Activating KIR/HLA-I combinations as a risk factor of adult B-ALL.

B-cell acute lymphoblastic leukemia (B-ALL), the most predominant type of ALL, is less common and incurable among adults. Regarding the pivotal role of NK cells in immune surveillance against hematological malignancies, studying the effective factors in regulating their function, particularly KIRs as the most important NK cell receptors and HLA-I molecules as their main ligands, is of importance. Since NK responses against malignant lymphoblasts are influenced by KIR signals, we did a case-control study on 154 adult patients with B-ALL and 181 healthy controls to investigate the correlation of KIR/HLA-I combinations with susceptibility to B-ALL in Iranians. The genotyping of KIR genes and HLA-I alleles was performed by PCR-SSP with 11 and 9 primer pairs, respectively. Our data revealed an increased frequency of activating (a)KIRs and aKIR/HLA-I combinations in our patients: KIR3DS1 (p = 0.009, OR = 1.81), Bx genotype (p = 0.038, OR = 1.81), KIR3DS1(+)/HLA-Bw4Thr80(+) (p = 0.004, OR = 3.61), and KIR3DS1(+)/HLA-B Bw4(+) (p = 0.037, OR = 1.76). The presence of inhibitory (i)KIRs in the absence of their cognate HLA-I ligands was also more frequent among the patients. However, the frequency of inhibitory combinations was more common in controls: KIR2DL1(+)/HLA-C2(+) (p = 0.027, OR = 0.57), KIR2DL2/3(+)/HLA-C1(+) (p = 0.004, OR = 0.5), and KIR3DL2(+)/HLA-A3/A11(+) (p = 0.0012, OR = 0.46). To sum up, the less inherited iKIR/HLA-I combinations might make individuals more susceptible to B-ALL because of inefficient education of NK cells.

The Effects of Resveratrol, Gallic Acid, and Piperine on the Expression of miR-17, miR-92b, miR-181a, miR-222, BAX, BCL-2, MCL-1, WT1, c-Kit, and CEBPA in Human Acute Myeloid Leukemia Cells and Their Roles in Apoptosis.

MicroRNAs (miRs) play a crucial role in the leukemogenesis and the prognosis of acute myeloid leukemia (AML). This study investigated the therapeutic effects of resveratrol, gallic acid, and piperine as natural anticancer agents on the HL-60 cell line and their roles in apoptosis. In this experimental study, quantitative analysis of miRs, including miR-17, miR-92b, miR-181a, and miR-222, were performed in 150 newly diagnosed patients with AML by real-time PCR assay. HL-60 cell viability as well as the expression of miRs, BAX, BCL-2, MCL-1, WT1, c-Kit, and CEBPA, were also assessed after transfection with the LNA-miRs and treatment with resveratrol, gallic acid, and piperine. The expression of miR-17 and miR-181a decreased significantly in LNA-anti-miRs. Although HL-60 cell viability decreased in LNA-anti-miR-222, miR-17, and miR-92b, blockade of miR-181a increased the cell viability. Besides, the cell viability increased merely in the piperine-treated group. Compared to untreated cells, miR-17 and miR-92b expression significantly increased in gallic acid- and resveratrol-treated cells. In HL-60 cells treated with resveratrol, gallic acid, and piperine, the expression of miR-181a was also increased significantly. The expression of BAX was also increased in resveratrol and piperine-treated groups. Compared to untreated cells, the expression of c-Kit increased significantly in the piperine-treated group; however, it decreased in the resveratrol-treated group. LNA-anti-miRs may be a promising agent for the treatment of AML. All three compounds used in this study showed anticancer effects, which can exert the desired outcome in patients with AML.

Investigating the trends of incidence rates of breast cancer in Southern Iran: a population based survey.

