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Abstract Effective targeting and delivery of large amounts of medications into the cancer cells enhance their therapeutic efficacy through saturation of cellular defensive mechanisms, which is the most privilege of nano drug delivery systems (NDDS) compared to traditional approaches. Herein, we designed dual-pH/redox responsive DTX-loaded poly (β-amino ester) (PBAS) micelles decorated with a chimeric peptide and TA1 aptamer. In vitro and in vivo results demonstrated that the designed nanoplatform possessed an undetectable nature in the blood circulation, but after exposure to the tumor microenvironment (TME) of 4T1 breast cancer, it suddenly changed into dual targeting nanoparticles (NPs) (containing two ligands, SRL-2 and TA1 aptamer). The dual targeting NPs destruction in the high GSH and low pH conditions of the cancer cells led to amplified DTX release (around 70% at 24 h). The IC50 value of DTX-loaded MMP-9 sensitive heptapeptide/TA1 aptamer-modified poly (β-amino ester) (MST@PBAS) micelles and free DTX after 48 h of exposure was determined to be 1.5 µg/ml and 7.5 µg/ml, respectively. The nano-formulated DTX exhibited cytotoxicity that was 5-fold stronger than free DTX (Pvalue˂0.001). Cell cycle assay test results showed that following exposure to MST@PBAS micelles, a considerable rise in the sub G1 population (48%) suggested that apoptosis by cell cycle arrest had occurred. DTX-loaded MST@PBAS micelles revealed significantly higher (Pvalue ˂ 0.001) levels of early apoptosis (59.8%) than free DTX (44.7%). Interestingly, in vitro uptake studies showed a significantly higher TME accumulation of dual targeted NPs (6-fold) compared to single targeted NPs (Pvalue

Abstract Background Recent studies have proved the role of autophagy in mesenchymal stem cell (MSCs) function and regenerative properties. How and by which mechanism autophagy modulation can affect the juxtacrine interaction of MSCs should be addressed. Here, the role of autophagy was investigated in the formation of tunneling nanotubes (TNTs) and homotypic mitochondrial donation. Methods MSCs were incubated with 15 µM Metformin (Met) and/or 3 µM 3-methyladenine (3-MA) for 48 h. The formation of TNTs was assessed using bright-field and SEM images. The mitochondria density and ΔΨ values were monitored using flow cytometry analysis. Using RT-PCR and protein array, the close interaction and shared mediators between autophagy, apoptosis, and Wnt signaling pathways were also monitored. The total fatty acid profile was assessed using gas chromatography. Result Data indicated the increase of TNT length and number, along with other cell projections after the induction of autophagy while these features were blunted in 3-MA-treated MSCs (p 0.05). We found that the inhibition/stimulation of autophagy can affect the protein, and transcription levels of several mediators related to Wnt and apoptosis signaling pathways involved in different cell bioactivities. Data confirmed the profound increase of mono and polyunsaturated/saturated fatty acid ratio in MSCs exposed to autophagy stimulator. Conclusions In summary, autophagy modulation could affect TNT formation which is required for homotypic mitochondrial donation. Thus, the modulation of autophagy creates a promising perspective to increase the efficiency of cell-based therapies.

Abstract Colorectal cancer (CRC) is deadly anaplastic changes in the gastrointestinal tract with high-rate mortality. In recent years, the application of phytocompounds has been extended along with different therapeutic protocols. Here, we monitored the effects of Thymoquinone (TQ) on autophagy via mitochondrial function after modulation of the Wnt/β-catenin signaling pathway. Human colorectal adenocarcinoma HT-29 cells were treated with TQ (60 µM) and 15 µM Wnt3a inhibitor (LGK974) for 48 h. The survival rate was evaluated using an MTT assay. The expression of Wnt-related factors (c-Myc, and Axin), angiogenesis (VE-Cadherin), and mitophagy-related factors (PINK1, OPTN) was assessed using real-time PCR assay. Protein levels of autophagy factors (Beclin-1, LC3, and P62) were monitored using western blotting. Using flow cytometry analysis, the intracellular accumulation of Rhodamine 123 was evaluated. The migration properties were analyzed using a scratch wound healing assay. Data indicated that TQ can reduce the viability of HT-29 cells compared to the control cells (p

