Rate, Risk Factors, and Outcomes of Invasive Fungal Infections in Patients with Hematologic Malignancies.

Background: Invasive fungal infections (IFIs) are a significant cause of mortality and morbidity in patients with hematological malignancies. Given the considerable prevalence and consequences of IFIs, hence revealing the exact cause of fungal infections, their rate, associated risk factors, and complications could contribute to reducing both financial and life costs, choosing targeted antifungal treatment, and avoiding unnecessary toxic treatments in individuals who are not suffering from mycoses. Materials and Methods: This prospective cross-sectional study was conducted in the first semester of 2019. All patients with hematologic malignancies (HM) admitted to Dr. Shariati Hospital were studied. Only those with probable/proven IFIs defined according to the last update of EORTC/MSG criteria were included in the study. The demographic and clinical data were recorded from the hospital information registration system using a questionnaire. Statistical analysis was performed using SPSS software version 24. Results: Out of 1109 HM patients hospitalized during the study period, 67 (6.04%) IFIs were diagnosed. Of these, 57 (85.04%) were aspergillosis, 7 (10.4%) were mucormycosis, and 3 patients developed other fungal infections. Males constituted 67.2% of the entire IFI population. The mean±SD age of the samples was 43.16 ± 13.8 years. The most common type of malignancy was AML. Lung imaging showed lesions associated with fungal infections in 52 cases (77.6%), with multiple nodules as the most prevalent pattern being observed in 64.2% of cases. Sinus involvement was evidenced in the PNS CT scan of 46 (68.6%) patients. The attributable mortality rate for IFIs was 62.7%. Both the types of IFI and malignancies had no significant relationship with the outcome of patients. Central venous catheter, mucositis, and antibiotic use were the most frequent risk factors. Conclusion:  IFI represents a frequent complication for HM patients with high mortality. Aspergillus species are the predominant etiology in these settings. Considering our results, in high-risk patients, manifestations of warning signs in the sinus and lungs, which would not be cleared despite receiving antibiotics, should raise the possibility of IFIs.

Good manufacturing practices production of human placental derived mesenchymal stem cells for therapeutic applications: focus on multiple sclerosis.

BACKGROUND: Among neurological diseases, multiple sclerosis (MS) affects mostly young adults and can cause long-term disability. While most medications with approval from regulatory agencies are very effective in treating MS disease, they are unable to repair the tissue damage found in the central nervous system (CNS). Consequently, Cell-based therapy particularly using mesenchymal stem/stromal cells (MSCs), holds promise for neuroprotection and tissue repair in MS treatment. Furthermore, placenta-derived MSCs (PLMSCs) have shown the potential to treat MS due to their abundance, noninvasive isolation from discarded tissues, no ethical problems, anti-inflammatory, and reparative properties. Accordingly, good manufacturing practices (GMPs) plays a crucial part in clinical SCs manufacturing. The purpose of our article is to discuss GMP-grade PLMSC protocols for treating MS as well as other clinical applications. METHODS AND RESULTS: Placental tissue obtained of a healthy donor during the caesarean delivery and PLMSCs isolated by GMP standards. Flow cytometry was used to assess the expression of the CD markers CD34, CD105, CD90, and CD73 in the MSCs and the mesodermal differentiation ability was evaluated. Furthermore, Genetic evaluation of PLMSCs was done by G-banded karyotyping and revealed no chromosomal instability. In spite of the anatomical origin of the starting material, PLMSCs using this method of culture were maternal in origin. CONCLUSIONS: We hope that our protocol for clinical manufacturing of PLMSCs according to GMP standards will assist researchers in isolating MSCs from placental tissue for clinical and pre-clinical applications.

The impact of malnutrition on mortality and complications of hematopoietic stem cell transplantation in patients with acute leukemia.

