Efficacy and safety of adoptive T-cell therapy in treating cytomegalovirus infections post-haematopoietic stem cell transplantation: A systematic review and meta-analysis.

Cytomegalovirus (CMV) infection poses significant risks in allogeneic haematopoietic stem cell transplant (allo-HSCT) recipients. Despite advances in antiviral therapies, issues such as drug resistance, side effects, and inadequate immune reconstitution remain. This systematic review and meta-analysis aim to evaluate the efficacy and safety of adoptive cell therapy (ATC) in managing CMV infections in allo-HSCT recipients. Adhering to preferred reporting items for systematic reviews and meta-analyses guidelines, we conducted a comprehensive database search through July 2023. A systematic review and meta-analysis were conducted on studies involving HSCT patients with CMV infections treated with ATC. The primary outcome was the response rate to ATC, and secondary outcomes included adverse events associated with ATC. The Freeman-Tukey transformation was applied for analysis. In the meta-analysis of 40 studies involving 953 participants, ATC achieved an overall integrated response rate of 90.16%, with a complete response of 82.59% and a partial response of 22.95%. ATC source, HLA matching, steroid intake, and age group markedly influenced response rates. Donor-derived T-cell treatments exhibited a higher response rate (93.66%) compared to third-party sources (88.94%). HLA-matched patients demonstrated a response rate of 92.90%, while mismatched patients had a lower rate. Children showed a response rate of 83.40%, while adults had a notably higher rate of 98.46%. Adverse events were minimal, with graft-versus-host disease occurring in 24.32% of patients. ATC shows promising response rates in treating CMV infections post-HSCT, with an acceptable safety profile. However, to establish its efficacy conclusively and compare it with other antiviral treatments, randomised controlled trials are essential. Further research should prioritise such trials over observational and one-arm studies to provide robust evidence for clinical decision-making.

Immunologic responses to the third and fourth doses of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines in cell therapy recipients: a systematic review and meta-analysis.

BACKGROUND: Multiple studies have provided evidence of suboptimal or poor immune responses to SARS-CoV-2 vaccines in recipients of hematopoietic stem cell transplantation (HSCT) and chimeric antigen receptor-T (CAR-T) cell therapy compared to healthy individuals. Given the dynamic nature of SARS-CoV2, characterized by the emergence of many viral variations throughout the general population, there is ongoing discussion regarding the optimal quantity and frequency of additional doses required to sustain protection against SARS-CoV2 especially in this susceptible population. This systematic review and meta-analysis investigated the immune responses of HSCT and CAR-T cell therapy recipients to additional doses of the SARS-CoV-2 vaccines. METHODS: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, the study involved a comprehensive search across PubMed, Scopus, Web of Science Core Collection, Embase, and Cochrane Biorxiv and medRxiv, focusing on the serological responses to the third and fourth vaccine doses in HSCT and CAR-T cell patients. RESULTS: This study included 32 papers, with 31 qualifying for the meta-analysis. Results showed that after the third dose, the seroconversion rate in HSCT and CAR-T cell therapy recipients who didn't respond to the second dose was 46.10 and 17.26%, respectively. Following the fourth dose, HSCT patients had a seroconversion rate of 27.23%. Moreover, post-third-dose seropositivity rates were 87.14% for HSCT and 32.96% for CAR-T cell therapy recipients. Additionally, the seropositive response to the fourth dose in the HSCT group was 90.04%. CONCLUSION: While a significant portion of HSCT recipients developed antibodies after additional vaccinations, only a minority of CAR-T cell therapy patients showed a similar response. This suggests that alternative vaccination strategies are needed to protect these vulnerable groups effectively. Moreover, few studies have reported cellular responses to additional SARS-CoV-2 vaccinations in these patients. Further studies evaluating cellular responses are required to determine a more precise assessment of immunogenicity strength against SARS-CoV-2 after additional doses.

Investigation of KIR/HLA relationship and other clinical variables after T-cell-replete haploidentical bone marrow transplantation in patients with acute myeloid leukemia (AML).