Abstract Background Primary healthcare centers (PHCs) serve as the cornerstone of accessible medical services in society, playing a crucial role in screening, detecting, and treating various health issues. This study aimed to investigate the prevalence of psychiatric disorders in middle-aged individuals who refer to PHCs and the potential of PHCs in diagnosing mental disorders. Methods This cross-sectional study was implemented at PHCs under the supervision of Mashhad University of Medical Sciences (MUMS) in northeast Iran in 2018. The enrolled subjects were middle-aged adults who had electronic medical records in SINA, an integrated health management system, and the electronic medical records of MUMS. The prevalence of psychiatric disorders by type and their relationship with demographic information was evaluated by a Chi-square test using SPSS 22. Results This study involved 218,341 middle-aged participants. Prevalence of psychiatric disorders was 8.59%, and depression (53.72%) and anxiety (42.02%) were the most common psychiatric disorders in both males and females. The prevalence of mental disorders was significantly higher in females than in males (88.18% vs. 18.81%; P

Background & Aims: Allergic disorders are one of the most critical health problems in the world. This study aimed to investigate the prevalence of childhood asthma and its related factors among urban-rural preschool children. Materials & Methods: In this descriptive cross-sectional study, children under 5 years referred to the Asthma, Allergy, and Immunology Clinic of Motahari Hospital were included. The children were divided into two groups: urban and rural group. A checklist in the form of a questionnaire (consisting of information about demographics, parental asthma, exposure to farm animals, and tobacco, adequate home air conditioning, use of antibiotics during the first year of life, maternal gestational age, type of delivery, birth weight, age of wheezing onset, length of breastfeeding, and siblings number) was filled by the parents of the children. Data were analyzed by using SPSS 21 software. Results: Of 149 children with asthma, 85 were boys (40.3%) and 61 were girls (59.7%). Among the compared risk factors of asthma between urban and rural patients, the statistically significant variables were Body Mass Index (BMI) which was high among urban children (p = 0.002), the number of siblings of children (urban = 74, rural = 75) (p < 0.001), age of wheezing onset (urban = 74, rural = 75) (p = 0.014), animal exposure (urban = 28.4%, rural = 46.7%) (p = 0.021), and cesarean section delivery (urban = 63.5%, rural = 37.3%) (p = 0.001) were statistically significant. Conclusion: The risk of asthma among preschool children is strongly predicted by their area of residence in early life. This risk increases further in children accompanied with other asthma risk factors such as passive smoking, type of delivery, exposure to animals, and other discussed factors.

Purpose: Drug resistance is a challenging issue in cancer chemotherapy. Cell death induction is one of the main strategies to overcome chemotherapy resistance. Notably, ferroptosis has been considered a critical cell death mechanism in recent years. Accordingly, in this study, the different cell death strategies focused on ferroptosis have been utilized to overcome cisplatin resistance in an in vitro lung cancer model. Methods: The physiological functions of Akt1 and GPX4, as critical targets for ferroptosis and apoptosis induction, were suppressed by siRNA or antagonistic agents in resistant A549 cells. Afterward, the interventions’ impacts on cell viability and reactive oxygen species (ROS) amount were analyzed by flow cytometry. Moreover, the alteration in the relevant gene and protein expression levels were quantified using Real-time PCR and western blot methods. Results: The result showed that the treatment with Akt1 siRNA reversed the cisplatin resistance in the A549 cell line through the induction of apoptosis. Likewise, the combination treatment of the GPX4 siRNA or FIN56 as ferroptosis inducers alongside cisplatin elevated ROS’s cellular level, reduced the cellular antioxidant genes level and increased the cisplatin cytotoxic effect. Conclusion: In conclusion, our study indicated that ferroptosis induction can be considered a promising cell death strategy in cisplatin-resistant cancer cells.

