Decoding the expression pattern of MUC3A in gastric adenocarcinoma: unveiling the key to successful immunotherapy.

AIMS: Despite the promise of immunotherapy for gastric adenocarcinoma, resistance is common, necessitating the validation of new targets. Based on our previous bioinformatics analysis, the MUC3A antigen emerged as a promising candidate for immunotherapy against gastric adenocarcinoma. However, a comprehensive understanding of its expression at protein level remains elusive, despite its crucial role in determining clinical response. We also sought to establish a connection between the expression pattern and relevant clinical variables of the disease, whenever feasible. METHODS: Immunohistochemistry was used to determine the percentage of MUC3A-positive tumor cells in primary (PT) and metastatic tumor (MT) sites of 190 gastric adenocarcinoma patients. We also evaluated the association between MUC3A expression and variables such as Lauren classification, history of neoadjuvant chemotherapy and/or radiotherapy, and overall patient survival. RESULTS: Median MUC3A expression was 50% in PT and 70% in MT sites, exhibiting a positive correlation. MT intestinal type showed significantly higher MUC3A expression compared to other types. Neoadjuvant therapy history did not affect MUC3A expression. Higher MUC3A expression correlated with improved survival. CONCLUSIONS: Based on our previous bioinformatics data and the consistently high expression of MUC3A on gastric tumor cells, we propose advancing experimental aspects of anti-MUC3A immunotherapy for gastric adenocarcinoma.

BI-847325, a selective dual MEK and Aurora kinases inhibitor, reduces aggressive behavior of anaplastic thyroid carcinoma on an in vitro three-dimensional culture.

BACKGROUND: Anaplastic thyroid carcinoma (ATC) is the most aggressive subtype of thyroid cancer. In this study, we used a three-dimensional in vitro system to evaluate the effect of a dual MEK/Aurora kinase inhibitor, BI-847325 anticancer drug, on several cellular and molecular processes involved in cancer progression. METHODS: Human ATC cell lines, C643 and SW1736, were grown in alginate hydrogel and treated with IC50 values of BI-847325. The effect of BI-847325 on inhibition of kinases function of MEK1/2 and Aurora kinase B (AURKB) was evaluated via Western blot analysis of phospho-ERK1/2 and phospho-Histone H3 levels. Sodium/iodide symporter (NIS) and thyroglobulin (Tg), as two thyroid-specific differentiation markers, were measured by qRT-PCR as well as flow cytometry and immunoradiometric assay. Apoptosis was assessed by Annexin V/PI flow cytometry and BIM, NFκB1, and NFκB2 expressions. Cell cycle distribution and proliferation were determined via P16, AURKA, and AURKB expressions as well as PI and CFSE flow cytometry assays. Multidrug resistance was evaluated by examining the expression of MDR1 and MRP1. Angiogenesis and invasion were investigated by VEGF expression and F-actin labeling with Alexa Fluor 549 Phalloidin. RESULTS: Western blot results showed that BI-847325 inhibits MEK1/2 and AURKB functions by decreasing phospho-ERK1/2 and phospho-Histone H3 levels. BI-847325 induced thyroid differentiation markers and apoptosis in ATC cell lines. Inversely, BI-847325 intervention decreased multidrug resistance, cell cycle progression, proliferation, angiogenesis, and invasion at the molecular and/or cellular levels. CONCLUSION: The results of the present study suggest that BI-857,325 might be an effective multi-targeted anticancer drug for ATC treatment.

Development of a Multiepitope Vaccine Against SARS-CoV-2: Immunoinformatics Study.

Background: Since the first appearance of SARS-CoV-2 in China in December 2019, the world witnessed the emergence of the SARS-CoV-2 outbreak. Due to the high transmissibility rate of the virus, there is an urgent need to design and develop vaccines against SARS-CoV-2 to prevent more cases affected by the virus. Objective: A computational approach is proposed for vaccine design against the SARS-CoV-2 spike (S) protein, as the key target for neutralizing antibodies, and envelope (E) protein, which contains a conserved sequence feature. Methods: We used previously reported epitopes of S protein detected experimentally and further identified a collection of predicted B-cell and major histocompatibility (MHC) class II-restricted T-cell epitopes derived from E proteins with an identical match to SARS-CoV-2 E protein. Results: The in silico design of our candidate vaccine against the S and E proteins of SARS-CoV-2 demonstrated a high affinity to MHC class II molecules and effective results in immune response simulations. Conclusions: Based on the results of this study, the multiepitope vaccine designed against the S and E proteins of SARS-CoV-2 may be considered as a new, safe, and efficient approach to combatting the COVID-19 pandemic.