BACKGROUND: KIR/HLA mismatch in hematopoietic stem cell transplantation (HSCT), particularly in patients with acute myeloid leukemia (AML), was related to decreased recurrence rates, improved engraftment, and a reduction in graft-versus-host disease, according to recent research (GVHD). Uncertainty exists about the impact of KIR/HLA mismatch on haploidentical-HSCTs treated with post-transplant cyclophosphamide (PTCy). We attempted to analyze the effects of KIR/HLA mismatch on clinical outcomes on transplant outcomes using the cohort of 54 AML patients who received a haplo-HSCT with PTCy. RESULTS: In contrast to KIR/HLA match, our findings showed that donor KIR/HLA mismatch was substantially associated with superior OS (HR, 2.92; (P = 0.04)). Moreover, donor KIR/HLA mismatch (KIR2DS1D/C2+ R and KIR2DS2D/C1+ R mismatch versus KIR2DL1D/C2- R mm, KIR2DL2/3D/C1- R mm and KIR3DL1D/Bw4- mm) was correlated with the improvements in OS (HR, 0.74; P = 0.085) and activating. KIR/HLA mismatch versus KIR/HLA match was significantly correlated with improvements in OS (HR, .46; P = 0.03) and inhibitory. KIR/HLA mismatch versus KIR/HLA match was enhancement in the OS (HR, .93; P = 0.06). Despite a higher rate of aGvHD (grade I-IV) in the patients with KIR/HLA mismatch compared to KIR/HLA matched (57% vs. 33% (p = 0.04). However, the KIR/HLA mismatch group saw a decreased relapse rate (3.2% vs. 23%, p = 0.04). CONCLUSION: This analysis shows the significance of KIR/HLA Incompatibility, other clinical variables like CMV, the relationship between donor/recipient and donor age, and the relationship between donor/recipient and donor age in the haplo-donor selection process. It also suggests that KIR and HLA mismatching between donor and recipient could be routinely performed for haplo-donor selection and may improve clinical outcomes after haplo-HSCTs with PTCy.

Phase I non-randomized clinical trial of allogeneic natural killer cells infusion in acute myeloid leukemia patients.

INTRODUCTION: A new type of immune cell transplantation called allogeneic NK cell infusion is proposed as a potential universal off-the-shelf cell product for adoptive immune cell therapy in hematologic malignancies. DESIGN: A multicentral phase I non-randomized clinical trial was conducted to assess the safety, feasibility, and potential efficacy of adoptively infused NK cells in patients with refractory/relapsed AML. We evaluated the feasibility of the trial by considering cell production, patient selection, and treatment protocol. METHOD: Allogeneic NK cells were produced from random healthy unrelated donors; 10 patients were selected according to the inclusion criteria and were included in two groups in case of NK cell dose escalation. Two cell infusions were given, spaced 7 days apart, following a lymphodepletion conditioning regimen of fludarabin-endoxan administered 7 days before the first infusion. The intervention safety was scored using Common Terminology Criteria for Adverse Events (CTCAE) based on variations in vital signs due to cell infusion. NK cell chimerism, tumor burden, and duration of relapse were considered to be components of efficacy. The pilot feasibility evaluation was checked using the CONSORT platform. RESULTS: The NK cell infusion procedure was well tolerated, and no grade 2-5 toxicities related (possible or probable) to PB-NK cell infusion were observed. Four patients developed grade 1 transient chills, headaches, vomiting, and bone pain following each PB-NK cell infusion that were not required hospitalization. One of these patients (p01) died because of severe acute respiratory syndrome. Of 9 evaluable patients, 6 (66.6%) showed stable disease (SD) and 3 (33.3%) presented progressive disease (PD). Of 6 SD patients, 2 (p08 and p09) remained alive in SD and 3 patients (p04, p05 and p07) converted to PD at 9 months after infusion of NK cells, and 1 (p03) was not evaluable due to follow-up loss. No patient achieved complete remission. CONCLUSION: The study demonstrated the feasibility and safety of adoptive transfer of random healthy unrelated donor PB-NK cells in refractory/relapsed AML patients and supports continued study in phase II clinical trials in relapsed/refractory AML patients.

In Vitro Generation of BK polyomavirus-specific T cells for adoptive cell therapy in refractory cystitis hemorrhagic patients after hematopoietic stem cell transplantation.

