Association of SLC19A1 Gene Polymorphisms and Its Regulatory miRNAs with Methotrexate Toxicity in Children with Acute Lymphoblastic Leukemia.

Methotrexate (MTX) is an anti-folate chemotherapeutic agent that is considered to be a gold standard in Acute Lymphoblastic Leukemia (ALL) therapy. Nevertheless, toxicities induced mainly due to high doses of MTX are still a challenge for clinical practice. MTX pharmacogenetics implicate various genes as predictors of MTX toxicity, especially those that participate in MTX intake like solute carrier family 19 member 1 (SLC19A1). The aim of the present study was to evaluate the association between SLC19A1 polymorphisms and its regulatory miRNAs with MTX toxicity in children with ALL. A total of 86 children with ALL were included in this study and were all genotyped for rs2838958, rs1051266 and rs1131596 SLC19A1 polymorphisms as well as the rs56292801 polymorphism of miR-5189. Patients were followed up (48, 72 and 96 h) after treatment with MTX in order to evaluate the presence of MTX-associated adverse events. Our results indicate that there is a statistically significant correlation between the rs1131596 SLC19A1 polymorphism and the development of MTX-induced hepatotoxicity (p = 0.03), but there is no significant association between any of the studied polymorphisms and mucositis or other side effects, such as nausea, emesis, diarrhea, neutropenia, skin rash and infections. In addition, when genotype TT of rs1131596 and genotype AA of rs56292801 are both present in a patient then there is a higher risk of developing severe hepatotoxicity (p = 0.0104).

Hybrid Nanogel Drug Delivery Systems: Transforming the Tumor Microenvironment through Tumor Tissue Editing.

The future of drug delivery offers immense potential for the creation of nanoplatforms based on nanogels. Nanogels present a significant possibility for pharmaceutical advancements because of their excellent stability and effective drug-loading capability for both hydrophobic and hydrophilic agents. As multifunctional systems, composite nanogels demonstrate the capacity to carry genes, drugs, and diagnostic agents while offering a perfect platform for theranostic multimodal applications. Nanogels can achieve diverse responsiveness and enable the stimuli-responsive release of chemo-/immunotherapy drugs and thus reprogramming cells within the TME in order to inhibit tumor proliferation, progression, and metastasis. In order to achieve active targeting and boost drug accumulation at target sites, particular ligands can be added to nanogels to improve the therapeutic outcomes and enhance the precision of cancer therapy. Modern "immune-specific" nanogels also have extra sophisticated tumor tissue-editing properties. Consequently, the introduction of a multifunctional nanogel-based drug delivery system improves the targeted distribution of immunotherapy drugs and combinational therapeutic treatments, thereby increasing the effectiveness of tumor therapy.

Immune Specific and Tumor-Dependent mRNA Vaccines for Cancer Immunotherapy: Reprogramming Clinical Translation into Tumor Editing Therapy.

Extensive research into mRNA vaccines for cancer therapy in preclinical and clinical trials has prepared the ground for the quick development of immune-specific mRNA vaccines during the COVID-19 pandemic. Therapeutic cancer vaccines based on mRNA are well tolerated, and are an attractive choice for future cancer immunotherapy. Ideal personalized tumor-dependent mRNA vaccines could stimulate both humoral and cellular immunity by overcoming cancer-induced immune suppression and tumor relapse. The stability, structure, and distribution strategies of mRNA-based vaccines have been improved by technological innovations, and patients with diverse tumor types are now being enrolled in numerous clinical trials investigating mRNA vaccine therapy. Despite the fact that therapeutic mRNA-based cancer vaccines have not yet received clinical approval, early clinical trials with mRNA vaccines as monotherapy and in conjunction with checkpoint inhibitors have shown promising results. In this review, we analyze the most recent clinical developments in mRNA-based cancer vaccines and discuss the optimal platforms for the creation of mRNA vaccines. We also discuss the development of the cancer vaccines' clinical research, paying particular attention to their clinical use and therapeutic efficacy, which could facilitate the design of mRNA-based vaccines in the near future.

Immunoengineering via Chimeric Antigen Receptor-T Cell Therapy: Reprogramming Nanodrug Delivery.