Synergistic effect of miR-9 overexpression and electrical induction on differentiation of conjunctiva mesenchymal stem cells into photoreceptor-like cells.

A variety of genes and materials can induce the differentiation of stem cells. The purpose of this work was to investigate the effect of microRNA-9 (miR-9) overexpression and electrical induction on the photoreceptor differentiation of Conjunctiva Mesenchymal Stem Cells (CJMSCs). In this study, an electroconductive scaffold (silk fibroin polymer (SF) and reduced graphene oxide (rGo) nanoparticles) was fabricated by electrospinning method, and its characteristics such as diameter, graphene distribution, compound, conductivity, and toxicity were evaluated by scanning and transmission electron microscopy (SEM and TEM), FTIR, electrochemical impedance spectroscopy, and MTT assay. The cells were transduced by a lentiviral vector carrying miR-9, then electrical induction was implied on mir-9-CJMSCs, cultivated on the fabricated scaffold, and the expressions of neural and photoreceptor marker genes were evaluated by RT-qPCR. A uniform, smooth appearance with lower diameter, uniform distribution of rGo nanoparticles across the fibers, and lower resistance were shown in SF-rGo fibrous scaffold. After electrical stimulation, lower and higher expression of neural marker genes and photoreceptor marker genes (Rhodopsin, PKC) were documented, respectively. Finally, we proposed that the combinational approach of miR-9 overexpression and electrical induction leads CJMSCs to photoreceptor-like cells.

Interpatient variability in mesothelin expression necessitates its evaluation before gastric cancer immunotherapy.

Aims: Mesothelin (MSLN) was applied for the immunotherapy of ovarian cancer and mesothelioma with a minimum expression of 60% to obtain a clinical response. Here, the authors evaluated MSLN expression as a potential target of gastric adenocarcinoma immunotherapy. Materials & methods: The expression of MSLN was evaluated by immunohistochemistry and was reported in primary tumor (PT) and metastatic tumor (MT) sites. Results: The results showed that only 17.1% and 13.5% of the patients had 60% or more MSLN expression in PT and MT sites, respectively. The expression of MSLN in PTs and MTs was not influenced by Lauren classification, neoadjuvant therapy or tumor stage. Conclusions: Interpatient variability in MSLN expression necessitates its evaluation before MSLN-based gastric cancer immunotherapy.

Long-term aerobic exercise training in type two diabetic patients alters the expression of miRNA-223 and its corresponding target, the P2RY12 receptor, attenuating platelet function.

BACKGROUND: Type two diabetes mellitus (T2DM) patients are prone to develop atherothrombotic events due to platelet hyper-reactivity stemming from platelet miRNA-223 down-regulation and over-expression of its corresponding target, P2RY12. OBJECTIVE: The study sought to determine the effects of long-term aerobic training on the expression levels of miRNA-223 and P2RY12 mRNA, and platelet function in T2DM patients. METHODS: Twenty-four patients with T2DM (age, 60.0±2.8 yrs.) were selected and randomly divided into two groups: aerobic exercise training (AET, n = 12) and control (CON, n = 12). The AET protocol was performed with moderate intensity for 12 weeks, while patients in the CON group followed their usual routine. Weight, body mass index (BMI), peak oxygen consumption (VO2peak), lipid profile, fasting blood glucose (FBG), glycated hemoglobin (HbA1c), insulin resistance index (HOMA-IR), platelet miRNA-223 and P2RY12 expression were measured before and after the period. RESULTS: There was a significant improvement in body weight, BMI, VO2peak, FBG, HbA1c, and HOMA-IR, after 12 weeks of AET (P < 0.01). Platelet aggregation decreased significantly after 12 weeks in the AET group compared with the CON (P < 0.001) group. Platelets' miRNA-223 and P2RY12 were significantly up- and down-regulated after AET in comparison with the CON group (P < 0.05), respectively. Moreover, the relative expression of miRNA-223 and P2RY12 significantly correlated with FBG changes following the intervention. CONCLUSIONS: It can be concluded that long-term moderate-intensity aerobic training might be effective for reducing the occurrence of atherothrombotic events leading to premature death in T2DM patients through the modulation of miRNA-223, P2RY12 receptor expression, and platelet function.

