RESUMO
Trained immunity enhances the responsiveness of immune cells to subsequent infections or vaccinations. Here we demonstrate that pre-vaccination with bacteria-derived outer-membrane vesicles, which contain large amounts of pathogen-associated molecular patterns, can be used to potentiate, and enhance, tumour vaccination by trained immunity. Intraperitoneal administration of these outer-membrane vesicles to mice activates inflammasome signalling pathways and induces interleukin-1ß secretion. The elevated interleukin-1ß increases the generation of antigen-presenting cell progenitors. This results in increased immune response when tumour antigens are delivered, and increases tumour-antigen-specific T-cell activation. This trained immunity increased protection from tumour challenge in two distinct cancer models.
Assuntos
Neoplasias , Imunidade Treinada , Animais , Camundongos , Interleucina-1beta , Vacinação , Neoplasias/prevenção & controle , Ativação Linfocitária , Antígenos de Neoplasias , BactériasRESUMO
Trained immunity refers to the innate immune system building memory-like features in response to subsequent infections and vaccinations. Compared with classical tumor vaccines, trained immunity-related vaccines (TIrV) are independent of tumor-specific antigens. Bacterial outer membrane vesicles (OMVs) contain an abundance of PAMPs and have the potential to act as TIrV-inducer, but face challenges in endotoxin tolerance, systemic delivery, long-term training, and trained tumor-associated macrophage (TAM)-mediated antitumor phagocytosis. Here, an OMV-based TIrV is developed, OMV nanohybrids (OMV-SIRPα@CaP/GM-CSF) for exerting vaccine-enhanced antitumor activity. In the bone marrow, GM-CSF-assisted OMVs train bone marrow progenitor cells and monocytes, which are inherited by TAMs. In tumor tissues, SIRPα-Fc-assisted OMVs trigger TAM-mediated phagocytosis. This TIrV can be identified by metabolic and epigenetic rewiring using transposase-accessible chromatin (ATAC) and transcriptome sequencing. Furthermore, it is found that the TIrV-mediated antitumor mechanism in the MC38 tumor model (TAM-hot and T cell-cold) is trained immunity and activated T cell response, whereas in the B16-F10 tumor model (T cell-hot and TAM-cold) is primarily mediated by trained immunity. This study not only develops and identifies OMV-based TIrV, but also investigates the trained immunity signatures and therapeutic mechanisms, providing a basis for further vaccination strategies.
Assuntos
Vacinas Anticâncer , Vesículas Extracelulares , Fator Estimulador de Colônias de Granulócitos e Macrófagos , Imunidade Treinada , Macrófagos Associados a TumorRESUMO
Thyroid cancer (TC) is the most prevalent endocrine malignant tumor. Surgery, chemotherapy, radiotherapy, and radioactive iodine (RAI) therapy are the standard TC treatment modalities. However, recurrence or tumor metastasis remains the main challenge in the management of anaplastic thyroid cancer (ATC) and radioiodine (RAI) radioactive iodine-refractory differentiated thyroid cancer (RR-DTC). Several multi-tyrosine kinase inhibitors (MKIs), or immune checkpoint inhibitors in combination with MKIs, have emerged as novel therapies for controlling the progression of DTC, medullary thyroid cancer (MTC), and ATC. Here, we discuss and summarize the molecular basis of TC, review molecularly targeted therapeutic drugs in clinical research, and explore potentially novel molecular therapeutic targets. We focused on the evaluation of current and recently emerging tyrosine kinase inhibitors approved for systemic therapy for TC, including lenvatinib, sorafenib and cabozantinib in DTC, vandetanib, cabozantinib, and RET-specific inhibitor (selpercatinib and pralsetinib) in MTC, combination dabrafenib with trametinib in ATC. In addition, we also discuss promising treatments that are in clinical trials and may be incorporated into clinical practice in the future, briefly describe the resistance mechanisms of targeted therapies, emphasizing that personalized medicine is critical to the design of second-line therapies.