BACKGROUND: The overall incidence of breast cancer is different all over the world and even within a nation. The present study aims to investigate the stratum-specific incidence trends of breast cancer in southern Iran. METHODS: In this retrospective cohort study, the data of Fars Population-Based Cancer Registry was used during 2001-2018. New cancer cases with ICD-O-3 codes C50.0 to C50.9 were categorized based on age group, morphology, and topography. Age-specific incidence rates of breast cancer were calculated during 2001-2018. Annual overall and truncated age-standardized incidence rates and their 95% Confidence Intervals (CIs) were also calculated. Afterward, the Annual Percentage Changes (APCs) of the age-specific and age-standardized incidence rates of breast cancer during 2001-2018 were calculated using Joinpoint regression software. RESULTS: An increasing trend was observed in the incidence of breast cancer among women during 2001-2018 (APC of age-standardized incidence rates: 9.5 (95% CI: 7.5, 11.5)).However, the trend was increasing less during the recent years. The APC of age-standardized rates decreased from 15.03 (95% CI: 10.4, 19.8) in 2007 to 6.15(95% CI: 4.0, 8.4) in 2018. The most common morphology of breast cancer was invasive ductal carcinoma (77.3% in females and 75.1% in males) and its trend was similar to the general trend of different types of breast cancer. The most common site of breast cancer was the upper outer quadrant. Most breast cancer cases were female and males accounted for 2.45% of the cases. Among females, 40-55 was the most prevalent age group. CONCLUSION: The incidence of breast cancer among women living in southern Iran showed an increasing trend from 2001 to 2018. However, the rate of increase exhibited a milder slope during the more recent years. Based on the higher prevalence of breast cancer in the 40-55 age group observed in the present study, it offers valuable insight into the potential reduction of the breast cancer screening age from 50 to 40 years for healthy Iranian women. However, before implementing such a policy change, it is crucial to conduct additional studies that specifically examine the cost-effectiveness, as well as the potential benefits and risks associated with this alteration.

Effect of once versus twice intracoronary injection of allogeneic-derived mesenchymal stromal cells after acute myocardial infarction: BOOSTER-TAHA7 randomized clinical trial.

BACKGROUND: Mesenchymal stromal cell (MSC) transplantation can improve the left ventricular ejection fraction (LVEF) after an acute myocardial infarction (AMI). Transplanted MSCs exert a paracrine effect, which might be augmented if repeated doses are administered. This study aimed to compare the effects of single versus double transplantation of Wharton's jelly MSCs (WJ-MSCs) on LVEF post-AMI. METHODS: We conducted a single-blind, randomized, multicenter trial. After 3-7 days of an AMI treated successfully by primary PCI, 70 patients younger than 65 with LVEF < 40% on baseline echocardiography were randomized to receive conventional care, a single intracoronary infusion of WJ-MSCs, or a repeated infusion 10 days later. The primary endpoint was the 6-month LVEF improvement as per cardiac magnetic resonance (CMR) imaging. RESULTS: The mean baseline EF measured by CMR was similar (~ 40%) in all three groups. By the end of the trial, while all patients experienced a rise in EF, the most significant change was seen in the repeated intervention group. Compared to the control group (n = 25), single MSC transplantation (n = 20) improved the EF by 4.54 ± 2%, and repeated intervention (n = 20) did so by 7.45 ± 2% when measured by CMR imaging (P < 0.001); when evaluated by echocardiography, these values were 6.71 ± 2.4 and 10.71 ± 2.5%, respectively (P < 0.001). CONCLUSIONS: Intracoronary transplantation of WJ-MSCs 3-7 days after AMI in selected patients significantly improves LVEF, with the infusion of a booster dose 10 days later augmenting this effect. TRIAL REGISTRATION: Trial registration: Iranian Registry of Clinical Trials, IRCT20201116049408N1. Retrospectively Registered 20 Nov. 2020, https://en.irct.ir/trial/52357.

Cytidine deaminase enzyme activity is a predictive biomarker in gemcitabine-treated cancer patients.

BACKGROUND: Gemcitabine is a chemotherapeutic agent, widely used for the treatment of many types of cancer. Cytidine deaminase (CDA) enzyme plays an important role in the metabolism of gemcitabine. This study aimed to assess the power of serum CDA residual activity in predicting drug efficacy and toxicity in gemcitabine-treated cancer patients. METHODS: This prospective observational study enrolled 63 patients with different types of malignancies who received gemcitabine chemotherapy between May 2019 and January 2022. Blood samples were obtained before the initiation of chemotherapy and serum CDA residual activity was determined using a modification of the Berthelot assay. The patients were followed up for at least 12 months up to 41 months. Overall survival was recorded and treatment-related toxicities were documented according to National Cancer Institute Common Terminology Criteria. RESULTS: Kaplan-Meier analysis showed that patients with a lower than median CDA value (≤ 8.06 U/mg protein) had a significantly longer survival compared to patients with higher CDA values (> 8.06 U/mg, P ˂ 0.005). Among several potentially involved factors, a significant association between CDA activity and overall survival was observed in univariate analysis (HR = 4.219, 95% CI 1.40-12.74, P = 0.011). On the other hand, the rate of anemia was significantly higher in low-CDA patients compared to high-CDA individuals (P < 0.05). CONCLUSION: These findings suggest that CDA activity could be a promising biomarker to predict survival and the occurrence of anemia in cancer patients treated with gemcitabine.

