 were considered statistically significant. All data from wet-lab experiments (cell viability assays and flow cytometry) were expressed as means ± SEM, and their differences were analyzed using GraphPad Prism software (Student's t test, p < 0.05).ResultsBy compiling all publicly available miRNA profiling data from The Cancer Genome Atlas (TCGA) Pan-Cancer Project, we reveal a small set of tumour-suppressing miRNAs (which we designate as 'normomiRs') that are highly expressed in 14 types of normal tissues but poorly expressed in corresponding tumour tissues. Interestingly, muscle-enriched miRNAs (e.g. miR-133a/b and miR-206) and miRNAs from DLK1-DIO3 locus (e.g. miR-381 and miR-411) constitute a large fraction of the normomiRs. Moreover, we define that the CCCGU motif is absent in the oncomiRs' seed sequences but present in a fraction of tumour-suppressive miRNAs. Finally, the gain of function of candidate normomiRs across several cancer cell types indicates that miR-206 and miR-381 exert the most potent inhibition on multiple cancer types in vitro.ConclusionOur results reveal a pan-cancer set of tumour-suppressing miRNAs and highlight the potential of miRNA-replacement therapies for targeting multiple types of tumour.

Objective(s): The growing trend of research demonstrates that dynamic expression of two metastasis repressor classes (metastasis suppressor genes and anti-metastatic miRNA) has a close relationship with tumor invasion and metastasis. Using different strategies, it was revealed that cellular levels of miR-31 and Breast cancer Metastasis Suppressor1 (BRMS1) protein, which are among the most significant modulators of metastasis, have a correlation with the cell’s capability for invading and metastasizing; cells containing higher levels of miR-31 or BRMS1 were less metastatic. This project was carried out to determine whether the combinations of miR-31 and BRMS1 genes are able to enhance the capability of repressing the claudin-low breast cancer cell (MDA-MB-231) invasion. Materials and Methods: This study used a restoration-based approach by miR-31 mimic and optimized BRMS1 gene sequences, which were cloned into a chimeric construct and transfected to the MDA-M231cells. Results: Our data revealed that the simultaneous expression of anti-metastasis miR and metastasis suppressor might inhibit migration and invasion in MDA-MB-231 cells efficiently.Conclusion: This combinatorial use of anti-metastatic miR and gene suggests a new therapeutic intervention for metastasis inhibition in MDA-MB-231.

Abstract Background In 2012, Venet et al. proposed that at least in the case of breast cancer, most published signatures are not significantly more associated with outcome than randomly generated signatures. They suggested that nominal p-value is not a good estimator to show the significance of a signature. Therefore, one can reasonably postulate that some information might be present in such significant random signatures. Methods In this research, first we show that, using an empirical p-value, these published signatures are more significant than their nominal p-values. In other words, the proposed empirical p-value can be considered as a complimentary criterion for nominal p-value to distinguish random signatures from significant ones. Secondly, we develop a novel computational method to extract information that are embedded within significant random signatures. In our method, a score is assigned to each gene based on the number of times it appears in significant random signatures. Then, these scores are diffused through a protein-protein interaction network and a permutation procedure is used to determine the genes with significant scores. The genes with significant scores are considered as the set of significant genes. Results First, we applied our method on the breast cancer dataset NKI to achieve a set of significant genes in breast cancer considering significant random signatures. Secondly, prognostic performance of the computed set of significant genes is evaluated using DMFS and RFS datasets. We have observed that the top ranked genes from this set can successfully separate patients with poor prognosis from those with good prognosis. Finally, we investigated the expression pattern of TAT, the first gene reported in our set, in malignant breast cancer vs. adjacent normal tissue and mammospheres. Conclusion Applying the method, we found a set of significant genes in breast cancer, including TAT, a gene that has never been reported as an important gene in breast cancer. Our results show that the expression of TAT is repressed in tumors suggesting that this gene could act as a tumor suppressor in breast cancer and could be used as a new biomarker.