Assuntos
Carcinoma Anaplásico da Tireoide , Neoplasias da Glândula Tireoide , Humanos , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/genética , Radioisótopos do Iodo/uso terapêutico , Anilidas/uso terapêutico , Carcinoma Anaplásico da Tireoide/tratamento farmacológico , Carcinoma Anaplásico da Tireoide/genética , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
Through inducing death receptor (DR) clustering to activate downstream signaling, tumor necrosis factor related apoptosis inducing ligand (TRAIL) trimers trigger apoptosis of tumor cells. However, the poor agonistic activity of current TRAIL-based therapeutics limits their antitumor efficiency. The nanoscale spatial organization of TRAIL trimers at different interligand distances is still challenging, which is essential for the understanding of interaction pattern between TRAIL and DR. In this study, a flat rectangular DNA origami is employed as display scaffold, and an "engraving-printing" strategy is developed to rapidly decorate three TRAIL monomers onto its surface to form DNA-TRAIL3 trimer (DNA origami with surface decoration of three TRAIL monomers). With the spatial addressability of DNA origami, the interligand distances are precisely controlled from 15 to 60 nm. Through comparing the receptor affinity, agonistic activity and cytotoxicity of these DNA-TRAIL3 trimers, it is found that ≈40 nm is the critical interligand distance of DNA-TRAIL3 trimers to induce death receptor clustering and the resulting apoptosis.Finally, a hypothetical "active unit" model is proposed for the DR5 clustering induced by DNA-TRAIL3 trimers.
Assuntos
Neoplasias , Receptores do Ligante Indutor de Apoptose Relacionado a TNF , Ligantes , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/genética , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/genética , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia , Apoptose , Fator de Necrose Tumoral alfa , Linhagem Celular TumoralRESUMO
Micro-nano biorobots based on bacteria have demonstrated great potential for tumor diagnosis and treatment. The bacterial gene expression and drug release should be spatiotemporally controlled to avoid drug release in healthy tissues and undesired toxicity. Herein, we describe an alternating magnetic field-manipulated tumor-homing bacteria developed by genetically modifying engineered Escherichia coli with Fe3O4@lipid nanocomposites. After accumulating in orthotopic colon tumors in female mice, the paramagnetic Fe3O4 nanoparticles enable the engineered bacteria to receive and convert magnetic signals into heat, thereby initiating expression of lysis proteins under the control of a heat-sensitive promoter. The engineered bacteria then lyse, releasing its anti-CD47 nanobody cargo, that is pre-expressed and within the bacteria. The robust immunogenicity of bacterial lysate cooperates with anti-CD47 nanobody to activate both innate and adaptive immune responses, generating robust antitumor effects against not only orthotopic colon tumors but also distal tumors in female mice. The magnetically engineered bacteria also enable the constant magnetic field-controlled motion for enhanced tumor targeting and increased therapeutic efficacy. Thus, the gene expression and drug release behavior of tumor-homing bacteria can be spatiotemporally manipulated in vivo by a magnetic field, achieving tumor-specific CD47 blockage and precision tumor immunotherapy.
Assuntos
Neoplasias do Colo , Nanopartículas , Neoplasias , Feminino , Animais , Camundongos , Imunoterapia , Neoplasias/patologia , Fagocitose , Neoplasias do Colo/terapia , BactériasRESUMO
The widespread preexisting immunity against virus-like particles (VLPs) seriously limits the applications of VLPs as vaccine vectors. Enabling technology for exogenous antigen display should not only ensure the assembly ability of VLPs and site-specific modification, but also consider the effect of preexisting immunity on the behavior of VLPs in vivo. Here, combining genetic code expansion technique and synthetic biology strategy, a site-specific modification method for hepatitis B core (HBc) VLPs via incorporating azido-phenylalanine into the desired positions is described. Through modification position screening, it is found that HBc VLPs incorporated with azido-phenylalanine at the main immune region can effectively assemble and rapidly conjugate with the dibenzocycolctyne-modified tumor-associated antigens, mucin-1 (MUC1). The site-specific modification of HBc VLPs not only improves the immunogenicity of MUC1 antigens but also shields the immunogenicity of HBc VLPs themselves, thereby activating a strong and persistent anti-MUC1 immune response even in the presence of preexisting anti-HBc immunity, which results in the efficient tumor elimination in a lung metastatic mouse model. Together, these results demonstrate the site-specific modification strategy enabled HBc VLPs behave as a potent antitumor vaccine and this strategy to manipulate immunogenicity of VLPs may be suitable for other VLP-based vaccine vectors.
