Hypoxia and programmed cell death-ligand 1 expression in the tumor microenvironment: a review of the effects of hypoxia-induced factor-1 on immunotherapy.

One useful cancer treatment approach is activating the patient's immune response against the tumor. In this regard, immunotherapy (IT) based on immune checkpoint blockers (ICBs) has made great progress in the last two decades. Although ITs are considered a novel approach to cancer treatment and have had good results in preclinical studies, their clinical success has shown that only a small proportion of treated patients (about 20%) benefited from them. Moreover, in highly progressed tumors, almost no acceptable response could be expected. In this regard finding the key molecules that are the main players of tumor immunosuppression might be helpful in overcoming the possible burdens. Hypoxia is one of the main components of the tumor microenvironment (TME), which can create an immunosuppressive microenvironment in various ways. For example, hypoxia is one of the main factors of programmed cell death ligand-1 (PD-L1) upregulation in tumor-infiltrating Myeloid-Derived Suppressor Cells (MDSCs). Therefore, hypoxia can be targeted to increase the efficiency of Anti-PD-L1 IT and has become one of the important issues in cancer treatment strategy. In this review, we described the effect of hypoxia in the TME, on tumor progression and immune responses and the challenges created by it for IT.

Radiotherapy Combination: Insight from Tumor Immune Microenvironment (TIME).

The view of Radiotherapy (RT) as a simple inducer of DNA damage resulting in tumor cell death has dramatically changed in recent years, and it is now widely accepted that RT can trigger an immune response which provides a sound basis for combining RT with immunotherapy. Given that, radiation can be delivered with different regimens, its effect on immune responses and Tumor Immune Microenvironment (TIME) may vary with dose and fractionation schedule. This fractional dose dependency may need to be more considered because of recent developments in RT delivery techniques making it possible to deliver precisely higher dosages per fraction (hypofractionation) while reducing exposure to normal tissues. Although combining radiotherapy with immunotherapy could be a promising strategy for synergistic enhancement of treatment efficacy, the selection of the best-matched combination of immunotherapy with each radiotherapy scheme remains to be addressed. Thus, for designing better therapeutic combinations, it is necessary to understand the immunological effects of RT. Here, we review the impact of conventional and different hypofractionation radiation schedules on the TIME. Subsequently, we highlight how knowing about these interactions may have implications for choosing a rational combination with targeted therapies.

VISTA and its ligands: the next generation of promising therapeutic targets in immunotherapy.

V-domain immunoglobulin suppressor of T cell activation (VISTA) is a novel negative checkpoint receptor (NCR) primarily involved in maintaining immune tolerance. It has a role in the pathogenesis of autoimmune disorders and cancer and has shown promising results as a therapeutic target. However, there is still some ambiguity regarding the ligands of VISTA and their interactions with each other. While V-Set and Immunoglobulin domain containing 3 (VSIG-3) and P-selectin glycoprotein ligand-1(PSGL-1) have been extensively studied as ligands for VISTA, the others have received less attention. It seems that investigating VISTA ligands, reviewing their functions and roles, as well as outcomes related to their interactions, may allow an understanding of their full functionality and effects within the cell or the microenvironment. It could also help discover alternative approaches to target the VISTA pathway without causing related side effects. In this regard, we summarize current evidence about VISTA, its related ligands, their interactions and effects, as well as their preclinical and clinical targeting agents.

Catalase-gold nanoaggregates manipulate the tumor microenvironment and enhance the effect of low-dose radiation therapy by reducing hypoxia.