INTRODUCTION: BKPyV associated hemorrhagic cystitis (BKPyV-HC) is a major and prevalent outcome of hematopoietic stem cell transplantation (HSCT) with no standard treatment option. Adoptive T cell therapy (ACT) against transplant-associated viruses has shown promising potential. We sought to produce virus-specific T cells (VSTs) against BKPyV with the aim of treating refractory HSCT-associated HC. METHODS: Peripheral blood mononuclear cells (PBMC) from healthy donors were isolated by Ficoll-Hypaque density gradient centrifugation. BKPyV-pulsed, monocyte-derived dendritic cells (mo-DCs) and T cells were co-cultured and expanded over 2-3 weeks with the addition of IL-2. The T cells were examined for various functional assays. RESULTS: Comparison analysis of Carboxyfluorescein diacetate succinimidyl ester (CFSE) indicated that the percentage of proliferated cells were significantly higher in donors (49.62 ± 7.09%) than controls (7.96 ± 4.55%). Furthermore, expanded T cells exhibited specificity to BKPyV antigens by IFN-γ ELISPOT assay. The expanded cells showed cytotoxic function versus human lymphoblastoid cell line (LCL). Final VST products mainly comprised of CD8/CD69 double-positive T cells, which were significantly higher in donors (46.8 ± 7.1%) than controls (16.91 ± 3.40%). CONCLUSION: In this study we demonstrated the feasibility of producing functional BKPyV-specific T cells in healthy donors using BKPyV PepMixes. These functional cells were able to proliferate and produce IFN-γ cytokine in response to BKPyV PepMixes. In addition, these T cells had cytotoxic ability against BKPyV antigen-expressing target cells.

Identification of miR-195-5p as a novel prognostic biomarker for colorectal cancer.

BACKGROUND: Recent evidence indicated that transcription patterns of microRNAs could be used as promising biomarkers for numerous cancers. It is stated that miR-195-5p could be used as a tumor suppressor in colorectal cancer (CRC). The purpose of the current work was to explore the transcription level of miR-195-5p and its clinical relevance in CRC patients. METHODS AND RESULTS: We used quantitative real-time polymerase chain reaction (qRT-PCR) to assess the tumor tissue sample of 140 CRC cases compared with normal adjacent tissue for the transcription of miR-195-5p and the clinicopathological relevance was statistically evaluated. We showed that tumor tissue miR-195-5p transcription was statistically downregulated in patients with CRC (median expression value 0.23, range 0.03-6.62) compared to normal adjacent tissue (median expression value 0.98, range 0.092-29.6, p < 0.001). The median transcription of miR-195-5p divided the CRC patients into miR-195-5p low-transcription (miR-195-5plow) and miR-195-5p high-transcription (miR-195-5phigh) groups. Furthermore, low miR-195-5p transcription level was statistically related with TNM stage, lymph node metastasis and tumor differentiation in CRC patients (all p-value < 0.05). Moreover, our results indicated that CRC cases with a decreased transcription level of miR-195-5p displayed a statistically shorter overall survival (OS) (p = 0.001) compared to higher miR-195-5p transcription. CONCLUSION: In conclusion, the finding proposes that miR-195-5p might be a valuable biomarker and a prognostic factor for CRC in the future.

Circulating miR-455-3p, miR-5787, and miR-548a-3p as potential noninvasive biomarkers in the diagnosis of acute graft-versus-host disease: a validation study.

Currently, acute graft-versus-host disease (aGVHD) diagnosis is based on clinical features and pathological findings. Until now, there is no non-invasive diagnostic test for aGVHD. MicroRNAs may act as promising predictive, diagnostic, or prognostic biomarkers for aGVHD. The purpose of the current study was to validate circulating microRNAs as diagnostic biomarkers to assist clinicians in promptly diagnosing aGVHD, so that treatment can be initiated earlier. In the present study, we evaluated six microRNAs (miR-455-3p, miR-5787, miR-6729-5p, miR-6776-5p, miR-548a-3p, and miR-6732-5p) selected from miRNA array data in 40 aGVHD patients compared to 40 non-GVHD patients with RT-qPCR. Target genes of differentially expressed microRNAs (DEMs) were predicted using Targetscan, miRanda, miRDB, miRWalk, PICTAR5, miRmap, DIANA, and miRTarBase algorithms, and their functions were analyzed using EnrichNet, Metascape, and DIANA-miRPath databases. The expressions of plasma miR-455-3p and miR-5787 were significantly downregulated, whereas miR-548a-3p was significantly upregulated in aGVHD patients compared to non-GVHD patients. Moreover, DEMs showed potentially high diagnostic accuracy for aGVHD. In silico analysis of DEMs provided valuable information on the role of DEMs in GVHD, immune regulation, and inflammatory response. Our study suggested that miR-455-3p, miR-5787, and miR-548a-3p could be used as potential noninvasive biomarkers in the diagnosis of aGVHD in addition to possible therapeutic targets in aGVHD.

