Investigating the effect of pre-transplant thrombocytopenia and anemia on the engraftment and long-term survival in multiple myeloma patients.

BACKGROUND: Autologous stem cell transplantation (ASCT) following high-dose melphalan is the standard treatment for Multiple Myeloma (MM). Despite new treatments, further investigation is needed to identify prognostic factors of ASCT. This study evaluated the impact of thrombocytopenia and anemia on the engraftment of MM patients after ASCT. MATERIALS AND METHODS: This retrospective study involved 123 MM patients who underwent ASCT with high-dose Melphalan. Successful engraftment is achieved when both platelets (Plt) and white blood cells (WBC) engraft successfully. We examined the statistically significant cut-offs for the prognostic factors on the admission day. Ultimately, the association of risk factors with the Plt and WBC engraftment and long-term survival were analyzed as the outcomes of interest. RESULTS: Spearman's correlation coefficient between Plt and WBC engraftment was 0.396 (p < 0.001). The engraftment in the patients with Plt < 140,000/µL was 17.4% slower (p = 0.036) and the odds of long-term survival was 72% lower (p = 0.016) than in patients with higher Plt. Patients with Hb < 11 g/dL were 12.7% slower in engraftment. Age over 47 was a significant factor in slower engraftment (p = 0.036) which decelerated the engraftment by 15.2%. CONCLUSION: Thrombocytopenia and anemia before transplantation are related to slower Plt/WBC engraftment and as prognostic factors might predict the long-term survival of MM patients following ASCT.

Novelty in improvement of CAR T cell-based immunotherapy with the aid of CRISPR system.

INTRODUCTION: Chimeric Antigen Receptor (CAR) T cells have tremendous potentials for cancer treatment; however, various challenges impede their universal use. These restrictions include the poor function of T cells in tumor microenvironments, the shortage of tumor-specific antigens and, finally, the high cost and time-consuming process, as well as the poor scalability of the method. Creative gene-editing tools have addressed each of these limitations and introduced next generation products for cell therapy. The clustered regularly interspaced short palindromic repeats-associated endonuclease 9 (CRISPR/Cas9) system has triggered a revolution in biology fields, as it has a great capacity for genetic manipulation. METHOD: In this review, we considered the latest development of CRISPR/Cas9 methods for the chimeric antigen receptor T cell (CAR T)-based immunotherapy. RESULTS: The ability of the CRISPR/Cas9 system to generate the universal CAR T cells and also potent T cells that are persistent against exhaustion and inhibition was explored. CONCLUSION: We explained CRISPR delivery methods, as well as addressing safety concerns related to the use of the CRISPR/Cas9 system and their potential solutions.

Maintenance therapy with Everolimus in patients with refractory or relapsing Hodgkin lymphoma after autologous stem cell transplantation.

Introduction: Patients with relapsing or primary refractory Hodgkin lymphoma, still have unsatisfactory outcomes after high dose chemotherapy followed by autologous stem cell transplantation (ASCT). Brentuximab Vedotin (BV) is the only approved agent for maintenance therapy for up to one year in these patients, however, this agent is often not available or affordable for many patients, especially in the developing countries. In this study, we used Everolimus as maintenance therapy after ASCT among patients with relapsing/refractory Hodgkin lymphoma. Materials and Methods: We collected the data of 20 patients with primary refractory or relapsing Hodgkin lymphoma who had undergone ASCT between June 2016 and June 2021. Everolimus was started at 10 mg daily on day +90 after ASCT for at least two years in patients with stable disease status, confirmed by imaging modalities. Patients were followed for disease status and drug side effects every 3 months. Results: In our single-arm case-series study, the median duration of treatment was 22.95 months. Except for three patients, who had progression, others had no progression and are still receiving Everolimus (85%). No serious side effect was seen. We had no mortality due to disease recurrence. Conclusion: Until now, results showed promising effects of Everolimus in patients with relapsing or primary refractory Hodgkin lymphoma as maintenance therapy after ASCT.

Association between nutritional status and biochemical markers among hematopoietic stem cell transplant candidates: a cross-sectional study.