Radiotherapy as a standard method for cancer treatment faces tumor recurrence and antitumoral unresponsiveness. Suppressive tumor microenvironment (TME) and hypoxia are significant challenges affecting efficacy of radiotherapy. Herein, a versatile method is introduced for the preparation of pH-sensitive catalase-gold cross-linked nanoaggregate (Au@CAT) having acceptable stability and selective activity in tumor microenvironment. Combining Au@CAT with low-dose radiotherapy enhanced radiotherapy effects via polarizing protumoral immune cells to the antitumoral landscape. This therapeutic approach also attenuated hypoxia, confirmed by downregulating hypoxia hallmarks, such as hypoxia-inducible factor α-subunits (HIF-α), vascular endothelial growth factor (VEGF), and EGF. Catalase stability against protease digestion was improved significantly in Au@CAT compared to the free catalase. Moreover, minimal toxicity of Au@CAT on normal cells and increased reactive oxygen species (ROS) were confirmed in vitro compared with radiotherapy. Using the nanoaggregates combined with radiotherapy led to a significant reduction of immunosuppressive infiltrating cells such as myeloid-derived suppressor cells (MDSCs) and regulatory T cells (T-regs) compared to the other groups. While, this combined therapy could significantly increase the frequency of CD8+ cells as well as M1 to M2 macrophages (MQs) ratio. The combination therapy also reduced the tumor size and increased survival rate in mice models of colorectal cancer (CRC). Our results indicate that this innovative nanocomposite could be an excellent system for catalase delivery, manipulating the TME and providing a potential therapeutic strategy for treating CRC.

Evaluation of Molecular-level Changes of Programmed Cell Death Ligand-1 after Radiation Therapy in a BALB/c CT26 Colorectal Mouse Tumor Model.

The effects of radiation therapy (RT) for cancer can be systemic and partially mediated by the immune system. However, radiation alone is unlikely to transform an immunosuppressive environment into an immunostimulatory one. Therefore, an effective combination of RT and immunotherapy may provide a new, more efficient treatment approach. Here, we investigated how the expression of programmed cell death-ligand 1 (PD-L1) in the tumor microenvironment varied in different RT regimens with the same biologically effective dose. In this study, female BALB/c mice inoculated with CT26 tumor cells were irradiated with 3 different RT regimens using the same BED of 40 gray (Gy). These included ablative RT (1*15 Gy), hypo-fractionated RT (2*10 Gy), and conventional (Hyper-fractionated) RT (10*3 Gy). PD-L1 expression was analyzed with immunohistochemical staining on days 2 and 20 and when the size of tumors had reached 2 cm2 after RT. All treated groups expressed PD-L1, but the group receiving single ablative high-dose RT showed higher expression compared to the other groups. No significant differences in PD-L1 expression were observed at different times in the same group. These findings showed that different regimens of RT have different effects on the TME, so a combination of RT and immune checkpoint blockade could be clinically used in cancer patients.

Improving water treatment using a novel antibacterial kappa-carrageenan-coated magnetite decorated with silver nanoparticles.

In this study, we aimed to fabricate an enhanced antibacterial agent to act against pathogenic bacteria in aqueous environments. To achieve this, silver nanoparticles (AgNPs) were inlaid on a kappa-carrageenan (KC) base and coated on Fe3O4 magnetic cores (Fe3O4@KC@Ag). Superparamagnetic Fe3O4 nanoparticles were designed at the center of the composite nanostructure, allowing magnetic recovery from aqueous media in the presence of a magnet. The synthesized nanoconjugate was characterized in each step using XRD, FT-IR, EDX, FE-SEM, TEM, DLS, VSM, and disk-diffusion antibacterial method. Results show that the nanocomposite system is formed, while the magnetic properties remain practically stable. The agglomeration of the AgNPs was decreased by the trap-like function of KC coating, which resulted in an improved antibacterial activity for the Fe3O4@KC@Ag formulation. These findings suggest that Fe3O4@KC@Ag nanocomposites could be promising agents for combating bacterial infections in aqueous environments.

Dual blockage of both PD-L1 and CD47 enhances the therapeutic effect of oxaliplatin and FOLFOX in CT-26 mice tumor model.