Molecular Genetics of Cleidocranial Dysplasia.

BACKGROUND: Cleidocranial dysplasia (CCD) is a genetic disorder with an autosomal dominant inheritance pattern. CCD characterized by abnormal clavicles, patent sutures and fontenelles, supernumerary teeth and short stature. Approximately 60-70% of CCD patients have mutations in the RUNX2 gene. The RUNX2 gene is an essential transcription factor for chondrocyte maturation, osteoblast differentiation and bone formation. Runx2 regulates mesenchymal cell proliferation in sutures and suture closure by inducing the signaling pathways of the genes of Fgf, Pthlh, hedgehog and Wnt. Material and Methods: We summarized molecular genetics aspects of CCD. Result: Approximately 94% of CCD patients have dental anomalies, the most common of which are supernumerary tooth. Dental anomalies are not determined solely by gene mutations of RUNX2, but are also affected by modifier genes, environmental factors, epigenetic factors and copy number variations. Conclusion: a definite diagnosis of CCD should include the patient's clinical history, symptoms and signs, as well as genetic analyses.

Association and in silico investigations of miR-302c insertion/deletion variant as a novel biomarker with susceptibility to gastric cancer.

Gastric cancer (GC) is the fifth most prevalent malignant tumor and the third most frequent cause of cancer mortality worldwide. rs199971565 is an insertion/deletion (INDEL) located in microRNA-302c (miR-302c) seed site, which may affect its function and biogenesis. There is no genetic association study investigating this INDEL with any disease till now. Thus, the current study was conducted to investigate the association of rs199971565 with susceptibility to GC in an Iranian population. In addition, in silico studies were performed to reveal the possible functional significance of this INDEL. A total of 378 subjects were genotyped through amplification refractory mutation system PCR (ARMS-PCR) after DNA extraction from peripheral blood by the salting out procedure. Also, in silico analyses were performed through databases and web tools including MiRNASNP V2.0, miRWalk V2.0, miRTarBase, DAVID V6.8, RNAfold, PHDcleave, miRmap, and STarMir. Results revealed that there was an association between rs199971565 and the incidence risk of GC under a recessive (P = .04, odds ratio [OR] = 18.73; 95% confidence interval [CI] = 1.07-326.95) model of inheritance. Also, compared to the Ins allele, the Del allele significantly increased the risk of GC (P = .01, OR = 2.02; 95% CI = 1.11-3.66). Further analyses showed no significant association in age and sex between two study groups (P = .216 and P = .798, respectively). In conclusion, for the first time, this study indicated the association and in silico investigations of rs199971565 and suggested it as a novel INDEL biomarker located in the seed site of miR-302c, which may have crucial roles in the susceptibility to GC and its incidence risk.

MicroRNAs as Potential Diagnostic, Prognostic, and Predictive Biomarkers for Acute Graft-versus-Host Disease.

Successful treatment of various hematologic diseases with allogeneic hematopoietic stem cell transplantation is often limited due to the occurrence of acute graft-versus-host disease (aGVHD). So far, there are no approved molecular biomarkers for the diagnosis and prediction of aGVHD at the clinical level due to our incomplete understanding of the molecular biology of the disease. Various studies have been conducted on animal models and humans to investigate the role of microRNAs in aGVHD pathogenesis to implicate them as biomarkers and therapeutic targets. Because of their high stability, tissue specificity, ease of measurement, low cost, and simplicity, they are excellent targets for biomarkers. In this review, we focused on microRNA expression profiling studies that were performed recently in both animal models and human cases of aGVHD to identify diagnostic and predictive biomarkers for this disease. The expression pattern of microRNAs can be specific to cells and tissues. Because aGVHD affects several organs, microRNA signatures in target tissues may help to understand the molecular pathology of the disease. Identification of organ-specific microRNAs in aGVHD can be promising to categorize patients for organ-specific therapies. Thus, microRNAs can be used as noninvasive diagnostic tests in clinic to improve prophylaxis, predict incidence and severity, and reduce morbidity.

