Long-term Survival of Multiple Myeloma Based on CBC Test at Diagnosis Using Defective Marshall-Olkin Cure Model

Introduction: As a malignant proliferative disorder, multiple myeloma (MM) is classified as a cancer of the immune system. Generally, a complete blood count (CBC) is the first test for a patient with symptoms of MM. Through CBC, physicians can monitor abnormalities in the blood. To normalize malignancies in their blood, patients must first go through conventional chemotherapy. Afterward, if eligible, subjects would receive high-dose therapy and hematopoietic stem cell transplantation (HSCT). Primarily, patients would be subjected to autologous hematopoietic stem cell transplantation (auto-HSCT). Materials and Methods: This retrospective cohort study consisted of 56 MM patients who were diagnosed between January 2010 and August 2016 and were followed up until February 2022. The survival rate of MM patients was assessed based on CBC test at the time of diagnosis. The clinical conditions, i.e., Thrombocytopenia, Leukopenia, and Anemia, were extracted from the CBC test and were used as the desired prognostic factors in companion with age at diagnosis. Overall survival based on the mentioned factors was analyzed using the defective Marshall-Olkin gompertz cure model, which was programmed in R software version 4.0.3. Results: The mean age at diagnosis was 52.76 (SD = 7.1). The probability of long-term survival for patients in this study was 46%, with five-year overall survival equaling 73.2%. Patients with thrombocytopenia had about 86% lower odds of long-term survival compared with patients with normal Platelet levels (Plt). Conclusion: The present study indicates that deficiency in Plt count is a significant factor leading to poor survival of MM patients

Addressing Heteroscedasticity in Correlated Binary Data: A Bayesian Mixed Effects Location Scale Approach

Introduction: The mixed effects logistic regression model is a common model for analysing correlated binary data as longitudinal data. The between and within subject variances are typically considered to be homogeneous but longitudinal data often show heterogeneity in these variances. This study proposes a Bayesian mixed effects location scale model to accommodate heteroscedasticity in binary data analysis. Methods: This study was carried out in two stages; first, the simulation study was used to evaluate the accuracy of the proposed model with the Bayesian approach and then the proposed model was applied to a real data. In simulation study, the data were generated from the mixed effects location scale model with different correlations between the random location effect and random scale effect and different sample sizes. In order to evaluate the accuracy of the estimations, the Root Mean Square Error, bias and Coverage Probability were calculated and the deviance information criterion was used to select the appropriate model. At the end we utilized this model to analyse uric acid levels of patients with haematological disorders. Results: The simulation results show the accuracy of model parameter estimates as well as the correlation between random location and scale effects. They also display that if a random scale effect is present in the data, it should be accounted for in model. Otherwise, the model is forced to assign the within subject variation due to these subject random effects to the error term. The results of real data are also in line with this. The odds of having normal UA levels increases by a factor of 26% per week. Due to the positive value of the covariance parameter, patients with higher mean of UA levels show higher variation in UA levels. Furthermore, the significance of the covariates in the between subject and within subject variances model, as well as the significance of the random scale variance determines the heterogeneity across subjects. Conclusion: Bayesian mixed effects location scale model provides a useful tool for analysing correlated binary data with heteroscedasticity because it considers data correlation and modelling mean and variance simultaneously. Furthermore, it improves the accuracy of statistical inference in longitudinal studies compared to classic mixed effects models

The Role of Pomalidomide-Based Epigenetic Effect on DNMT Genes Expression in Myeloma Cell Line