Colorectal cancer is a poorly immunogenic. Such property can be reverted by using ICD. However, ICD inducers can also induce the expression of inhibitory checkpoint receptors CD47 and PD-L1 on tumor cells, making CRC tumors resistant to mainly CD8 T cell killing and macrophage-mediated phagocytosis. In this study, we examined the therapeutic effect of Oxaliplatin and FOLFOX regimen in combination with blocking antibodies against CD47 and PD-L1. FOLFOX and Oxaliplatin treatment lead to an increase in CD47 and PD-L1 expression on CT-26 cells invitro and invivo. Combining blocking antibodies against CD47 and PD-L1 with FOLFOX leads to a significant increase in survival and a decrease in tumor size. This triple combining regimen also leads to a significant decrease in Treg and MDSC and a significant increase in CD8 + INF-γ + lymphocytes and M1/M2 macrophage ratio in the tumor microenvironment. Our study showed triple combining therapy with FOLFOX, CD47 and PD-L1 is an effective treatment regimen in CT-26 mice tumor model and may consider as a potential to translate to the clinic.

Combining ablative radiotherapy and anti CD47 monoclonal antibody improves infiltration of immune cells in tumor microenvironments.

Radiotherapy as an anti-tumor treatment can stimulate the immune system. However, irradiated tumor cells express CD47 to escape the anti-tumor immune response. Anti- CD47 Immunotherapy is a possible way to tackle this problem. This study evaluated the effect of single high dose radiotherapy combined with an anti-CD47 monoclonal antibody (αCD47 mAb) in CT26 tumor-bearing BALB/c mice. We assessed the tumors volume and survival in mice 60 days after tumor implantation. Also, immune cell changes were analyzed by flow cytometry in tumors, lymph nodes, and spleen. Combination therapy enhanced the anti-tumor response in treated mice by increasing CD8+ T cells and M1 macrophages and decreasing M2 macrophages and myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment (TME). Also, our results showed that combination therapy increased survival time in mice compared to other groups. Furthermore, tumor volumes remarkably decreased in mice that received a single high dose RT plus αCD47 mAb. In conclusion, we showed that combining RT and αCD47 mAb improved the immune cell population in TME, regressed tumor growth, and increased survival in tumor-bearing mice.

Design and characterization of Persian gum/polyvinyl alcohol electrospun nanofibrous scaffolds for cell culture applications.

Biocompatible electrospun nanofiber scaffolds were fabricated in this study using Persian gum (PG) and poly (vinyl alcohol) (PVA) to build an artificial extracellular matrix for cell growth. The preparation procedure involves mixing various ratios of PG/PVA to be electrospun and seeded with L929 fibroblasts. Upon addition of PG up to 60% to the solutions, a 30% decrease to around 240 µs·cm-1 is found in electrical conductivity which is in the range of semi-conductive polymers, whereas the surface tension is increased to around 3%. The fabricated scaffolds were characterized by morphological, chemical, thermal and structural analyses including SEM, FTIR spectroscopy, DSC, XRD, and tensile stress. The results showed that incorporation of 50% PG to the polymer solutions causes the formation of nanofibers with the least bead-shaped segments. All ratios of nanofibers containing PG showed significant biocompatibility with the cultured cells, which is presumably due to the radical scavenging feature of PG. The MTT and SEM analyses demonstrated that the scaffolds containing 50% PG possess the optimal cell compatibility, adhesion and proliferation properties. The fabricated PG/PVA cell culture scaffolds are potentially appropriate for wound dressing and cell culture applications in biomedicine.

Tetracycline removal enhancement with Fe-saturated nanoporous montmorillonite in a tripartite adsorption/desorption/photo-Fenton degradation process.

The adsorption and photo-Fenton degradation of tetracycline (TC) over Fe-saturated nanoporous montmorillonite was analyzed. The synthesized samples were characterized using XRD, FTIR, SEM, and XRF analysis, and the adsorption and desorption of TC onto these samples, as well as the antimicrobial activity of TC during these processes, were analyzed at different pH. Initially, a set of adsorption/desorption experiments was conducted, and surprisingly, up to 50% of TC adsorbed was released from Mt structure. Moreover, the desorbed TC had strong antibacterial activity. Then, an acid treatment (for the creation of nanoporous layers) and Fe saturation of the montmorillonite were applied to improve its adsorption and photocatalytic degradation properties over TC. Surprisingly, the desorption of TC from modified montmorillonite was still high up to 40% of adsorbed TC. However, simultaneous adsorption and photodegradation of TC were detected and almost no antimicrobial activity was detected after 180 min of visible light irradiation, which could be due to the photo-Fenton degradation of TC on the modified montmorillonite surface. In the porous structures of modified montmorillonite high, ˙OH radicals were created in the photo-Fenton reaction and were measured using the Coumarin technique. The ˙OH radicals help the degradation of TC as proposed in an oxidation process. Surprisingly, more than 90% of antimicrobial activity of the TC decreased under visible light (after 180 min) when desorbed from nanoporous Fe-saturated montmorillonite compared to natural montmorillonite. To the best of our knowledge, this is the first time that such a high TC desorption rate from an adsorbent with the least residual antimicrobial activity is reported which makes nanoporous Fe-saturated montmorillonite a perfect separation substance of TC from the environment.