Identification of MiR-125a as a Novel Plasma Diagnostic Biomarker for Chronic Lymphoblastic Leukemia.

Background: Chronic lymphocytic leukemia (CLL) is a type of malignancy in which the bone marrow makes too many lymphocytes. MicroRNAs (miRNAs) are endogenous short (~22-nucleotides) non-protein-coding regulatory RNA molecules with key roles in cellular and molecular processes linked to different cancers including CLL. Re-cently, some investigations have demonstrated that miR-125a downregulation is correlated with the expression of P53, NRG1 and ERBB2. Methods: In this study, samples including 38 patients with CLL and 25 healthy individuals were collected. We used quantitative real-time PCR (qRT-PCR) to assess the expression of miR-125a in plasma of the CLL patients in comparison with healthy controls. Moreover, we used the Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway analysis on miR-125a targets in the DAVID database in order to investigate the potential role of miR-125a in cancer pathways. MiR-125a exerted a variety of roles in the cancer pathway via downregulating target genes including ERBB2. Results: The expression of miR-125a dramatically decreased (~2-fold) in the patients with CLL compared with the healthy controls (p = 0.03). Furthermore, overexpression of miR-125a was associated with different CLL staging and B symptoms (all at p < 0.05). The KEGG pathway enrichment analysis demonstrated the eight statistically related KEGG signaling pathways with miR-125a targetome. Conclusions: The results suggested that the miR-125a expression level could be a novel potential biomarker for CLL prognosis.

Methylomics of breast cancer: Seeking epimarkers in peripheral blood of young subjects.

Critical roles of epigenomic alterations in the pathogenesis of breast cancer have recently seized great attentions toward finding epimarkers in either non-invasive or semi-non-invasive samples as well as peripheral blood. In this way, methylated DNA immunoprecipitation microarray (MeDIP-chip) was performed on DNA samples isolated from white blood cells of 30 breast cancer patients compared to 30 healthy controls. A total of 1799 differentially methylated regions were identified including SLC6A3, Rab40C, ZNF584, and FOXD3 whose significant methylation differences were confirmed in breast cancer patients through quantitative real-time polymerase chain reaction. Hypermethylation of APC, HDAC1, and GSK1 genes has been previously reported in more than one study on tissue samples of breast cancer. Methylation of those aforementioned genes in white blood cells of our young patients not only relies on their importance in breast cancer pathogenesis but also may highlight their potential as early epimarkers that makes further assessments necessary in large cohort studies.

A nanocomposite consisting of silica-coated magnetite and phenyl-functionalized graphene oxide for extraction of polycyclic aromatic hydrocarbon from aqueous matrices.

In this study, graphene oxide was covalently immobilized on silica-coated magnetite and then modified with 2-phenylethylamine to give a nanocomposite of type Fe3O4@SiO2@GO-PEA that can be applied to the magnetic solid-phase extraction of polycyclic aromatic hydrocarbons (PAHs) from water samples. The resulting microspheres (Fe3O4@SiO2@GO-PEA) were characterized by Fourier transform-infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), CHNS elemental analysis, and vibrating sample magnetometry (VSM) techniques. The adsorbent possesses the magnetic properties of Fe3O4 nanoparticles that allow them easily to be separated by an external magnetic field. They also have the high specific surface area of graphene oxide which improves adsorption capacity. Desorption conditions, extraction time, amount of adsorbent, salt concentration, and pH were investigated and optimized. Following desorption, the PAHs were quantified by gas chromatography with flame ionization detection (GC-FID). The limits of detection (at an S/N ratio of 3) were achieved from 0.005 to 0.1µg/L with regression coefficients (R2) higher than 0.9954. The relative standard deviations (RSDs) were below 5.8% (intraday) and 6.2% (inter-day), respectively. The method was successfully applied to the analysis of PAHs in environmental water samples where it showed recoveries in the range between 71.7% and 106.7% (with RSDs of 1.6% to 8.4%, for n=3). The results indicated that the Fe3O4@SiO2@GO-PEA microspheres had a great promise to extraction of PAHs from different water samples.