Background: Morphine is an analgesic drug from the opium family that directly affects central nervous system (CNS) to reduce pain. Naloxone is a pure opioid antagonist that eliminates their respiratory suppressive effects in CNS. The aim of present study was to compare the effect of morphine on testes, and serum level of cholesterol and testosterone in male rats. Methods: In this experimental study, 18 mature male Wistar rats were selected, and randomly divided in 3 equal groups. The groups received normal saline, morphine alone (5 mg/kg), or combination of morphine (5 mg/kg) and naloxone (0.4 mg/kg) subcutaneously 4 days in week for 7 weeks. After one week, the histological structure of testes was studied microscopically, and serum levels of cholesterol and testosterone were determined and compared between the groups. Findings: In histology, degeneration of some seminipherous tubules and increase of distance between them was seen in morphine group; these changes were not seen in morphine-naloxone and control groups. There was not any significant difference between the groups in terms of serum level of cholesterol and testosterone. Conclusion: Our study suggests that morphine can result in changes in the structure of the testes but the effect of morphine-naloxone on rats was only changes in body weight.

Objective: microRNAs (miRNAs) play important role in progression of tumorigenesis. They can target self-renewal and epithelial-mesenchymal transition (EMT) abilities in tumor cells, especially in cancer stem cells (CSCs). The objective of this study was to implement data mining to identify important miRNAs for targeting both self-renewal and EMT. We also aimed to evaluate these factors in mammospheres as model of breast cancer stem cells (BCSCs) and metastatic tumor tissues. Materials and Methods: In this experimental study, mammospheres were derived from MCF-7 cells and characterized for the CSCs properties. Then expression pattern of the selected miRNAs in spheroids were evaluated, using the breast tumor cells obtained from seven patients. Correlation of miRNAs with self-renewal and EMT candidate genes were assessed in mammospheres and metastatic tumors. Results: The results showed that mammospheres represented more colonogenic and spheroid formation potential than MCF-7 cells (P

Background and Aim: There is increasing evidence that cancer cells in addition to multiple genetic mutations, also acquire epigenetic abnormalities during development, maintenance, and progression. By utilizing the reprogramming technology as a tool to introduce the ‘pressure’ to alter epigenetic regulations, we might be able to clarify the epigenetic behavior that is unique to cancer cells. So far, iPSCs have been generated from normal primary cells, but it is unclear whether human primary cancer cell can be reprogrammed. We investigated the production of the iPS cells from the pancreatic adenocarcinoma cells using defined transcription factors. Materials and Methods: We sought to reprogram patient derived xenograft from human PDAC, by introducing lentiviral mediated induction of Yamanaka Factors (OSKM) and characterized of induced cells by Alkaline Phosphatase staining, Real-Time PCR and immunostaining. Ethical Considerations: This study with research ethics code EC/93/1025 has been approved by research ethics committee at Royan Institute. Findings: Alkaline Phosphatase staining, Real-Time PCR and immunostaining showed that induction with the OSKM results in generating iPS cell line from fibroblast cells but not from PDAC PDX cells .We showed that, PDAC cells could not fully reprogrammed by the expression of 4 transcription factors. Conclusion: This study demonstrated that the PDAC-PDX cancer cells were distinct from PDAC induced cells with regard to their epigenetic modifier genes expression pattern, although the expression of pluripotency genes did not increased significantly in the induced PDAC cells.