Design of polysaccharidicAloe veragel incorporated PVA/tetracycline electrospun cell culture scaffolds for biomedical applications.

In this study, hybrid nanofibrous 3D scaffolds containingAloe vera(AV), polyvinyl alcohol (PVA) and tetracycline hydrochloride (TCH) are fabricated by electrospinning for cell culture applications. The role of polysaccharides present in AV gel is found to enhance the biocompatibility of the nanofibrous scaffolds. Different combinations of the polymers were selected to produce homogenous nanofibers with favorable mean fiber diameter and tensile strength. The surface morphology of the products was studied by SEM and it is found that the mean fiber diameter is decreased to about 188 nm upon addition of the AV component. The electrospun scaffolds were investigated by FT-IR spectroscopy to reveal the chemical structure of the samples and their crystallinity was studied by XRD. The hydrophilicity of the scaffolds was tested by optical contact angle measurements and their mechanical strength was examined by tensile strength tests. It is found that PVA is the main component contributing the mechanical stability of the scaffold structure. The fabricated scaffolds presented a more pronounced inhibitory effect against Gram-positive bacterial strains ofS. aureusandB. cereus. Cell culture experiments using fibroblast L929 murine cells reveals that the AV/PVA/TCH scaffolds are promising for cell growth and the cells are capable of achieving a proper cell adhesion and proliferation. The cell viability experiment by MTT assay exhibits the contributing role of AV gel to L929 cell viability on the AV/PVA/TCH scaffolds.

Comprehensive analysis of ceRNA networks to determine genes related to prognosis, overall survival, and immune infiltration in clear cell renal carcinoma.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is one of the common subtypes of kidney cancer. Circular RNAs (circRNAs) act as competing endogenous RNAs (ceRNAs) to affect the expression of microRNAs (miRNAs), and hence the expression of genes involved in the development and progression of ccRCC. However, these interactions have not been sufficiently explored. METHODS: The differential expression of circRNAs (DEC) was extracted from the GEO database, and the expression of circRNAs was analyzed by the Limma R package. The interaction of miRNAs with circRNAs was predicted using (cancer-specific circRNA database) CSCD and circinteractome database. The genes affected by the miRNAs were predicted by miRwalk version 3, and the differential expression was retrieved using TCGA. Functional enrichment was assessed and a PPI network was created using DAVID and Cytoscape, respectively. The genes with significant interactions (hub-genes) were screened, and the total survival rate of ccRCC patients was extracted from the Gene Expression Profiling Interactive Analysis (GEPIA) database. To confirm the expression of OS genes we used the Immunohistochemistry (IHC) data and TCGA database. The correlation between gene expression and immune cell infiltration was investigated using TIMER2.0. Finally, potential drug candidates were predicted by the cMAP database. RESULTS: Four DECs (hsa_circ_0003340, hsa_circ_0007836, hsa_circ_0020303, and hsa_circ_0001873) were identified, along with 11 interacting miRNAs (miR-1224-3p, miR-1294, miR-1205, miR-1231, miR-615-5p, miR-940, miR-1283, and miR-1305). These miRNAs were predicted to affect 1282 target genes, and function enrichment was used to identify the genes involved in cancer biology. 18 hub-genes (CCR1, VCAM1, NCF2, LAPTM5, NCKAP1L, CTSS, BTK, LILRB2, CD53, MPEG1, C3AR1, GPR183, C1QA, C1QC, P2RY8, LY86, CYBB, and IKZF1) were identified from a PPI network. VCAM1, NCF2, CTSS, LILRB2, MPEG1, C3AR1, P2RY8, and CYBB could affect the survival of ccRCC patients. The hub-gene expression was correlated with tumor immune cell infiltration and patient prognosis. Two potantial drug candidates, naphazoline and lithocholic acid could play a role in ccRCC therapy, as well other cancers. CONCLUSION: This bioinformatics analysis brings a new insight into the role of circRNA/miRNA/mRNA interactions in ccRCC pathogenesis, prognosis, and possible drug treatment or immunotherapy.