Abstract As a platinum-containing anticancer drug, cisplatin is the keystone for treating many malignancies. Nephrotoxicity is the main dose-limiting toxicity, and several hydration therapies and supplementary strategies are utilized to reduce cisplatin-induced kidney damage, so the discovery and development of effective and safe antitumor drugs are still on the path of human health. Herein, a new four-coordinated Pt complex [Pt(TSC)Cl] using N(4)-phenyl-2-formylpyridine thiosemicarbazone (HTSC) was synthesized and characterized by single-crystal X-ray diffraction, 1HNMR, FT-IR, LC/MS and CHN elemental analysis. The Pt(TSC)Cl complex revealed antiproliferative activity against A549, MCF-7 and Caco-2 cell lines with a low micromolar IC50 (200–1.75 µM). Specifically, the Pt(TSC)Cl complex displayed more selectivity in Caco-2 cells (IC50 = 2.3 µM) than cisplatin (IC50 = 107 µM) after 48 h of treatment. Moreover, compared with cisplatin, a known nephrotoxic drug, the Pt(TSC)Cl complex exhibited lower nephrotoxicity against Hek293 normal cells. We also found that the Pt(TSC)Cl complex can effectively prevent cancer cell propagation in sub-G1 and S phases and induce apoptosis (more than 90%). Real time PCR and western analysis demonstrated that the expression pattern of apoptotic genes and proteins is according to the intrinsic apoptosis pathway through the Bax/Bcl-2-Casp9-Casp3/Casp7 axis. Collectively, our findings indicated that the Pt(TSC)Cl complex triggers apoptosis in Caco-2 cell lines, while low nephrotoxicity was shown and may be considered a useful anticancer drug candidate for colorectal cancers for further optimization and growth.

Abstract B cell maturation antigen (BCMA), a transmembrane glycoprotein member of the tumor necrosis factor receptor superfamily 17 (TNFRSF17), highly expressed on the plasma cells of Multiple myeloma (MM) patients, as well as the normal population. BCMA is used as a biomarker for MM. Two members of the TNF superfamily proteins, including B-cell activating factor (BAFF) and A proliferation-inducing ligand (APRIL), are closely related to BCMA and play an important role in plasma cell survival and progression of MM. Despite the maximum specificity of the monoclonal antibody technologies, introducing the tumor-specific antigen(s) is not applicable for all malignancies, such as MM that there plenty of relatively specific antigens such as GPCR5D, MUC1, SLAMF7 and etc., but higher expression of BCMA on these cells in comparison with normal ones can be regarded as a relatively exclusive marker. Currently, different monoclonal antibody (mAb) technologies applied in anti-MM therapies such as daratuzumab, SAR650984, GSK2857916, and CAR-T cell therapies are some of these tools that are reviewed in the present manuscript. By the way, the structure, function, and signaling of the BCMA and related molecule(s) role in normal plasma cells and MM development, evaluated as well as the potential side effects of its targeting by different CAR-T cells generations. In conclusion, BCMA can be regarded as an ideal molecule to be targeted in immunotherapeutic methods, regarding lower potential systemic and local side effects.

Abstract Purpose The authors developed nanostructured lipid carriers (NLCs) loaded with sirolimus (SRL) and cyclosporine (CsA) to improve their therapeutic efficacy in recurrent pregnancy loss (RPL) patients. Methods Mono‐delivery and co‐delivery of SRL and CsA by NLCs (S‐NLCs, C‐NLCs, and S‐C‐NLCs) were developed. The MTT assay was used to study the optimum dose of formulations. PCR, Western blotting, and ELISA were also conducted. Results Well‐designed nanodrugs with a suitable size, zeta potential, desirable encapsulation efficiency drug loading, and cellular uptake confirmed optimum formulations. Based on cell viability, the amounts of SRL and CsA could be reduced greatly due to the co‐delivery by NLCs. Following S‐NLCs and C‐NLCs interventions in T cells of patients with RPL and immune abnormality, a significant difference was observed in transcription factors and cytokine levels of Th1, Th17, and Tregs compared with healthy samples. Thus, a higher level of pro‐inflammatory cytokines (IFN‐γ, TNF‐α, IL‐17, and IL‐21) and their regulators (T‐bet and RORγt), as well as a lower level of an anti‐inflammatory cytokine (IL‐10) and its regulatory (Foxp3), were observed. However, no significant difference was found following the S‐C‐NLCs intervention. Conclusions S‐C‐NLCs effectively balance the immune responses in peripheral T cells in RPL patients to induce maternal immune tolerance.