Objective: Ex vivo expansion is a promising strategy to overcome the low number of human umbilical cord blood hematopoietic stem cells (hUCB-HSCs). Although based on the obtained results in unnatural physiological condition of irradiated genetically immune-deficient mouse models, there has always been concern that the expanded cells have less engraftment potential. The purpose of this study was to investigate effect of common ex vivo expansion method on engraftment potential of hUCB-mononuclear cells (MNCs), using normal fetal mouse, as a model with more similarity to human physiological conditions. Materials and Methods: In this experimental study, briefly, isolated hUCB-MNCs were cultured in common expansion medium containing stem cell factor, Flt3 ligand and thrombopoietin. The unexpanded and expanded cells were transplanted to the fetal mice on gestational days of 11.5-13.5. After administration of human hematopoiesis growth factors (hHGFs), presence of human CD45+ cells, in the peripheral blood of recipients, was assessed at various time points after transplantation. Results: The expanded MNCs showed 32-fold increase in the expression of CD34+38- phenotype and about 3-fold higher clonogenic potential as compared to the uncultured cells. Four weeks after transplantation, 73% (19/26) of expanded-cell recipients and 35% (7/20) of unexpanded-cell recipients were found to be successfully engrafted with human CD45+ cells. The engraftment level of expanded MNCs was significantly (1.8-fold) higher than unexpanded cells. After hHGFs administration, the level was increased to 3.2, 3.8 and 2.6-fold at respectively 8, 12, and 16 weeks of post transplantation. The increased expression of CXCR4 protein in expanded MNCs is a likely explanation for the present findings. Conclusion: The presented data showed that expanded MNCs compared to unexpended cells are capable of more rapid and higher short-term engraftment in normal fetal mouse. It could also be suggested that in utero transplantation (IUT) of normal fetal mice could be an appropriate substitute for NOD/SCID mice in xenotransplantation studies.

Pathogen suppression and induced systemic resistance are suitable alternative biocontrol strategies for integrated plant disease management and potentially comprise a sustainable alternative to agrochemicals. The use of Actinobacteria as biocontrol agents is accepted in practical sustainable agriculture, and a short overview on the plant-beneficial members of this phylum and recent updates on their biocontrol efficacies are the two topics of this review. Actinobacteria include a large portion of microbial rhizosphere communities and colonizers of plant tissues that not only produce pest-antagonistic secondary metabolites and enzymes but also stimulate plant growth. Non-pathogenic Actinobacteria can also induce systemic resistance against pathogens, but the mechanisms are still poorly described. In the absence of a pathogen, a mild defense response is elicited under jasmonic acid and salicylic acid signaling that involves pathogenesis-related proteins and secondary plant metabolites. Priming response partly includes the same compounds as the response to a sole actinobacterium, and the additional involvement of ethylene signaling has been suggested. Recent amplicon sequencing studies on bacterial communities suggest that future work may reveal how biocontrol active strains of Actinobacteria can be enriched in plant rhizosphere.

Notch suppression by gamma-secretase inhibitors is a valid approach against melanoma. However, most of studies have evaluated the short-term effect of DAPT on tumor cells or even cancer stem cells. In the present study, we surveyed the short-term and long-term effects of DAPT on the stem cell properties of A375 and NA8 as melanoma cell lines. The effects of DAPT were tested both in vitro and in vivo using xenograft models. In A375 with B-raf mutation, DAPT decreased the level of NOTCH1, NOTH2, and HES1 as downstream genes of the Notch pathway. This was accompanied by enhanced apoptosis after 24 h treatment, arrest in the G2−M phase, and impaired ability of colony and melanosphere formation at the short term. Moreover, tumor growth also reduced during 13 days of treatment. However, long-term treatment of DAPT promoted tumor growth in the xenograft model and enhanced the number and size of colonies and spheroids in vitro. The gene expression studies confirmed the up-regulation of Wnt and Notch downstream genes as well as AXIN1, CSNK2A3, and CEBPA2 following the removal of Notch inhibitor in vitro and in the xenograft model. Moreover, the Gompertz-based mathematical model determined a new drug resistance term in the present study. Our data supported that the long-term and not short-term inhibition of Notch by DAPT may enhance tumor growth and motility through up-regulation of AXIN1, CSNK2A3, and CEBPA2 genes in B-raf mutated A375 cells.