Biocompatibility of electrospun cell culture scaffolds made from balangu seed mucilage/PVA composites.

Synthesis of Balangu (Lallemantia royleana) seed mucilage (BSM) solutions combined with polyvinyl alcohol (PVA) was studied for the purpose of producing 3D electrospun cell culture scaffolds. Production of pure BSM nanofibers proved to be difficult, yet integration of PVA contributed to a facile and successful formation of BSM/PVA nanofibers. Different BSM/PVA ratios were fabricated to achieve the desired nanofibrous structure for cell proliferation. It is found that the optimal bead-free ratio of 50/50 with a mean fiber diameter of ≈180 nm presents the most desirable scaffold structure for cell growth. The positive effect of PVA incorporation was approved by analyzing BSM/PVA solutions through physiochemical assays such as electrical conductivity, viscosity and surface tension tests. According to the thermal analysis (TGA/DSC), incorporation of PVA enhanced thermal stability of the samples. Successful fabrication of the nanofibers is verified by FT-IR spectra, where no major chemical interaction between BSM and PVA is detected. The crystallinity of the electrospun nanofibers is investigated by XRD, revealing the nearly amorphous structure of BSM/PVA scaffolds. The MTT assay is employed to verify the biocompatibility of the scaffolds. The cell culture experiment using epithelial Vero cells shows the affinity of the cells to adhere to their nanofibrous substrate and grow to form continuous cell layers after 72 h of incubation.

Production and characterization of biocompatible nanofibrous scaffolds made ofß-sitosterolloaded polyvinyl alcohol/tragacanth gum composites.

Electrospun polyvinyl alcohol (PVA) and tragacanth gum (TG) were used to develop nanofibrous scaffolds containing poorly water-solubleß-Sitosterol (ß-S). Different concentrations and ratios of the polymeric composite includingß-S (10% w v-1) in PVA (8% w v-1) combined with TG (0.5 and 1% w v-1) were prepared and electrospun. The synthesis method includes four electrospinning parameters of solution concentration, feeding rate, voltage, and distance of the collector to the tip of the needle, which are independently optimized to achieve uniform nanofibers with a desirable mean diameter for cell culture. The collected nanofibers were characterized by SEM, FTIR, and XRD measurements. A contact angle measurement described the hydrophilicity of the scaffold. MTT test was carried out on the obtained nanofibers containing L929 normal fibroblast cells. The mechanical strength, porosity, and deterioration of the scaffolds were well discussed. The mean nanofiber diameters ranged from 63 ± 20 nm to 97 ± 46 nm. The nanofibers loaded withß-S were freely soluble in water and displayed a remarkable biocompatible nature. The cultured cells illustrated sheet-like stretched growth morphology and penetrated the nanofibrous pores of the PVA/ß-S/TG scaffolds. The dissolution was related to submicron-level recrystallization ofß-S with sufficient conditions for culturing L929 cells. It was concluded that electrospinning is a promising technique for poorly water-solubleß-S formulations that could be used in biomedical applications.

Quince seed mucilage coated iron oxide nanoparticles for plasmid DNA delivery.

