Suppressor Factor Research Articles

Prognostic Significance and Immunological Role of FBXO5 in Human Cancers: A Systematic Pan-Cancer Analysis.

F-box protein 5 (FBXO5), an essential subunit of the ubiquitin protein ligase complex, is increasingly recognized to exhibit important biological effects in regulating tumor occurrence and progression. The present research was intended to systematically investigate the latent roles of FBXO5 in prognosis and immunological function across cancers. Pan-cancer analyses of FBXO5 were performed based upon publicly available online databases, mainly including the Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), UCSC Xena, cBioPortal, and ImmuCellAI, revealing the possible relationships between FBXO5 and prognosis, DNA methylation, tumor microenvironment (TME), infiltration of immune cells, immune-related genes, immune checkpoints, tumor mutation burden (TMB), and microsatellite instability (MSI). The results suggested that FBXO5 was expressed at a high level in numerous tumor cell lines with significant upregulation in most cancers as opposed to normal tissues. Of note, elevated expression of FBXO5 was significantly related to an unfavorable prognosis in many cancer types. Furthermore, DNA methylation and TME were confirmed to display evident correlation with the expression of FBXO5 in several malignancies. Moreover, FBXO5 expression was remarkably positively correlated with the levels of infiltrating Treg cells and Tcm cells in most tumors, but negatively correlated with tumor-infiltrating CD8+ T cells, NK/NKT cells, and Th2 cells. Meanwhile, FBXO5 was demonstrated to be co-expressed with the genes encoding immune activating and suppressive factors, chemokines, chemokine receptors, and major histocompatibility complex (MHC). Immune checkpoints, TMB, and MSI were also overtly associated with FBXO5 dysregulation among diverse kinds of cancers. Additionally, the enrichment analyses showed close relationships between FBXO5 expression and the processes related to cell cycle and immune inflammatory response. These findings provided a detailed comprehension of the oncogenic function of FBXO5. Because of its crucial roles in cancer immunity and tumorigenesis, FBXO5 may serve as a novel prognostic indicator and immunotherapeutic target for various malignancies.

Chondroitin Sulfates Control Invasiveness of the Basal-Like Breast Cancer Cell Line MDA-MB-231 Through ROR1

Extracellular and cell surface chondroitin sulfates (CSs) regulate cancer cell properties, including proliferation and invasion. Thus, it is necessary to understand the mechanisms underlying their roles in cancer. Although we have shown that CS has an inherent ability to enhance the invasive activity of the human triple-negative breast cancer cell line MDA-MB-231, its molecular mechanism remains elusive. Here, we focused on receptor tyrosine kinase-like orphan receptor 1 (ROR1) and dickkopf WNT signaling pathway inhibitor 1 (DKK1). MDA-MB-231 cells express high levels of ROR1; their invasive potential depends on ROR1 signaling. Although accumulating evidence has demonstrated that ROR1 is associated with aggressive breast-cancer phenotypes, the whole picture of its biological function remains poorly understood. In this study, we examined whether CS controls ROR1 function. Surface plasmon resonance analysis indicated that CSs were bound to ROR1 in the presence of WNT5A. The invasive activity of MDA-MB-231 cells enhanced by CSs was completely suppressed by ROR1 knockdown. In addition, knockdown of the CS biosynthetic enzymes CHST11 and CHST15 inhibited invasive activity, even in the presence of ROR1. These results suggest that CS is required to induce an ROR1-dependent, aggressive MDA-MB-231 phenotype. ROR1 signaling in MDA-MB-231 cells activated c-Jun N-terminal kinase (JNK), leading to increased invasive potential; moreover, exogenous CSs activated JNK. MDA-MB-231 cells express DKK1, a tumor suppressor factor that binds to CS, at high levels. Knockdown of DKK1 enhanced CS-stimulated tumor invasion activity of MDA-MB-231 cells, suggesting that DKK1 sequesters CS to block ROR1/JNK signaling. These results showed that CSs promotes cancer aggressiveness through the ROR1−JNK axis in MDA-MB-231 cells.