Following its therapeutic effect in hematological metastasis, chimeric antigen receptor (CAR) T cell therapy has gained a great deal of attention during the last years. However, the effectiveness of this treatment has been hampered by a number of challenges, including significant toxicities, difficult access to tumor locations, inadequate therapeutic persistence, and manufacturing problems. Developing novel techniques to produce effective CARs, administer them, and monitor their anti-tumor activity in CAR-T cell treatment is undoubtedly necessary. Exploiting the advantages of nanotechnology may possibly be a useful strategy to increase the efficacy of CAR-T cell treatment. This study outlines the current drawbacks of CAR-T immunotherapy and identifies promising developments and significant benefits of using nanotechnology in order to introduce CAR transgene motifs into primary T cells, promote T cell expansion, enhance T cell trafficking, promote intrinsic T cell activity and rewire the immunosuppressive cellular and vascular microenvironments. Therefore, the development of powerful CART cells can be made possible with genetic and functional alterations supported by nanotechnology. In this review, we discuss the innovative and possible uses of nanotechnology for clinical translation, including the delivery, engineering, execution, and modulation of immune functions to enhance and optimize the anti-tumor efficacy of CAR-T cell treatment.

Olanzapine's Cytogenetic Effect on T Lymphocytes in Systemic Lupus Erythematosus and Rheumatoid Arthritis Patients: In Vitro Study.

OBJECTIVES: This study will investigate olanzapine's cytogenetic behavior in cultured human T lymphocytes in patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). METHODS: Three olanzapine solutions were added in cultures of peripheral blood lymphocytes of healthy individuals, SLE, and RA patients. After 72 hours of incubation, the cultured lymphocytes were plated on glass slides and stained with the fluorescence plus Giemsa method. Sister chromatid exchanges (SCEs), proliferation rate index (PRI), and mitotic index (MI) were measured with the optical microscope. RESULTS: There was a statistically significant (p=0.001) dose-dependent increase of SCEs in SLE and RA patients compared to healthy individuals and a statistically significant (p=0.001) reduction of PRI and MI in the highest concentration in the SLE group. Moreover, Spearman's rank correlation coefficient was applied to calculate the correlation between SCEs, PRI, and MI. Negative significant correlations were noticed for both patient groups concerning SCEs-PRI alterations and SCEs-MI alterations. Conversely, positive correlations were noticed for both patient groups for PRI-MI alterations.  Conclusions: Olanzapine affects T lymphocytes from SLE and RA patients by modifying DNA replication procedures and DNA damage response. Considering the use of olanzapine in neuropsychiatric symptoms of SLE, further in vivo studies are necessary to evaluate its effect on human DNA.

Tumor cell metabolic reprogramming and hypoxic immunosuppression: driving carcinogenesis to metastatic colonization.

A significant factor in the antitumor immune response is the increased metabolic reprogramming of immunological and malignant cells. Increasing data points to the fact that cancer metabolism affects not just cancer signaling, which is essential for maintaining carcinogenesis and survival, but also the expression of immune cells and immune-related factors such as lactate, PGE2, arginine, IDO, which regulate the antitumor immune signaling mechanism. In reality, this energetic interaction between the immune system and the tumor results in metabolic competition in the tumor ecosystem, limiting the amount of nutrients available and causing microenvironmental acidosis, which impairs the ability of immune cells to operate. More intriguingly, different types of immune cells use metabolic reprogramming to keep the body and self in a state of homeostasis. The process of immune cell proliferation, differentiation, and performance of effector functions, which is crucial to the immune response, are currently being linked to metabolic reprogramming. Here, we cover the regulation of the antitumor immune response by metabolic reprogramming in cancer cells and immune cells as well as potential strategies for metabolic pathway targeting in the context of anticancer immunotherapy. We also discuss prospective immunotherapy-metabolic intervention combinations that might be utilized to maximize the effectiveness of current immunotherapy regimes.

Engineered multifunctional nanocarriers for controlled drug delivery in tumor immunotherapy.