This study investigates the potential of iron oxide nanoparticles (Fe3O4) and quince seed mucilage as combined genetic carriers to deliver plasmid DNA (pDNA) through the gastrointestinal system. The samples are characterized by x-ray diffraction (XRD), zeta potential, dynamic light scattering, FT-IR spectroscopy, field emission scanning electron microscopy and vibrating sample magnetometry. The stability of pDNA loading on the nanocarriers and their release pattern are evaluated in simulated gastrointestinal environments by electrophoresis. The XRD patterns reveal that the nanocarriers could preserve their structure during various synthesis levels. The saturation magnetization (Ms) of the Fe3O4cores are 56.48 emu g-1without any magnetic hysteresis. Not only does the loaded pDNA contents experience a remarkable stability in the simulated gastric environment, but also, they could be released up to 99% when exposed to an alkaline environment similar to the intestinal fluid of fish. The results indicate that the synthesized nanoparticles could be employed as efficient low-cost pDNA carriers.

Evaluationof the New Outer Membrane Protein A Epitope-based Vaccines for Mice Model of Acinetobacter baumannii Associated Pneumonia and Sepsis Infection.

Nosocomial infections caused by Acinetobacter baumannii (A. baumannii) nosocomial infections caused by Acinetobacter baumannii (A. baumannii) are considered as a global serious problem in hospitalized patients because of emerging antibiotic resistance. Immunotherapy approaches are promising to prevent such infections. In our previous study, five antigenic epitopes of outer membrane protein A (OmpA), as the most dangerous virulence molecule in A. baumanii, were predicted in silico. In this study, the investigators evaluated some immunological aspects of the peptides. Five peptides were separately injected into C5BL/6 mice; then the cytokine production (interleukin-4 and interferon-gamma) of splenocytes and opsonophagocytic activity of immunized serum were assessed. To identify the protective function of the peptides, animal models of sepsis and pneumonia infections were actively and passively immunized with selected peptides and pooled sera of immunized mice, respectively. Then, survival rates of them were compared with the non-infected controls. Based on the results, activated spleen cells in P127 peptide-immunized mice exhibited an increase level of IFN-γ compared with the other experimental groups, but not about the IL-4 concentration. The results of opsonophagocytic assay revealed an appropriate killing activity of produced antibodies against A. baumannii in a dose-dependent manner. Further, the survival rates of the mice under passive immunization with the immunized sera or active immunization with P127 peptide were significantly more than those in the control group. Moreover, the survival rate of the P127 peptide immunized group was considerably higher than that among the other peptide-immunized group. In conclusion, findings indicated that peptides derived from outer membrane protein-A can be used as a promising tool for designing the epitope-based vaccines against infections caused by A. baumannii.

Flooding or drought which one is more offensive on pepper physiology and growth?

Both extreme usage of water in agriculture i.e., drought and flooding affect physiological and growth aspects of the plant as well as gene expression undertaken in water absorption. These affect depend on the stress duration i.e., shock or gradual stress exposer. The factorial experiment based on CRD with 10 replicates was conducted to investigate the physiological and water relation as well as aquaporin expression in (Capsicum annuum L.). Drought stress was applied gradually from - 2, - 3, - 4 to - 5 MPa during 8 days but in shock stress - 5 MPa applied at one time. The gradual flooding stress adjusted with changing the aeration duration from 15 to 0 min gradually every 2 days and for the shock- flooding, peppers keep in a nutrient solution without aeration in a sealed container. Results showed that both extreme water stress had a deleterious effect on the growth and physiological parameter of pepper for a longer duration. Antioxidant, proline, fluorescence chlorophyll stimulate in the gradual period except for ABA content, which is higher in shock stress. PIP1expression showed a reverse effect in leaf and root at flooding i.e., PIP1expression raised in root while it was reduced in leaf at shock-flooding. The highest PIP1expression was observed in gradual-drought of root and gradual duration of drought and flooding stress in leaf. In the physiological aspect of plant response to stress in pepper, results showed an enhanced in proline and phenol content to help osmotic adjustment and keep water status in moderate condition. Conclusively, shocked stress first, motivated these defense systems, and then in the next step, the other adaptive mechanism like gene expression activated to help pepper face stress. On the other hand, shock stress showed down-regulation, but when the stress lasted for a longer time results in up-regulation.

CAR-T cells: Early successes in blood cancer and challenges in solid tumors.