Antigen receptor‐engineered Tregs inhibit CNS autoimmunity in cell therapy using nonredundant immune mechanisms in mice

CD4+FOXP3+ Tregs are currently explored to develop cell therapies against immune‐mediated disorders, with an increasing focus on antigen receptor‐engineered Tregs. Deciphering their mode of action is necessary to identify the strengths and limits of this approach. Here, we addressed this issue in an autoimmune disease of the CNS, EAE. Following disease induction, autoreactive Tregs upregulated LAG‐3 and CTLA‐4 in LNs, while IL‐10 and amphiregulin (AREG) were increased in CNS Tregs. Using genetic approaches, we demonstrated that IL‐10, CTLA‐4, and LAG‐3 were nonredundantly required for the protective function of antigen receptor‐engineered Tregs against EAE in cell therapy whereas AREG was dispensable. Treg‐derived IL‐10 and CTLA‐4 were both required to suppress acute autoreactive CD4+ T‐cell activation, which correlated with disease control. These molecules also affected the accumulation in the recipients of engineered Tregs themselves, underlying complex roles for these molecules. Noteworthy, despite the persistence of the transferred Tregs and their protective effect, autoreactive T cells eventually accumulated in the spleen of treated mice. In conclusion, this study highlights the remarkable power of antigen receptor‐engineered Tregs to appropriately provide multiple suppressive factors nonredundantly necessary to prevent autoimmune attacks.

Pulmonary Neuroendocrine Cells and Small Cell Lung Carcinoma: Immunohistochemical Study Focusing on Mechanisms of Neuroendocrine Differentiation.

Neuroendocrine (NE) differentiation has been histochemically detected in normal and cancer tissues and cells. Immunohistochemical analyses have provided a more detailed understanding of NE biology and pathology. Pulmonary NE cells are a rare lung epithelial type, and small cell carcinoma of the lung (SCLC) is a high-grade NE tumor. Pulmonary NE and SCLC cells share common mechanisms for NE differentiation. Neural or NE cell lineage-specific transcription factors, such as achaete-scute homologue 1 (Ascl1) and insulinoma-associated protein 1 (INSM1), are crucial for the development of pulmonary NE cells, and NE differentiation is influenced by the balance between Ascl1 and the suppressive neural transcription factor, hairy-enhancer of split 1, a representative target molecule of the Notch signaling pathway.In this review, we discuss the importance of Ascl1 and INSM1 in identifying pulmonary NE and SCLC cells and introduce Ascl1-related molecules detected by comparative RNA-sequence analyses. The molecular classification of SCLC based on the expression of lineage-specific transcription or co-transcription factors, including ASCL1, NEUROD1, POU2F3, and YAP1, was recently proposed. We attempted to characterize these 4 SCLC subtypes using integrated immunohistochemical studies, which will provide insights into the molecular characteristics of these subtypes and clarify the inter- and intratumor heterogeneities of SCLC.

Effectiveness of phosphodiesterase type 5 inhibitors on the treatment of thin endometrium and pregnancy outcomes: An systematic review

Phosphodiesterase type 5 (PDE5) inhibitors are thought to play a role in increasing endometrial thickness and increasing the success rate of pregnancy outcomes. This study was done to investigate the effects of PDE5 inhibitors on infertile women with thin endometrium and pregnancy outcomes. In this systematic review, all randomized controlled trials (RCTs) and observational studies were retrieved from databases including Institute for Scientific Information (ISI), PubMed, and Scopus by interesting keywords. A checklist was designed to collect necessary data and pregnancy outcomes, and the required items were recorded. PDE5 inhibitors through various mechanisms such as induction of vasodilatory effect through the effect on NO/cGMP signaling on vascular smooth muscle, through regulating cells proliferation and induction angiogenesis by increasing the expression of tumor suppressor factor (p53), and vascular endothelial growth factor A (VEGF-A) and downregulating inflammation by downregulating proinflammatory cytokines, affect endometrial thickness that eventually increases and pregnancy outcomes. Although PDE5s inhibitors increase endometrial thickness by different mechanisms, especially in women with thin endometrial, this does not necessarily mean that they induce a positive effect in all situations. However, their positive effects on pregnancy outcome may be affected by the time of administration, type of infertility treatment, underlying diseases such as pelvic disorders and inflammation. So in this regard, there are still ambiguous aspects that required further RCTs study in this area.