Abstract Adjuvant-aided combination chemotherapy is one of the most effective ways of cancer treatment by overcoming the multidrug resistance (MDR) and reducing the side-effects of anticancer drugs. In this study, Conferone (Conf) was used as an adjuvant in combination with Doxorubicin (Dox) for inducing apoptosis to MDA-MB-231 cells. Herein, the novel biodegradable amphiphilic β-cyclodextrin grafted poly maleate-co-PLGA was synthesized by thiol-ene addition and ring-opening process. Micelles obtained from the novel copolymer showed exceptional properties such as small size of around 34.5 nm, CMC of 0.1 μg/mL, and cell internalization of around 100% at 30 min. These novel engineered micelles were used for combination delivery of doxorubicin-conferone with high encapsulation efficiency of near 100% for both drugs. Our results show that combination delivery of Dox and Conf to MDA-MB-231 cells had synergistic effects (CI

Purpose: Cognitive dysfunction is common in individuals with depression and these cognitive deficits may be associated with a risk of suicide. Therefore, the identification of the cognitive functions of depressed patients and the introduction of effective interventions on these factors are highly important. This study aimed to compare the effectiveness of repetitive Transcranial Magnetic Stimulation (rTMS) and Theta Burst Stimulation (TBS) to improve selective attention, working memory, and response time of depressed individuals with and without a history of suicide. Materials and Methods: This applied quasi-experimental study was conducted based on a pretest-posttest design. The population included 40 depressed patients referring to the clinics of Mashhad, Iran, in 2020. The samples were divided into four groups, namely individuals with a history of suicide subjected to treatment with rTMS, without a history of suicide receiving treatment with rTMS, with a history of suicide undergoing treatment with TBS, and without a history of suicide administered with TBS (n = 10 each). The data were collected using the Stroop Color and Word Test, Corsi block test, and reaction time tests and statistically analyzed using multivariate analysis of covariance. Results: The results confirmed the effectiveness of the intervention on the congruent reaction time, incongruent reaction time, working memory, simple reaction time, and selective reaction time in all four study groups (P < 0.05). The results of multivariate analysis of covariance showed that the group had a significant effect on the variables of congruent reaction time, simple reaction time, and selective reaction time (P < 0.05); however, it had no significant effect on the variables of incongruent reaction time and working memory (P > 0.05). Conclusion: Compared to the rTMS method, the TBS had a greater effect on the variables of congruent reaction time, simple reaction time, and selective reaction time.

Purposes: Effective and selective T-cell activation and proliferation during the T-cell expansion phase of a cellular adoptive immunotherapy method, challenging because recent studies revealed the importance of each subtype of T-cells in different immunologic strategies against tumors, like CAR-T cell therapies. Artificial antigen presenting cells (aAPCs) regarded as a natural way to manipulate T-cell subtypes activation and specific proliferation. In the current study, we utilized K562 cells based aAPC method expressing the ICOSL molecule, to evaluate T-cell subtypes differentiation rate and functional status. Methods: CD3+T-cells isolated and, co-cultured with ICOSL expressing K562 cells. After 4, 6, and 10 days selective CD markers of T-cell subtypes and each subtype’s activity-related genes levels evaluated by qPCR methods. Results: During the culture period, CD4+ Th related phenotype reduced continuously, and in day 10th of culture CD4+ T-cell’s population significantly reduced (P=0.029). In contrast, the CD8+ population ratio was ascending during the study period but was not statistically significant. FoxP3+CD25-, Treg population ratio was significantly increased during the time in comparison with the control group, as well as memory T-cell phenotypic marker, CD127+, expressing cells ratio. T-cell subpopulations activity-related genes expression levels evaluated too, and the Th1 related IL-2 and INF-γ reductions observed alongside regulatory T-cells gene (IL-10) and Cytotoxic T-cell’s related gene (Geranzym-A) elevations. Conclusion: We concluded that the K562-ICOSL based aAPC system is working and effective in T-cell short to medium culture periods, and this approach preparing relatively selective milieu for CD8+ T-Cell differentiation and much less Treg differentiation.