An outlook on antigen-specific adoptive immunotherapy for viral infections with a focus on COVID-19.

Although not a standard-of-care yet, adoptive immunotherapeutic approaches have gradually earned a place within the list of antiviral therapies for some of fatal and hard-to-treat viral diseases. To maintain robust antiviral immunity and to effectively target the viral particles and virally-infected cells, immune cells capable of recognizing the viral antigens are required. While conventional vaccination can induce these cells in vivo; another option is to prime and generate antigen-specific immune cells ex vivo. This approach has been successfully trialed for virulent opportunistic viral infections after bone marrow transplantation. Amid the crisis of SARS-CoV2 pandemic, which has been followed by the success of certain early-authorized vaccines; some institutions and companies have explored the effects of viral-specific adoptive cell transfers (ACTs) in trials, as alternative treatments. Aimed at outlining a perspective on antigen-specific adoptive immunotherapy for viral infections, this review article specifically provides an appraisal of ACT-based studies/trials on SARS-CoV2 infection.

In vitro effects of tropisetron and granisetron against Echinococcus granulosus (s.s.) protoscoleces by involvement of calcineurin and calmodulin.

BACKGROUND: Cystic echinococcosis (CE) is a disease caused by the larval stage of Echinococcus granulosus sensu lato  (s.l.). The treatment of CE mainly relies on the use of benzimidazoles, which can commonly cause adverse side effects. Therefore, more efficient treatment options are needed. Drug repurposing is a useful approach for advancing drug development. We have evaluated the in vitro protoscolicidal effects of tropisetron and granisetron in E. granulosus sensu stricto (s.s.) and assessed the expression of the calcineurin (CaN) and calmodulin (CaM) genes, both of which have been linked to cellular signaling activities and thus are potentially promising targets for the development of drugs. METHODS: Protoscoleces (PSC) of E. granulosus (s.s.) (genotype G1) obtained from sheep hepatic hydatid cysts were exposed to tropisetron and granisetron at concentrations of 50, 150 and 250 µM for various periods of time up to 10 days. Cyclosporine A (CsA) and albendazole sulfoxide were used for comparison. Changes in the morphology of PSC were investigated by light microscopy and scanning electron microscopy. Gene expression was assessed using real-time PCR at the mRNA level for E. granulosus calcineurin subunit A (Eg-CaN-A), calcineurin subunit B (Eg-CaN-B) and calmodulin (Eg-CaM) after a 24-h exposure at 50 and 250 µM, respectively. RESULTS: At 150 and 250 µM, tropisetron had the highest protoscolicidal effect, whereas CsA was most effective at 50 µM. Granisetron, however, was less effective than tropisetron at all three concentrations. Examination of morphological alterations revealed that the rate at which PSC were killed increased with increasing rate of PSC evagination, as observed in PSC exposed to tropisetron. Gene expression analysis revealed that tropisetron at 50 µM significantly upregulated Eg-CaN-B and Eg-CaM expression while at 250 µM it significantly downregulated both Eg-CaN-B and Eg-CaM expressions; in comparison, granisetron decreased the expression of all three genes at both concentrations. CONCLUSIONS: Tropisetron exhibited a higher efficacy than granisetron against E. granulosus (s.s.) PSC, which is probably due to the different mechanisms of action of the two drugs. The concentration-dependent effect of tropisetron on calcineurin gene expression might reflect its dual functions, which should stimulate future research into its mechanism of action and evaluation of its potential therapeutical effect in the treatment of CE.

Evaluation of miR-122 Serum Level and IFN-λ3 Genotypes in Patients with Chronic HCV and HCV-Infected Liver Transplant Candidate.