AIM: Candidates of Hematopoietic Stem Cell Transplantation (HSCT) may be at nutritional risk due to decreased oral intake, high nutritional requirements and nutrient malabsorption. The aim of this study was to evaluate the association between nutritional status and blood biomarkers in candidates of HSCT. METHODS: A total of 278 patients aged 18-65 years old were recruited and their baseline demographic and clinical characteristics were recorded. All subjects underwent nutritional status analysis using Nutritional Risk Screening (NRS-2002). Blood biomarkers including C-reactive protein (CRP), Erythrocyte Sedimentation Rate (ESR), hemoglobin, albumin and total protein as well as CRP-albumin ratio (CAR) and Body Mass Index (BMI) were measured and compared between two groups based on Nutritional Risk Screening (NRS-2002) within 24 h of admission in Bone Marrow Transplant ward. RESULTS: The results showed that undernourished patients (NRS ≥ 3) had significantly higher inflammatory markers including ESR, CRP and CAR as well as lower BMI and serum albumin and hemoglobin concentrations (P < 0.05); however, no significant association was observed in terms of total protein even after adjusting for confounders (P > 0.05). CONCLUSIONS: This study revealed that BMI combined with biochemical markers are the appropriate parameters for assessment of nutritional status in HSCT candidates. Furthermore, the nutritional status was verified to be significantly associated with systematic inflammation.

Cytokine-Induced Memory-Like NK Cells: Emerging strategy for AML immunotherapy.

Acute myeloid leukemia (AML) is a heterogeneous disease developed from the malignant expansion of myeloid precursor cells in the bone marrow and peripheral blood. The implementation of intensive chemotherapy and hematopoietic stem cell transplantation (HSCT) has improved outcomes associated with AML, but relapse, along with suboptimal outcomes, is still a common scenario. In the past few years, exploring new therapeutic strategies to optimize treatment outcomes has occurred rapidly. In this regard, natural killer (NK) cell-based immunotherapy has attracted clinical interest due to its critical role in immunosurveillance and their capabilities to target AML blasts. NK cells are cytotoxic innate lymphoid cells that mediate anti-viral and anti-tumor responses by producing pro-inflammatory cytokines and directly inducing cytotoxicity. Although NK cells are well known as short-lived innate immune cells with non-specific responses that have limited their clinical applications, the discovery of cytokine-induced memory-like (CIML) NK cells could overcome these challenges. NK cells pre-activated with the cytokine combination IL-12/15/18 achieved a long-term life span with adaptive immunity characteristics, termed CIML-NK cells. Previous studies documented that using CIML-NK cells in cancer treatment is safe and results in promising outcomes. This review highlights the current application, challenges, and opportunities of CIML-NK cell-based therapy in AML.

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.

Survival protection of patients undergoing hematopoietic stem cell transplantation: grounded theory.

PURPOSE: For patients with blood malignancies, hematopoietic stem cell transplantation (HSCT) is a significant challenge. These patients have hope to be completely cured after the transplantation, but deal with the dread of dying at the same time. This study presents a deep understanding of the psychological process of the treatment including perception, emotion, interactions, and its consequences in patients undergoing HSCT. METHODS: This study utilized a qualitative method based on the Strauss and Corbin Approach toward the grounded theory. The research population comprised all patients undergoing HSTC in Taleghani Hospital (Tehran, Iran) who were able to communicate effectively. The data were collected through deep and unstructured interviews with consenting patients. The sampling started with a purposive method and continued until the theoretical saturation was met. The 17 participants were interviewed individually and the data were analyzed via Strauss and Corbin Approach (2015). RESULTS: According to the findings of the present study, the threat to survival was the main concern of patients during the transplant process. The patients tried to cope with the threat to survival through strategies that were conceptualized as survival protection. These strategies led to the consequences such as debris removal and fondness for life, through which the patients rebuilt themselves, while on the alert for transplant rejection. CONCLUSION: The results suggested that dealing with HSCT affects personal and social aspects of a patient's life. This means, taking measures to facilitate psychological affairs and financial expenses, increasing the nursing manpower, and helping patients to reduce tension play a vital role to improve their fighting spirit.