Platelet-derived microparticles (PMPs) are a group of micrometer-scale extracellular vesicles released by platelets upon activation that are responsible for the majority of microvesicles found in plasma. PMPs’ physiological properties and functions have long been investigated by researchers. In this regard, a noticeable area of studies has been devoted to evaluating the potential roles and effects of PMPs on cancer progression. Clinical and experimental evidence conflictingly implicates supportive and suppressive functions for PMPs regarding cancer. Many of these functions could be deemed as a cornerstone for future considerations of PMPs usage in cancer targeted therapy. This review discusses what is currently known about PMPs and provides insights for new and possible research directions for further grasping the intricate interplay between PMPs and cancer.

Purpose: Acute myeloid leukemia (AML) is the most prevalent acute leukemia in adults. It possesses different cytogenetic and molecular features. The expression of Wilms tumor-1 (WT1), brain and acute leukemia, cytoplasmic (BAALC) and ETS-related gene (ERG) might be considered as prognostic factors in AML patients. The aim of this study was to determine the mRNA expressions of WT-1, BAALC and ERG genes in bone marrow of mononuclear cells and their effects on complete remission in the Iranian AML patients, pre- and post- chemotherapy. Methods: Forty AML patients with normal karyotype were evaluated. The mRNA gene expressions were measured with quantitative real-time PCR in bone marrow of mononuclear cells of AML patients at the baseline and after chemotherapy. The subtypes of AML and flow cytometry panel were also assessed. Complete remission (CR) after the treatment was addressed for all patients. Results: The mRNA expressions of WT-1, BAALC and ERG were significantly decreased after the treatment (p= 0.001, 0.017, 0.036). WT-1 mRNA expression was inversely correlated with CR after chemotherapy (P =0.024). There was also significant correlation between baseline expression of BAALC and CR (P=0.046). No significant correlation was observed between ERG and CR pre- and post- chemotherapy (P =0.464 and 0.781). There was also significant correlation between BAALC mRNA expression and CD34+ (P

Background: B-cell lymphoma 2 (BCL-2) and BCL-2 associated X (BAX) polymorphisms are important in the apoptosis process, response to treatment and survival in Acute Lymphoblastic Leukemia (ALL) patients. We aimed to investigate the effect of these genes with other predictors corresponding to the survival of ALL patients with an appropriate frailty survival model. Methods: Our study was performed in 2020 on sixty-two cases of childhood aged 3-16 (year) with ALL disease who were selected by convenience sampling from the two hospitals of Tabriz, Iran. RFLPPCR method was used for genotyping the promoter region of the BAX and BCL-2 genes. We used different frailty survival models, to control heterogeneity between individuals due to unmeasured factors affecting their survival. All analyses were implemented using Stata 16. Results: Based on the result of log-logistic model along with frailty gamma, the proportional odds (standard error) of survival for a CC allele of BCL-2 patient compared to a AA allele patient were 6.0 (1.47); P

Purpose: Because of different potentials of T-cell subtypes in T-cell based cellular immunotherapy approaches such as CAR-T cell therapies; Regarding the high cost of the serum-free specific culture media, having distinct control on T-cell subset activation, expansion and differentiation seem crucial in T-cell expansion step of cell preparation methods. By the way, there was no clear data about the effect of acellular Wharton’s Jelly (AWJ) on T-cells expansion, activation or differentiation status. So, we have launched to study the effect of AWJ on T-cell’s immunobiological properties. Methods: CD3+ T-cells were isolated from healthy bone marrow allogeneic donors, sorted by FACS method and cultured on either routine phyto-hemagglutinin complemented and different concentrations of AWJ, lag phase and doubling time of the cells calculated from cell growth curve. After 3, 7 and 14-days T-cell subtypes cell markers and cell activity related genes expression rate have been evaluated by flow cytometry and real-time polymerase chain reaction (PCR) methods respectively. Results: AWJ in a 1:1 ratio compared with contemporary lymphocyte culture media showed significant activating and proliferative capacities. The introduced condition has not affected the frequency of CD4+ subpopulation of T-cells, but significantly increased even CD8+ cells and immune-activator genes in T-cells. The regulatory and memory subsets of T-cells in this study have not affected significantly. Conclusion: the study results revealed that AWJ can be utilized as a supportive substance to increase the memory properties of the T-cells, gives control to design a selective medium for expanding and differentiating memory T-cells, relatively.