Evaluating the Efficacy of Modified BeEAM(Bendamustine, Etoposide, Cytarabine, Melphalan) Regimen as Conditioning for Autologous Stem Cell Transplantation in Relapsed or Refractory Lymphoma: An Experience from Two Centers of a Developing Country.

Background: High-dose chemotherapy followed by Autologous SCT (stem cell transplantation) is a treatment of choice for relapsed and refractory lymphoma. Due to cost, toxicity, and shortage of Carmustine, we decided to conduct a phase 2 clinical trial to evaluate the safety and efficacy of Bendamustine instead of Carmustine in a previously used BEAM-like protocol. Materials and Methods:102 patients (median age,37) with Hodgkin(n=54) and non-Hodgkin lymphoma(n=48) were recruited and transplanted in two centers. After stem cell harvesting, a modified BeEAM regimen was administered to all the patients. Overall survival and disease-free survival (DFS) at two years were calculated as the study's primary endpoints. Results: Neutrophil and platelet recovery were observed after a median of 12 and 13 days, and all the patients were engrafted. Fever was observed in 25(24.5%) with only two documented infections. The only grade III toxicities were mucositis (20%) and nausea (15.6%). No transplant-related mortality (TRM) was observed after 100 days. After a median follow-up of 37(range 25-48) months, 68(66.6%) patients were in complete remission while 21 patients were in partial response, and 16 patients (15.6%) developed progressive disease, among which 13 (12.7%) had died. The OS at two years was (89 of 102, 87.3%), and the DFS rate was 68 of 102(66.7%). Conclusion: Our study showed that modified BeEAM is a safe, effective, and feasible conditioning regimen for ASCT in lymphoma instead of the BEAM regimen.

Association of killer cell immunoglobulin-like receptors and their cognate HLA class I ligands with susceptibility to acute myeloid leukemia in Iranian patients.

Acute myeloid leukemia (AML) is one of the most prevalent leukemia in adults. Among the various NK receptors, killer immunoglobulin-like receptors (KIRs) carry out indispensable roles in NK cell development and function through engaging with class I human leukocyte antigens (HLA-I) as their ligands. Besides divergent KIR and HLA loci, KIR/HLA-I combinations have a significant effect on NK cell response. In this case-control study, we aimed to verify the association of KIR/HLA-I combinations with susceptibility to AML in the Southwestern Iranian population. KIR and HLA genotyping was performed with PCR-SSP by some novel primers for 181 patients with AML and 181 healthy controls. According to our results, the frequencies of KIR3DS1 (p = 0.0001, OR = 2.32, 95% CI 1.51-3.58), KIR2DS4fl (p = 0.02, OR = 1.53, 95% CI 1.05-2.21), CxT4 genotypes (p = 0.03, OR = 2.0, 95% CI 1.05-3.82), and T4 gene cluster (p = 0.01, OR = 1.99, 95% CI 1.17-3.41) were significantly higher in patients than controls, while C1/C2 genotype (p = 0.00002, OR = 0.39, 95% CI 0.25-0.61), HLA-A Bw4 (p = 0.02, OR = 0.6, 95% CI 0.38-0.94), and HLA-A*11 (p = 0.03, OR = 0.57, 95% CI 0.34-0.95) alleles were more frequent in controls. In addition, inhibitory (i)KIR/HLA-I combinations analysis revealed higher frequencies of KIR2DL1( +)/HLA-C2( +), KIR2DL2/3( +)/HLA-C1( +), KIR3DL1( +)/HLA-A Bw4( +), and KIR3DL2( +)/HLA-A*03/11( +) in the control group (p = 0.002, OR = 0.49, 95% CI 0.3-0.78; p = 0.04, OR = 0.62, 95% CI 0.39-0.99; p = 0.04, OR = 0.63, 95% CI 0.4-0.99; and p = 0.03, OR = 0.62, 95% CI 0.4-0.95, respectively). Overall, the number of iKIR/HLA-I combinations was more in the control group. Moreover, KIR3DS1( +)/HLA-B Bw4Ile80( +) and the sum of HLA-B Bw4/A Bw4 combined with KIR3DS1 as activating KIR/HLA-I combinations were more frequent among patients than controls (p = 0.01, OR = 1.99, 95% CI 1.14-3.49 and p = 0.005, OR = 1.97, 95% CI 1.22-3.19, respectively). In conclusion, our results postulate that inhibitory combinations play a protective role against AML by developing potent NK cells during education. It is noteworthy that KIR/HLA-I combination studies can be applicable in donor selection for allogeneic NK cell therapy in hematological malignancies.