New approaches to cancer immunotherapy have been developed, showing the ability to harness the immune system to treat and eliminate cancer. For many solid tumors, therapy with checkpoint inhibitors has shown promise. For hematologic malignancies, adoptive and engineered cell therapies are being widely developed, using cells such as T lymphocytes, as well as natural killer (NK) cells, dendritic cells, and potentially others. Among these adoptive cell therapies, the most active and advanced therapy involves chimeric antigen receptor (CAR)-T cells, which are T cells in which a chimeric antigen receptor is used to redirect specificity and allow T cell recognition, activation and killing of cancers, such as leukemia and lymphoma. Two autologous CAR-T products have been approved by several health authorities, starting with the U.S. Food and Drug Administration (FDA) in 2017. These products have shown powerful, inducing, long-lasting effects against B cell cancers in many cases. In distinction to the results seen in hematologic malignancies, the field of using CAR-T products against solid tumors is in its infancy. Targeting solid tumors and trafficking CAR-T cells into an immunosuppressive microenvironment are both significant challenges. The goal of this review is to summarize some of the most recent aspects of CAR-T cell design and manufacturing that have led to successes in hematological malignancies, allowing the reader to appreciate the barriers that must be overcome to extend CAR-T therapies to solid tumors successfully.

Sphingomyelin liposome bearing whole Leishmania lysate antigens induce strong Th2 immune response in BALB/c mice.

OBJECTIVES: Whole Leishmania lysate antigens (WLL) has been shown to be effective to tackle leishmaniasis in murine models. Although liposomes can be considered as promising vaccines, the activity of phospholipase-A (PLA) in WLL, breeds difficulties to preparing stable liposomal WLL. One strategy to overcome this shortcoming is to use lipids such as sphingomyelin (SM) which is resistant against PLA. This study aim is formulating stable SM liposomes containing WLL and comparing their adjuvant effects with another first generation vaccine , i.e. solube Leishmania Antigen (SLA) liposomes in BALB/c mice. MATERIALS AND METHODS: BALB/c mice were immunized subcutaneously, three times with 2-week intervals, with Empty-liposome (E-lipo), Particulate WLL, Liposome-WLL, Liposome-SLA and control Buffer, three times every 2-week. Protection was assessed through measuring the swollen footpads and the load of parasites in the spleen. Other factors were used to assess the response of immune system by means of IgG subclasses, IL-4 and IFN-γ levels and intracellular cytokine assay in cultured splenocytes. RESULTS: Although liposomal WLL were stable in terms of physicochemical properties, mice received Liposome-WLL did not reduce footpad swelling. The load of parasites in spleen and levels of IL-4- were also higher compared to other immunized groups. In terms of IgG isotypes, no considerable difference observed in mice received Liposome-WLL or other formulations. CONCLUSION: Liposome-WLL could be a suitable vaccine delivery system when a Th2 response is desired. Also, further studies are warranted to fully understand the role of sphingomyelin in inducing an immune response.

Serum Levels of Soluble Fas and Fas Ligand in Iranian Women with Pre-eclampsia.

BACKGROUND: The precise responsible mechanism of pre-eclampsia remains controversial however, recent data suggest a main role of the abnormal activation of the adaptive immune system and Apoptosis. In this study, we have measured serum levels of Fas/Fasl as two important members of extrinsic apoptotic pathway in patient with pre-eclampsia. METHODS: 207 participants including 99 pre-eclampsia patients and 108 age and sex-matched normal pregnant women were involved in the case-control study. Plasma sample from each participant was collected and stored at -20 °C until batch processing.Serum levels of Fas and Fas ligand were measured by ELISA for each participant including 99 pre-eclampsia patients and 108 normal pregnant women. Following a test of statistical normality, nonparametric data were analyzed by Mann-Whitney. RESULTS: sFas levels in case group was significantly higher than controls; 584 (397-892) pg/ml in cases opposed to 341 (213-602) pg/ml in controls (p value< 0.01). sFasL in pre-eclampsia women was a little lower than controls; 255 (173-318) pg/ml and in case group compared to 265.5 (184-381.5) pg/ml in controls. CONCLUSION: We have found the increased levels of sFas in patients with pre-eclampsia in compare with the healthy pregnant women. It seems that abnormality in sFAS is related with pre-eclampsia.