Assuntos
Vírus da Hepatite B , Vacinas de Partículas Semelhantes a Vírus , Animais , Camundongos , Vírus da Hepatite B/genética , Vacinas de Partículas Semelhantes a Vírus/genética , Antígenos de Neoplasias , Camundongos Endogâmicos BALB CRESUMO
In tumor nanovaccines, nanocarriers enhance the delivery of tumor antigens to antigen-presenting cells (APCs), thereby ensuring the robust activation of tumor antigen-specific effector T-cells to kill tumor cells. Through employment of their high immunogenicity and nanosize, we have developed a "Plug-and-Display" delivery platform on the basis of bacterial outer membrane vesicles (OMVs) for tumor nanovaccines (NanoVac), which can rapidly display different tumor antigens and efficiently eliminate lung metastases of melanoma. In this study, we first upgraded the NanoVac to increase their antigen display efficiency. However, we found that the presence of a subcutaneous xenograft seriously hampered the efficiency of NanoVac to eliminate lung metastases, with the subcutaneous xenograft mimicking the primary tumor burden in clinical practice. The primary tumor secreted significant amounts of granulocyte colony-stimulating factor (G-CSF) and altered the epigenetic features of granulocyte monocyte precursor cells (GMPs) in the bone marrow, thus disrupting systemic immunity, particularly the function of APCs, and ultimately resulting in NanoVac failure to affect metastases. These changes in the systemic immune macroenvironment were plastic, and debulking surgery of primary tumor resection reversed the dysfunction of APCs and failure of NanoVac. These results demonstrate that, in addition to the formulation design of the tumor nanovaccines themselves, the systemic immune macroenvironment incapacitated by tumor development is another key factor that cannot be ignored to affect the efficiency of tumor nanovaccines, and the combination of primary tumor resection with NanoVac is a promising radical treatment for widely metastatic tumors.
Assuntos
Procedimentos Cirúrgicos de Citorredução , Neoplasias Pulmonares , Humanos , Células Apresentadoras de Antígenos , Linfócitos T , Antígenos de NeoplasiasRESUMO
Restoring sodium iodide symporter (NIS) expression and function remains a major challenge for radioiodine therapy in anaplastic thyroid cancer (ATC). For more efficient delivery of messenger RNA (mRNA) to manipulate protein expression, a lipid-peptide-mRNA (LPm) nanoparticle (NP) is developed. The LPm NP is prepared by using amphiphilic peptides to assemble a peptide core and which is then coated with cationic lipids. An amphiphilic chimeric peptide, consisting of nine arginine and hydrophobic segments (6 histidine, C18 or cholesterol), is synthesized for adsorption of mRNA encoding NIS in RNase-free conditions. In vitro studies show that LP(R9H6) m NP is most efficient at delivering mRNA and can increase NIS expression in ATC cells by more than 10-fold. After intratumoral injection of NIS mRNA formulated in optimized LPm NP, NIS expression in subcutaneous ATC tumor tissue increases significantly in nude mice, resulting in more iodine 131 (131 I) accumulation in the tumor, thereby significantly inhibiting tumor growth. Overall, this work designs three arginine-rich peptide nanoparticles, contributing to the choice of liposome cores for gene delivery. LPm NP can serve as a promising adjunctive therapy for patients with ATC by restoring iodine affinity and enhancing the therapeutic efficacy of radioactive iodine.