miR-155 and miR-92 levels in ALL, post-transplant aGVHD, and CMV: possible new treatment options.

BACKGROUND: Acute lymphoblastic leukemia (ALL) is a malignancy that leads to altered blast cell proliferation, survival, and maturation and eventually to the lethal accumulation of leukemic cells. Recently, dysregulated expression of various micro-RNAs (miRNAs) has been reported in hematologic malignancies, especially ALL. Cytomegalovirus infection can induce ALL in otherwise healthy individuals, so a more detailed evaluation of its role in ALL-endemic areas like Iran is required. METHODS: In this cross-sectional study, 70 newly diagnosed adults with ALL were recruited. The expression level of microRNA-155(miR-155) and microRNA-92(miR-92) was evaluated by real-time SYBR Green PCR. The correlations between the miRNAs mentioned above and the severity of disease, CMV infection, and acute graft vs. host disease after hematopoietic stem cell transplantation (HSCT) were assessed. B cell and T cell ALL distinction in the level of miRNAs was provided. RESULTS: After the statistical analysis, our results indicated a marked increase in the expression of miR-155 and miR-92 in ALL patients vs. healthy controls (*P = 0.002-*P = 0.03, respectively). Also, it was shown that the expression of miR-155 and miR-92 was higher in T cell ALL compared to B cell ALL (P = 0.01-P = 0.004, respectively), CMV seropositivity, and aGVHD. CONCLUSION: Our study suggests that the plasma signature of microRNA expression may act as a powerful marker for diagnosis and prognosis, providing knowledge outside cytogenetics. Elevation of miR-155 in plasma can be a beneficial therapeutic target for ALL patients, with consideration of higher plasma levels of miR-92 and miR-155 in CMV + and post-HSCT aGVHD patients.

Philadelphia Chromosome Positive Chronic Myelogenous Leukemia Blastic Crisis in A Patient with Unusual Primary Myelofibrosis Characteristics; A Case Report.

INTRODUCTION: Myeloproliferative neoplasms (MPNs) are divided into BCR-ABL positive Chronic myeloid leukemia (CML) and BCR-ABL negative MPNs including Polycythemia vera (PV), Essential Thrombocythemia (ET) and Primary myelofibrosis (PMF). Evaluation of the Philadelphia chromosome in MPNs is a diagnostic requirement for classic CML. CASE REPORT: In 2020, a 37-year-old woman with negative cytogenetic testing for Janus kinase2 (JAK2), Calreticulin (CALR), myeloproliferative leukemia virus oncogene (MPL), and positive for BCR-ABL1 mutation with reticular fibrosis in bone marrow was diagnosed as CML. Some years ago, the patient had been diagnosed with PMF with evidence of histiocytic necrotizing lymphadenitis or Kikuchi-Fujimoto disease (KFD). The BCR-ABL fusion gene was initially evaluated which was negative. Then, Cutaneous squamous cell carcinoma (cSCC) was confirmed by Dermatopathologist with palpable splenomegaly and high white blood cell (WBC) count with basophilia. Finally, BCR-ABL was detected positive by the fluorescence in situ hybridization (FISH) and quantitative real-time polymerase chain reaction (qRT-PCR). In fact, the co-occurrence of PMF with CML was identified. CONCLUSION: This case study highlighted the importance of some cytogenetic methods in the detection and classification of MPNs. It is recommended that physicians pay more attention to it and be aware of the planning treatment.

