COVID-19 in patients with anemia and haematological malignancies: risk factors, clinical guidelines, and emerging therapeutic approaches.

Extensive research in countries with high sociodemographic indices (SDIs) to date has shown that coronavirus disease 2019 (COVID-19) may be directly associated with more severe outcomes among patients living with haematological disorders and malignancies (HDMs). Because individuals with moderate to severe immunodeficiency are likely to undergo persistent infections, shed virus particles for prolonged periods, and lack an inflammatory or abortive phase, this represents an overall risk of morbidity and mortality from COVID-19. In cases suffering from HDMs, further investigation is needed to achieve a better understanding of triviruses and a group of related variants in patients with anemia and HDMs, as well as their treatment through vaccines, drugs, and other methods. Against this background, the present study aimed to delineate the relationship between HDMs and the novel COVID-19, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Besides, effective treatment options for HDM cases were further explored to address this epidemic and its variants. Therefore, learning about how COVID-19 manifests in these patients, along with exploiting the most appropriate treatments, may lead to the development of treatment and care strategies by clinicians and researchers to help patients recover faster. Video Abstract.

Mechanism of action and therapeutic potential of dimethyl fumarate in ischemic stroke.

Dimethyl fumarate (DMF) is an immunomodulatory drug currently approved for the treatment of multiple sclerosis and psoriasis. Its benefits on ischemic stroke outcomes have recently come to attention. To date, only tissue plasminogen activators (tPAs) and clot retrieval methods have been approved by the FDA for the treatment of ischemic stroke. Ischemic conditions lead to inflammation through diverse mechanisms, and recanalization can worsen the state. DMF and the nuclear factor erythroid-derived 2-related factor 2 (Nrf2) pathway it regulates seem to be important in postischemic inflammation, and animal studies have demonstrated that the drug improves overall stroke outcomes. Although the exact mechanism is still unknown, studies indicate that these beneficial impacts are due to the modulation of immune responses, blood-brain barrier permeability, and hemodynamic adjustments. One major component evaluated before, during, and after tPA therapy in stroke patients is blood pressure (BP). Recent studies have found that DMF may impact BP. Both hypotension and hypertension need correction before treatment, which may delay the appropriate intervention. Since BP management is crucial in managing stroke patients, it is important to consider DMF's role in this matter. That being said, it seems further investigations on DMF may lead to an alternative approach for stroke patients. In this article, we discuss the mechanistic roles of DMF and its potential role in stroke based on previously published literature and laboratory findings.

The Immune Response and Effectiveness of COVID-19 Therapies.

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is highly pathogenic with relatively high mortality and morbidity. In addition to pneumonia, acute respiratory distress syndrome, and microembolic disorder, a high proportion of patients with SARS-CoV-2 develop lymphopenia and cytokine storm disorder. This review explores the underlying mechanisms behind the pathogenesis of SARS-CoV-2, especially the immune mechanisms, which could be potentially used as therapeutic targets for the management of COVID-19.

Association of the costimulatory molecule gene polymorphisms and active cytomegalovirus infection in hematopoietic stem cell transplant patients.

Determinative associations may exist between costimulatory molecule gene polymorphisms with a variety of post hematopoietic stem cell transplantation (HSCT) viral related clinical outcomes especially acute graft versus host disease (aGVHD). Therefore in this study the associations between costimulatory molecule gene polymorphisms including: cytotoxic T-lymphocyte antigen-4 (CTLA4), programmed cell death-1 (PD-1), inducible T cell costimulator (ICOS), and cluster differentiation 28 (CD28) with active cytomegalovirus (CMV) infection were evaluated in HSCT patients. The 72 allogeneic HSCT patients with and without aGVHD were enrolled in this cross sectional study between years: 2004-2011. The single nucleotide polymorphisms in loci of the costimulatory molecules including: CTLA4 gene (-318 C/T, 1722 T/C, 1661 A/G, +49 A/G), PD-1 gene (PD-1.3 A/G, PD-1.9 C/T), ICOS gene (1720 C/T), and CD28 gene (+17 C/T) were analyzed in studied HSCT patients by PCR-RFLP methods. The active CMV infection was evaluated in fresh EDTA-treated blood samples of each allogeneic HSCT patients by CMV antigenemia kit according to manufacturer's instruction. Active CMV infection was found in 11 of 72 (15.27 %) of allogeneic HSCT patients. The T allele and TT genotype of the CD28 +17 C/T were significantly higher frequency in active CMV infected allogeneic HSCT patients experienced aGVHD. The G allele and GG genotype of the CTLA4 -1661 A/G were significantly higher frequent in active CMV infected allogeneic HSCT patients experienced low grade of aGVHD. Finally, finding of significant associations between CD28 +17 C/T and CTLA4 -1661 A/G genotypes with CMV active infection in allogeneic HSCT patients experienced aGVHD emphasize on the importance of the genetic pattern of costimulatory genes in outcomes of active CMV infection in HSCT patients needs completed studies.