BACKGROUND: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are the most common markers of liver damage, but serum level interpretation can be complicated. In hepatocytes, microRNA-122 (miR-122) is the most abundant miRs and its high expression in the serum is a characteristic of liver disease. OBJECTIVE: We aimed to compare the circulatory level of miR-122 in patients with Chronic Hepatitis C (CHC), Hepatitis C Virus (HCV) infected Liver Transplant Candidates (LTC) and healthy controls to determine if miR-122 can be considered as an indicator of chronic and advanced stage of liver disease. METHODS: MiR-122 serum level was measured in 170 Interferon-naïve (IFN-naïve) CHC patients, 62 LTC patients, and 132 healthy individuals via TaqMan real-time PCR. Serum levels of miR-122 were normalized to the serum level of Let-7a and miR-221. Also, the ALT and AST levels were measured. RESULTS: ALT and AST activities and the expression of circulatory miR-122 were similar in the CHC and LTC groups, but it had significantly increased compared to healthy individuals (P<0.001 and P<0.001, respectively). Up-regulation of miR-122 in the sample of patients with normal ALT and AST activities was also observed, indicating that miR-122 is a good marker with high sensitivity and specificity for diagnosing liver damage. CONCLUSION: miR-122 seemed to be more specific for liver diseases in comparison with the routine ALT and AST liver enzymes. Since the lower levels of circulating miR-122 were observed in the LTC group compared to the CHC group, advanced liver damages might reduce the release of miR-122 from the hepatocytes, as a sign of liver function deficiency.

A Systems Biology Approach for miRNA-mRNA Expression Patterns Analysis in Rheumatoid Arthritis.

OBJECTIVE: Considering the molecular complexity and heterogeneity of rheumatoid arthritis (RA), the identification of novel molecular contributors involved in RA initiation and progression using systems biology approaches will open up potential therapeutic strategies. The bioinformatics method allows the detection of associated miRNA-mRNA as both therapeutic and prognostic targets for RA. METHODS: This research used a system biology approach based on a systematic re-analysis of the RA-related microarray datasets in the NCBI Gene Expression Omnibus (GEO) database to find out deregulated miRNAs. We then studied the deregulated miRNA-mRNA using Enrichr and Molecular Signatures Database (MSigDB) to identify novel RA-related markers followed by an overview of miRNA-mRNA interaction networks and RA-related pathways. RESULTS: This research mainly focused on mRNA and miRNA interactions in all tissues and blood/serum associated with RA to obtain a comprehensive knowledge of RA. Recent systems biology approach analyzed seven independent studies and presented important RA-related deregulated miRNAs (miR-145-5p, miR-146a-5p, miR-155-5p, miR-15a-5p, miR-29c-3p, miR- 103a-3p, miR-125a-5p, miR-125b-5p, miR-218); upregulation of miR-125b is shown in the study (GSE71600). While the findings of the Enrichr showed cytokine and vitamin D receptor pathways and inflammatory pathways. Further analysis revealed a negative correlation between the vitamin D receptor (VDR) and miR-125b in RA-associated gene expression. CONCLUSION: Since vitamin D is capable of regulating the immune homeostasis and decreasing the autoimmune process through its receptor (VDR), it is regarded as a potential target for RA. According to the results obtained, a comparative correlation between negative expression of the vitamin D receptor (VDR) and miR-125b was suggested in RA. The increasing miR-125b expression would reduce the VitD uptake through its receptor.

miRNA-146a Improves Immunomodulatory Effects of MSC-derived Exosomes in Rheumatoid Arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is a severe inflammatory joint disorder, and several studies have taken note of the probability that microRNAs (miRNAs) play an important role in RA pathogenesis. MiR-146 and miR-155 arose as primary immune response regulators. Mesenchymal stem cells (MSCs) immunomodulatory function is primarily regulated by paracrine factors, such as exosomes. Exosomes, which serve as carriers of genetic information in cell-to-cell communication, transmit miRNAs between cells and have been studied as vehicles for the delivery of therapeutic molecules. AIMS: The current research aimed to investigate the therapeutic effect of miR-146a/miR-155 transduced mesenchymal stem cells (MSC)-derived exosomes on the immune response. METHODS: Here, exosomes were extracted from normal MSCs with over-expressed miR-146a/miR-155; Splenocytes were isolated from collagen-induced arthritis (CIA) and control mice. Expression levels miR-146a and miR-155 were then monitored. Flow cytometry was performed to assess the impact of the exosomes on regulatory T-cell (Treg) levels. Expression of some key autoimmune response genes and their protein products, including retinoic acid-related orphan receptor (ROR)-γt, tumor necrosis factor (TNF)-α, interleukin (IL)-17, -6, -10, and transforming growth factor (TGF)-ß in the Splenocytes was determined using both quantitative real-time PCR and ELISA. The results showed that miR-146a was mainly down-regulated in CIA mice. Treatment with MSC-derived exosomes and miR-146a/miR-155-transduced MSC-derived exosomes significantly altered the CIA mice Treg cell levels compared to in control mice. RESULTS: Ultimately, such modulation may promote the recovery of appropriate T-cell responses in inflammatory situations such as RA. CONCLUSION: miR-146a-transduced MSC-derived exosomes also increased forkhead box P3 (Fox- P3), TGFß and IL-10 gene expression in the CIA mice; miR-155 further increased the gene expressions of RORγt, IL-17, and IL-6 in these mice. Based on the findings here, Exosomes appears to promote the direct intracellular transfer of miRNAs between cells and to represent a possible therapeutic strategy for RA. The manipulation of MSC-derived exosomes with anti-inflammatory miRNA may increase Treg cell populations and anti-inflammatory cytokines.