Objective Cadherin-1 (CDH1) plays an important role in the metastasis, while expression of this protein is under control of epigenetic changes on its gene promoter. Therefore we evaluated both DNA methylation (DNAmet) and histone modification marks of CDH1 in prostate cancer stem like cells (PCSLCs). Materials And Methods In this experimental study, we isolated PCSLCs using cell surface marker and prostaspheroid formation, respectively. The cells isolated from both methods were characterized and then the levels of H3K4me2, H3K27me3, H3K9me2/3 and H3K9ac as well as DNAmet were assessed in CDH1 promoter of the isolated cells. Results The CD44+ CD49hi cells were not validated as PCSLCs. However, prostaspheres overexpressed stemness related genes and had higher ability of invasion potential, associated with reduction in CDH1 expression. Epigenetic status analysis showed that CDH1 promoter was hypo-methylated. Histone modifications of H3K9ac and H3K4me3 were significantly reduced, in parallel with an increased level of H3K27me3. Conclusion Our results suggest that slight decrease of DNAmet of the CpG island in CDH1 promoter does not significantly contribute to the change of CDH1 expression. Therefore, histone modifications are responsible in repressing CDH1 in PCSLCs.

Introduction: Health care workers are exposed to percutaneous injuries. They are at risk of infection from bloodborne pathogens during routine clinical duties. Adherence to standard precautions can protect health care workers. The purpose of this study was to assess the level of knowledge of physicians about standard precautions and the use of information resources in the field of infection control. Material and Methods: A cross-sectional survey was conducted during January and March 2015, on 308 physicians working in the five academic hospitals affiliated with Mashhad University of Medical Sciences. Demographic and additional related data were obtained by questionnaire from all participants. Data were analyzed in SPSS 16. Result: most of the participants were Specialists and female (60.7%). Specialists for some items related to standard precautions scores were over 90%; However for items related to “knowing the standard precautions, a goal of standard precautions and washing hand after taking off the gloves” scores were below 70%. There was no significant difference in knowledge of standard precautions among different medical groups (p-value=0.87). The most frequently mentioned information sources by specialists (90%) were “local instructions” but residents and interns (76%) preferred “discussion with colleagues” as the first source information in relation to standard precautions. The most Specialists had not received enough training about standard precautions (52.2%). Conclusion: There is a need for guidelines for training the standard precautions among health care workers.

Objective: Human amniotic membrane (HAM) is used as a supporter for limbal stem cell (LSC) expansion and corneal surgery. The aim of study is to use HAM extracts from healthy donors to enhance proliferation of LSCs in vitro and in vivo. Materials and Methods: In this interventional experimental study, the effective and cytotoxic doses of the amniotic membrane extract eye drops (AMEED) was assessed by adding different concentrations of AMEED (0-2.0 mg/ml) to LSC cultures for 14 days. Subsequently, the expression levels of ATP-binding cassette sub-family G member 2 (ABCG2, a putative stem cell marker), cytokeratin 3 (K3, corneal maker), K12 and K19 (corneal-conjunctival cell makers) were assessed by real-time polymerase chain reaction (PCR). In the second step, the corneal epithelium of 10 rabbits was mechanically removed, and the right eye of each rabbit was treated with 1 mg/ml AMEED [every 2 hours (group 1) or every 6 hours (group 2)]. The left eyes only received an antibiotic. The corneal healing process, conjunctival infection, degree of eyelid oedema, degree of photophobia, and discharge scores were evaluated during daily assessments. Finally, corneal tissues were biopsied for pathologic evidences. Results: In comparison to the positive control [10% foetal bovine serum (FBS)], 0.1-1 mg/ml AMEED induced LSC proliferation, upregulated ABCG2, and downregulated K3. There were no remarkable differences in the expression levels of K12 and K19 (P>0.05). Interestingly, in the rabbits treated with AMEED, the epithelium healing duration decreased from 4 days in the control group to 3 days in the two AMEED groups, with lower mean degrees of eyelid oedema, chemosis, and infection compared to the control group. No pathologic abnormalities were observed in either of the AMEED groups. Conclusion: AMEED increases LSCs proliferation ex vivo and accelerates corneal epithelium healing in vivo without any adverse effects. It could be used as a supplement for LSC expansion in cell therapy.