Assuntos
Iodo , Carcinoma Anaplásico da Tireoide , Neoplasias da Glândula Tireoide , Animais , Camundongos , Linhagem Celular Tumoral , Radioisótopos do Iodo/uso terapêutico , Lipídeos , Lipossomos , Camundongos Nus , Peptídeos , RNA Mensageiro , Carcinoma Anaplásico da Tireoide/terapia , Carcinoma Anaplásico da Tireoide/genética , Carcinoma Anaplásico da Tireoide/metabolismo , Neoplasias da Glândula Tireoide/radioterapia , Neoplasias da Glândula Tireoide/genética , HumanosRESUMO
Genetic predisposition and disruption of host gut microbiota and immune system can result in inflammatory bowel disease (IBD). Here, we show that miRNA-149-5p (miR-149-5p) and miRNA-149-3p (miR-149-3p) play crucial roles in IBD. Mice lacking miR-149-3p were considerably more susceptible to dextran sulfate sodium (DSS)-induced colitis than wild-type (WT) mice, accompanied by more serious inflammatory symptoms and increased gene expression of certain inflammatory cytokines. Both miR-149-5p and miR-149-3p suppressed colon inflammatory response in vitro and in vivo. Furthermore, we found significant differences in the composition of the gut microbiota between WT and miR-149-3p-/- mice by 16S rRNA sequencing. Co-housing endowed susceptibility to WT mice against DSS-induced colitis compared with the WT control group. However, susceptibility of miR-149-3p-/- mice against DSS-induced colitis was still present after antibiotic treatment. These findings suggest that the deletion of miR-149-3p altered gut microbiota and influenced pathogenesis of intestinal inflammation, but sensitivity of miR-149-3p-/- mice to DSS-induced colitis is not conferred by microbiota. In addition, we identified the roles of miR-149-5p and miR-149-3p in colon inflammation, which may serve as an attractive therapeutic tool for colitis or IBD, and even colitis-associated carcinoma.
RESUMO
Tumor vaccines, a type of personalized tumor immunotherapy, have developed rapidly in recent decades. These vaccines evoke tumor antigen-specific T cells to achieve immune recognition and killing of tumor cells. Because the immunogenicity of tumor antigens alone is insufficient, immune adjuvants and nanocarriers are often required to enhance anti-tumor immune responses. At present, vaccine carrier development often integrates nanocarriers and immune adjuvants. Among them, outer membrane vesicles (OMVs) are receiving increasing attention as a delivery platform for tumor vaccines. OMVs are natural nanovesicles derived from Gram-negative bacteria, which have adjuvant function because they contain pathogen associated molecular patterns. Importantly, OMVs can be functionally modified by genetic engineering of bacteria, thus laying a foundation for applications as a delivery platform for tumor nanovaccines. This review summarizes 5 aspects of recent progress in, and future development of, OMV-based tumor nanovaccines: strain selection, heterogeneity, tumor antigen loading, immunogenicity and safety, and mass production of OMVs.
Assuntos
Vacinas Anticâncer , Neoplasias , Adjuvantes Imunológicos , Antígenos de Neoplasias , Membrana Externa Bacteriana , Humanos , Neoplasias/prevenção & controle , Moléculas com Motivos Associados a PatógenosRESUMO
The most immune cells infiltrating tumor microenvironment (TME), tumor-associated macrophages (TAMs) closely resemble immunosuppressive M2-polarized macrophages. Moreover, tumor cells exhibit high expression of CD47 "don't eat me" signal, which obstructs macrophage phagocytosis. The precise and efficient activation of TAMs is a promising approach to tumor immunotherapy; however, re-education of macrophages remains a challenge. Bacteria-derived outer membrane vesicles (OMVs) are highly immunogenic nanovesicles that can robustly stimulate macrophages. Here, an OMV-based controllable two-way adaptor is reported, in which a CD47 nanobody (CD47nb) is fused onto OMV surface (OMV-CD47nb), with the outer surface coated with a polyethylene glycol (PEG) layer containing diselenide bonds (PEG/Se) to form PEG/Se@OMV-CD47nb. The PEG/Se layer modification not only mitigates the immunogenicity of OMV-CD47nb, thereby remarkedly increasing the dose that can be administered safely through intravenous injection, but also equips the formulation with radiation-triggered controlled release of OMV-CD47nb. Application of radiation to tumors in mice injected with the nanoformulation results in remodeling of TME. As two-way adaptors, OMV-CD47nb activates TAM phagocytosis of tumor cells via multiple pathways, including induction of M1 polarization and blockade of "don't eat me" signal. Moreover, this activation of TAMs results in the stimulation of T cell-mediated antitumor immunity through effective antigen presentation.