Gut microbiota intervention by pre and probiotics can induce regulatory T cells and reduce the risk of severe acute GVHD following allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Acute graft-versus-host disease (aGVHD) is one of the leading causes of limitation and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Numerous studies have shown that changes in the gut microbiome diversity increased post-transplant problems, including the occurrence of aGVHD. Probiotics and prebiotics can reconstitute the gut microbiota and thus increase bacterial metabolites such as short-chain fatty acids (SCFAs) that have immunomodulatory effects preventing aGVHD in recipients of allo-HSCTs. METHODS/STUDY DESIGN: We conducted a pilot randomized clinical trial to investigate whether oral synbiotics are associated with the prevention or reduction in occurrence/severity and mitigate complications of aGVHD following allo-HSCT. A commercially available synbiotic mixture containing high levels of 7 safe bacterial strains plus fructo-oligosaccharides as a prebiotic was administered to allo-HSCT recipients. Out of 40 allo-HSCT patients, 20 received daily a synbiotic 21 days prior to transplantation (days -21 to day 0). In contrast, in the control group 20 recipients of allo-HSCT did not receive a symbiotic therapy. RESULTS: Within first 100 days of observation, the incidence of severe (grade III/IV) aGVHD in the a synbiotic-therapy group was 0% (0 out of 20 patients), whereas it was 25% (5 out of 20 patients) in the control group (P = 0.047). The median percentage of CD4 + CD25 + Foxp3+ regulatory T cells (Tregs) among CD4+ lymphocytes on day 28 after HSCT in the synbiotic group was higher (2.54%) than in control group (1.73%; P = 0.01). There was no difference in Treg cells on day 7 after HSCT between two groups. However, the median percentage and the absolute count of Tregs in patients who experience aGVHD was significantly lower on days 7 and 28 after HSCT (both P < 0.05). The overall 12-month survival (OS) rate was higher (90%) in the symbiotic-treated patients than in the control group (75%), but the difference was not statistically significant (P = 0.234). CONCLUSION: Our preliminary findings suggest that synbiotic intake before and during the conditioning regimen of allo-HSCT patients may lead to a reduction in the incidence and severity of aGVHD through the induction of CD4 + CD25 + Foxp3+ regulatory T cells, thus contributing to the improvement of transplant outcomes. Much larger studies are needed to confirm our observations.

MicroRNA-125b as a valuable predictive marker for outcome after autologous hematopoietic stem cell transplantation.

BACKGROUND: Relapse is a frequent occurrence in autologous hematopoietic stem cell transplantation (AHSCT), and early relapse after AHSCT results in poor survival and low quality of life. Predictive marker determination for AHSCT outcomes could be helpful in the prevention of relapse through personalized medicine. Here the predictive value of circulatory microRNAs (miRs) expression for AHSCT outcomes was studied. METHODS: 50 MM and lymphoma candidates for AHSCT participated in this study. Two plasma samples were obtained before AHSCT from each candidate; one before mobilization and the other after conditioning. Extracellular vesicles (EVs) were isolated by ultracentrifugation. miR-125b, miR-126, miR-150, and miR-155 expression were analyzed in both plasma and EVs using real time polymerase chain reaction analysis. Other data related to AHSCT and its outcomes were also collected. The predictive value of miRs and other factors for outcomes was assessed by multi-variant analysis. RESULTS: By 90 weeks follow up after AHSCT, multi-variant and ROC analysis showed miR-125b as a predictive marker for relapse, high lactate dehydrogenase (LDH), and high erythrocyte sedimentation rate (ESR). The cumulative incidence of relapse, high LDH, and high ESR increased with an increase in circulatory miR-125b expression. CONCLUSION: miR-125b could be applicable in prognosis evaluation and also create a possible new targeted therapy opportunity for enhanced outcomes and survival after AHSCT. TRIAL REGISTRATION: The study was retrospectively registered. Ethic code No: IR.UMSHA.REC.1400.541.