The appearance of chemoresistance in cancer is a major issue. The main barriers to conventional tumor chemotherapy are undesirable toxic effects and multidrug resistance. Cancer nanotherapeutics were developed to get around the drawbacks of conventional chemotherapy. Through clinical evaluation of thoughtfully developed nano delivery systems, cancer nanotherapeutics have recently offered unmatched potential to comprehend and combat drug resistance and toxicity. In different design approaches, including passive targeting, active targeting, nanomedicine, and multimodal nanomedicine combination therapy, were successful in treating cancer in this situation. Even though cancer nanotherapy has achieved considerable technological development, tumor biology complexity and heterogeneity and a lack of full knowledge of nano-bio interactions remain important hurdles to future clinical translation and commercialization. The recent developments and advancements in cancer nanotherapeutics utilizing a wide variety of nanomaterial-based platforms to overcome cancer treatment resistance are covered in this article. Additionally, an evaluation of different nanotherapeutics-based approaches to cancer treatment, such as tumor microenvironment targeted techniques, sophisticated delivery methods for the precise targeting of cancer stem cells, as well as an update on clinical studies are discussed. Lastly, the potential for cancer nanotherapeutics to overcome tumor relapse and the therapeutic effects and targeted efficacies of modern nanosystems are analyzed.

Tumor-Infiltrating Dendritic Cells: Decisive Roles in Cancer Immunosurveillance, Immunoediting, and Tumor T Cell Tolerance.

The tumor microenvironment plays a key role in progression of tumorigenesis, tumor progression, and metastasis. Accumulating data reveal that dendritic cells (DCs) appear to play a key role in the development and progression of metastatic neoplasia by driving immune system dysfunction and establishing immunosuppression, which is vital for tumor evasion of host immune response. Consequently, in this review, we will discuss the function of tumor-infiltrating DCs in immune cell signaling pathways that lead to treatment resistance, tumor recurrence, and immunosuppression. We will also review DC metabolism, differentiation, and plasticity, which are essential for metastasis and the development of lung tumors. Furthermore, we will take into account the interaction between myeloid cells and DCs in tumor-related immunosuppression. We will specifically look into the molecular immune-related mechanisms in the tumor microenvironment that result in reduced drug sensitivity and tumor relapse, as well as methods for combating drug resistance and focusing on immunosuppressive tumor networks. DCs play a crucial role in modulating the immune response. Especially, as cancer progresses, DCs may switch from playing an immunostimulatory to an inhibitory role. This article's main emphasis is on tumor-infiltrating DCs. We address how they affect tumor growth and expansion, and we highlight innovative approaches for therapeutic modulation of these immunosuppressive DCs which is necessary for future personalized therapeutic approaches.

Peripheral Osteoma of the Mandibular Condyle-Case Series.

The purpose of this article is to present four new cases of peripheral osteoma of the mandibular condyle and the literature review. A retrospective study of files from our Department of Oral and Maxillofacial Surgery over the last 6 years revealed four cases of peripheral osteomas located in the area of the mandibular condyle. Diagnostic procedure included clinical, radiographic, and histologic criteria. Gardner's syndrome was excluded from patient history and clinical evaluation. One patient had only an aesthetic disturbance, with facial swelling, and the other three patients presented disturbances of the mandibular function, including deviation during mouth opening along with malocclusion. Three of the patients were male and one was female; all were of middle age (45-65 years old). The proposed surgical treatment was accepted by half of the patients, while the remaining half declined the operation after a confirmation of the diagnosis. Peripheral osteomas of the maxillofacial region are uncommon, and some cases with multiple osteomas are related to Gardner's syndrome. An osteoma of the mandibular condyle is very rare and surgical treatment is challenging for the surgeon with regards to the approach selection and the related complications. In the two cases that accepted the proposed surgical treatment, no recurrence and no complication was observed.

Engineered Hybrid Treg-Targeted Nanosomes Restrain Lung Immunosuppression by Inducing Intratumoral CD8+T Cell Immunity.