Risk Factors for the Occurrence of Asymptomatic Brain Lesions in Patients with ß-Thalassemia: a Systematic Review and Meta-Analysis.

BACKGROUND: Several factors, including increased platelet aggregation, decreased platelet survival, decreased antithrombotic factors cause a hypercoagulable state in thalassemia patients. This is the first meta-analysis designed to summarize the association of age, splenectomy, gender, and serum ferritin and hemoglobin levels with the occurrence of asymptomatic brain lesions in thalassemia patients using MRI. METHODS: This systematic review and meta-analysis was conducted according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) checklist. We searched four major databases and included eight articles for this review. The quality of the included studies was assessed based on the Newcastle-Ottawa Scale checklist. Meta-analysis was performed using STATA 13. Odds ratio (OR) and standardized mean difference (SMD) were considered as effect sizes for comparing the categorical and continuous variables, respectively. RESULTS: The pooled OR for splenectomy in patients with brain lesions compared to those without lesions was 2.25 (95% CI 1.22 - 4.17, p = 0.01). The pooled analysis for SMD of age between patients with/without brain lesions was statistically significant, 0.4 (95% CI 0.07 - 0.73, p = 0.017). The pooled OR for the occurrence of silent brain lesions was not statistically significant in males compared to females, 1.08 (95% CI 0.62 - 1.87, p = 0.784). The pooled SMD of Hb and serum ferritin in positive brain lesions compared to negatives were 0.01 (95% CI -0.28, 0.35, p = 0.939) and 0.03 (95% CI -0.28, 0.22, p = 0.817), respectively, which were not statistically significant. CONCLUSIONS: Older age and splenectomy are risk factors for developing asymptomatic brain lesions in ß-thalassemia patients. Physicians should consider a careful assessment of high-risk patients for starting prophylactic treatment.

Are the Costimulatory Molecule Gene Polymorphisms (CTLA-4) Associated With Infection in Organ Transplantation? A Meta-Analysis.

Organ transplantation has been linked to certain gene polymorphisms. The effect of gene polymorphisms-associated organ transplantation gene on infection, on the other hand, is yet unknown. The research studying the link between the CTLA-4 rs5742909, rs733618, rs4553808, rs231775, and polymorphisms of the organ transplantation gene and infection were found in PubMed, Web of Science, Scopus, and Embase, and the published articles from 2012 to 2020 were gathered. For the best estimation of the intended results, a random-effects model was used in this meta-analysis. In this study, 1,567 studies were initially included and 9 eligible studies were eligible for further analyses. A significant correlation between CTLA4+49 [A/G-231775 odds ratio (OR) = 077, 0.59-0.95] and CTLA4 [rs5742909TT OR: 0.09, 0.27-0.45] gene polymorphism with infection in organ transplantation was observed. Also, no significant association was found between other CTLA4 gene polymorphisms with infection in organ transplantation. Further studies involving gene-gene and gene-diet interactions should be conducted to investigate this association with infection.

Selenium Supplementation Alter the Frequency of Th17 but not Th1/Th2 Lymphocytes in Diffuse Large B Cell Lymphoma Patients.

BACKGROUND: Selenium (Se) is a micronutrient, which has recently been proven to have a positive effect on the immune system of cancer patients, but the underlying mechanism is not clearly defined. In this randomized controlled trial, we evaluated the effect of three-month Se supplementation on the profile of CD4+ T-helper subsets including IFN-γ+/IL-4- Th1, IFN-γ-/IL-4+ Th2, and CD4+IL-17+ Th17 cells in sixteen diffuse large B cell lymphoma (DLBCL) patients at stable remission phase who consumed Se (Se+) compared to the fourteen control patients who did not receive Se (Se-). METHODS: The frequency of IFN-γ+/IL-4- Th1, IFN-γ-/IL-4+ Th2, and CD4+IL-17+ Th17 lymphocytes was determined using a four-color flow cytometry method. RESULTS: The results revealed that three-month Se supplementation significantly decreased the proportion of CD4+IL-17+ Th17 lymphocytes but not IFN-γ+/IL-4- Th1 and IFN-γ-/IL-4+ Th2 subtypes in DLBCL patients at stable remission. Change in the percentage of IFN-γ+/IL-4- Th1, IFN-γ-/IL-4+ Th2, and CD4+IL-17+ Th17 cells did not significantly differ between Se+ and Se- groups. No positive correlation was observed between changes in different Th subpopulations in both Se+ and Se- groups. CONCLUSIONS: Taken together, three-month Se supplementation can reduce the proportion of CD4+IL-17+ Th17 cells in DLBCL patients at stable remission phase. Larger population and longer follow-up of patients is necessary to specify the clinical significance of Se supplementation on the popularity of T-helper cells in DLBCL patients.