Hsp70, in Combination with IL-15 and PD-1 Blocker, Interferes with The Induction of Cytotoxic NK Cells in Relapsed Acute Myeloid Leukemia Patients.

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 cell activators to control AML. Therefore, the study aims to find the best formulation of Hsp70, human PD-1 (Programmed cell 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) by using magnetic activation cell sorting (MACS) and were activated using the different combinations of Hsp70, PD-1 blocker, and IL-15 and then followed by immunophenotyping, functional assays to estimate their killing potential, and evaluation 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<0.05) reduced after NK cell activation by the different formulas of IL-15, Hsp70, and PD-1 blocker. The expression of NKG2A in the treated NK cells was reduced particularly in the IL-15 (P<0.01) and IL-15+PD-1 blocker (P<0.05) groups. The addition of Hsp70 increased its expression. The cytotoxic effect of NK cells increased in all groups, especially in IL-15+PD-1 blocker besides increasing interferon-gamma (IFN-γ), Granzymes, and perforin expression (P<0.05). All IL-15+PD-1 blocker group changes were associated with the upregulation of PIK3CB and AKT-1 as key factors of NK cell activation. The presence of Hsp70 reduced IFN-γ releasing, and down-regulation of PIK3CB, AKT-1, Granzymes, and Perforin (P<0.05). CONCLUSION: We suggested the combination of IL-15 and PD-1 blocker could enhance the killing potential of AMLNK cells. Moreover, Hsp70 in combination with IL-15 and PD-1 blocker interferes activation of AML-NK cells through unknown mechanisms.

Patient and Physician Perspectives in the Management of Immune Thrombocytopenia in Iran: Responses from the ITP World Impact Survey (I-WISh).

Data describing physicians' and patients' perspectives towards immune thrombocytopenia (ITP) management and impact of disease in Iran are limited. This ITP World Impact Survey was conducted between October 2019 and October 2020. Of the 114 patients included in the survey, 17 were aged ≤18 years. Forty-seven physicians, including 22 pediatric hematologists, participated in the survey. Fatigue and anxiety around stable platelet counts were frequent patient-reported symptoms at diagnosis and at survey completion. According to physicians, "watch-and-wait" was the preferred treatment option for mean (standard deviation) proportion of 50.1 (24.1) and 48.6 (21.8) of their adult and pediatric patients, respectively, following first diagnosis. Per adult and pediatric hematologists, the most prescribed treatments for newly diagnosed patients based on available answers were steroids (100%, n = 20/20; 89%, n = 16/18), respectively. Forty percent of adult (n = 10/25) and 38% of pediatric hematologists (n = 8/21) reported that ITP reduced patients' quality of life. Energy levels (46%, n = 52/112) and ability to concentrate on everyday activities (42%, n = 47/113) were the most affected aspects of patients' lives. This I-WISh study in Iran underlined the negative impact of ITP on patients.

NK cell therapy in relapsed refractory multiple myeloma.

Recent advances in adoptive cell therapy have considerably changed the paradigm of cancer immunotherapy. Although current immunotherapies could cure many patients with multiple myeloma (MM), relapsed/refractory MM (RR/MM) is still challenging in some cases. Natural killer (NK) cells are innate immune cells that exert effective cytotoxic activity against malignant cells like myeloma cells. In addition to their antitumor properties, NK cells do not induce graft versus host disease following transplantation. Therefore, they provide a promising approach to treating RR/MM patients. Currently, attempts have been made to produce large-scale and good manufacturing practices (GMP) of NK cells. Ex vivo expanded/activated NK cells derived from the own patient or allogenic donors are potential options for NK cell therapy in MM. Besides, novel cell-based products such as NK cell lines and chimeric antigen receptor (CAR)-NK cells may provide an off-the-shelf source for NK cell therapy. Here, we summarized NK cell activity in the MM microenvironment and focused on different NK cell therapy methods for MM patients.