Upregulation of lnc-FOXD2-AS1, CDC45, and CDK1 in patients with primary non-M3 AML is associated with a worse prognosis.

Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy with an unfavorable outcome. The present research aimed to identify novel biological targets for AML diagnosis and treatment. In this study, we performed an in-silico method to identify antisense RNAs (AS-RNAs) and their related co-expression genes. GSE68172 was selected from the AML database of the Gene Expression Omnibus and compared using the GEO2R tool to find DEGs. Antisense RNAs were selected from all the genes that had significant expression and a survival plot was drawn for them in the GEPIA database, FOXD2-AS1 was chosen for further investigation based on predetermined criteria (logFC ≥|1| and P < 0.05) and its noteworthy association between elevated expression level and a marked reduction in the overall survival (OS) in patients diagnosed with AML. The GEPIA database was utilized to investigate FOXD2-AS1-related co-expression and similar genes. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and gene ontology (GO) function analysis of the mentioned gene lists were performed using the DAVID database. The protein-protein interaction (PPI) network was then constructed using the STRING database. Hub genes were screened using Cytoscape software. Pearson correlation analysis was conducted using the GEPIA database to explore the relationship between FOXD2-AS1 and the hub genes. The transcription of the selected coding and non-coding genes, including FOXD2-AS1, CDC45, CDC20, CDK1, and CCNB1, was validated in 150 samples, including 100 primary AML non-M3 blood samples and 50 granulocyte colony stimulating factor (G-CSF)-mobilized healthy donors, using quantitative Real-Time PCR (qRT-PCR). qRT-PCR results displayed significant upregulation of lnc-FOXD2-AS1, CDC45, and CDK1 in primary AML non-M3 blood samples compared to healthy blood samples (P = 0.0032, P = 0.0078, and P = 0.0117, respectively). The expression levels of CDC20 and CCNB1 were not statistically different between the two sets of samples (P = 0.8315 and P = 0.2788, respectively). We identified that AML patients with upregulation of FOXD2-AS1, CDK1, and CDC45 had shorter overall survival (OS) and Relapse-free survival (RFS) compared those with low expression of FOXD2-AS1, CDK1, and CDC45. Furthermore, the receiver operating characteristic (ROC) curve showed the potential biomarkers of lnc -FOXD2-AS1, CDC45, and CDK1 in primary AML non-M3 blood samples. This research proposed that the dysregulation of lnc-FOXD2-AS1, CDC45, and CDK1 can contribute to both disease state and diagnosis as well as treatment. The present study proposes the future evolution of the functional role of lnc-FOXD2-AS1, CDC45, and CDK1 in AML development.

Comprehensive analysis of the role of ubiquitin-specific peptidases in colorectal cancer: A systematic review.

BACKGROUND: Colorectal cancer (CRC) is the third most frequent and the second most fatal cancer. The search for more effective drugs to treat this disease is ongoing. A better understanding of the mechanisms of CRC development and progression may reveal new therapeutic strategies. Ubiquitin-specific peptidases (USPs), the largest group of the deubiquitinase protein family, have long been implicated in various cancers. There have been numerous studies on the role of USPs in CRC; however, a comprehensive view of this role is lacking. AIM: To provide a systematic review of the studies investigating the roles and functions of USPs in CRC. METHODS: We systematically queried the MEDLINE (via PubMed), Scopus, and Web of Science databases. RESULTS: Our study highlights the pivotal role of various USPs in several processes implicated in CRC: Regulation of the cell cycle, apoptosis, cancer stemness, epithelial-mesenchymal transition, metastasis, DNA repair, and drug resistance. The findings of this study suggest that USPs have great potential as drug targets and noninvasive biomarkers in CRC. The dysregulation of USPs in CRC contributes to drug resistance through multiple mechanisms. CONCLUSION: Targeting specific USPs involved in drug resistance pathways could provide a novel therapeutic strategy for overcoming resistance to current treatment regimens in CRC.