BACKGROUND & AIMS: Malnutrition is common in hematopoietic stem cell transplantation (HSCT) patients. However, there are few studies on the association between malnutrition and post-transplant outcomes, with inconsistent results. No standard screening tool has been established for malnutrition in these patients. Previous research suggests the Global Leadership Initiative on Malnutrition (GLIM) criteria is effective in predicting outcomes in other cancers. This study investigates the link between malnutrition based on the GLIM criteria with mortality and complications following allogeneic HSCT. METHODS: This single-center, observational, longitudinal, and prospective study of 98 adult leukemia patients at the Hematology Center of Shariati Hospital in Tehran, Iran, monitored patients before transplantation until 100 days after the procedure, focusing on overall survival and mortality as a primary outcome, and secondary endpoints including oral mucositis, acute GVHD, infection during hospitalization, and readmission rates. RESULTS: This study involved 98 allogeneic HSCT patients with a median age of 38 years old, 64.3 % with acute myeloid leukemia (AML), and 35.7 % with acute lymphoblastic leukemia (ALL). Among them, 26.5 % were categorized as malnourished based on GLIM criteria. During 100 days of follow-up, 13 patients died, but there was no significant difference in overall survival and mortality between malnourished and well-nourished patients. Malnourished patients demonstrated a noticeable upward trend in the incidence of oral mucositis, hospital readmission, and infection during their hospitalization. It is important to highlight that although this observed trend is discernible, it did not attain statistical significance in statistical analyses (P > 0.05). CONCLUSION: The current study determined that, when assessed using the GLIM criteria, malnutrition did not exert a statistically significant influence on survival, mortality, or complications within the specified age range of 18-55 years, underscoring its limited impact on this cohort of younger patients.

Comparison of three malnutrition screening tools prior to allogeneic hematopoietic stem-cell transplantation.

Background: Previous studies have shown that malnutrition before hematopoietic stem cell transplantation (HSCT) is associated with poor patient prognoses. There is inconsistency among studies on which nutritional status screening tool is appropriate for malnutrition diagnosis before allo-HSCT. The present study aimed to compare nutritional screening tools in patients with leukemia before allo-HSCT. Methods: An observational, cross-sectional, and single-center study was conducted in Tehran, Iran. One hundred four adults allo-HSCT candidates aged 18-55 years with leukemia were selected sequentially. Malnutrition assessment was done using three tools, the Global Leadership Initiative on Malnutrition (GLIM), nutritional risk screening 2002 (NRS-2002) and European Society for Clinical Nutrition and Metabolism (ESPEN) criteria. The agreement between malnutrition assessment tools was evaluated with Cohen's kappa. Results: The agreement between GLIM and NRS-2002 was perfect (κ = 0.817, p < 0.001), while the agreement between GLIM and ESPEN was fair (κ = 0.362, p < 0.001). The agreement between NRS-2002 and ESPEN was fair (κ = 0.262, p < 0.001). We also found a moderate agreement for all tools (κ = 0.489, p < 0.001). Conclusion: NRS-2002 is an accepted tool for screening malnutrition in hospitalized patients. In the current study, the GLIM criterion perfectly agreed with the NRS-2002. Further studies in the HSCT setting are needed to introduce a valid tool.

Whole-body low-dose CT can be of value in prostate cancer decision-making: a retrospective study on 601 patients.

OBJECTIVES: To evaluate the diagnostic value of whole-body low-dose computed tomography (CT) to detect bone metastasis in prostate cancer (PCa) patients and its possible utility in therapeutic decision-making. Also, to determine the valuable CT features for lesion characterisation. METHODS: This IRB-approved retrospective study reviewed PCa patients who underwent 68Ga-PSMA PET/CT in our centre from March 2017 to August 2022. Two board-certified radiologists and one nuclear medicine specialist reported all whole-body low-dose CT scans separately, unaware of the 68Ga-PSMA-PET results. The per-lesion and per-patient diagnostic performances were calculated. Also, the significance of CT features was evaluated. Moreover, the inter-observer agreement was analysed. A two-tailed p value < 0.05 was considered significant. RESULTS: From 727 reviewed PCa patients, 601 (mean age = 68.7 ± 8.1) were found to be eligible, including 211 (35.1%) referrals for initial staging and 390 (64.9%) for evaluating the extent of the disease after biochemical recurrence. Per-patient diagnostic analysis for three reviewers showed 81.0-89.4% sensitivity and 96.6-98.5% specificity in detecting osteo-metastasis. It was able to correctly detect high-burden disease based on both CHAARTED and LATITUDE criteria. Regarding the value of underlying CT features, size > 1 cm, ill-defined borders, presence of soft-tissue component, and cortical destruction were statistically in favour of metastasis. Also, Hu > 900 was in favour of benign entities with 93% specificity. CONCLUSIONS: Although not as accurate as 68Ga-PSMA PET/CT, whole-body low-dose CT might precisely classify PCa patients considering therapeutic decision-making. Additionally, we proposed diagnostic CT features that could help radiologists with better characterisation of the detected lesions. CRITICAL RELEVANCE STATEMENT: The whole-body low-dose CT can be considered valuable in the clinical decision-making of prostate cancer patients. This modality may obviate performing multiple imaging sessions and high-cost scans in patients diagnosed with the high-burden disease.