Expansion of cord blood stem cells in fibronectin-coated microfluidic bioreactor

ABSTRACT Background: Hematopoietic stem/progenitor cell transplantation is the main treatment option for hematological malignancies and disorders. One strategy to solve the problem of low stem cell doses used in transplantation is pre-transplant expansion. We hypothesized that using fibronectin-coated microfluidic channels would expand HSPCs and keep self-renewal potential in a three-dimensional environment, compared to the conventional method. We also compared stem cell homing factors expression in microfluidic to conventional cultures. Materials and methods: A microfluidic device was created and characterized by scanning electron microscopy. The CD133+ cells were collected from cord blood and purified. They were subsequently cultured in 24-well plates and microfluidic bioreactor systems using the StemSpan serum-free medium. Eventually, we analyzed cell surface expression levels of the CXCR4 molecule and CXCR4 mRNA expression in CD133+ cells cultured in different systems. Results: The expansion results showed significant improvement in CD133+ cell expansion in the microfluidic system than the conventional method. The median expression of the CXCR4 in the expanded cell was lower in the conventional system than in the microfluidic system. The CXCR4 gene expression up-regulated in the microfluidic system. Conclusion: Utilizing microfluidic systems to expand desired cells effectively is the next step in cell culture. Comparative gene expression profiling provides a glimpse of the effects of culture microenvironments on the genetic program of HSCs grown in different systems.

Survival of Patients with Acute Myeloid Leukemia after Allogeneic Stem Cell Transplantation: An Experience in Developing Country.

Background: Allogeneic stem cell transplantation (allo-SCT) is the highest potential treatment for long-term survival as post-remission therapy for acute myeloid leukemia (AML). The aim of this study was to estimate the overall survival (OS) of patients with AML after allo-SCT and to identify the factors affecting them as a prognostic factor for the survival of patients. Material and Methods: In this retrospective cohort study, data of patients with AML who underwent allo-SCT at Taleghani bone marrow transplantation and cell therapy center in Tehran, Iran, from May 2009 to September 2016 were used. A total of 101 patients were enrolled and death time was considered as a failure event for them. Kaplan-Meier method, log-Rank tests, and Cox proportional hazard model were used to evaluate OS and to identify the risk factors of patient's survival. The SPSS software version 21 was used for the analysis of data and P<0.05 was considered as a significant level. Results: Of 101 patients with AML, 49 (48.5%) were males. The median age at allo-SCT was 32.76 years and 42 patients (41.6%) died. The 5-year OS and disease-free survival (DFS) was 56% (95%CI: 51-61%) and 52% (95%CI: 57-47%), respectively. Multivariate analysis by Cox regression indicated that OS has a significant relationship with primary WBC count and relapse (P=0.001). Conclusion: Our results showed that allo-SCT has nearly the same outcome in developing countries and the WBC count and relapse are effective factors on the chance of survival in AML patients after allo-SCT.

Potential and challenges of placenta-derived decidua stromal cell therapy in inflammation-associated disorders.

Decidual stromal cells (DSCs) isolated from maternal part of placenta, like mesenchymal stromal cells (MSCs), are able to inhibit alloreactivity in-vitro but in a superior way which makes them an attractive alternative for anti-inflammatory therapies. In alloreactivity, when a strong immune response is developed against alloantigens, DSCs develop an anti-inflammatory environment, both through cell-to-cell contact and soluble factors, to prevent the adverse effects of alloantigens. In alloreactivity-associated inflammation, proinflammatory cytokines can be released and then involved in the up-regulation of inflammatory reactions which is one of the main causes of inflammatory related disorders. According to the preclinical and clinical studies, DSCs could be promising alternatives for the treatment of inflammatory-related diseases for which no definitive and successful treatment has been found yet. Here we first present the DSCs functions in creating the anti-inflammatory environment, their immunomodulatory effects, and their advantages over MSCs. Then, preclinical and clinical studies using DSCs for treatment of inflammatory disease including: graft-versus-host-disease (GVHD) after allogeneic hematopoi-etic stem cell transplantation (Allo-HSCT), COVID-19-associated Acute Respiratory Distress Syndrome (ARDS) and in particular, Infertility-related disorders, are presented. Finally, the challenges of using DSCs in clinical settings will be described.