Evaluation of H3 histone methylation and colony formation in erythroid progenitors treated with thalidomide and sodium butyrate.

OBJECTIVES: ß-thalassemia and sickle cell disease are hemoglobinopathies with reduced/absent ß chains in the former and dysfunctional ß chains in the latter. In both conditions, up-regulation of hemoglobin F through demethylation can alleviate the symptoms. This can be attained with drugs such as thalidomide and sodium butyrate. MATERIALS AND METHODS: This study was performed on erythroid progenitors derived from CD133+ cord blood stem cells. Erythroid progenitors were treated with thalidomide and sodium butyrate in single and combined groups. Colony-formation potential in each group was evaluated by the colony assay. Real-time polymerase chain reaction (RT-PCR) was used to evaluate the effect of these drugs on histone H3 lysine 27 (H3K27) methylation patterns. FINDINGS: Compared to other treatment groups, CD133+ cells treated with thalidomide alone produced more hematopoietic colonies. Thalidomide alone was also more effective in decreasing H3K27 methylation. CONCLUSIONS: Thalidomide shows superiority to sodium butyrate as a hypomethylating agent in this cell culture study, and it has the potential to become conventional treatment for sickle cell disease and ß-thalassemia.

Evaluation of the Mitigation Effect of Spirulina Against Lung Injury Induced by Radiation in Rats.

BACKGROUND: Some compounds have been investigated to mitigate the effect of radiation on the lung, such as pneumonitis and fibrosis. OBJECTIVE: This study aimed to examine the mitigation efficiency of Spirulina compared to the effect of Metformin. METHODS: 25 male Wistar rats were allotted in five groups: control, Spirulina, Radiation, Radiation plus Spirulina, and Radiation plus Metformin. Rat chest regions were irradiated by 15 Gray (Gy) xradiation using aLINAC. Forty-eight hours after irradiation, treatment with Spirulina and Metformin began. Eighty days after irradiation, all rats were sacrificed, and their lung tissues were removed for histopathological, and biochemical assays. RESULTS: The results demonstrated that irradiation increased MDA (Malondialdehyde) levels while suppressing the SOD (superoxide dismutase) and GPx(glutathione peroxidase) activity in the irradiated group. MDA levels in lung tissues were reduced with Metformin but not with Spirulina. Both Metformin and Spirulina increased the SOD and GPx activity in lung tissue. Moreover, histopathological evaluations showed extensive changes in the lung tissue including infiltration of lymph cells around the bronchioles and blood vessels, thickening of the alveolar wall, and the disruption of the alveolar structure, as well as accumulation of collagen fibers. Administration of Spirulina and Metformin significantly reduced pathological changes in lung tissue, although the effect of Metformin was greater than that of Spirulina. CONCLUSION: Spirulina could mitigate radiation-induced lung injury moderately, although Metformin is more effective than Spirulina as a mitigator agent.

Evaluating the Mitigation Effect of Spirulina Against Radiation-Induced Heart Injury.

BACKGROUND: During a radiological or nuclear disaster, exposure to a high dose of ionizing radiation usually results in cardiovascular diseases such as heart failure, attack, and ischemia. OBJECTIVE: The purpose of this study was to examine the mitigation effects of Spirulina in comparison to Metformin's. METHODS: 25 male Wistar rats were randomly assigned to five groups (5 rats in each): for the control group, rats did not receive any intervention. In group 2, spirulina was administered orally to rats. In group 3, rats were irradiated to the chest region with 15 Gray(Gy) x-radiation. In groups 4 and 5, rats were irradiated in the same way as group 3. Forty-eight hours after irradiation, treatment with Spirulina and Metformin began. All rats were sacrificed after ten weeks, and their heart tissues were removed for histopathological and biochemical assays. RESULTS: Results showed an elevation in Malondialdehyde (MDA) and decreasing superoxide dismutase (SOD) activity. Moreover, pathological changes of radiation were irregularities in the arrangement of myofibrils, proliferation, migration of mononuclear cells, vacuolation of the cytoplasm, and congestion. Administration of spirulina enhanced the SOD activity while did not affect MDA level and pathological change in heart tissue. Despite spirulina, metformin had a considerable effect on pathological lesions and decreased the level of MDA. CONCLUSION: Reactive oxygen species (ROS) may be involved in the late effects of radiationinduced heart injury, and scavenging these particles may contribute to reduced radiation side effects. Based on these results, Spirulina had no effect on radiation-induced cardiac damage, while metformin did. Higher Spirulina doses given over a longer period of time will likely have a greater heart-mitigate effect.