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.

Minimal Residual Disease Detection Using Gene Scanning Analysis, Fluorescent Fragment Analysis, and Capillary Electrophoresis for IgH Rearrangement in Adult B-Lineage Acute Lymphoblastic Leukemia: A Cross-Sectional Study.

OBJECTIVE: Minimal residual disease (MRD) is considered the greatest prognostic factor in acute lymphoblastic leukemia (ALL). MRD is a valuable tool for anticipating impending relapse and treatment response assessment. The objective of the present study was to investigate whether the detection of IgH gene rearrangement using polymerase chain reaction (PCR)-based GeneScan analysis could be a complementary method to monitor MRD along with the quantitative realtime PCR (qPCR). MATERIALS AND METHODS: In this cross-sectional study, we valued the MRD levels, based on the GeneScanning analysis (GSA), and then compared the data with quantitative real-time polymerase chain reaction at different time points in peripheral blood (PB) samples of adult B-lineage ALL patients (n=35). The specific polymerase chain reaction (PCR) primers for IGH gene FR-1 and fluorescence-labeled J-primer were used and analyzed by capillary gel electrophoresis on a sequencer. The results of this study were compared with the previously reported MRD results obtained by the IGH rearrangements allele-specific oligonucleotide (ASO) -qPCR methods. RESULTS: The total concordance rate was 86.7%, with a P<0.001. MRD results obtained by GSA and ASO-qPCR methods were concordant in all diagnostic samples and samples on the 14th and 28th days of induction therapy. The results of these 2.5 years' follow-ups demonstrated a significant correlation between the two techniques (r=0.892, P<0.001). CONCLUSION: It seems that the PCR-based GeneScan analysis of IGH gene rearrangement detection may be a valuable molecular technique to distinguish monoclonality from polyclonality. And also, it may be a precise tool to detect the residual leukemic DNA in the PB follow-up samples of patients.

The Economic Burden of Acute Myeloid Leukemia in Iran.

Background: Cancer imposes a significant economic burden on the health system and society. Acute myeloid leukemia (AML) is the third deadliest leukemia and is one of the leading health problems worldwide. The present study aimed to estimate the economic burden of AML in Iran for 2020. Methods: In this study, we estimated a prevalence-based on the cost-of-illness of the AML in Iran. A societal perspective was considered, in which the direct costs and productivity losses with the adoption of the human capital approach in the AML cases were estimated for 2020. Moreover, in the present study, several resources including national cancer registry reports, hospital records, occupational data, and interviews with experts were cited. Results: Approximately 98% of patients with AML received induction therapy. The AML economic burden was $33,243,107.39. Indirect costs accounted for 60% (21,593,764.4$) of this amount, and direct medical costs and direct non-medical costs make up for 19% (6,359,380.88$) and 16% (5,289,962.11$) of this estimated economic burden, respectively. Conclusion: The economic burden of AML in Iran is very remarkable and due to the increasing prevalence of this disease, it is expected to increase gradually. Having insights into the costs associated with the disease provide an excellent opportunity for health policymakers and managers to effectively improve resource allocation.

A Panel of Circulating microRNAs as a Potential Biomarker for the Early Detection of Gastric Cancer.