Objective: Methamphetamine (METH) increases dopamine, norepinephrine and serotonin concentrations in the synaptic cleft, and induces hyperactivity. The current management of acute METH poisoning relies on supportive care and no specific antidote is available for treatment. The main objective of this review was to present the evidence for effectiveness of the herbal medicine in alleviating the adverse effects of METH abuse. Materials and Methods: Literature search was performed using the following electronic databases: MEDLINE, Scopus, PubMed and EMBASE. Results: Plant-derived natural products ginseng and sauchinone reduced METH-induced hyperactivity, conditioned place preference and neurological disorder. Garcinia kola decreased METH-induced hepatotoxicity, raised METH lethal dose, and restored the METH-impaired cognitive function. Repeated administration of baicalein resulted in attenuation of acute binge METH-induced amnesia via dopamine receptors. Activation of extracellular-regulated kinase in the hypothalamus by levo-tetrahydropalmatine facilitated the extinction of METH-induced conditioned place preference and reduced the hyperactivity. Other herbal medicine from various parts of the world were also discussed including hispidulin, silymarin, limonene, resveratrol, chlorogenic acid and barakol. Conclusion: Based on the current study, some natural products such as ginseng and levo-tetrahydropalmatine are promising candidates to treat METH abuse and poisoning. However, clinical trials are needed to confirm these finding.

Introduction: Due to the time constraints in the nursing system, it seems necessary to assess the time management competency of clinical nurses. Time management has sociocultural nature. Existing time management tools have not considered social aspects of time management. The purpose of this study was to design a questionnaire for assessing the social component of time management competency in clinical nurses population. Methods: This research was carried out with a explanatory sequential mixed methods design. First, qualitative study and using the grounded theory method, the concept of social components of time management competency of clinical nurses was explained. Based on quotations, the items of the initial questionnaire was generated and then the face and content validity was determined by using the quantitative and qualitative methods. The construct validity was determined with the exploratory factor analysis. The reliability was approved with the measurement of internal consistency using Cronbach's alpha coefficient and the stability assessed using a test-retest (Interclass correlation coefficient) method.. Results: Of the first 41 items, 36 items entered into the exploratory factor analysis after calculating the impact score of items with values higher than 1.5, content validity ratio higher than 0.53, content validity index higher than 0.79, and item analysis. In construct validity step, 29 items was grouped into 6 factors. The internal consistency of the questionnaire was 0.858 and the stability (ICC) of the questionnaire was 0.906. These 6 factors explained 46.714 % of the variance of the Questionnaire Conclusion: The questionnaire, according to its designation, can be used to assess the social components of time management competency of clinical nurses.

Abstract Cancer stem cells obtain energy demand through the activation of glycolysis and lipolysis. It seems that the use of approached targeting glycolysis and lipolysis could be an effective strategy for the inhibition of cancer stem cells. In the current experiment, we studied the potential effect of glycolysis and lipolysis inhibition on cancer stem cells differentiation and mesenchymal–epithelial-transition capacity. Cancer stem cells were enriched from human ovarian cells namely SKOV3 by using MACS technique. Cells were exposed to Lonidamine, an inhibitor of glycolysis, and TOFA, a potent inhibitor of lipolysis for 7 days in endothelial differentiation medium; EGM-2 and cell viability was studied by MTT assay. At the respective time point, the transcription level of genes participating in EMT such as Zeb-1, -2, Vimentin, Snail-1, -2 and VE-cadherin were measured by real-time PCR analysis. Our data noted that the inhibition of lipolysis and glycolysis could decrease cell viability compared to the control of cancer stem cells. The inhibition of glycolysis prohibited the expression of Zeb-1, Snails, and Vimentin while increased endothelial differentiation rate indicated by the expression of VE-cadherin. In contrast, the inhibition of lipolysis increased EMT associated genes and reduced endothelial differentiation rate by suppressing the transcription of VE-cadherin. Notably, the simultaneous inhibition of glycolysis and lipolysis had moderate effects on the transcription of EMT genes. We concluded that the modulation of the metabolic pathway of glycolysis in ovarian CSCs is more effective than the inhibition of lipolysis in the control of angiogenesis potential and stemness feature.