Introduction: Tumor immunotherapy is a key therapeutic paradigm for the treatment of several malignancies. However, in metastatic lung cancer, classical immunotherapy regimes are ineffective due to regulatory T cell (Treg)-related immunosuppression and tumor relapse. Materials: To address this issue, we designed specific biocompatible Treg-targeted nanocarriers (NCs) as a model of immune-based nanotherapy, in order to target Treg-related immunosuppression in the lung tumor microenvironment. This is achieved through the combination of Dasatinib and Epacadostat integrated into biodegradable nanosomes which can inhibit and reverse Treg-supporting immunosuppression. Flow cytometry and immunofluorescence analysis, PET/CT scan, PTT/PA imaging and the Balb/c tumor model were used to explore the anti-tumor effect of Treg-targeted NCs both in vitro and in vivo. Results: Findings reveal that NC treatment triggered substantial tumor cell apoptosis and drastically decreased tumor volume followed by downregulation of Ki-67 antigen expression, respectively. Drug circulation time was also increased as shown by biodistribution analysis accompanied by greater accumulation in lung and peripheral tissues. Intratumoral Th1 cytokines' expression was also increased, especially TNF-A, IL-12 by 42%, and IL-6 by 18% compared to PBS treatment. In addition, the presence of mature CD80+/CD86+dendritic cells (DCs) revealed T cell enrichment and a decline in MDSC infiltration and myeloid subsets. Interestingly, a significant decline of Gr/CD11b myeloid cell population in blood and tissue samples was also observed. This immune activation can be attributed to the enhanced PTT efficiency and tumor targeting ability of the nanospheres which under near infrared (NIR) exposure can prompt highly efficient tumor ablation. We also demonstrated their therapeutic efficacy against 4T1 metastatic breast cancer model. Additionally, the photothermal therapy in combination with PD-L1 checkpoint blockade therapy exerted long-term tumor control over both primary and distant tumors. Discussion: Overall, our findings present a novel nano-enabled platform for the inhibition of Treg-dependent immunosuppression in NSCLC and provide a novel nanotherapeutic strategy for the treatment of metastatic neoplasia.

Molecular and Immune Phenotypic Modifications during Metastatic Dissemination in Lung Carcinogenesis.

The tumor microenvironment plays a key role in the progression of lung tumorigenesis, progression, and metastasis. Recent data reveal that disseminated tumor cells (DTCs) appear to play a key role in the development and progression of lung neoplasiaby driving immune system dysfunction and established immunosuppression, which is vital for evading the host immune response. As a consequence, in this review we will discuss the role and function of DTCs in immune cell signaling routes which trigger drug resistance and immunosuppression. We will also discuss the metabolic biology of DTCs, their dormancy, and their plasticity, which are critical for metastasis and drive lung tumor progression. Furthermore, we will consider the crosstalk between DTCs and myeloid cells in tumor-related immunosuppression. Specifically, we will investigate the molecular immune-related mechanisms in the tumor microenvironment that lead to decreased drug sensitivity and tumor relapse, along with strategies for reversing drug resistance and targeting immunosuppressive tumor networks. Deciphering these molecular mechanisms is essential for preclinical and clinical investigations in order to enhance therapeutic efficacy. Furthermore, a better understanding of these immune cell signaling pathways that drive immune surveillance, immune-driven inflammation, and tumor-related immunosuppression is necessary for future personalized therapeutic approaches.

Epigenetic editing and tumor-dependent immunosuppressive signaling in head and neck malignancies.

Head and neck cancer (HNC) comprises a heterogeneous variety of malignant tumors, characterized by a relatively high tumor mutation burden. Previous data have revealed that immune system dysfunction appears to serve a key role in the development and progression of HNC and established immunosuppression is vital for evading the host immune response. Despite progress in chemotherapy and radiotherapy, the survival rate of patients with HNC is still low. Therefore, the present review discusses the development of novel immunotherapy approaches based on the various immune cell signaling routes that trigger drug resistance and immunosuppression. Additionally, the present review discusses the epigenetic alterations, including DNA methylation, histone modifications, chromatin remodeling and non-coding RNAs that drive and support HNC progression. Furthermore, the role of cancer-associated fibroblasts, tumor macrophages and myeloid cells in tumor-related immunosuppression are considered. Specifically, the molecular immune-related mechanisms in the tumor microenvironment, which lead to decreased drug sensitivity and tumor relapse, and strategies for reversing drug resistance and targeting immunosuppressive tumor networks are discussed. Deciphering these molecular mechanisms is essential for preclinical and clinical investigations in order to enhance therapeutic efficacy. Furthermore, an improved understanding of these immune cell signaling pathways that drive immune surveillance, immune-driven inflammation and tumor-related immunosuppression is necessary for future personalized HNC-based therapeutic approaches.