Objective: To compare the healing effects of dried and acellular human amniotic membrane and Mepitel for coverage of split-thickness graft donor site (STGDS). Methods: Twenty patients who underwent STGDS regeneration surgery in identical anatomic regions were enrolled in this randomized controlled clinical trial conducted in Hazrate Fatemeh hospital (Iran). Patients were randomly assigned in 3 groups of wound dressing; group A by Mepitel, group B AmiCare (Dried amniotic membrane) and group C OcuReg-A (Acellular amniotic membrane). Re-epithelization rate (healing time), pain sensation, scar formation and infection rate were assessed till complete healing was achieved.Results: Our results showed no significant difference between Amicare, OcuReg-A and Mepitel in the features analyzed by us including: Re-epithelization rate (healing time) P value; 0.573, Pain sensation P value: day 4 th: 0.131, day8 th: 0.93 and day 12 th: 0.365, Scar formation P value>0.05 and Infection rate.Conclusion: Our findings confirmed the safety and efficacy of AmiCare (dried amniotic membrane) and OcuReg-A (Acellular amniotic membrane) in treatment of split-thickness donor site in comparison with Mepitel as a standard wound dressing.Trial registration number: IRCT201511118177N12.

Background: The minimization of adverse food-drug interactions will improve patient care by optimizing the therapeutic effects and maintaining proper nutritional status. Aim: The aim of the present study was to find the main factors that may place the hospitalized patients at risk of potential food-drug interactions. Method: This cross-sectional, descriptive study was conducted on 400 inpatients admitted to the Department of Internal Medicine of a teaching hospital in Mashhad, Northeast Iran, within 20 March 2013 to 20 April 2013. The potential food-drug interactions were evaluated for 19 commonly prescribed medications. The main factors (e.g., age, gender, education level, number of medications, and duration of the disease) that may place the patients at risk of potential food-drug interactions were analyzed for each patient. Results: Out of the 19 commonly prescribed medications, 17 drugs (89%) were not properly used with respect to meal. Furthermore, 14 commonly prescribed drugs were found to have a high frequency (≥50%) of potential food-drug interactions. Most of the patients (n=359, 89.8%) consumed their medicines at inappropriate time with respect to meals. The results of a multiple logistic regression after adjustment for confounders revealed that the age [β=0.005, CI: 0.0-0.01; P=033], number of medications [β=0.1, CI: 0.083-0.117; P

BACKGROUND: The use of personal protective equipment (especially face masks) has increased in different communities amid the COVID-19 pandemic. Therefore, the present study aimed to assess knowledge and performance of Iranian general population in wearing face masks. MATERIALS AND METHODS: The present study is a cross-sectional study conducted using a valid and reliable questionnaire on 1843 eligible individuals. The questionnaires were shared by Link (www.porsall.com) in groups and social networks. Data were analyzed using SPSS (Version 24.0, SPSS Inc., Chicago, IL). RESULTS: The mean age of the participants was 42.84 years (standard deviation: 16.84). The majority had inadequate and low knowledge of masks (69.2%), nearly 30% had moderate (30.1%), and few had adequate and high knowledge of masks. The individuals' knowledge on when to wear a mask was also assessed and the results showed poor and low in 42.2%, 46.9% moderate and high performance in 10.7%. The participants' performance on how to properly wear a mask was also assessed and 12% showed poor, 69.3% showed moderate, and 18.7% showed high performance. Safe removal of masks was also assessed, and the results showed 52% low and poor, 27.6% moderate, and 20.3% high performance. A significant and direct correlation was found between the overall score knowledge and performance regarding use of masks (P < 0.001). CONCLUSION: The results showed poor to moderate knowledge and performance of majority of Iranian general population regarding the masks. Therefore, further effective training courses and action plans are needed in Iran given the importance of masks for the prevention of COVID-19, especially in public places. Educational package about how to use the mask and its benefits, through the media and health centers is recommended.