Background: The high mortality rate of Gastric Cancer (GC) is a consequence of delayed diagnosis. The early diagnosis of GC could increase the five-year survival rate among patients. We aimed to find a panel of microRNAs (miRNA) for the detection of GC in the early stages. Methods: In this case-control study, we selected consistently upregulated miRNAs from the results of 12 high-throughput miRNA profiling studies in GC. In the profiling phase, the differential expressions of 13 candidate miRNAs were analyzed by quantitative reverse-transcription PCR (qRT-PCR) in two pooled RNA samples prepared from the plasma of eight GC patients and eight matched controls. In the validation phase, significantly upregulated miRNAs from the profiling phase were further evaluated in the plasma samples of 97 patients with stage I-IV gastric adenocarcinoma and 100 healthy controls. Results: In the profiling phase, six miRNAs (miR-18a, 21, 25, 92a, 125b and 221) were significantly upregulated in the GC patients compared to the controls (p<0.05). However, in the validation phase, only significant up-regulation of miR-18a, 21 and 125b was confirmed (p<0.05). A panel of miR-18a/21/125b was able to detect GC patients with stage I-IV from the controls (p<0.001; AUC=0.92, sensitivity=86%; specificity=85%). In addition, the panel could distinguish the early-stage GC (I+II) from the control group with an AUC of 0.83, a sensitivity of 83%, and a specificity of 75%. Conclusion: A panel of circulating miR18a/21/125b could be suggested as a potential biomarker for the early detection of GC.

Ocular Manifestations of Newly Diagnosed Acute Leukemia Patients.

Purpose: To present primary ocular manifestations in acute leukemia. Methods: This cross-sectional descriptive hospital-based study evaluated all newly diagnosed leukemia patients of three referral hospitals of Tehran University of Medical Sciences in 2015-2016 and Mahak Hospital in Tehran in 2017. Exclusion criteria included the patients with the previous history of chemotherapy, cases of relapsing disease, and the patients with a history of ocular disease or other systemic conditions with ophthalmic manifestations. Results: A total of 85 patients (170 eyes) were evaluated in our study, including 29 children (34.1%) and 43 females (50.6%). The mean patient age was 37.84 ± 11.91 years in the adult group and 6.28 ± 4.70 years in the pediatric category. Ophthalmic involvement was seen in 27 patients (31.8%), including 6 pediatric patients (20.7%) and 21 adult patients (37.5%). Two patients (2.3%) had direct infiltration by leukemic cells and 76 patients (89.41%) of patients were asymptomatic. There was a correlation between ophthalmic involvement and platelet count and hemoglobin level. In patients with ocular signs, higher mortality rates were observed. Conclusions: At the time of diagnosis in acute leukemia patients, complete ophthalmic evaluation including dilated fundus examination is suggested as ocular involvement in these patients is common and sometimes asymptomatic. Ophthalmic involvement in leukemic patients should be identified in a timely manner, particularly in individuals with low platelet counts and hemoglobin levels, due to the potential prognostic relevance.

Do high-mobility group box 1 gene polymorphisms affect the incidence of differentiation syndrome in acute promyelocytic leukemia?

BACKGROUND: Differentiation syndrome (DS) is an inflammatory complication seen in some patients with acute promyelocytic leukemia (APL) undergoing differentiation therapy with all-trans retinoic acid (ATRA) and/or arsenic trioxide (ATO). It is unknown how DS occurs, but it is believed that it is caused by inflammatory cytokines release from differentiating leukemic cells. High mobility group box-1 (HMGB1) is a DNA-binding protein that acts as a cytokine outside of cells and may play a role in inflammation. This study was conducted to determine whether HMGB1 polymorphisms (rs1360485, rs2249825 and rs1060348) are associated with the incidence of differentiation syndrome in acute promyelocytic leukemia patients treated with all-trans retinoic acid and arsenic trioxide. METHODS: One hundred and thirty APL patients and 100 healthy controls were included. Seventeen patients with differentiation syndrome were selected according to the PETHEMA criteria. Tetra-primer ARMS polymerase chain reaction (tetra-ARMS PCR) was used to determine the genotype distribution of polymorphisms. DNA sequencing was done to validate the results. RESULTS: In both healthy and APL patients, AA was the most frequent genotype in rs1360485 followed by AG and GG. CC, CG, and GG were the most frequent genotypes in rs2249825 polymorphism in the order mentioned. CC was more frequent than CT, and CT was more frequent than TT in rs1060348. There was no correlation between HMGB1 polymorphisms and the incidence of differentiation syndrome based on genetic models (p-value > 0.05). CONCLUSIONS: HMGB1 polymorphisms are not probably associated with DS development in APL patients treated with ATRA and ATO.

Blockade of Nuclear Factor-Κb (NF-Κb) Pathway Using Bay 11-7082 Enhances Arsenic Trioxide-Induced Antiproliferative Activity in U87 Glioblastoma Cells.