Assuntos
Membrana Externa Bacteriana , Antígeno CD47 , Animais , Linhagem Celular Tumoral , Preparações de Ação Retardada/metabolismo , Imunoterapia , Macrófagos , Camundongos , Fagocitose , Polietilenoglicóis/metabolismo , Microambiente TumoralRESUMO
BACKGROUND: Cluster of differentiation 147 (CD147) overexpression plays a key role in the proliferation, differentiation, invasion, metastasis, and prognosis of hepatocellular carcinoma (HCC). The aim of this study was to explore the relationship between rs6757 and the HCC risk in the South Chinese population, and the functional significance of rs6757 by affecting the efficacy of microRNA-3976 (miR-3976) binding to the CD147 3'-UTR. METHODS: We performed a retrospective case-control study to analyze the association between rs6757 and the risk of HCC. We chose candidate microRNAs with the potential of interacting with rs6757 through a series of silico analyses. A luciferase reporter gene assay was implemented to detect the binding extent of microRNAs to each polymorphic allele of rs6757. RESULTS: An obvious association between rs6757 and the risk of HCC was detected in C vs. T (OR = 1.826, 95% CI [1.263-2.642]), CC vs. TT (OR = 4.513, 95% CI [1.510-13.489]), dominant genetic model (OR = 1.824, 95% CI [1.120-2.965]), and recessive genetic model (OR = 3.765, 95% CI [1.286-11.020]). Bioinformatics analysis indicated that miR-3976 binding sites containing the rs6757-T allele had lower free energies than those with the C allele, the lower free energies, the higher affinities. Luciferase activity was remarkably decreased by miR-3976 binding to the CD147 3'-UTR bearing rs6757 T allele, which could be reversed by miR-3976 inhibitors. Furthermore, miR-3976 reduced the luciferase expression in a manner of dose-dependent when cotransfected with constructs with the CD147-TT-pSICHECK2. CONCLUSIONS: The research we have done suggests that rs6757 confers the CD147 allele-specific translational suppression by miR-3976, which provides a theoretical basis for antineoplastic therapy targeting CD147.
Assuntos
Basigina/metabolismo , Carcinoma Hepatocelular , Neoplasias Hepáticas , MicroRNAs , Sítios de Ligação , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Estudos de Casos e Controles , Linhagem Celular Tumoral , China , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , MicroRNAs/genética , MicroRNAs/metabolismo , Estudos RetrospectivosRESUMO
The complex gastrointestinal environment and the intestinal epithelial barrier constrain the design and effectiveness of orally administered tumour vaccines. Here we show that outer membrane vesicles (OMVs) fused to a tumour antigen and produced in the intestine by ingested genetically engineered bacteria function as effective tumour vaccines in mice. We modified Escherichia coli to express, under the control of a promoter induced by the monosaccharide arabinose, a specific tumour antigen fused with the protein cytolysin A on the surface of OMVs released by the commensal bacteria. In mice, oral administration of arabinose and the genetically engineered E. coli led to the production of OMVs that crossed the intestinal epithelium into the lamina propria, where they stimulated dendritic cell maturation. In a mouse model of pulmonary metastatic melanoma and in mice bearing subcutaneous colon tumours, the antigen-bearing OMVs inhibited tumour growth and protected the animals against tumour re-challenge. The in situ production of OMVs by genetically modified commensal bacteria for the delivery of stimulatory molecules could be leveraged for the development of other oral vaccines and therapeutics.
Assuntos
Vacinas Anticâncer , Escherichia coli , Animais , Antígenos de Neoplasias/metabolismo , Arabinose/metabolismo , Membrana Celular , Escherichia coli/genética , CamundongosRESUMO
Therapeutic mRNA vaccination is an attractive approach to trigger antitumor immunity. However, the mRNA delivery technology for customized tumor vaccine is still limited. In this work, bacteria-derived outer membrane vesicles (OMVs) are employed as an mRNA delivery platform by genetically engineering with surface decoration of RNA binding protein, L7Ae, and lysosomal escape protein, listeriolysin O (OMV-LL). OMV-LL can rapidly adsorb box C/D sequence-labelled mRNA antigens through L7Ae binding (OMV-LL-mRNA) and deliver them into dendritic cells (DCs), following by the cross-presentation via listeriolysin O-mediated endosomal escape. OMV-LL-mRNA significantly inhibits melanoma progression and elicits 37.5% complete regression in a colon cancer model. OMV-LL-mRNA induces a long-term immune memory and protects the mice from tumor challenge after 60 days. In summary, this platform provides a delivery technology distinct from lipid nanoparticles (LNPs) for personalized mRNA tumor vaccination, and with a "Plug-and-Display" strategy that enables its versatile application in mRNA vaccines.