Colorectal cancer (CRC) is a widespread and lethal cancer throughout the world. Nowadays there is considerable debate about the efficacy of conventional methods in CRC treatment. Though targeting vital molecular pathways, as well as induction of various forms of cell death by safe probiotic yeast components are regarded as potential therapeutic modalities against CRC. Hence, here we aimed to investigate the inhibitory role of the EPSs of Kluyveromyces marxianus and Pichia kudriavzevii on different colon cancer cell lines. In this regard, several cellular and molecular experiments were performed. Here, we found that both EPSs can induce apoptosis which were confirmed by DAPI and Annexin V/PI assays. Further, our data showed that the EPSs could not act via ferroptotic pathways, however, they could hinder the AKT-1, mTOR, and JAK-1 pathways, and induce apoptosis. Therefore, the probiotic yeast EPSs present beneficial effects and may provide as a novel molecular-targeted therapeutics for combating CRC.

Objective DNA methylation is a well-studied epigenetic mechanism that is a potent arm of the gene expression controlling machinery. Since the hypoxic situation and the various cells of bone marrow microenvironment, e.g. mesenchymal stem cells, play a role in the in vivo and in vitro biology of leukemic cells, we decided to study the effects of hypoxia and mesenchymal stem cells (MSCs) on the promoter methylation pattern of BAX and BCL2 genes. Materials and Methods In this experimental study, the co-culture of MOLT-4 cells with MSCs and treatment with CoCl2 was done during 6, 12, and 24 hour periods. Total DNA was extracted using commercial DNA extraction kits, and sodium bisulfite (SBS) treatment was performed on the extracted DNA. Methylation specific polymerase chain reaction (MSP) was used to evaluate the methylation status of the selected genes’ promoter regions. Results The BAX and BCL2 promoters of untreated MOLT-4 cells were in partial methylated and fully unmethylated states, respectively. After incubating the cancer cells with CoCl2and MSCs, the MSP results after 6, 12, and 24 hours were the same as untreated MOLT-4 cells. In other words, the exposure of MOLT-4 cells to the hypoxia-mimicry agent and MSCs in various modes and different time frames showed that these factors have exerted no change on the methylation signature of the studied fragments from the promoter region of the mentioned genes. Conclusion Hypoxia and MSCs actually have no notable effect on the methylation status of the promoters of BAX and BCL2 in the specifically studied regions. DNA methylation is probably not the main process by which MSCs and CoCl2 induced hypoxia regulate the expression of these genes. Finally, we are still far from discovering the exact functional mechanisms of gene expression directors, but these investigations can provide new insights into this field for upcoming studies.

Objective: Mesenchymal stem cells (MSCs) are multipotent stromal cells that can differentiate into a variety of cell types. They control the process of hematopoiesis by secreting regulatory cytokines and growth factors and by the expression of important cell adhesion molecules for cell-to-cell interactions. This investigation was intended to examine the effect of bone marrow (BM)-derived MSCs on the differentiation of HL-60 cells according to morphological evaluation, flow cytometry analysis, and gene expression profile. Materials and Methods: The BM-MSCs were cultured in Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum (FBS). After the third passage, the BM-MSCs were irradiated at 30 Gy. To compare how the HL-60 cells differentiated in groups treated differently, HL-60 cells were cultured in RPMI-1640 and supplemented with 10% FBS. The HL-60 cells were seeded into six-well culture plates and treated with all-trans-retinoic acid (ATRA), BM-MSCs, or BM-MSCs in combination with ATRA, while one well remained as untreated HL-60 cells. The expression levels of the granulocyte subsetspecific genes in the HL-60 cells were assayed by real-time polymerase chain reaction. Results: Our results revealed that BM-MSCs support the granulocytic differentiation of the human promyelocytic leukemia cell line HL-60. Conclusion: Based on the results of this study, we concluded that BM-MSCs may be an effective resource in reducing or even preventing ATRA's side effects and may promote differentiation for short medication periods. Though BM-MSCs are effective resources, more complementary studies are necessary to improve this differentiation mechanism in clinical cases.