Effects of Exogenous Transferrin on the Regulation of Iron Metabolism and Erythropoiesis in Iron Deficiency With or Without Anemia.

Erythropoietic response is controlled not only by erythropoietin but also by iron. In addition to its role in iron delivery, transferrin also functions as a signaling molecule, with effects on both iron homeostasis and erythropoiesis. We investigated hematologic parameters, iron status and expression of key proteins, including the hepatic iron regulatory protein hepcidin and the suppressive erythroid factor Erfe, in mice subject to dietary iron deficiency with and without anemia. The acute effect of iron on these parameters was investigated by administration of exogenous iron-loaded transferrin (holoTf) in each of the mouse models. Serum iron in mice with iron deficiency (ID) is modestly lower with hematologic parameters maintained by utilization of iron stores in mice with ID. As expected, erythropoietin expression and concentration, along with marrow Erfe are unaffected in ID mice. Administration of holoTf restores serum iron and Tf saturation levels to those observed in control mice and results in an increase in hepcidin compared to ID mice not treated with holoTf. The expression of the Bmp signaling molecule Bmp6 is not significantly increased following Tf treatment in ID mice. Thus, the expression level of the gene encoding hepcidin, Hamp1, is increased relative to Bmp6 expression in ID mice following treatment with holoTf, leading us to speculate that Tf saturation may influence Bmp sensitivity. In mice with iron deficiency anemia (IDA), decreased hematologic parameters were accompanied by pronounced decreases in serum and tissue iron concentrations, and an increase in serum erythropoietin. In the absence of exogenous holoTf, the greater serum erythropoietin was not reflected by an increase in marrow Erfe expression. HoloTf administration did not acutely change serum Epo in IDA mice. Marrow Erfe expression was, however, markedly increased in IDA mice following holoTf, plausibly accounting for the lack of an increase in Hamp1 following holoTf treatment in the IDA mice. The increase in Erfe despite no change in erythropoietin suggests that Tf acts to increase erythropoietin sensitivity. These observations underscore the importance of Tf in modulating the erythropoietic response in recovery from iron deficiency anemia, with implications for other stress erythropoiesis conditions.

The long non-coding RNA LIMT inhibits metastasis of hepatocellular carcinoma and is suppressed by EGF signaling

BackgroundThe long non-coding RNA LIMT (lncRNA inhibiting metastasis) acts as a tumor suppressor factor in some cancers. However, the biological role of LIMT in hepatocellular carcinoma (HCC) has not been explored.Methods and ResultsQuantitative real-time PCR was performed to evaluate the expression of LIMT in HCC tissue. The effects of LIMT on tumor growth and metastasis were assessed by in vitro experiments, including colony formation and transwell assays, and in vivo in nude mouse models. Western blot analysis was used to evaluate the expression levels of proteins associated with epithelial-mesenchymal transition (EMT). LIMT expression was significantly lower in HCC than in normal liver tissue. Functionally, overexpression of LIMT repressed the proliferation, invasion, and EMT of HCC cells, while LIMT knockdown increased proliferation, invasion, and EMT of HCC cells in vitro. Furthermore, LIMT overexpression suppressed HCC growth and metastasis while silencing of LIMT had an opposite effect in vivo. Finally, LIMT overexpression reversed EGF-induced EMT.ConclusionsOur results suggest that LIMT could play an anti-cancer effect in HCC and might be a potential novel therapeutic target in HCC.