The mRNA Expression of PTEN, LEF1, JAK3, LC3 and p62/SQSTM1 Genes in Patients with Chronic Myeloid Leukemia.

INTRODUCTION: Chronic myeloid leukemia (CML) is a progressive myeloproliferative disorder resulting from forming a chimeric BCR-ABL gene. The proteins derived from this gene can affect some genes from various signaling pathways such as PI3K/AKT/Wnt/catenin/JAK/Stat involved in proliferation, differentiation, cell death, and genes related to autophagy. Imatinib is the first-line treatment for CML patients, with durable and proper responses in Iranian children and adult CML patients. Hence, we aimed to evaluate the mRNA expression of some selected key genes from those pathways in patients with CML before and under treatment. METHODS: In the case-control study, the mRNA expression of PTEN, LEF1, JAK3, LC3 and p62 genes were measured in 51 CML patients (6 patients before treatment and 45 patients under treatment with imatinib mesylate) and 40 healthy controls using the Real-time PCR method. RESULTS: The mRNA expression of PTEN and P62 were significantly higher in newly diagnosed patients than in controls (P<0.0001 and P = 0.0183, respectively), while the expression of the LC3 gene was significantly lower in the untreated newly diagnosed group than in control subjects (P = 0.0191). The expression level of PTEN, LEF1, JAK3 and P62 genes were significantly decreased in patients under treatment than in the group before treatment (P = 0.0172, P = 0.0002, P = 0.0047 and P = 0.0038, respectively). A positive correlation was seen between the gene expression of P62 and BCR-ABL in the patients under treatment (r 0529, P = 0.016). CONCLUSION: Our findings showed that the changes in expression of these genes were related to the patient's treatment. Due to the key role of these genes in proliferation, differentiation and tumor suppression, it is proposed that these genes may be helpful for follow-up of treatment in CML patients.

Triggering of lymphocytes by CD28, 4-1BB, and PD-1 checkpoints to enhance the immune response capacities.

Tumor infiltrating lymphocytes (TILs) usually become exhausted and dysfunctional owing to chronic contact with tumor cells and overexpression of multiple inhibitor receptors. Activation of TILs by targeting the inhibitory and stimulatory checkpoints has emerged as one of the most promising immunotherapy prospectively. We investigated whether triggering of CD28, 4-1BB, and PD-1 checkpoints simultaneously or alone could enhance the immune response capacity of lymphocytes. In this regard, anti-PD-1, CD80-Fc, and 4-1BBL-Fc proteins were designed and produced in CHO-K1 cells as an expression host. Following confirmation of the Fc fusion proteins' ability to bind to native targets expressed on engineered CHO-K1 cells (CHO-K1/hPD-1, CHO-K1/hCD28, CHO-K1/hCTLA4, and CHO-K1/h4-1BB), the effects of each protein, on its own and in various combinations, were assessed in vitro on T cell proliferation, cytotoxicity, and cytokines secretion using the Mixed lymphocyte reaction (MLR) assay, 7-AAD/CFSE cell-mediated cytotoxicity assay, and a LEGENDplex™ Human Th Cytokine Panel, respectively. MLR results demonstrated that T cell proliferation in the presence of the combinations of anti-PD-1/CD80-Fc, CD80-Fc/4-1BBL-Fc, and anti-PD-1/CD80-Fc/4-1BBL-Fc proteins was significantly higher than in the untreated condition (1.83-, 1.91-, and 2.02-fold respectively). Furthermore, anti-PD-1 (17%), 4-1BBL-Fc (19.2%), anti-PD-1/CD80-Fc (18.6%), anti-PD-1/4-1BBL-Fc (21%), CD80-Fc/4-1BBL-Fc (18.5%), and anti-PD-1/CD80-Fc/4-1BBL-Fc (17.3%) significantly enhanced cytotoxicity activity compared to untreated condition (7.8%). However, concerning the cytokine production, CD80-Fc and 4-1BBL-Fc alone or in combination significantly increased the secretion of IFN-γ, TNF-α, and IL-2 compared with the untreated conditions. In conclusion, this research establishes that the various combinations of produced anti-PD-1, CD80-Fc, and 4-1BBL-Fc proteins can noticeably induce the immune response in vitro. Each of these combinations may be effective in killing or destroying cancer cells depending on the type and stage of cancer.