Background: BCL-2 is the most important anti-apoptotic regulator and Bax is a pro-apoptotic protein. The status of these parameters or the ration of BCL-2 to BAX is important in malignant cell fate as well as normal cells. Methods: Sixty-two ALL patients and 62 healthy sex-and age-matched controls were studied. After genotyping, the promoter region of the BAX and BCL-2 genes by RFLP-PCR method the patients were classified in nine prognostic groups, after that, the overall survival ratio of each score was compared with others pair-wise or between groups. Results: The frequencies of the AA, AC, CC alleles of the BCL-2 C-938A polymorphism in patient group were 33 (53.23%), 18 (29.03%), 11 (17.74%), and in the control group were 13 (21.0%), 27 (43.5%), 22 (35.5%), respectively (P=0.003). Also, the frequencies of AA, AG, GG alleles of the BAX G-248A SNP were 15 (24.2%), 24 (38.7%), 23 (37.1%) in ALL group and 13 (21.0%), 25 (40.3%), 24 (38.7%) (p>0.05) in the control group. The survival time estimation and ratio were significantly different between different SNPs in BCL-2 (P=0.002). Conclusion: These findings showed that the BCL-2 promoter region polymorphism is more reliable than BAX gene promoter polymorphism in any ALL scoring system. But the establishment of complete scoring system requires further more clinical and laboratory findings along with genetic polymorphisms is necessary

In the publication of this article [1], there is an error in one of the contributing author names.

Background: Chemotherapy plays a very important role in the treatment of leukemia but the resistance properties of the lymphoblasts limit the effect of chemotherapy. One of the main mechanisms of resistance to chemotherapy is the increased expression of MDR1 gene. The aim of this study was to explore the effect of resveratrol on the expression of MDR1 gene in leukemic lymphoblast of new cases of acute lymphoblastic leukemia (ALL) patients in vitro. Methods: Separation of lymphoblasts of 5 new case ALL patients from peripheral blood was performed by ficoll density gradient centrifugation. Lymphoblasts were cultured in RPMI 1640 medium. Lymphoblasts were treated with 50µmol/L resveratrol for 48 h. Total RNA was extracted with guanidine isothiocyanate. RNA was converted to cDNA. Real time PCR was used to detect mRNA expression of MDR1. Results: The results of gene detection showed that the expression of MDR1 did not change significantly in the patients however, in one patient expression of MDR1 increased upon treatment with resveratrol. Conclusion: The results of this study did not support resveratrol as a compound to reverse multidrug resistance in leukemic lymphoblasts.

MSCs are multipotent progenitors which reside in bone marrow. They support hematopoietic stem cells homing, self renewal and differentiation in bone marrow. They can also differentiate into osteoblasts, adipocytes, chondrocytes, myocyates and many other tissues. In vivo, when trauma happens, MSCs operate cell renewal and migrate to the damaged tissues to regenerate that injury. In vitro, MSCs are able to proliferate and differentiate to a variety of cell lineages. This makes them a very hopeful tool for cell-based regenerative therapy for large bone defects, maxillofacial skeletal reconstruction, cardiovascular and spinal cord injury and so many other defects. The most important characteristic that make MSCs an excellent tool for cell replacement is their ability to escape from immune rejection. For therapeutic purposes they usually isolated from human bone marrow or fat and they should proliferate in order to reach an adequate number for implantation. Conventionally DMEM medium supplemented with 10% FBS is used for their expansion, but currently autologous platelet rich products are replaced FBS. Platelet granules contain so many growth factors that can support MSCs proliferation.