A Comprehensive Cancer-Associated MicroRNA Expression Profiling and Proteomic Analysis of Human Umbilical Cord Mesenchymal Stem Cell-Derived Exosomes

Background:The mesenchymal stem cells (MSCs) have enormous therapeutic potential owing to their multi-lineage differentiation and self-renewal properties. MSCs express growth factors, cytokines, chemokines, and non-coding regulatory RNAs with immunosuppressive, anti-tumor, and migratory properties. MSCs also release several anti-cancer molecules via extracellular vesicles, that act as pro-apoptotic/tumor suppressor factors. This study aimed to identify the stem cell-derived secretome that could exhibit anti-cancer properties through molecular profiling of cargos in MSC-derived exosomes.Methods:Human umbilical cord mesenchymal stem cells (hUCMSCs) were isolated from umbilical cord tissues and culture expanded. Subsequently, exosomes were isolated from hUCMSC conditioned medium and characterized by DLS, electron microscopy. Western blot for exosome surface marker protein CD63 expression was performed. The miRNA profiling of hUCMSCs and hUCMSC-derived exosomes was performed, followed by functional enrichment analysis.Results:The tri-lineage differentiation potential, fibroblastic morphology, and strong expression of pluripotency genes indicated that isolated fibroblasts are MSCs. The isolated extracellular vesicles were 133.8 ± 42.49 nm in diameter, monodispersed, and strongly expressed the exosome surface marker protein CD63. The miRNA expression profile and gene ontology (GO) depicted the differential expression patterns of high and less-expressed miRNAs that are crucial to be involved in the regulation of apoptosis. The LCMS/MS data and GO analysis indicate that hUCMSC secretomes are involved in several oncogenic and inflammatory signaling cascades.Conclusion:Primary human MSCs released miRNAs and growth factors via exosomes that are increasingly implicated in intercellular communications, and hUCMSC-exosomal miRNAs have a critical influence in regulating cell death and apoptosis of cancer cells.Graphical abstract

Heightened levels of circulating cell-free DNA predict aggressive onset of experimental glioblastoma

Abstract Glioblastoma (GBM) is an incurable and aggressive form of brain cancer that is associated with severe peripheral immunosuppression. This immunosuppression is a critical barrier to patient survival and the success of immune modulatory therapies. Using the murine GL261 model of GBM, we recapitulated major features of peripheral immunosuppression observed in patients including spleen atrophy, T cell lymphopenia, and T cell sequestration within the bone marrow. We determined that peripheral immunosuppression in GBM is multifaceted and involves release of novel circulating soluble factors that are found in the serum of glioma-bearing mice. This high molecular weight species potently inhibits T cell proliferation in vitro. Cell-free extracellular DNA has been recently identified as an immune suppressive factor in circulation. We, therefore, assessed cell-free DNA levels in the GL261 model. We determined that serum isolated from glioma-bearing mice harbor significantly higher concentrations of double stranded and single stranded cell-free DNA compared to healthy controls. Serial assessment of DNA concentrations in serum of glioma-bearing mice indicated that the most prominent increase was concurrent with end-stage disease. These findings provide a tractable approach to investigate the cellular source and immune suppressive effects of cell-free DNA in the leading murine model of GBM. Supported by K99NS117799

Problems of the thin endometrium. New possibilities of FDE-5 inhibitors

The article is devoted to a review of the literature about the thin endometrium and its correction today. The problem of thin endometrium is very significant in cases of unsuccessful embryo implantation. There is no generally accepted approach to the definition of “thin endometrium” and ways of its correction in the literature. Phosphodiesterase type 5 (PDE5) inhibitors are considered to play a role in increasing endometrial thickness and improving pregnancy outcomes. Their action consists of various mechanisms, in particular, such as the induction of vasodilating effect through the effect on signaling to vascular smooth muscle, through the regulation of cell proliferation and induction of angiogenesis by increasing the expression of tumor suppressor factor (p53) and vascular endothelial growth factor A, the inhibition of inflammation by reducing the regulation of proinflammatory cytokines. Although PDE5 inhibitors increase the endometrial thickness through the various mechanisms, especially in women with thin endometrium, it does not necessarily mean that they have a positive effect in all clinical situations. Meanwhile, the successful outcome may be affected by the time of use of the drug, the type of infertility treatment, the main diseases such as pelvic disorders and inflammation. Therefore, there are ambiguous issues that need further research in this problem. Oral PDE5 inhibitors are also used as first-line therapy for the treatment of erectile dysfunction (ED), they have proven effectiveness, tolerability, action and couple satisfaction. Avanafil is the only selective inhibitor of the PDE5 isoenzyme with a low frequency of side effects compared to other drugs in this group. The high tolerability of these drugs has made them an attractive tool for the study of further physiological functions outside the ED with benefits for many non-sexual consequences.