Assuntos
Vacinas Anticâncer , Nanopartículas , Animais , Bactérias , Vacinas Anticâncer/genética , Lipossomos , Camundongos , RNA MensageiroRESUMO
Tumor antigens released from tumor cells after local photothermal therapy (PTT) can activate the tumor-specific immune responses, which are critical for eliminating the residual lesions and distant metastases. However, the limited recognition efficiency of released tumor antigens by the immune system and the immunosuppressive microenvironment lead to ineffective antitumor immunity. Here, an in situ multifunctional vaccine based on bacterial outer membrane vesicles (OMVs, 1-MT@OMV-Mal) is developed by surface conjunction of maleimide groups (Mal) and interior loading with inhibitor of indoleamine 2, 3-dioxygenase (IDO), 1-methyl-tryptophan (1-MT). 1-MT@OMV-Mal can bind to the released tumor antigens after PTT, and be efficiently recognized and taken up by dendritic cells. Furthermore, in situ injection of 1-MT@OMV-Mal simultaneously overcomes the immune inhibition of IDO on tumor-infiltrating effector T cells, leading to remarkable inhibition on both primary and distant tumors. Together, a promising in situ vaccine based on OMVs to facilitate immune-mediated tumor clearance after PTT through orchestrating antigen capture and immune modulation is presented.
Assuntos
Neoplasias , Vacinas , Antígenos de Neoplasias , Membrana Externa Bacteriana , Humanos , Imunidade , Imunoterapia , Neoplasias/terapia , Terapia Fototérmica , Microambiente TumoralRESUMO
Nanocarriers with intrinsic immune adjuvant properties can activate the innate immune system while delivering tumor antigen, thus efficiently facilitating antitumor adaptive immunity. Bacteria-derived outer membrane vesicles (OMVs) are an excellent candidate due to their abundance of pathogen associated molecular patterns. However, during the uptake of OMVs by dendritic cells (DCs), the interaction between lipopolysaccharide and toll-like receptor 4 induces rapid DC maturation and uptake blockage, a phenomenon we refer to as "maturation-induced uptake obstruction" (MUO). Herein we decorated OMV with the DC-targeting αDEC205 antibody (OMV-DEC), which endowed the nanovaccine with an uptake mechanism termed as "not restricted to maturation via antibody modifying" (Normandy), thereby overcoming the MUO phenomenon. We also proved the applicability of this nanovaccine in identifying the human tumor neoantigens through rapid antigen display. In summary, this engineered OMV represents a powerful nanocarrier for personalized cancer vaccines, and this antibody modification strategy provides a reference to remodel the DC uptake pattern in nanocarrier design.
RESUMO
INTRODUCTION: Farnesoid X receptor (FXR), a member of nuclear receptors, functionally regulates bile acid, glucose and lipid homeostasis. It is also worth noting that FXR plays a suppressor role in cancer and inflammation. However, the contribution of FXR to esophageal squamous cell carcinoma (ESCC) remains unknown. METHODS: The role of FXR activation in ESCC progression was evaluated in ESCC cell lines KYSE150 and EC109 in vitro and BALB-C nude mice in vivo. In vitro, FXR synthetic ligand GW4064 was used to detect the effects on ESCC cell proliferation, migration, apoptosis and cell cycles. To assess the effects of GW4064 on ESCC development in vivo, a xenograft tumor model was constructed. And ERK1/2 activity was evaluated by immunoblot analysis. RESULTS: FXR synthetic ligand GW4064 impaired esophageal squamous cell carcinoma (ESCC) proliferation and migration, induced apoptosis and cell cycle arrest in vitro, accompanied by inhibition of some inflammatory genes and promotion of pro-apoptotic genes. We then found that FXR activation decreased the phosphorylation levels of ERK1/2 induced by tumor necrosis factor-α (TNF-α) in ESCC cells. Consistent with these results, GW4064 suppressed ESCC tumorigenesis in a xenograft model and suppressed the phosphorylation of ERK1/2 in tumors. DISCUSSION: These findings identify that activating FXR may serve as a promising therapy or adjuvant therapeutic tool for controlling ESCC development.