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.

Dysregulated Expression of MiR-19b, MiR-25, MiR-17, WT1, and CEBPA in Patients with Acute Myeloid Leukemia and Association with Graft versus Host Disease after Hematopoietic Stem Cell Transplantation.

Elham JamaliObjectives Acute myeloid leukemia (AML) is a blood malignancy characterized by the proliferation of aberrant cells in the bone marrow and blood that interfere with normal blood cells. We have investigated whether changes in the level of micro-ribonucleic acid (miR)-19b, miR-17, and miR-25, Wilms' tumor (WT1), and CCAAT enhancer-binding protein α (CEBPA) genes expression affect disease prognosis and clinical outcome in AML patients. Materials and Methods The expression level of miR-19-b, miR-17, and miR-25, as well as WT1 and CEBPA genes in a group of patients and controls as well as different risk groups (high, intermediate, and favorite risk), M3 versus non-M3, and graft-versus-host disease (GvHD) versus non-GvHD patients were assessed using a quantitative SYBR Green real-time polymerase chain reaction method. Results When compared with the baseline level at the period of diagnosis before chemotherapy, the expression of miR-19b and miR-17 in AML patients increased significantly after chemotherapy. The level of miR-19b and miR-25 expression in AML patients with M3 and non-M3 French-American-British subgroups differ significantly. MiR-19b and miR-25 expression was elevated in GvHD patients, while miR-19b and miR-25 expression was somewhat decreased in GvHD patients compared with non-GvHD patients, albeit the difference was not statistically significant. Also, patients with different cytogenetic aberrations had similar levels of miR-19-b and miR-25 expression. Conclusion MiR-19b, miR-17, and miR-25 are aberrantly expressed in AML patients' peripheral blood leukocytes, which may play a role in the development of acute GvHD following hematopoietic stem cell transplantation.

Cloning of Bacillus subtilis phytase gene construct in Escherichia coli.

BACKGROUND AND OBJECTIVES: Phytase has a hydrolysis function of phytic acid, which yields inorganic phosphate. Bacillus species can produce thermostable alkaline phytase. The aim of this study was to isolate and clone a Phytase gene (Phy) from Bacillus subtilis in Escherichia coli. MATERIALS AND METHODS: In this study, the extracellular PhyC gene was isolated from Bacillus subtilis Phytase C. After purification of the bands, DNA fragment of Phy gene was cloned by T/A cloning technique, and the clone was transformed into Escherichia coli. Afterward, the pGEM-Phy was transferred into E. coli Top-10 strain and the recombinants were plated on LB agar containing 100 µg/ml ampicillin. The colonization of 1171 bp of gene Phytase C was confirmed by PCR. The presence of gene-targeting in vector was confirmed with enzymatic digestion by XhoI and XbaI restriction enzymes. RESULTS: The Phytase gene was successfully cloned in E. coli. The result of cloning of 1171 bp Phytase gene was confirmed by PCR assay. CONCLUSION: Our impression of this article is that several methods, such as using along with microbial, plant phytase reproduction, or low-phytic acid corn may be the better way from a single phytase.

Expression Levels of Il-6 and Il-18 in Acute Myeloid Leukemia and Its Relation with Response to Therapy and Acute GvHD After Bone Marrow Transplantation.

Cytokines seem to play a crucial role in physiological and pathological conditions of acute myeloid leukemia (AML). The aim of this study was to evaluate the expression levels of interleukins-6 (IL-6) and IL-18 in patients with AML and its correlation with response to therapy and graft versus host disease (GvHD) after bone marrow transplantation. The expression levels of IL-6 and IL-18 genes were done in all patients and compared with matched control. Complete remission (CR) was used for evaluation of the effects of these cytokines on response to treatment in patients group. The expression level of these cytokines was also evaluated in patients who underwent bone marrow transplantation and experienced acute GvHD in compare with patients without aGvHD. Il-6 gene expression level was significantly higher in these patients in comparison with control but Il-18 gene expression level was not statistically significant compared to control group. Il-6 and also Il-18 expression levels were significantly higher in patients without a response to treatment according to CR compared to patient's whit response to treatment as well as patients experienced aGvHD after bone marrow transplantation. IL-6 and Il-18 are important markers in the progression of the disease and could be considered as a prognostic marker in acute leukemia. It is recommended that more studies with larger study groups and more involved cytokines are needed for more evaluation of the cytokine roles in pathophysiology and progression of acute leukemia.

