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Background: Multiple organ dysfunction syndrome (MODS) is common after sepsis and increases mortality. Lactate (Lac) can assess the prognosis of patients. Albumin (Alb) is closely associated with inflammatory response in sepsis patients. This work evaluated the predictive value of Lac/Alb for prognosis of sepsis patients. Methods: Data of 160 sepsis patients were retrospectively collected. Lac and Alb levels were measured upon admission, at 24 hours and 48 hours later. Using 0.45 as the cutoff value for Lac/Alb, patients were rolled into high-level (HL) and low-level (LL) groups. MODS rates and mortality rates were analyzed. Receiver operating characteristic (ROC) curves were utilized to evaluate the predictive value of 48-hour Lac/Alb for patient prognosis. Correlation between Lac/Alb and APACHE II and SOFA scores was assessed. Results: The 12-month follow-up revealed 52 deaths (32.5%), and MODS occurred in 49 cases (30.6%) on the 7th day. The MODS group possessed elevated Lac and Lac/Alb and decreased Alb to the N-MODS group (P<0.05), and similar results were observed by comparison the survival and death group (P<0.05). The sensitivity, specificity, and area under the ROC curve (AUC) of Lac/Alb in predicting MODS were 81.63%, 85.59%, and 0.89, respectively, while those in predicting death were 94.23%, 88.89%, and 0.91, respectively. Lac/Alb was positively correlated with APACHE II and SOFA scores (r=0.718 and 0.808, respectively). Conclusions: Lac/Alb was linked to MODS and mortality in sepsis patients and can be based to predict adverse outcomes.
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[This corrects the article DOI: 10.3389/fimmu.2023.1332057.].
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BACKGROUND: Striatin interacting protein 2 (STRIP2) is a core component of the striatin-interacting phosphatase and kinase (STRIPAK) complexes, which is involved in tumor initiation and progression via the regulation of cell contractile and metastasis. However, the underlying molecular mechanisms of STRIP2 in non-small cell lung cancer (NSCLC) progression remain largely unknown. METHODS: The expressions of STRIP2 and IGF2BP3 in human NSCLC specimens and NSCLC cell lines were detected using quantitative RT-PCR, western blotting, and immunohistochemistry (IHC) analyses. The roles and molecular mechanisms of STRIP2 in promoting NSCLC progression were investigated in vitro and in vivo. RESULTS: Here, we found that STRIP2 expression was significantly elevated in NSCLC tissues and high STRIP2 expression was associated with a poor prognosis. Knockdown of STRIP2 suppressed tumor growth and metastasis in vitro and in vivo, while STRIP2 overexpression obtained the opposite effect. Mechanistically, P300/CBP-mediated H3K27 acetylation activation in the promoter of STRIP2 induced STRIP2 transcription, which interacted with insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) and upregulated IGF2BP3 transcription. In addition, STRIP2-IGF2BP3 axis stimulated m6A modification of TMBIM6 mRNA and enhanced TMBIM6 stability. Consequently, TMBIM6 involved NSCLC cell proliferation, migration and invasion dependent on STRIP2 and IGF2BP3. In NSCLC patients, high co-expression of STRIP2, IGF2BP3 and TMBIM6 was associated with poor outcomes. CONCLUSIONS: Our findings indicate that STRIP2 interacts with IGF2BP3 to regulate TMBIM6 mRNA stability in an m6A-dependent manner and may represent a potential prognostic biomarker and therapeutic target for NSCLC.
Subject(s)
Apoptosis Regulatory Proteins , Carcinoma, Non-Small-Cell Lung , Cytoskeletal Proteins , Lung Neoplasms , Membrane Proteins , RNA-Binding Proteins , Humans , Apoptosis Regulatory Proteins/metabolism , Carcinoma, Non-Small-Cell Lung/pathology , Cell Line, Tumor , Cell Proliferation , Gene Expression Regulation, Neoplastic , Lung Neoplasms/pathology , Membrane Proteins/metabolism , Cytoskeletal Proteins/metabolism , RNA-Binding Proteins/metabolismABSTRACT
Greenblatt and his team have unveiled vertebral skeletal stem cells (vSSCs) as a critical player in the landscape of bone metastasis. This commentary delves into the transformative discoveries surrounding vSSCs, emphasizing their distinct role in bone metastasis compared to other stem cell lineages. We illuminate the unique properties and functions of vSSCs, which may account for the elevated susceptibility of vertebral bones to metastatic invasion. Furthermore, we explore the exciting therapeutic horizons opened by this newfound understanding. These include potential interventions targeting vSSCs, modulation of associated signaling pathways, and broader implications for the treatment and management of bone metastasis. By shedding light on these game-changing insights, we hope to pave the way for novel strategies that could revolutionize the prognosis and treatment landscape for cancer patients with metastatic bone disease.