Multiple myeloma (MM) is clonal B-cell malignancy characterized by the progressive proliferation of malignant plasma cells and accumulation of monoclonal immunoglobulin (M-spike) in blood and urine. Pomalidomide is an immunomodulatory agent which has potentially suppressed myeloma cell progression, especially in drug-resistant cases. As epigenetic modifications have an important role in gene regulation and because of the revealing role of DNA-Methyltransferase 1 (DNMT1) overexpression in myeloma pathogenesis, in this study DNMT1, 3a and 3b genes expression of U266 myeloma cell line treated with pomalidomide have been evaluated. In this study after treatment of U266 cells with 1 μM pomalidomide for 48 hours, total RNA extraction and cDNA synthesis was performed. Gene expression of DNMT1, 3a and 3b has been evaluated using real time PCR technique. The result of this study show that pomalidomide can downregulate the expression of DNMT1, 3a, and 3b in 48 hours of treatment as 0.049, 0.058 and 0.055, respectively as comparing with untreated control (P<0.05). Based on these results we conclude that pomalidomide has desired effect on epigenetic modification by downregulation of DNMTs genes expression and has been considered as an effective drug for inhibition of myeloma proliferation

Signaling pathways involved in chronic myeloid leukemia pathogenesis: the importance of targeting Musashi2-Numb signaling to eradicate leukemia stem cells

Objective(s): Chronic myeloid leukemia (CML) is a myeloid clonal proliferation disease defining by the presence of the Philadelphia chromosome that shows the movement of BCR-ABL1. In this study, the critical role of the Musashi2-Numb axis in determining cell fate and relationship of the axis to important signaling pathways such as Hedgehog and Notch that are essential for self-renewal pathways in CML stem cells will be reviewed meticulously.Materials and Methods: In this review, a PubMed search using the keywords of Leukemia, signaling pathways, Musashi2-Numb was performed, and then we summarized different research works.Results: Although tyrosine kinase inhibitors such as Imatinib significantly kill and remove the cell with BCR-ABL1 translocation, they are unable to target BCR-ABL1 leukemia stem cells. The main problem is stem cells resistance to Imatinib therapy. Therefore, the identification and control of downstream molecules/ signaling route of the BCR-ABL1 that are involved in the survival and self-renewal of leukemia stem cells can be an effective treatment strategy to eliminate leukemia stem cells, which supposed to be cured by Musashi2-Numb signaling pathway.Conclusion: The control of molecules /pathways downstream of the BCR-ABL1 and targeting Musashi2-Numb can be an effective therapeutic strategy for treatment of chronic leukemia stem cells. While Musashi2 is a poor prognostic marker in leukemia, in treatment and strategy, it has significant diagnostic value

Homing and mobilization of hematopoietic stem cells

Hematopoietic stem and progenitor cells (HSPCs) are non-stop travelers throughout body in both time and space. Understanding the mechanism of HSPCs homing and mobilization is important to enhance the efficacy at bone marrow transplantation and cellular therapy. Mobilized HSPCs has largely replaced than the use of bone marrow as a source of stem cells for both allogeneic and autologous stem cell transplantation. This review describes the specific factors which play a key role in homing and mobilization of HSPCs, includes SDF-1 and its receptor CXCR4, proteases (MMPs and CPM). Moreover, chemokines inducing rapid HPSCs mobilization would be discussed. In this article we showed that many factors such as adhesion molecules and SDF-1/CXCR4 have critical roles in homing hematopoietic stem cells and G.CSF, MMPs, adhesion molecules and ROS involvement in mobilization of stem cells. According to above, we can be rich the peripheral blood of HSPCS using of this factors and antagonist for this receptors on the osteoblastic cells or/and HSPCs to bone marrow transplant

Virus-Specific T Cells: Promising Adoptive T Cell Therapy Against Infectious Diseases Following Hematopoietic Stem Cell Transplantation

Hematopoietic stem cell transplantation (HSCT) is a life-saving therapy for various hematologic disorders. Due to the bone marrow suppression and its long recovery period, secondary infections, like cytomegalovirus (CMV), Epstein-Bar virus (EBV), and adenovirus (AdV), are the leading causes of morbidity and mortality in HSCT cases. Drug resistance to the antiviral pharmacotherapies makes researchers develop adoptive T cell therapies like virus-specific T cell therapy. These studies have faced major challenges such as finding the most effective T cell expansion methods, isolating the expected subtype, defining the functionality of the end-cell population, product quality control, and clinical complications after the injection. This review discusses the viral infections after HSCT, T cells characteristics during chronic viral infection, application of virus-specific T cells (VSTs) for refractory infections, standard methods for producing VSTs and their limitation, clinical experiences on VSTs, focusing on outcomes and side effects that can be helpful in decision-making for patients and further researches