Cytokine Levels in Patients with ß-Thalassemia Major and Healthy Individuals: a Systematic Review and Meta-Analysis.

BACKGROUND: Cytokine levels in patients with ß-thalassemia major (ß-TM) have been assessed in several studies. Accordingly, a wide variety of immune disturbances has been shown in patients with thalassemia. Recurrent transfusions cause iron overload, which induces an increase in the production of cytokines. However, no systematic approach or meta-analysis has been done to provide a clear feature of cytokine levels in ß-TM. The present meta-analysis aimed to summarize the existing evidence regarding different levels of cytokines in patients with Β-TM compared to healthy controls. METHODS: This study was performed according to the PRISMA checklist. A systematic search was done in Web of Science (ISI), Scopus, and PubMed databases. The quality of the included studies was assessed based on the New-castle-Ottawa Scale. Meta-analysis was run via STATA 13 software. The standardized mean difference was considered the effect size for comparing the continuous variables. RESULTS: This meta-analysis included 16 studies conducted on 805 ß-TM patients and 624 healthy individuals (with the mean age of 16.10 ± 4.33 and 16.22 ± 3.78, respectively). The results showed significantly higher levels of Tumor Necrosis Factor-alpha (TNF-α), Interleukin-6 (IL-6), and IL-10 in patients with ß-TM compared to the healthy controls. CONCLUSION: The results indicated that the levels of both inflammatory and anti-inflammatory cytokines were higher in patients with ß-TM compared to the healthy population, which could be associated with higher levels of oxidative markers in these patients. Further studies are suggested to evaluate the difference in cytokine levels among different types of thalassemia.

Comparing the effects of SMS-based education with group-based education and control group on diabetes management: a randomized educational program.

BACKGROUND: The high prevalence of diabetes and the importance of long-term follow-up of these patients encourage finding an inexpensive and applicable educational method to control the disease. Distance education based on mobile technology and Short message service (SMS) can be an effective way to manage this disease by eliminating time and place limitations. Due to the world's high penetration rate, SMS is one of the best ways to transfer information and health education. OBJECTIVE: This study aimed to compare the effect of SMS- and group-based education in managing diabetes type 2 and compare them with a control group. METHOD: A total of 168 patients with diabetes type 2 under the coverage of three family physician clinics were randomly allocated into three groups. The education was conducted in 12 one-hour sessions once a week in the group-based arm, and a daily short message was sent to the participants in the SMS group. The control group also underwent routine care at the family physician clinic. The duration of the education was 3 months. At baseline and 3 months later, fasting blood sugar (FBS), 2 hours postprandial sugar (2hppBS), and HBA1c, as well as diabetes self-management questionnaire score (DSMQ), were measured. RESULTS: The comparison of the three groups in terms of changes in FBS (P-value: 0.001), 2hppBS (8 P-value: < 0.001) and HbA1c (P-value: < 0.001) were significantly different after 3 months. In pairwise analysis, 2hppBS was the only significantly different parameter between the group- and SMS-based education (P-value: 0.035). CONCLUSION: Although the effect of both educational methods via SMS or group education was better than the control group in controlling diabetes, these two methods were not statistically different. Due to spending a lot of time and money on group-based education, it is better to replace it with education by SMS.

Transplantation of mesenchymal stem cells for prevention of acute myocardial infarction induced heart failure: study protocol of a phase III randomized clinical trial (Prevent-TAHA8).