Molecular mechanism of microRNAs regulating apoptosis in osteosarcoma.

Osteosarcoma is a primary malignant bone tumor with no effective treatment. Apoptosis, one of the programmed cell death, is any pathological form of cell death mediated by intracellular processes. Under the pathological state, the de-regulated regulation of apoptosis can disrupt the balance between cell proliferation and death, causing osteosarcoma proliferation and metastasis. As carcinogenic or tumor suppressor factors, microRNAs (miRNAs) regulate apoptosis of osteosarcoma cells by regulating apoptosis-related genes and apoptosis-related signaling pathways, such as mitochondrial apoptosis pathway, death receptor pathway, and endoplasmic reticulum pathway. Meanwhile as these abnormal miRNAs can be stored and transported by exosomes, detecting exosomes can be seen an effective method to diagnose osteosarcoma in the early stage. This review provides the current knowledge of miRNAs and their target genes related to the apoptosis of osteosarcoma, summarizes abnormal expression and regulation of miRNAs and signaling pathways in osteosarcoma and prospects the detection of exosome as a method for early diagnosis of osteosarcoma.

Morphologic, immunophenotypic, and molecular genetic comparison study in patients with clonal cytopenia of undetermined significance, myelodysplastic syndrome, and acute myeloid leukemia with myelodysplasia-related changes: A single institution experience.

Next-generation sequencing (NGS) analysis showed clonal cytopenia of undetermined significance (CCUS) as an immediate precursor to myelodysplastic syndrome (MDS). We evaluated and compared morphologic, multiparametric flow cytometry (MFC), and molecular genetic findings in patients with CCUS (n=37), MDS (n=75), and acute myeloid leukemia with myelodysplasia-related changes (AML-MRC, n=24). CCUS patients showed variable MFC abnormalities including >2% CD34+ myeloblasts (5.8%), altered antigen expression on myeloblasts, monocytes, and granulocytes (1.2, 1.5, and 0.2/case), abnormal maturation of myeloblasts (45.8%), decreased hematogones (17.6%), and decreased side scatter (SSC) of granulocytes (11.4%). CCUS patients with high-risk mutations showed significantly more MFC abnormalities. However, CCUS patients with >20% variant allelic fraction (VAF) did not show more MFC aberrations than the rest of the group. MDS patients showed significantly more MFC abnormalities compared with CCUS patients (p=7.8E-05-0.047). Low-grade MDS patients showed significantly fewer MFC abnormalities compared with high-grade MDS or AML-MRC patients (p=1.89E-05-0.04). AML-MRC patients showed significantly elevated blast counts, more antigen aberrations, decreased hematogones, and decreased SSC of granulocytes compared with CCUS patients (p=2.0E-05-0.01). CCUS patients carried predominantly TET2/DNMT3A/ASXL1 mutations. They harbored fewer mutations in gene coding splicing factors compared with MDS patients (p=.0001-.02) and fewer mutations in tumor suppressor and transcription factor genes compared with AML-MRC patients (p=.0006-.02). CCUS is an immediate precursor to low-grade MDS. The progression from CCUS to MDS to AML-MRC is a stepwise process that requires acquisition of mutations in splicing, transcription factor, and tumor suppressor genes with accumulations of additional MFC abnormalities.

Changes in the Mitochondrial Dynamics and Functions Together with the mRNA/miRNA Network in the Heart Tissue Contribute to Hypoxia Adaptation in Tibetan Sheep.