Genetic Variation of Costimulatory Molecules, Including Cytotoxic T-Lymphocyte Antigen 4, Inducible T-Cell Costimulator, Cluster Differentiation 28, and Programmed Cell Death 1 Genes, in Iranian Patients With Leukemia.

OBJECTIVES: There are limited studies about the possible relationship between genetic variations of costimulatory genes and susceptibility to hematologic malignancies like leukemia and lymphoma. MATERIALS AND METHODS: This cross-sectional study included 59 leukemia patients. The polymorphisms of costimulatory molecules, including the CTLA-4 gene (-318 C/T, -1722 T/C, -1661 A/G, +49 A/G), PD-1 gene (1.3 A/G, 1.9 C/T), ICOS gene (1720 C/T), and CD28 gene (17 C/T), were analyzed by polymerase chain reaction-restriction fragment length polymorphism methods. RESULTS: Our results showed that the TT genotype and T allele of the CTLA-4 -318 T/C polymorphism, the AA genotype of CTLA-4 +49 A/G polymorphism, and the CT genotype of PD-1 1.9 C/T polymorphism were significantly higher in healthy controls (P < .05). However, the AG genotype of the CTLA-4 +49 A/G, the CC genotype of the PD-1 1.9 C/T, and the CT genotype of the CD28 +17C/T polymorphism were significantly increased in patients with leukemia (P < .05). When the genotype frequency of costimulatory genes was compared between different leukemia groups, we observed that the A allele of the CTLA-4 +49 A/G and the CC genotype and C allele of the CD28 +17 C/T polymorphism were significantly higher in patients with acute leukemia than in those with chronic leukemia (P < .05). Among leukemia patients, the AA genotype of CTLA-4 +49A/G polymorphism was significantly increased in patients with acute myeloid leukemia, whereas the AG genotype was more prevalent in patients with acute lymphoblastic leukemia (P < .05). CONCLUSIONS: We show for the first time that genetic variations of costimulatory molecules CTLA-4, CD28, and PD-1 may be associated with susceptibility of Iranian patients to leukemia.

Relation between costimulatory molecule polymorphism and hepatitis B infections in hematopoietic stem cell transplant recipients.

OBJECTIVES: Costimulatory gene polymorphisms have been proposed to affect the hepatitis B virus pathogenesis by affecting regulation of immune responses. The association between costimulatory molecule gene polymorphisms including CTLA4, PD.1, ICOS, and CD28 with hepatitis B virus infection has been evaluated in hematopoietic stem cell transplant patients. MATERIALS AND METHODS: In a cross-sectional study, single-nucleotide polymorphisms in the loci of the costimulatory molecules were analyzed in 3 study groups. Hepatitis B virus infection was evaluated in plasma samples of each allogeneic and autologous hematopoietic stem cell transplant patients by a third generation HBsAg enzyme-linked immunosorbent assay kit according to the manufacturer 's instructions. RESULTS: Hepatitis B virus infection was found in 19 of 72 allogeneic (26.3%) and 26 of 59 autologous patients (44.1%). The T allele of CTLA4-318 and CC genotype of CD28+17 polymorphisms are significantly more frequent in hepatitis B virus-infected allogeneic hematopoietic stem cell transplant patients. The CC genotype of CD28 +17 was seen more frequently in hepatitis B virus-infected allogeneic hematopoietic transplant patients. The C allele of the PD.1.9 was seen more frequently in hepatitis B virus-infected allogeneic hematopoietic patients experiencing graft-versus-host disease. Also, the frequency of CT genotype and T allele of the PD.1.9 was significantly increased in hepatitis B virus-infected allogeneic hematopoietic stem cell transplant patients experiencing low-grade graft-versus-host disease. CONCLUSIONS: Associations of CTLA4 -318 and CD28 +17 with hepatitis B virus infection in allogeneic hematopoietic stem cell transplant patients was reported, also it was determined that PD.1.9 genotypes and hepatitis B virus infection in allogeneic hematopoietic stem cell transplant patients experiencing low-grade graft-versus-host disease was associated. However, better evaluations of the relations between costimulatory gene polymorphisms with hepatitis B virus infection in hematopoietic stem cell transplant patients requires further investigations.