BACKGROUND: Results from recent clinical trials on bone marrow mononuclear cell (BM-MNC) transplantation show that this intervention can help reduce the incidence of heart failure (HF) after acute myocardial infarction (AMI). However, no study has evaluated the effect of the transplantation of mesenchymal stem cells (MSCs) on a clinical endpoint such as HF. METHODS: This single-blinded, randomized, multicenter trial aims to establish whether the intracoronary infusion of umbilical cord-derived Wharton's jelly MSCs (WJ-MSCs) helps prevent HF development after AMI. The study will enroll 390 patients 3 to 7 days following AMI. Only patients aged below 65 years with impaired LV function (LVEF < 40%) will be included. They will be randomized (2:1 ratio) to either receive standard care or a single intracoronary infusion of 107 WJ-MSCs. The primary outcome of this study is the assessment of HF development during long-term follow-up (3 years). DISCUSSION: Data will be collected until Nov 2024. Thereafter, the analysis will be conducted. Results are expected to be ready by Dec 2024. We will prepare and submit the related manuscript following the CONSORT guidelines. This study will help determine whether or not the infusion of intracoronary WJ-MSCs in patients with AMI will reduce the incidence of AMI-induced HF. TRIAL REGISTRATION: ClinicalTrials.gov NCT05043610 , Registered on 14 September 2021 - retrospectively registered.

Investigating the impact of modified mindfulness-based stress reduction (MBSR) program on occupational burnout and other mental health status among nonmedical staff in a hospital: a randomized controlled trial.

OBJECTIVE: Burnout is a prolonged psychological response to a longstanding interpersonal stressor at work. It can progress to other mental illnesses, such as anxiety and depression. In today's society, burnout has become widespread, and it is currently a serious challenge in health systems. This study intended to investigate the impact of mindfulness training on burnout and depression, anxiety, and stress of nonmedical staff in a hospital in Shiraz-Iran. METHOD: Fifty nonmedical staff in a Shiraz-Iran hospital were enrolled in this two groups' randomized controlled trial. The intervention group was trained by a modified mindfulness-based stress reduction (MBSR) program, and the control group received no intervention. The outcome was assessed by the Copenhagen burnout inventory (CBI) and DASS-21 questionnaire on three occasions including before T0, immediately after T1, and 3 months after the intervention T2. RESULTS: Comparing the score changes between intervention and control groups showed that the reduction of work­distaste­related burnout, client­related burnout, anxiety, and stress scores in the intervention group was significantly more than in the control group in the time interval from T0 to T1. The scores in the intervention group in three subscales of CBI, including work­characteristic­related burnout, work­distaste­related burnout, and client­related burnout, decreased significantly immediately after the training (T1) compared to before (T0). Also, the scores did not change significantly after 3 months following training. CONCLUSIONS: Mindfulness training can be used as an effective way to improve occupational burnout, anxiety, and stress in occupations other than health professionals. Its effect is stable for at least a few months. It is recommended that future studies focus on investigating the feasible way to integrate this training into the working environment. Forthcoming studies should also determine whether the impact of this intervention will last longer and find possible ways to extend its influence.

Pain, Fatigue, Nausea, and Vomiting as the Predictors of Anxiety in Patients Undergoing Hematopoietic Stem Cell Transplantation: A Prospective Cohort Study.

The primary outcome was to assess the correlation between anxiety and pain, fatigue, nausea, and vomiting. The secondary outcome was to determine the predictive roles of pain, fatigue, nausea, and vomiting in anxiety among patients undergoing Hematopoietic Stem Cell Transplantation (HSCT). The present prospective cohort study was conducted on 200 patients treated by HSCT referred to the centers affiliated to Shiraz University of Medical Sciences. The data were collected using Spielberger Anxiety Questionnaire, Numerical Pain Scale, Brief Fatigue Inventory, and Rhodes Nausea and Vomiting Index. The data were analyzed using Spearman's test and multiple regression analysis. The means of state anxiety, trait anxiety, pain, fatigue, and nausea, vomiting, and retching were 41.67 (SD = 9.71), 43.78 (SD = 9.00), 3.79 (SD = 2.79), 4.23 (SD = 2.48), and 6.31 (SD = 7.53), respectively. The results showed that the participants with higher pain and fatigue scores had higher anxiety levels. Those with more nausea and vomiting had higher anxiety levels, as well. This indicated that fatigue, pain, severity and frequency of nausea, and type of HSCT were the predictors of trait anxiety. The results also showed the predictor role of pain, fatigue, and type of HSCT in state anxiety. The findings revealed a correlation between anxiety and pain, fatigue, nausea, and vomiting among the HSCT patients. The results also showed fatigue and pain as the predictors of anxiety among these patients. Yet, future studies are recommended to determine the other factors contributing to anxiety amongst HSCT patients.