Simple SummaryLong-term exposure to hypoxia, a major source of cellular stress, can induce hypoxia-related diseases and even death. Mitochondria play an important role in mediating the energy production response to hypoxia, but little is known about the mechanisms involved. Tibetan sheep are mainly distributed across the Qinghai–Tibet Plateau, where they have adapted well to hypoxia after long-term adaptation. In this work, a systematic analysis of the blood indexes, tissue morphology, mRNA and miRNA expression regulation, and changes in the mitochondrial function of Tibetan sheep at different altitudes was carried out to provide insights into the mechanism of animal adaptation to hypoxia and the progression of hypoxia-related illness.This study aimed to provide insights into molecular regulation and mitochondrial functionality under hypoxia by exploring the mechanism of adaptation to hypoxia, blood indexes, tissue morphology, mRNA/miRNA regulation, mitochondrial dynamics, and functional changes in Tibetan sheep raised at different altitudes. With regard to blood indexes and myocardial morphology, the HGB, HCT, CK, CK-MB, LDH, LDH1, SOD, GPX, LDL level, and myocardial capillary density were significantly increased in the sheep at higher altitudes (p < 0.05). The RNA-seq results suggested the DEmRNAs and DEmiRNAs are mainly associated with the PI3K-Akt, Wnt, and PPAR signaling pathways and with an upregulation of oncogenes (CCKBR, GSTT1, ARID5B) and tumor suppressor factors (TPT1, EXTL1, ITPRIP) to enhance the cellular metabolism and increased ATP production. Analyzing mRNA–miRNA coregulation indicated the mitochondrial dynamics and functions to be significantly enriched. By analyzing mitochondrial dynamics, mitochondrial fusion was shown to be significantly increased and fission significantly decreased in the heart with increasing altitude (p < 0.05). There was a significant increase in the density of the mitochondria, and a significant decrease in the average area, aspect ratio, number, and width of single mitochondrial cristae with increasing altitudes (p < 0.05). There was a significant increase in the NADH, NAD+ and ATP content, NADH/NAD+ ratio, and CO activity, while there was a significant decrease in SDH and CA activity in various tissues with increasing altitudes (p < 0.05). Accordingly, changes in the blood indexes and myocardial morphology of the Tibetan sheep were found to improve the efficiency of hemoglobin-carrying oxygen and reduce oxidative stress. The high expression of oncogenes and tumor suppressor factors might facilitate cell division and energy exchange, as was evident from enhanced mitochondrial fission and OXPHOS expression; however, it reduced the fusion and TCA cycle for the further rapid production of ATP in adaptation to hypoxia stress. This systematic study has for the first time delineated the mechanism of hypoxia adaptation in the heart of Tibetan sheep, which is significant for improving the ability of the mammals to adapt to hypoxia and for studying the dynamic regulation of mitochondria during hypoxia conditions.

Hypoxia Is a Dominant Remodeler of the Effector T Cell Surface Proteome Relative to Activation and Regulatory T Cell Suppression

Immunosuppressive factors in the tumor microenvironment (TME) impair T cell function and limit the antitumor immune response. T cell surface receptors and surface proteins that influence interactions and function in the TME are proven targets for cancer immunotherapy. However, how the entire surface proteome remodels in primary human T cells in response to specific suppressive factors in the TME remains to be broadly and systematically characterized. Here, using a reductionist cell culture approach with primary human T cells and stable isotopic labeling with amino acids in cell culture–based quantitative cell surface capture glycoproteomics, we examined how two immunosuppressive TME factors, regulatory T cells (Tregs) and hypoxia, globally affect the activated CD8+ surface proteome (surfaceome). Surprisingly, coculturing primary CD8+ T cells with Tregs only modestly affected the CD8+ surfaceome but did partially reverse activation-induced surfaceomic changes. In contrast, hypoxia drastically altered the CD8+ surfaceome in a manner consistent with both metabolic reprogramming and induction of an immunosuppressed state. The CD4+ T cell surfaceome similarly responded to hypoxia, revealing a common hypoxia-induced surface receptor program. Our surfaceomics findings suggest that hypoxic environments create a challenge for T cell activation. These studies provide global insight into how Tregs and hypoxia remodel the T cell surfaceome and we believe represent a valuable resource to inform future therapeutic efforts to enhance T cell function.

Uncontrolled HIV and inflammation is associated with intracranial saccular aneurysm presence.