Background: Glioblastoma (GBM), the most aggressive and common form of glioma, accounts for over 13,000 death per year in the United States which indicates the importance of developing novel strategies for the treatment of this fatal malignancy. Although Arsenic trioxide (ATO) hinders the growth and survival of GBM cells, the requirement of concentrations higher than 4 µM for triggering apoptotic cell death has questioned its safety profile. Since the NF-κB signaling pathway plays a crucial role in tumorigenesis and chemo-resistance, targeting this oncogenic pathway may sensitize GBM cells to lower concentrations of ATO. Methods: Anti-tumor effects of ATO as monotherapy and in combination with Bay 11-7082 were determined using MTT, crystal violet staining, Annexin V/PI staining and scratch assays. Quantitative reverse transcription-PCR (qRT-PCR) analysis was applied to elucidate the molecular mechanisms underlying the anti-tumor activity of this combination therapy. Results: Our results revealed that ATO and Bay 11-7082 synergistically inhibited the proliferation and survival of GBM cells. Also, it was revealed that NF-κB inhibition using Bay 11-7082 enhanced the inhibitory effects of ATO on migration of GBM cells via suppressing the expression of NF-κB target genes such as TWIST, MMP2, ICAM-1, and cathepsin B. Furthermore, combination treatment of GBM cells with ATO and Bay 11-7082 significantly induce apoptotic cell death coupled with downregulation of NF-κB anti-apoptotic target genes including Bcl-2 and IAP family members. Conclusion: Altogether, these findings suggest that combination therapy with ATO and Bay 11-7082 may be a promising strategy for the treatment of GBM.

A Post-Marketing Surveillance Study to Evaluate the Safety Profile of AlvotereⓇ (Docetaxel) in Iranian Patients Diagnosed with Different Types of Cancers Receiving Chemotherapy.

BACKGROUND: Docetaxel is a clinically well established antimitotic chemotherapy medication. Labeled docetaxel indications are breast cancer, gastric cancer, head and neck cancer, non-small cell lung cancer, and prostate cancer. OBJECTIVE: This is a Phase IV study to evaluate the safety profile of docetaxel (Alvotere; NanoAlvand, Iran) in Iranian patients diagnosed with different types of cancers receiving chemotherapy regimens with docetaxel. METHODS: Patients who received Alvotere as a part of their chemotherapy regimen were enrolled in this Phase IV, observational, multicenter, open-label study. Alvotere was administrated as a single agent or in combination with other chemotherapy agents. Safety parameters in each cycle were assessed, and the related data were recorded in booklets. FINDINGS: A total of 411 patients with different types of cancers were enrolled from 25 centers in Iran. The most common malignancies among participants were breast cancer (49.88%), followed by gastric cancer (22.63%). Participants' mean age was 53.33 years, and the mean total dose used in each cycle was 132 mg. According to the results, 341 patients experienced at least 1 adverse event, that the most common was alopecia (41.12%). In total, 92 (22.38%) patients had at least 1 adverse event of grade 3 or 4, and 25 (6.08%) patients showed 54 serious adverse events, which the causality assessment for all was possibly related to Alvotere. There was a significant difference between men and women in the incidence of skin and subcutaneous tissue disorders (55.63% in women vs 41.73% in men; P = 0.009). Also, the incidence of gastrointestinal disorders, nervous system disorders, skin and subcutaneous tissue disorders, hepatic enzymes increase, and fluid retention was significantly higher (P < 0.05) in patients receiving anthracyclines in their chemotherapy regimens. CONCLUSIONS: The findings of this open-label, observational, multicenter, postmarketing surveillance showed that Alvotere appears to have an acceptable safety profile in Iranian cancer patients receiving chemotherapeutic regimens. (Curr Ther Res Clin Exp. 2022; 82:XXX-XXX) © 2022 Elsevier HS Journals, Inc.

A focus on allogeneic mesenchymal stromal cells as a versatile therapeutic tool for treating multiple sclerosis.