RESUMO
Clinical studies have shown similarities in the genetic background and biological functional characteristics between Hashimoto's thyroiditis (HT) and papillary thyroid carcinoma (PTC), and that HT may increase risks of PTC. Here, we set to determine the gene expression specificity of HT and PTC by screening related genes or co-expressed genes and exploring their genetic correlation. Referencing the Oncomine database, HT-related genes were discovered to be expressed in many different types of thyroid cancer, such as TSHR that is highly expressed in thyroid cancer. An in-depth genetic analysis and verification of 35 cancer and paracancerous tissue pairs from patients with thyroid cancer, and 35 tissues and blood cells pairs from patients with Hashimoto's thyroiditis was conducted. Gene chip technology research showed that TSHR, BACH2, FOXE1, RNASET2, CTLA4, PTPN22, IL2RA and other HT-related genes were all expressed in PTC, in which TSHR was significantly over-expressed in PTC patients sensitive to radioactive iodine therapy, while BACH2 was significantly under-expressed in these patients. The biologically significant candidate Tag SNP highlighted from HT-related genes was screened by the high-throughput detection method. Somatic mutations in patients with HT and PTC were detected by target region capture technique, and 75 mutations were found in patients with HT and PTC. The upstream regulatory factors of the different genes shared by HT and PTC were analyzed based on Ingenuity Pathway Analysis (IPA), and it was found that HIF-1α and PD-L1 could be used as important upstream regulatory signal molecules. These results provide a basis for screening key diagnostic genes of PTC by highlighting the relationship between some HT-related genes and their polymorphisms in the pathogenesis of PTC.
RESUMO
BACKGROUND: To compare the clinical outcomes of transepithelial photorefractive keratectomy (TPRK) with femtosecond laser-assisted in situ keratomileusis (FS-LASIK) for correction of high myopia. METHODS: In this prospective, non-randomised, cohort study, 85 eyes of 46 patients treated with TPRK and 80 eyes of 42 patients treated with FS-LASIK were included. All eyes were highly myopic (spherical equivalent refraction <- 6.00 diopters). Both TPRK and FS-LASIK were performed by Schwind Amaris 750S excimer laser. Visual acuity, refraction, corneal high order aberration (HOA) and other variables were analyzed before and at 1, 3, 6, 12 months after surgery. RESULTS: At 12 months after surgery, uncorrected logMAR distance visual acuity (UDVA) in the TPRK and FS-LASIK groups was - 0.04 ± 0.04 and - 0.01 ± 0.08, respectively (P = 0.039). Corrected logMAR distance visual acuity (CDVA) was - 0.06 ± 0.05 and - 0.04 ± 0.05 in both groups (P = 0.621). For UDVA, 86% of eyes in the TPRK group and 80% in the FS-LASIK group remained unchanged or improved one or more logMAR lines (P = 0.314), compared to preoperative CDVA. For CDVA, 97% of eyes in the TPRK group and 90% in the FS-LASIK group remained unchanged or improved one or more lines (P = 0.096), compared to preoperative CDVA. Spherical equivalent refraction was - 0.05 ± 0.39 and - 0.26 ± 0.47 in both groups (P = 0.030). 87% of eyes in the TPRK group and 73% in the FS-LASIK group achieved ±0.50 D target refraction (P = 0.019). All 85 eyes (100%) in the TPRK group and 75 eyes (92%) in the FS-LASIK group were within ±1.00 D of target (P = 0.003). Root mean square (RMS) of corneal total HOA and vertical coma in the TPRK group were lower compared with the FS-LASIK group (P < 0.001 for both variables). CONCLUSIONS: TPRK and FS-LASIK showed good safety, efficacy and predictability for correction of high myopia. Clinical outcomes of TPRK were slightly better than FS-LASIK.