To study biomarkers of inflammation in cerebrovascular disease, exploring modifiable and non-modifiable biochemical and clinical risk factors associated with the presence of intracranial saccular aneurysms (ISAs) in an HIV-positive cohort. A cross-sectional community-based study was used to study blood biomarkers of inflammation as predictors of cerebrovascular disease, specifically the presence of ISAs in persons with HIV. Potential biochemical and clinical predictors of ISA presence were identified. Time of flight magnetic resonance angiography and magnetic resonance imaging data identified the presence of ISAs in an HIV-positive cohort. Quantitative assays for neuroinflammatory biomarkers were performed on plasma blood samples. Lasso regression models were used to identify neuroinflammatory biomarkers and clinical risk factors associated with ISAs. Eight of 72 participants had radiographically identified ISAs. ISAs were more common in non-Hispanic black participants (18.5% vs. 0% presence in nonblack patients). Participants with well controlled HIV (defined as CD4+ count >200 cells/ml and undetectable viral load at time of magnetic resonance imaging) had lower odds of ISAs (odds ratio: 0.19, 95% confidence interval 0.05-0.79) independent of age, sex, ethnicity and vascular risk factors. Macrophage inflammatory protein-1 p, an HIV- suppressive factor detected in participant blood samples, was inversely associated with aneurysm presence. Well controlled HIV is associated with fewer ISAs. The identification of non-modifiable and modifiable risk factors contributing to ISA formation may provide valuable insight to impact clinical practice and inform the pathophysiology underlying ISA formation.

Ribosomal Proteins and Cancer

The translation process consists of translation factors and ribosomes. Ribosomal components include ribosomal proteins (RP) and ribosomal RNA. Many RPs are involved in assembling ribosomal particles and or stabilizing important regions of rRNA. Besides their conventional roles, RPs have been reported to exhibit secondary functions that have not yet been fully characterized in other cellular processes such as DNA repair, apoptosis, drug resistance, proliferation, and growth inhibition. Since cancer cells require a large amount of protein, they need ribosomes that work much more efficiently than normal cells. Several tumor suppressors and oncogenic proteins control the progression of cancer cells by regulating ribosome biogenesis and protein synthesis. Interestingly, free RPs also have diverse roles in tumorigenesis or tumor suppression. The physiological link between RPs and cancers has been extensively reviewed and elucidated on several pathways, including their interaction with the p53-MDM2 complex. The first evidence of an association between RPs and cancer came from observing the haploinsufficiency of eS4 in Turner Syndrome and eS19 mutation in Diamond-Blackfan Anemia. In the following years, the roles of different RPs in various cancer types such as colorectal cancer, breast cancer, lung adenocarcinoma, T-cell acute lymphoblastic leukemia, prostate cancer, breast cancer, gastric carcinomas, ovarian cancer, and liver cancer have been the subject of research. Apart from their effects on carcinogenesis, it was also emphasized that RPs could be evaluated as predictive biomarkers for diagnosis, prognosis, and treatment for some cancer types. In addition, some studies have been conducted on the use of these proteins in cancer treatment. Identifying novel extra-ribosomal functions of some RPs has identified these proteins as a new class of oncogenic or tumor suppressor factors. Suppression and stimulation of the expression of these novel oncogenic and tumor suppressor proteins, respectively, are considered could open up new therapeutic strategies in cancer therapy.

Circular RNA CDK6 suppresses cervical cancer proliferation and metastasis by sponging miR-449a

ABSTRACT Cervical cancer is a malignant tumor that severely threatens female health. Recently, more and more studies indicated that circRNA could function as a tumor activator or suppressor in cervical cell development. Therefore, we aimed to study the effect of circRNA CDK6 (circCDK6) on the development and biological behavior of cervical cancer. We used quantitative real-time PCR (qRT-PCR) to examine the circCDK6 expression level in cervical cancer cell lines. RNA-fluorescence in situ hybridization confirmed the location of circCDK6 and miR-449a in HeLa and CaSki cells, respectively. Then, the biological function of silencing circCDK6 in cellular proliferation, metastasis, and Epithelial-Mesenchymal Transition (EMT)-related process was determined. We also performed RNA Binding Protein Immunoprecipitation (RIP) and Dual-luciferase reporter assay to determine the relationship between the circCDK6 and miR-449a. Finally, the results showed that circCDK6 level remarkably increased in several cervical cancer cells, especially in Hela and CaSki cells. The miR-449a was further confirmed to be a potential target of circCDK6, and its expression increased by silencing circCDK6. The circCDK6 participated in tumorigenesis and cancer progression and might serve as a tumor suppressive factor in cervical cell progression via Epithelial-MesenchymalTransition (EMT) process by regulating miR-449a.