The potency of hsa-miR-9-1 overexpression in photoreceptor differentiation of conjunctiva mesenchymal stem cells on a 3D nanofibrous scaffold.

MiRNAs are small non-coding RNAs that are ordinarily involved in modulating mRNAs and stem cell differentiation. 3D nanofibrous scaffolds have an important role in the differentiation of stem cells due to their similarity to the extracellular matrix (ECM). In the present study, we tried to introduce a new approach to guiding the differentiation of conjunctiva mesenchymal stem cells (CJMSCs) into photoreceptor-like cells by hsa-miR-9-1 delivery on both 2D and 3D substrates. First, the CJMSCs were transduced by a lentiviral vector carrying miR-9 (pCDH + hsa-miR-9-1) and then cell transduction efficacy verified by using fluorescent microscopy, flow cytometry, and qPCR analyses. Silk Fibroin-poly-L-lactic acid (SF-PLLA) scaffold was fabricated by the electrospinning technique while the scaffold characteristics including morphology, chemical properties, and biocompatibility were evaluated by SEM, FTIR, and MTT assays, respectively. Then, the miR-9-CJMSCs were seeded on both TCPS and the scaffold; photoreceptor gene and protein expressions were evaluated by RT-qPCR and immunostaining after 14 and 21 days of transduction. More than 80% of CJMSCs were transduced and miR-9 expression was significantly higher in miR-9-CJMSCs compared with empty vector (EV)-CJMSCs. SEM and FTIR confirmed the fabrication of the SF/PLLA hybrid structure. RT-qPCR and immunostaining analyses showed that the specific photoreceptor genes and proteins were expressed in miR-9 transduced CJMSCs. Mir-9 induced CJMSCs into photoreceptor-like cells in a time-dependent manneron on both TCPS and nanofibrous scaffold.We have proved that hsa-miR-9-1 has the potency to guide the photoreceptor differentiation of mesenchymal stem cells and promote retinal regeneration.

Unfolded protein response-mediated modulation of mesenchymal stem cells.

The endoplasmic reticulum (ER) receives unfolded proteins predestined for the secretory pathway or to be incorporated as transmembrane proteins. The ER has to accommodate the proper folding and glycosylation of these proteins and also to properly incorporate transmembrane proteins. However, under various circumstances, the proteins shuttling through the ER can be misfolded and undergo aggregation, which causes activation of the unfolded protein response (UPR). The UPR is mediated through three primary pathways: activating transcription factor-6, inositol-requiring enzyme-1 (IRE1), and PKR-like endoplasmic reticulum kinase, which up-regulate ER folding chaperones and temporarily suppress protein translation. The UPR can be both cytoprotective and/or cytotoxic depending on the duration of UPR activation and the type of host cell. Proteostasis controls stem cell function, while stress responses affect stem cell identity and differentiation. The present review aimed to explore and discuss the effects of the UPR pathways on mesenchymal stem cells.

MicroRNA-7 promotes neural differentiation of trabecular meshwork mesenchymal stem cell on nanofibrous scaffold.