Hepatitis A and E in the Mediterranean: A systematic review.

Hepatitis A (HAV) and Hepatitis E (HEV) considered to be major public health threats worldwide. Although, both infections are more common in developing countries, an increased number of HAV and HEV cases have been reported in developed countries. This systematic review analyzes epidemiological profiles of HAV and HEV in the Mediterranean countries. By using PRISMA guideline, we searched for articles from 2010 to 2020 referring HAV and HEV outbreaks from online databases: Scopus, PubMed and Springerlink. From 33265 unique publications initially captured, data was extracted from 101 articles investigating country and year of outbreak, transmission mode, vehicle of infection, mean age and sex of patients, symptoms reported, vaccination applied and diagnostic method. Our results indicate that occurrence of HAV and HEV in Mediterranean countries had increased with main transmission vehicle reported as food or water and transmission point as refugee camps. More results (countries, differences, other characteristics). Thus, public health authorities should give a priority to face up challenges regarding the prevalence of both viruses and control strategies to prevent upcoming outbreaks.

Kras-driven intratumoral heterogeneity triggers infiltration of M2 polarized macrophages via the circHIPK3/PTK2 immunosuppressive circuit.

Intratumoral heterogeneity in lung cancer is essential for evasion of immune surveillance by tumor cells and establishment of immunosuppression. Gathering data reveal that circular RNAs (circRNAs), play a role in the pathogenesis and progression of lung cancer. Particularly Kras-driven circRNA signaling triggers infiltration of myeloid-associated tumor macrophages in lung tumor microenvironment thus establishing immune deregulation, and immunosuppression but the exact pathogenic mechanism is still unknown. In this study, we investigate the role of oncogenic Kras signaling in circRNA-related immunosuppression and its involvement in tumoral chemoresistance. The expression pattern of circRNAs HIPK3 and PTK2 was determined using quantitative polymerase chain reaction (qPCR) in lung cancer patient samples and cell lines. Apoptosis was analyzed by Annexin V/PI staining and FACS detection. M2 macrophage polarization and MDSC subset analysis (Gr1-/CD11b-, Gr1-/CD11b+) were determined by flow cytometry. Tumor growth and metastatic potential were determined in vivo in C57BL/6 mice. Findings reveal intra-epithelial CD163+/CD206+ M2 macrophages to drive Kras immunosuppressive chemoresistance through myeloid differentiation. In particular, monocytic MDSC subsets Gr1-/CD11b-, Gr1-/CD11b+ triggered an M2-dependent immune response, creating an immunosuppressive tumor-promoting network via circHIPK3/PTK2 enrichment. Specifically, upregulation of exosomal cicHIPK3/PTK2 expression prompted Kras-driven intratumoral heterogeneity and guided lymph node metastasis in C57BL/6 mice. Consequent co-inhibition of circPTK2/M2 macrophage signaling suppressed lung tumor growth along with metastatic potential and prolonged survival in vivo. Taken together, these results demonstrate the key role of myeloid-associated macrophages in sustaining lung immunosuppressive neoplasia through circRNA regulation and represent a potential therapeutic target for clinical intervention in metastatic lung cancer.

Correlation of miR-146a-5p plasma levels and rs2910164 polymorphism with left ventricle outflow tract obstruction in hypertrophic cardiomyopathy.

OBJECTIVE: Hypertrophic cardiomyopathy (HCM) is a genetic disease of the myocardium that is characterized by phenotypic variability among patients. miR-146a is a small non-coding RNA that is well known for its role in inflammation and myocardial hypertrophy. The aim of this study is to evaluate the role of miR-146a as a candidate genetic factor influencing HCM phenotype. METHODS: In this study, 140 HCM patients and 112 control individuals were genotyped for the rs2910164 single nucleotide polymorphism (SNP) in the MIR146A gene; using this data, the correlation between different genotypes and clinical features of the disease were determined. Additionally, plasma levels of miR-146a-5p were determined in 50 HCM patients and 30 control individuals by using qPCR. RESULTS: The incidence of GC and CC genotypes were significantly lower in HCM patients (odds ratio (OR) = 0.5 [0.3-0.8], p = 0.007). The GC/CC genotypes in the dominant genetic model positively correlated with the presence of left ventricle outflow tract (LVOT) obstruction (OR = 2.3 [1.2-4.7] and p = 0.018), a higher left ventricle mass index (118 ± 47 g/m2 vs 92 ± 42 g/m2 and p = 0.02), and increased left ventricle end-diastolic diameter (4.66 ± 0.64cm vs 4.39 ± 0.7cm and p = 0.026). Atrial fibrillation was significantly higher in patients homozygous for the C allele (OR = 10.6 [2-55], p = 0.003). Interestingly, the plasma levels of miR-146a-5p were significantly increased in HCM patients with LVOT obstruction. CONCLUSION: Our findings indicate that the C allele of the rs2910164 SNP might be under negative selection in HCM patients. Additionally, plasma levels of miR-146a-5p and GC/CC genotypes are indicative of the obstructive phenotype in HCM patients.