Multiple sclerosis (MS) is a central nervous system (CNS) chronic illness with autoimmune, inflammatory, and neurodegenerative effects characterized by neurological disorder and axonal loss signs due to myelin sheath autoimmune T cell attacks. Existing drugs, including disease-modifying drugs (DMD), help decrease the intensity and frequency of MS attacks, inflammatory conditions, and CNS protection from axonal damage. As they cannot improve axonal repair and show side effects, new therapeutic options are required. In this regard, due to their neuroprotection properties, immunomodulatory effects, and the ability to differentiate into neurons, the transplantation of mesenchymal stromal cells (MSCs) can be used for MS therapy. The use of adipose-derived MSCs (AdMSCs) or autologous bone marrow MSCs (BMSCs) has demonstrated unexpected effects including the invasive and painful isolation method, inadequate amounts of bone marrow (BM) stem cells, the anti-inflammatory impact reduction of AdMSCs that are isolated from fat patients, and the cell number and differentiation potential decrease with an increase in the age of BMSCs donor. Researchers have been trying to search for alternate tissue sources for MSCs, especially fetal annexes, which could offer a novel therapeutic choice for MS therapy due to the limitation of low cell yield and invasive collection methods of autologous MSCs. The transplantation of MSCs for MS treatment is discussed in this review. Finally, it is suggested that allogeneic sources of MSCs are an appealing alternative to autologous MSCs and could hence be a potential novel solution to MS therapy.

Investigation of the Osteopontin isoforms expression in patients with acute myeloid leukemia.

Acute myeloid leukemia (AML) is one of the major hematological malignancies. Advances in molecular research have greatly improved our understanding of the process of leukemia formation in AML. Osteopontin (OPN) is a novel molecule that mediates critical processes for cancer progression. The aim of this study was to investigate the relative expression of OPN gene isoforms in AML patients on days 0, 14, and 28 after chemotherapy. The bone marrow samples were collected from 40 newly diagnosed AML patients (24 male and 16 female with a mean age of 30 years) at the initial time of diagnosis, 14 and 28 days after treatment. The peripheral blood samples of 10 healthy individuals were also collected as the control group. The expression of OPN isoforms was investigated by Real-Time Quantitative PCR. The expression of VEGFc/STAT3/CXCR4 was also investigated by Real-Time PCR. Findings indicated that OPNb and OPNc isoforms had significantly overexpression in AML patients on 14 and 28 days after treatment compared to normal samples (P < 0.05). The level of OPNb and OPNc isoforms was increased significantly in M0, M1, and M2 subgroups with overexpression of VEGFc/STAT3/CXCR4, 28 days after starting chemotherapy (P < 0.05). Our results suggested that OPNb and OPNc isoforms play a major role in cancer relapse. Therefore, they can be used as a valuable prognostic and diagnostic biomarker for relapse of the AML disease. However, these findings need confirmation with further studies.

The effect of caspase-9 in the differentiation of SH-SY5Y cells.

Neuroblastoma is the most common solid malignant tumor in infants and young children. Its origin is the incompletely committed precursor cells from the autonomic nervous system. Neuroblastoma cells are multipotent cells with a high potency of differentiation into the neural cell types. Neural differentiation leads to the treatment of neuroblastoma by halting the cell and tumor growth and consequently its expansion. Caspases are a family of proteins involved in apoptosis and differentiation. The present study aimed to investigate the potential role of caspase-9 activation on the differentiation of the human neuroblastoma SH-SY5Y cells. Here we investigated the caspase-9 and 3/7 activity during 1,25-dihydroxycholecalciferol (D3)-mediated differentiation of SH-SY5Y cells and took advantage of the inducible caspase-9 system in putting out the differentiation of the neuroblastoma cells. D3-induced differentiation of the cells could lead to activation of caspase-9 and caspase-3/7, astrocyte-like morphology, and increased expression of Glial fibrillary acidic protein (GFAP). By using the inducible caspase-9 system, we showed differentiation of SH-SY5Y cells to astrocyte-like morphology and increased level of GFAP expression. Furthered studies using a specific caspase-9 inhibitor showed inhibition of differentiation mediated by D3 or caspase-9 to astrocyte-like cells. These results show the potency of caspase-9 to direct differentiation of the human neuroblastoma SH-SY5Y cells into cells showing an astrocyte-like morphology.

The impact of ICAM-1, CCL2 and TGM2 gene polymorphisms on differentiation syndrome in acute promyelocytic leukemia.