The purpose of this study was to investigate miR-7 overexpression effects on neural differentiation of mesenchymal stem cells (MSCs) on both two-dimensional (2D) and three-dimensional (3D) culture systems. We upregulated miR-7 through lentiviral vector in trabecular meshwork MSCs (TMMSCs) and polymers of poly l-lactic acid/polycaprolactone fibrous scaffold were fabricated by electrospinning and characterized using scanning electron microscopy (SEM) and Fourier transform infrared (FTIR). Neural markers expression was evaluated through quantitative-polymerase chain reaction (q-PCR) and immunostaining. The results showed that the high percentage of cell transduction (84.9%) and miR-7 expression (folds: 677.93 and 556.4) was detected in TMMSCs-miR-7(+). SEM and FTIR established the fabrication of the hybrid scaffold. q-PCR analysis showed that on days 14 and 21 of transduction, the expression level of Nestin and glial fibrillary acidic protein (GFAP) genes were significantly higher in the scaffold (3D) compared with tissue culture polystyrene (2D) culture. The expression of microtubule-associated protein-2 (MAP-2) and GFAP genes in TMMSCs-miR-7(+) cells were significantly higher than those miR-7(-) cells after 21 days of cell culture. Also, MAP-2 and Nestin proteins were detected in TMMSCs-miR-7(+) cells. Our results demonstrate that miR-7 is involved in neural differentiation of TMMSCs and scaffold can improve differentiate into glial and neural progenitor cells. These findings provided some information for future use of microRNAs and scaffold in tissue engineering and cell therapy for neurological diseases.

ANTXR1 (TEM8) overexpression in gastric adenocarcinoma makes the protein a potential target of immunotherapy.

BACKGROUND: Despite the promise of immunotherapy for gastric adenocarcinoma, choices for the selection of effective antigenic targets are very limited. Previously published data and our own in-house computational analysis have suggested that ANTXR1 is a potential target, simultaneously expressed in malignant tumor cells and the endothelial cells of the tumors. However, the expression pattern of ANTXR1 protein in clinical samples of gastric adenocarcinoma has not been fully evaluated. METHODS: Using immunohistochemistry (IHC), we recorded the percentage of ANTXR1 positive cells separately in tumor cells and endothelial cells in the primary tumor, non-tumor gastric tissue adjacent to the primary tumor, and tumor in metastatic sites of 140 gastric adenocarcinoma patients. We also evaluated the association of ANTXR1 expression with the Lauren histological classification of the primary tumors, the patient's history of neoadjuvant chemotherapy and/or radiotherapy, and the patient's overall survival. RESULTS: ANTXR1 was expressed in a mean of 73.89 ± 30.12% of tumor cells and 13.55 ± 20.53% of endothelial cells in the primary tumors. Intestinal adenocarcinomas had lower ANTXR1 expression in the tumor cells and higher ANTXR1 expression in the endothelial cells of the tumor regions, and a history of neoadjuvant therapy was associated with increased ANTXR1 expression in the endothelial cells of the tumor regions. Finally, above median expression of ANTXR1 in the tumor cells of the tumor regions was associated with significantly lower overall patient survival. CONCLUSIONS: Our findings suggest that ANTXR1 is a promising candidate for preclinical and clinical evaluation for gastric adenocarcinoma immunotherapy.

Generation of CD19-Targeted Chimeric Antigen Receptor T Cells.

BACKGROUND: Current advancements in the field of chimeric antigen receptor (CAR) therapy, particularly U.S. FDA approval of Kymriah and Yescarta, heralds a new era of cancer treatment. This rapid progress in technology has urged more countries and institutions to keep pace with the fast-growing and developing technology of producing CAR T cell-based therapies in the race to develop new cancer-targeting drugs. Hence, for stepping in line with global advances and to pave the way for subsequent preclinical and clinical studies, we have established a development protocol for a cancer-targeting CAR T cell; we have chosen CD19 CAR T cell as a well-defined model to set-up T cell expansion, activation, and viral transduction as the prerequisites for diverse CAR T cell therapies. METHODS: T cells from peripheral blood mononuclear cells (PBMCs) were activated and expanded. CD19 CAR lentiviral particles were produced in the Lenti-X™ 293T Cell Line using PolyFect Transfection Reagent. RESULTS: Activation protocol resulted in (65 ± 4%; P = 0.046) increase in the rate of activated T cells 24 hours after the initiation of the procedure. The expansion methodology resulted in a high purity of the T cell population (96 ± 3%) in the pool of PBMCs within 14 days of the procedure. Finally, 35 ± 6% of T cells were transduced with CD19 lentivirus with MOI of 3. CONCLUSION: Collectively, the results of this study prove that we have successfully overcome the first hurdle on the road to reach CAR T cell technology which is the prerequisite for developing preclinical and clinical phases of CAR therapy in settings with basic resources.