Cancer immunotherapy via stem cell-derived NK cells.

NK cells are the first sentinels of the immune system that can recognize and eradicate transformed cells. Their activation without a need for additional signaling have attracted great attention on the use of NK cells as a promising option in cancer immunotherapy. However, the large-scale production of NK cells for successful NK cells therapy is a challenge that needs to be tackled. Engineering NK cells to avoid tumor escape and improve their antitumor potency are the other matters of focus that have widely been studied in the recent years. This paper reviews the most recent advances in the stem cell-derived NK cell technology and discusses the potential of the engineered NK cells for clinical applications in cancer immunotherapy.

NK cells are important cells in our body's defense system that can find and destroy tumor cells. These cells are made in bone marrow (in adults) or umbilical cord (in the embryonic period) from a population of cells called stem cells, and then released into the blood and lymph. Stem cells are the early ancestral cells that can differentiate into multiple cell types. Because the number and function of NK cells in a tumor context are reduced, thus we can use these stem cells to make lots of NK cells for treatment purposes. Scientists can also make these cells even better at killing tumors by changing them to have special sensors. In the end, NK cells are like superheroes that fight and kill tumor cells, and using stem cells to make them is a really promising way to help treat malignant diseases.

Evaluation of Safety and Immunogenicity of a Recombinant Receptor-Binding Domain (RBD)-Tetanus Toxoid (TT) Conjugated SARS-CoV-2 Vaccine (PastoCovac) in Recipients of Autologous Hematopoietic Stem Cell Transplantation Compared to the Healthy Controls; A Prospective, Open-Label Clinical Trial.

Background: The urgent need for prompt SARS-CoV-2 immunization of hematopoietic stem cell transplant (HSCT) recipients in an endemic area raises many challenges regarding selecting a vaccine platform appropriate for HSCT recipients being economical for widespread use in developing countries. Methods: The trial is a prospective, single-group, open-label study to investigate the safety and serologic response of two doses of the recombinant receptor-binding domain (RBD)-Tetanus Toxoid (TT) conjugated SARS-CoV-2 vaccine (PastoCovac) early after autologous (auto) HSCT. For this reason, a total of 38 patients who completed the two-dose SARS-CoV-2 RBD-based vaccine between three to nine months after auto-HSCT and had an available anti-spike serologic test at three predefined time points of baseline and after the first and second doses and 50 healthy control individuals were included in the analysis. The primary outcome was defined as an increase in IgG Immune status ratio (ISR) to the cut-off value for the positive result (≥1.1) in the semiquantitative test. Findings: The median time between auto-HSCT and vaccination was 127 days. No participant reported any significant adverse effects (Grade 3). Pain at the injection site was the most common adverse event. The ISR increased significantly (p < 0.001) during the three-time point sampling for both patients and healthy control groups. In patients, the mean ISR increased from 1.39 (95% CI: 1.13−1.65) at baseline to 2.48 (1.93−3.03) and 3.73 (3.13−4.38) following the first and second dosages, respectively. In multivariate analysis, the higher count of lymphocytes [OR: 8.57 (95% CI: 1.51−48.75); p = 0.02] and history of obtaining COVID-19 infection before transplantation [OR: 6.24 (95% CI: 1.17−33.15); p = 0.03] remained the predictors of the stronger immune response following two doses of the RBD-TT conjugated vaccine. Moreover, we found that the immunogenicity of the COVID-19 vaccine shortly after transplantation could be influenced by pre-transplant COVID-19 vaccination. Interpretation: The RBD-TT conjugated SARS-CoV-2 vaccine was safe, highly immunogenic, and affordable early after autologous transplants. Funding: This work was mainly financed by the Hematology-Oncology-Stem Cell Transplantation Research Center (HORCSCT) of Tehran University and the Pasteur Institute of Iran.