Association of Interleukin 10 (IL-10) Gene Polymorphism (819T > C) with Susceptibility to Acute Myeloid Leukemia: A Meta-Analysis.

BACKGROUND: Studies reported an association between interleukin (IL)-10 -819T>C polymorphism and the risk of developing Acute myeloid leukemia (AML), however due to inconsistency among these results, relationship between IL-10 -819T>C polymorphism and AML remained unclear. We herein performed this meta-analysis to investigate the association of IL-10 -819T >C polymorphism with the risk of AML. METHODS: A systematic search through PubMed, Embase, Scopus, Cochrane Library and OpenGrey was performed from inception to Jan 2021. Odds ratios (OR) with their corresponding 95% confidence intervals (CI) for five possible genetic models were calculated. Heterogeneity was assessed using the Cochran Q test and the I2 statistic. A total of 404 AML cases and 635 healthy controls were included in our meta-analysis. RESULTS: Our results indicated no statically significant association between IL-10 -819T>C polymorphism and the risk of developing AML; dominant model (OR=0.87, 95% CI=0.42-1.81); recessive model (OR=1.17, 95% CI = 0.43-3.16); allelic model (OR=1.00, 95% CI=0.54-1.88); CC vs. TT (OR=1.00,95% CI=0.30-3.36); and TC vs. TT (OR=0.80, 95%CI =0.46-1.37). CONCLUSION: IL-10 -819T > C polymorphism is not associated with the risk of AML. However further studies focusing on other parameters such as sex, gene-gene interactions and environmental factors are required to reveal the true association of IL-10 -819T > C polymorphism with AML.

The effects of Sorafenib and Natural killer cell co-injection in combinational treatment of hepatocellular carcinoma; an in vivo approach.

BACKGROUND: Natural killer cells (NKC) and Sorafenib (Sor) are two important agents for the treatment of hepatocellular carcinoma (HCC). Over the past decade, the interaction of Sor and NKC against HCC has been widely challenging. This study aimed to assess the efficacy of NKC & Sor for the treatment of HCC in vivo. METHODS: Subcutaneous xenograft models of HCC were established in nude mice. For safety assessment of treatment, the kidney and liver functions were analyzed. Paraffin embedded tumor sections were histopathologically studied and immunohistochemistry (IHC) tests were done to evaluate the angiogenesis (CD34) and proliferation (Ki67) indexes. The terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay was performed to identify the tumor cells undergoing apoptosis. The serum levels of tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) were measured by enzyme-linked immunosorbent assay (ELISA) and expression levels of major inflammatory cytokines and cytoplasmic granules in xenograft HCC were quantified using real-time PCR. RESULTS: NKC & Sor significantly inhibited necrosis and apoptosis in tumor cells and increased angiogenesis and proliferation of HCC compared to the monotherapy of NKC or Sor alone. The serum levels of TNF-α, IFN-γ as well as the expression levels of TNF-α, IFN-γ, interleukins (ILs)-1, 6, 10, granzyme-B and perforin in the xenograft HCC tissues of the treated mice with NKC & Sor were significantly lower than those of treated with NKC or Sor alone. CONCLUSION: Therapy with the specific dosage of NKC & Sor could not inhibit the HCC xenograft growth rate through a synergistic effect in a mouse model of HCC.

Highlighting the interaction between immunomodulatory properties of mesenchymal stem cells and signaling pathways contribute to Graft Versus Host Disease management.