MSLN (Mesothelin), ANTXR1 (TEM8), and MUC3A are the potent antigenic targets for CAR T cell therapy of gastric adenocarcinoma.

Gastric adenocarcinoma is usually diagnosed in late stages, necessitating the use of different therapeutic modalities. Currently, antibody-based therapies have also been approved through with limited clinical efficacy. Reinforcing antibody-based immunotherapy by using chimeric antigen receptor (CAR) T cells may enhance the approach. However, the cells can cause severe on-target and off-tumor toxicities owing to their higher sensitivity to low-level antigen expressions. To address the need for safe and reliable targets, we made a bioinformatics pipeline by which we screened overexpressed genes in the disease for off-tumor sites in many normal tissues. Our inspection showed that MSLN (Mesothelin), ANTXR1 (TEM8), and MUC3A are the probable targets of CAR T cell therapy in gastric adenocarcinoma. The proposed antigenic targets might respond to the need to simultaneously target multiple antigens in a tumor matrix to prevent resistance.

Addressing cancer immunotherapy research in Iran: adoptive cell therapy on the horizon.

Recent advances in immunotherapeutic modalities have profoundly changed the prospect of cancer treatment. These modalities mainly focus on modulating the immune response toward tumor cells by using monoclonal antibodies, cancer vaccines, adoptive cell transfer or combination of these methods. In the last few years, Iranian scientists have conducted several projects in these arenas. Here, we provide an overview of these studies and analyze the quality and trend of publications in each sub-specialty of the field. In addition, the contribution of different universities and scientific institutes is assessed. This study may benefit scientific community and policymakers to plan future cancer immunotherapies in Iran and other countries.

Aerobic training improves platelet function in type 2 diabetic patients: role of microRNA-130a and GPIIb.

AIMS: MicroRNAs (miRs) that are mediators of gene expression have been implicated in type 2 diabetes mellitus (T2DM). Platelet hyper-reactivity is one of the most important disorders in T2DM patients. In this study, we explored the effects of aerobic training (AT) on platelet aggregation and Glycoprotein IIb (GPIIb) receptor and miR-130a expression. METHODS: In a quasi-experimental controlled trial, 24 sedentary, eligible female participants with T2DM were selected (age 61.92 ± 3.63) and divided into AT and control (CON) groups based on their peak oxygen consumption (VO2peak). AT protocol was performed three times per week in non-consecutive days on a treadmill with mean intensity (60-75% VO2peak) for 8 weeks, while the control group refrained from any type of exercise training. Two blood samples were taken before and after this period. Real-time PCR was used to determine the expression of platelet GPIIb and miR-130a. Moreover, platelet indices (PLT, MPV, PDW, and PCT), collagen-induced platelet aggregation and glycemic variables were measured. RESULTS: Analyses of data showed that anthropometric variables, VO2peak and glycemic control improved significantly (P < 0.01) after AT. Furthermore, MPV, PDW (P < 0.01), and platelet aggregation (P < 0.001) decreased significantly following AT compared with control group. Platelet GPIIb expression down-regulated significantly (P < 0.05) in AT group but up-regulation of miR-130a expression was not significant between two groups (P > 0.05). CONCLUSIONS: Platelet hyper-reactivity in T2DM females might be decreased not only by glycemic control and amelioration of anthropometric and platelet indices, but also the down-regulation of GPIIb following AT. However, more research is needed to determine the effects of exercise training on platelet miR-130a.

Antigenic targets of CAR T Cell Therapy. A retrospective view on clinical trials.

Chimeric antigen receptor (CAR) T cell therapy is anticipated to be increasingly implemented in the context of cancer treatment after two current FDA approval of anti-CD19 CAR-T cells (Kymriah™ & Yescarta™). The success of CD19 is mainly attributable to the proper selection of the antigen, CD19, as the target of the disease, highlighting the importance of target selection for other CAR therapies. Therefore, here we performed a global analysis of targets that are the prime focus for various CAR T cell therapies in human clinical trials.