BACKGROUND: Although arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) are well-tolerated and effective treatments for Acute Promyelocytic Leukemia (APL), Differentiation Syndrome (DS) is a lethal side effect in some patients. The pathogenesis of DS is complex and not well understood; however, it is considered as an inflammatory response due to cytokines release of differentiated cells. Moreover, adhesion molecules that are widely expressed on the surface of differentiated cells and gene expression changes of transglutaminase2 (TGM2) are mechanisms involved in the development of DS. The purpose of this study was to assess the association of single nucleotide polymorphisms (SNP) of Intercellular Adhesion Molecule-1 (ICAM-1), chemokine (C-C motif) ligand 2 (CCL2) and TGM2 as inflammatory factors with differentiation syndrome susceptibility. METHODS: DNA was extracted from 133 APL patients and 100 normal controls. Assessment according to the PETHEMA criteria revealed that 13.5% of these patients experienced differentiation syndrome. Tetra-ARMS PCR and PCR-RFLP were done to amplify DNA fragments in APL patients with and without DS. Then DNA sequencing was done to validate the results. SNPStats, SPSS and Finch TV were used to analyze the results. RESULTS: A significant correlation was found between rs4811528 in the TGM2 gene and differentiation syndrome susceptibility (P = 0.002, 95% CI = 1.74-18.81, OR = 5.72) while rs5498 in ICAM-1, rs1024611 in CCL2, and rs7270785 in TGM2 genes showed no correlation with differentiation syndrome. The G allele of rs7270785 and rs4811528 showed a haplotypic association with differentiation syndrome (P = 0.03, 95% CI = 1.13-13.86, OR = 3.96). CONCLUSIONS: AA genotype of the TGM2 SNP (rs4811528) may be a risk factor for development of DS in patients with APL following the use of ATRA/ATO.

Synthesis, characterization, and in vitro evaluation of the starch-based α-amylase responsive hydrogels.

Controlled-release drug delivery systems are promising platforms in medicine. Among various types of material in drug delivery, hydrogels are interesting ones. They are water-soluble and tissue compatible polymers with a high capacity to carry and release drugs in a controllable manner. In this study, we introduce the synthesis, characterization, and application of an α-amylase responsive hydrogel in controlled drug delivery. The newly synthesized starch-based hydrogels structurally characterized by means of Fourier-transform infrared spectroscopy and scanning electron microscopy. A proapoptotic drug, doxorubicin, was loaded into the hydrogels and the controlled release of the drug was assessed in the presence of α-amylase and ultimately it was evaluated to controlled-drug release in vitro and subsequently in killing cancer cells. Our results highlight the effectiveness of temporal drug delivery using α-amylase responsive hydrogels in killing cancer cells.

Potential of therapeutic plasmapheresis in treatment of COVID-19 patients: Immunopathogenesis and coagulopathy.

Therapeutic plasmapheresis (TP) is the process of the separation and removal of plasma from other blood components and is considered as an adjunctive treatment strategy to the discarded abnormal agent in the management of respiratory viral pandemics. This article reviews the mechanisms of immunopathogenesis and coagulopathy induced by SARS-CoV-2 and the potential benefits of TP as adjunctive treatment in critically COVID-19 patients.

Treatment protocols for BK virus associated hemorrhagic cystitis after hematopoietic stem cell transplantation.

Hematopoietic stem cell transplantation (HSCT) represents a vital curative choice for many disease. However its outcome can be hampered by a variety of transplant associated complications. Hemorrhagic cystitis (HC) considered as one of the major difficulties after HSCT. HC symptoms comprise hematuria, dysuria, burning during urination, urinary frequency, urgency and incontinency, abdominal or suprapubic pain, urinary obstruction, and renal or bladder damage. There are a lot of causes for HC development. BK virus reactivation is one of the major causes of HC after HSCT. There is still no standard and approved treatment protocol for BK virus associated HC (BKV-HC). Treatment of HC is according to the local standard operating procedures, depending on the cause and severity. In this study we will review the current treatments available for this disease. We have divided the therapeutic procedures into 5 categories including conservative therapy, complimentary options, surgical procedures, pharmacological treatments and adoptive cell therapy. We believe that comparing the advantages and disadvantages of different therapies make it easier to choose the best treatment protocol. In addition, we had a greater focus on adoptive cell therapy, because it is a relatively new introduced method and might be a logical alternative to conventional treatments for refractory patients. In total, no definitive recommendation is possible for current available treatments because these procedures have only been utilized sporadically in a limit number of patients. Furthermore, a number of treatment options are only experimental and definitely need more effort.