Background Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) has been increasingly used as a therapeutic approach for hematological malignancies. Several potential strategies have been developed for treating or preventing allo-HSCT complications, specifically graft-versus-host disease (GVHD). GVHD could significantly affect the morbidity and mortality of patients after allo-HSCT. Curative treatment and prophylaxis regimens for GVHD could reduce GVHD incidence and improve survival rate. Among these therapeutic strategies, mesenchymal stem cell (MSCs) mediated immunomodulation has been explored widely in clinical trials. MSCs immunomodulation ability in GVHD correlates with the interactions of MSCs with innate and adaptive immune cells. However, signaling pathways responsible for MSCs' impact on GVHD regulation, like JAK/STAT, NOTCH, MAPK/ERK, and NFκß signaling pathways, have not been clearly described yet. This review aims to illuminate the effect of MSCs-mediated immunomodulation in GVHD management after allo-HSCT representing the role of MSCs therapy on signaling pathways in GVHD. Conclusion MSCs could potentially modulate immune responses, prevent GVHD, and improve survival after allo-HSCT. Previous studies have investigated different signaling pathways' contributions to MSCs immunoregulatory ability. Accordingly, targeting signaling pathways components involved in MSCs related GVHD regulation is proven to be beneficial.

Expansion of cord blood stem cells in fibronectin-coated microfluidic bioreactor.

BACKGROUND: Hematopoietic stem/progenitor cell transplantation is the main treatment option for hematological malignancies and disorders. One strategy to solve the problem of low stem cell doses used in transplantation is pre-transplant expansion. We hypothesized that using fibronectin-coated microfluidic channels would expand HSPCs and keep self-renewal potential in a three-dimensional environment, compared to the conventional method. We also compared stem cell homing factors expression in microfluidic to conventional cultures. MATERIALS AND METHODS: A microfluidic device was created and characterized by scanning electron microscopy. The CD133+ cells were collected from cord blood and purified. They were subsequently cultured in 24-well plates and microfluidic bioreactor systems using the StemSpan serum-free medium. Eventually, we analyzed cell surface expression levels of the CXCR4 molecule and CXCR4 mRNA expression in CD133+ cells cultured in different systems. RESULTS: The expansion results showed significant improvement in CD133+ cell expansion in the microfluidic system than the conventional method. The median expression of the CXCR4 in the expanded cell was lower in the conventional system than in the microfluidic system. The CXCR4 gene expression up-regulated in the microfluidic system. CONCLUSION: Utilizing microfluidic systems to expand desired cells effectively is the next step in cell culture. Comparative gene expression profiling provides a glimpse of the effects of culture microenvironments on the genetic program of HSCs grown in different systems.

Azithromycin oral suspension in prevention and management of oral mucositis in patients undergoing hematopoietic stem cell transplantation: a randomized controlled trial.

OBJECTIVES: This study aimed to investigate the effects of azithromycin suspension on oral mucositis in patients undergoing hematopoietic stem cell transplantation (HSCT). METHODS AND MATERIAL: The study was designed as a single-blind randomized controlled trial in Taleghani medical center affiliated to Shahid Beheshti University of Medical Sciences Tehran Iran. Patients undergoing HSCT were randomly assigned to intervention or control groups. Azithromycin suspension was administered twice daily by gargling for 30 s and swallowing, on the first day of chemotherapy for patients in the intervention group. Graded oral mucositis (OM) occurrence based on National Cancer Institute Common Toxicity Criteria (NCI-CTC) scale (grade 0 to 5) was considered the main outcome, and the Numerical Rating Scale (NRS:0-10) measured the severity of OM symptoms. RESULTS: In a duration of 15 months, 88 patients were randomly assigned and finally 70 patients were evaluable for study outcomes (randomized 1:1 to azithromycin versus no-azithromycin). The incidence and duration of the mucositis significantly improved in the intervention group compared to the control. Azithromycin use was consistent with a lower rate of dryness (P < 0.001), dysphagia (P < 0.001), and loss of sense of taste (P < 0.001). Also, in the intervention group, lower intensity of pain due to mucositis (P = 0.01) and lower duration of mucositis were observed (p = 0.045). No significant adverse drug reaction was observed in patients receiving azithromycin. CONCLUSION: Based on the result from this study, azithromycin suspension is an effective option in the prevention and treatment of chemotherapy-induced OM. Further study is needed to assess the effect of azithromycin and comparison with other therapeutic options. TRIAL REGISTRATION: Iranian Registry of Clinical Trials: IRCT201603093210N13.