Treg-dependent immunosuppression triggers effector T cell dysfunction via the STING/ILC2 axis.

Lung cancer remains the leading cause of cancer-related deaths and despite extensive research, the survival rate of lung cancer patients remains significantly low. Recent data reveal that aberrant Kras signaling drives regulatory T cells (Tregs) present in lung tumor microenvironment to establish immune deregulation and immunosuppression but the exact pathogenic mechanism is still unknown. In this study, we investigate the role of oncogenic Kras in Treg-related immunosuppression and its involvement in tumor-associated metabolic reprogramming. Findings reveal Tregs to prompt GATA3/NOS2-related immunosuppression via STING inhibition which triggers a decline in CD4+ T infiltration, and a subsequent increase in lung metastatic burden. Enhanced Treg expression was also associated with low T/MDSC ratio through restriction of CD8+CD44+CD62L- T effector cells, contributing to a tumor-promoting status. Specifically, TIM3+/LAG3+ Tregs prompted Kras-related immunosuppressive chemoresistance and were associated with T cell dysfunction. This Treg-dependent immunosuppression correlated with CD8 T cell exhaustion phenotype and ILC2 augmentation in mice. Moreover, enhanced Treg expression promoted activation-induced cell death (AICD) of T lymphocytes and guided lymph node metastasis in vivo. Overall, these findings demonstrate the multifaceted roles of Tregs in sustaining lung immunosuppressive neoplasia through tumor microenvironment remodeling and provide new opportunities for effective metastasis inhibition, especially in chemoresistant tumors.

Exosomal lncRNA PCAT-1 promotes Kras-associated chemoresistance via immunosuppressive miR-182/miR-217 signaling and p27/CDK6 regulation.

Immunosuppressive chemoresistance is a major burden in lung cancer. Recent data reveal that long noncoding RNAs (lncRNAs) present in the lung tumor microenvironment are implicated in chemoresistant-related immune deregulation, and metastasis but their exact pathogenic role is still unknown. In this study, we investigate the role of lncRNA PCAT-1 in chemoresistant immunosuppression and its involvement in tumor stroma remodeling. Findings reveal PCAT-1 to regulate Kras-related lung chemoresistance through increased expression of the immunosuppressive micrornas miR-182/miR217 in lung tissues, thus promoting a pre-metastatic niche formation and a subsequent increase in lung metastatic burden. Elevated expression of PCAT-1 negative regulates p27/CDK6 expression by inducing G0/G1 cell cycle arrest through AMPK augmentation, contributing to a tumor-promoting status. Furthermore, PCAT-1 triggered fibroblast differentiation followed by CAF/myofibroblast secretion in TME triggering a CD133/SOX2-related stem cell phenotype. Subsequent PCAT-1 knockdown impaired CAF-mediated stromal activation, and reversed chemoresistance and tumor growth in vivo. Overall, these findings demonstrate the versatile roles of PCAT-1 in sustaining lung immunosuppressive neoplasia through tumor microenvironment remodeling and provide new opportunities for effective metastasis inhibition, especially in chemoresistant tumors.

Dual photothermal MDSCs-targeted immunotherapy inhibits lung immunosuppressive metastasis by enhancing T-cell recruitment.