A 16 Month Survey of Cyclosporine Utilization Evaluation in Allogeneic Hematopoietic Stem Cell Transplant Recipients

Abstract Objectives: Graft versus host disease (GVHD) is a life threatening reaction in the stem cell transplantation process. Nowadays Cyclosporine is the most commonly utilized agent for GVHD prophylaxis and it has a major role in successful transplantation. Cyclosporine has been applied for many years in this field but it could be stated that currently no general consensus is available for its optimal method of administration. Conditions related to cyclosporine administration and possible related adverse reactions observed closely in our patients with the aim of constructing a comprehensive practice guideline in the future. Patients and Methods: Allogeneic stem cell transplant recipients who have been taking cyclosporine were monitored during and after their hospitalization while recording all observations on predefined questionnaires on the basis of periodic clinical and laboratory examinations for a 16 month period. Results: Mean recorded duration of infusions was 1.44 ± 0.68 h and by twice daily administration, means intravenous and oral dose was 101.85 ± 22.03 mg and 219.28 ± 63.9 mg, respectively. A mean CsA trough level after about 12 h of specified unique doses was 223 ± 65 ng/mL. We found hypertension, nephrotoxicity, neurotoxicity, hypertension, and dyslipidemia in about 14, 20, 48, and 94 percent of patients. Conclusions: This study proposed that permanent guidance of healthcare team according to a fixed and standard method of cyclosporine administration routine with using efficient facilities and protocols would be helpful considerably for an optimal pharmacotherapy

A Mixture Cure Model for Interval Censorship with a Change Point based on Age Threshold on Hodgkin Lymphoma Patients after Stem Cell Transplantation: A Cure Model with Change Point for Hodgkin Lymphoma Patients

Abstract Introduction: Hodgkin lymphoma (HL) is one of the best curable cancers. Many researches have validated the benefit of hematopoietic stem cell transplant (HSCT) for patients with relapsed or primary resistant HL. This analysis aimed to identify an effective change point in patients' age, the cure fraction before and after the change point, and significant prognostic factors on the cure fraction before and after the change point for these patients after HSCT in Iran. Materials and Methods: In this retrospective cohort study, there were 156 patients with HL who underwent HSCT from 2007 to 2014 with 18 months of follow up in Tehran, Iran. The survival time was set as the time interval between transplantation and the recurrence of HL. Also, the change point and the cure fraction before and after the change point were estimated using the Bayesian estimation method and log-normal distribution. Results: The estimated cure fraction was 79.2% for all patients. In susceptible cases, the mean survival time was 999 days (2.7 years). Also, the three and five-year survival rates were 82.1% and 80.0%, respectively. The effective change point in the age at transplantation of patients was 35 years, and the cure fraction before the change point was 84.5 % and after the change point was 60.6%. Conclusion: The study concluded that the age of 35 years is a significant change point in the age at transplantation. If individuals underwent HSCT with HL before the age of 35, they have a higher survival rate (recurrent of HL) than those underwent HSCT after 35. Keywords: Hodgkin Lymphoma, Mixture Cure Model, Change Point, Interval Censorship,Bayesian Metho

Expansion of CD133 +umbilical Cord Blood Derived Hematopoietic Stem Cells on Biocompatible Microwells

Umbilical cord blood (UCB) as a source of hematopoetic Stem / Progenitor cells (HSPCs) used for umbilical cord blood transplantation (UCBT). The main obstacle in application of this source as an appropriate source of HSPCs is low volume of this product. So ex vivo expansion of these cells in a microenvironment which mimic body condition is important .In current study, we designed biocompatible microwells in which collagene type I is coated by softlitography method. Our findings designated that in 3-Dimensional (3D) microenvironment CD133+ UCB derived HSC expanded significantly compared to 2-Dimensional (2D) microenvironment