Advances in CAR-T Cell Genetic Engineering Strategies to Overcome Hurdles in Solid Tumors Treatment.

During this last decade, adoptive transfer of T lymphocytes genetically modified to express chimeric antigen receptors (CARs) emerged as a valuable therapeutic strategy in hematological cancers. However, this immunotherapy has demonstrated limited efficacy in solid tumors. The main obstacle encountered by CAR-T cells in solid malignancies is the immunosuppressive tumor microenvironment (TME). The TME impedes tumor trafficking and penetration of T lymphocytes and installs an immunosuppressive milieu by producing suppressive soluble factors and by overexpressing negative immune checkpoints. In order to overcome these hurdles, new CAR-T cells engineering strategies were designed, to potentiate tumor recognition and infiltration and anti-cancer activity in the hostile TME. In this review, we provide an overview of the major mechanisms used by tumor cells to evade immune defenses and we critically expose the most optimistic engineering strategies to make CAR-T cell therapy a solid option for solid tumors.

Activating transcription factor 3 mediates apoptotic functions through a p53-independent pathway in human papillomavirus 18 infectedHeLa cells.

Activating transcription factor 3 (ATF3) is the first p53 stability regulator that interferes with the ubiquitination of p53. However, the E6 oncoprotein of high-risk human papillomaviruses (HPVs) binds to and induces proteasome-dependent degradation of the host p53 protein. Herein, we investigate the effects of ATF3overexpression on cell cycle progression andapoptosis in HPV-18-infected HeLa cells, and further examinewhether ATF3 could alter the apoptosis level of HeLa cells through the inhibition of E6-mediated p53 degradation. Cytological function of HeLa cells prior and subsequent to the overexpression of ATF3 was assessed using cell cycle and annexin V/PI flow cytometry analysis. Western blotting assays revealed no significant effect of ATF3 on the levels of p53 and E6 in HeLa cells. However, annexin V stainingdemonstrated increases in apoptosis. ATF3 acts as a tumor suppressor factor in HPV18-related cervical cancer which mediates apoptotic functions through a p53-independent pathway.

Regulatory T Cell Apoptosis during Preeclampsia May Be Prevented by Gal-2.

There are several open questions to be answered regarding the pathophysiology of the development of preeclampsia (PE). Numerous factors are involved in its genesis, such as defective placentation, vascular impairment, and an altered immune response. The activation of the adaptive and innate immune system represents an immunologic, particularity during PE. Proinflammatory cytokines are predominantly produced, whereas immune regulatory and immune suppressive factors are diminished in PE. In the present study, we focused on the recruitment of regulatory T cells (Tregs) which are key players in processes mediating immune tolerance. To identify Tregs in the decidua, an immunohistochemical staining of FoxP3 of 32 PE and 34 control placentas was performed. A clearly reduced number of FoxP3-positive cells in the decidua of preeclamptic women could be shown in our analysis (p = 0.036). Furthermore, CCL22, a well-known Treg chemoattractant, was immunohistochemically evaluated. Interestingly, CCL22 expression was increased at the maternal-fetal interface in PE-affected pregnancies (psyncytiotrophoblast = 0.035, pdecidua = 0.004). Therefore, the hypothesis that Tregs undergo apoptosis at the materno-fetal interface during PE was generated, and verified by FoxP3/TUNEL (TdT-mediated dUTP-biotin nick end labeling) staining. Galectin-2 (Gal-2), a member of the family of carbohydrate-binding proteins, which is known to be downregulated during PE, seems to play a pivotal role in T cell apoptosis. By performing a cell culture experiment with isolated Tregs, we could identify Gal-2 as a factor that seems to prevent the apoptosis of Tregs. Our findings point to a cascade of apoptosis of Tregs at the materno-fetal interface during PE. Gal-2 might be a potential therapeutic target in PE to regulate immune tolerance.