Immunosuppressive chemoresistance is a major barrier in lung cancer treatment. However, the immunosuppressive mechanisms responsible for lung cancer cell chemoresistance and tumor relapse are still unknown. In this study, we introduce a model of precise immunosuppressive-based nanotherapy by designing and delivering biocompatible MDSC-targeted nanocarriers (NCs) into the lung tumor microenvironment. This is accomplished by conjugating l-Norvaline and Sunitinib integrated into biodegradable nanosomes in order to facilitate inhibition of tumor-supporting immunosuppression. Findings show that treatment with NCs increased apoptosis and significantly reduced tumor volume and Ki-67 antigen expression respectively. Biodistribution analysis revealed an increase in drug circulation time, as well as a greater accumulation in lung and peripheral tissues. Furthermore, an upregulation of tumor infiltrating lymphocytes expression was observed, especially CD8+ T cells by 27%, and CD4+ T cells by 7% compared to PBS treatment. The presence of CD161+ (NK1.1) cells revealed NK cell activation followed by decreased MDSC infiltration and MDSC subsets were characterized by the reduction of Gr/CD11b cell population in blood and tissue samples. In addition, these nanospheres, showed increased PTT efficiency and tumour targeting ability as evidenced by highly efficient tumour ablation under near infrared (NIR) exposure. Significant tumor reduction was observed due to recruitment of cytotoxic T-lymphocytes, followed by downregulation of immunosuppressive Foxp3+ Treg cells. Taken together, our findings provide a novel nanodrug delivery strategy for the inhibition of MDSC-related immunosuppression in lung tumor microenvironment and provide a new approach for the efficient treatment of metastatic cancer.

Carboplatin chemoresistance is associated with CD11b+/Ly6C+ myeloid release and upregulation of TIGIT and LAG3/CD160 exhausted T cells.

Immunosuppressive chemoresistance is a major barrier in lung cancer treatment. Tumor immunosuppressive environments mediated by myeloid-derived suppressor cells (MDSCs) play a key role in chemotherapy induced MDSC development and differentiation but their mechanistic role has not been elucidated. Here, we define a role for carboplatin based chemotherapy in potentiating an MDSC-dependent pathway that triggers the chemoresistance mechanism. Findings reveal MDSC differentiation and activation of IL-13/IL-33-mediated pathway through VCAM/RANTES following carboplatin treatment. Furthemore, secretion of T regulatory IL-10-producing CD4+Foxp3+ cells was increased followed by expression of co-inhibitory receptor TIGIT on T cells, leading to a dysfunctional T cell phenotype. These cells were characterized by an immunosuppressive phenotype with impaired activation, proliferation and cytokine production. Lung cancer tissues expressed CD155, which bound TIGIT receptors and inactivated CD8 T cells. This TIGIT expression on tumor-infiltrating T cells was found to be associated with tumor progression and was linked to functional exhaustion of T cells. In addition, the presence of plasmacytoid dendritic cells (pDCs) exposed to tumor-derived factors further enhanced tumor progression through IL-10 production and up-regulation of the inducible co-stimulatory ligand (ICOS-L). Deciphering these deranged immune mechanisms and how they are impacted by chemotherapy induction is essential for incorporation of novel immune-based strategies in order to restore immunity and inhibit the immunosuppressive phenotype of metastatic lung cancer.

The genetic population structure and temporal genetic stability of gilthead sea bream Sparus aurata populations in the Aegean and Ionian Seas, using microsatellite DNA markers.

We examined 662 gilthead sea bream Sparus aurata from wild samples of the species in the Aegean and Ionian Seas, using 20 EST-linked microsatellite markers, in three multiplex panels, as well as seven anonymous loci. Most of the markers were revealed to be highly polymorphic. We found low genetic differentiation between the sampling stations/areas with total FST 0.002 (P < 0.05). Based on comparison of five temporal samples, our results indicate genetic data consistency over time for all tested samples, pointing to stable populations, despite reported repeated escape events. Our results confirm the genetic population structure previously observed in these specific areas, using by far more markers than in previous studies in both coding and non-coding DNA loci. The limited genetic structure and the temporal genetic stability indicate neither major genetic differentiation of local populations by geographic isolation nor influence from anthropogenic factors. These results provide a baseline for future reference in any management programme of both wild and farmed population of S. aurata as well as of other aquaculture species with a potential introgression among farmed and wild populations.