Objective: The diverse clinical applications for human mesenchymal stem cells (hMSCs) in cellular therapy and regenerative medicine warrant increased focus on developing adequate culture supplements devoid of animal-derived products. In the present study, we have investigated the feasibility of umbilical cord blood-platelet lysate (UCB-PL) as a standard substitute for fetal bovine serum (FBS) and human peripheral blood-PL (PB-PL). Materials and Methods: In this experimental study, platelet concentrates (PC) from UCB and human PB donors were frozen, melted, and sterilized to obtain PL. Quality control included platelet cell counts, sterility testing (viral and microbial), total protein concentrations, growth factor levels, and PL stability. The effects of UCB-PL and PB-PL on hMSCs proliferation and differentiation into osteocytes, chondrocytes, and adipocytes were studied and the results compared with FBS. Results: UCB-PL contained high levels of protein content, platelet-derived growth factor- AB (PDGF-AB), and transforming growth factor (TGF) compared to PB-PL. All growth factors were stable for at least nine months post-storage at -70˚C. hMSCs proliferation enhanced following treatment with UCB-PL. With all three supplements, hMSCs could differentiate into all three lineages. Conclusion: PB-PL and UCB-PL both were potent in hMSCs proliferation. However, PB promoted osteoblastic differentiation and UCB-PL induced chondrogenic differentiation. Because of availability, ease of use and feasible standardization of UCB-PL, we have suggested that UCB-PL be used as an alternative to FBS and PB-PL for the cultivation and expansion of hMSCs in cellular therapy.

Exosomes are nano vesicles from the larger family named Extracellular Vesicle (EV)s which are released by various cells including tumor cells, mast cells, dendritic cells, B lymphocytes, neurons, adipocytes, endothelial cells, and epithelial cells. They are considerable messengers that can exchange proteins and genetic materials between the cells. Within the past decade, Tumor derived exosomes (TEX) have been emerged as important mediators in cancer initiation, progression and metastasis as well as host immune suppression and drug resistance. Although tumor derived exosomes consist of tumor antigens and several Heat Shock Proteins such as HSP70 and HSP90 to stimulate immune response against tumor cells, they contain inhibitory molecules like Fas ligand (Fas-L), Transforming Growth Factor Beta (TGF-β) and Prostaglandin E2 (PGE2) leading to decrease the cytotoxicity and establish immunosuppressive tumor microenvironment (TME). To bypass this problem and enhance immune response, some macromolecules such as miRNAs, HSPs and activatory ligands have been recognized as potent immune inducers that could be used as anti-tumor agents to construct a nano sized tumor vaccine. Here, we discussed emerging engineered exosomes as a novel therapeutic strategy and considered the associated challenges.

Background. Gastrosphere, an enriched cellular population with stem-like properties believed to be responsible for an escape from immune-mediated destruction. Th17 and Treg cells play a major role in gastric cancer; however, their interaction with gastrospheres remained elusive. Method. Peripheral blood mononuclear cells were isolated from healthy donors and were cultured with conditioned media of MKN-45 (parental) cells as well as gastrospheres’ conditioned media in the context of mixed lymphocyte reaction and in the presence of anti-CD3/CD28 beads. The proliferation was evaluated using CFSE staining; the percentages of CD4+CD25+FoxP3+ Treg and CD4+IL-17+ Th17 cells and IFN-γ+cells and the production of IL-17, TGF-β, and IL-10 were assessed by flow cytometry and ELISA, respectively. Finally, the cytotoxic potential of induced immune cells was measured by examining the secretion of lactate dehydrogenase from target cells. Results. The results revealed a decreased expansion of PBMCs postexposure to gastrospheres’ conditioned medium which was concomitant with an increased percentage of Th17 and an enhanced Th17 to Treg ratio. The conditioned media of gastrospheres enhanced the secretion of IL-10 and IL-17 and decreased TGF-β. Interestingly, immune cells induced by gastrospheres showed significant cytotoxicity in terms of producing IFN-γ and death induction in target cells. All these changes were related to the upregulation of IL-6, IL-10, and IL-22 in gastrospheres compared to parental cells. Conclusion. Our study showed that the condition media of gastrospheres can potentially induce Th17 with increasing in their cytotoxic effect. Based on our knowledge, the present study is the first study that emphasizes the role of gastrospheres in the induction of antitumor Th17 cells. However, it should be confirmed with complementary studies in vivo.