Subject(s)
Bone Neoplasms , Humans , Bone Neoplasms/therapy , Stem CellsABSTRACT
Cancer immunotherapy has emerged as a promising strategy for the treatment of cancer, with the tumor microenvironment (TME) playing a pivotal role in modulating the immune response. CD47, a cell surface protein, has been identified as a crucial regulator of the TME and a potential therapeutic target for cancer therapy. However, the precise functions and implications of CD47 in the TME during immunotherapy for cancer patients remain incompletely understood. This comprehensive review aims to provide an overview of CD47's multifaced role in TME regulation and immune evasion, elucidating its impact on various types of immunotherapy outcomes, including checkpoint inhibitors and CAR T-cell therapy. Notably, CD47-targeted therapies offer a promising avenue for improving cancer treatment outcomes, especially when combined with other immunotherapeutic approaches. The review also discusses current and potential CD47-targeted therapies being explored for cancer treatment and delves into the associated challenges and opportunities inherent in targeting CD47. Despite the demonstrated effectiveness of CD47-targeted therapies, there are potential problems, including unintended effects on healthy cells, hematological toxicities, and the development if resistance. Consequently, further research efforts are warranted to fully understand the underlying mechanisms of resistance and to optimize CD47-targeted therapies through innovative combination approaches, ultimately improving cancer treatment outcomes. Overall, this comprehensive review highlights the significance of CD47 as a promising target for cancer immunotherapy and provides valuable insight into the challenges and opportunities in developing effective CD47-targeted therapies for cancer treatment.
Subject(s)
CD47 Antigen , Neoplasms , Humans , Immunotherapy , Membrane Proteins , Tumor Microenvironment , Neoplasms/therapyABSTRACT
Receptor tyrosine kinases (RTKs) play a crucial role in cellular signaling and oncogenic progression. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) have become the standard treatment for advanced non-small cell lung cancer (NSCLC) patients with EGFR-sensitizing mutations, but resistance frequently emerges between 10 to 14 months. A significant factor in this resistance is the role of human EGFR 3 (HER3), an EGFR family member. Despite its significance, effective targeting of HER3 is still developing. This review aims to bridge this gap by deeply examining HER3's pivotal contribution to EGFR TKI resistance and spotlighting emerging HER3-centered therapeutic avenues, including monoclonal antibodies (mAbs), TKIs, and antibody-drug conjugates (ADCs). Preliminary results indicate combining HER3-specific treatments with EGFR TKIs enhances antitumor effects, leading to an increased objective response rate (ORR) and prolonged overall survival (OS) in resistant cases. Embracing HER3-targeting therapies represents a transformative approach against EGFR TKI resistance and emphasizes the importance of further research to optimize patient stratification and understand resistance mechanisms.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/pharmacology , Receptor, ErbB-3/genetics , Receptor, ErbB-3/metabolism , Drug Resistance, Neoplasm/genetics , ErbB Receptors/metabolismABSTRACT
Immunotherapy has been the fifth pillar of cancer treatment in the past decade. Chimeric antigen receptor (CAR) T-cell therapy is a newly designed adoptive immunotherapy that is able to target and further eliminate cancer cells by engaging with MHC-independent tumor-antigens. CAR T-cell therapy has exhibited conspicuous clinical efficacy in hematological malignancies, but more than half of patients will relapse. Of note, the efficacy of CAR T-cell therapy has been even more disappointing in solid tumors. These challenges mainly include (1) the failures of CAR T-cells to treat highly heterogeneous solid tumors due to the difficulty in identifying unique tumor antigen targets, (2) the expression of target antigens in non-cancer cells, (3) the inability of CAR T-cells to effectively infiltrate solid tumors, (4) the short lifespan and lack of persistence of CAR T-cells, and (5) cytokine release syndrome and neurotoxicity. In combination with these characteristics, the ideal CAR T-cell therapy for solid tumors should maintain adequate T-cell response over a long term while sparing healthy tissues. This article reviewed the status, clinical application, efficacy, safety, and challenges of CAR T-cell therapies, as well as the latest progress of CAR T-cell therapies for solid tumors. In addition, the potential strategies to improve the efficacy of CAR T-cells and prevent side effects in solid tumors were also explored.
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There is a worldwide pandemic of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection; yet our understanding remains limited on the characteristic of antibodies, especially for dynamic long-term tracking. Sequential serum samples were collected up to 416 days post onset of symptoms (POS) from 102 patients who were hospitalized with coronavirus disease 2019 (COVID-19). Immunoglobulin (Ig)G, IgM, and IgA levels targeting SARS-CoV-2 spike 1 receptor-binding domain (S1-RBD), spike 2 extracellular domain (S2-ECD), and nucleocapsid protein (N) were quantified as well as neutralizing activity. We were pleasantly surprised to find that the antibody remained detective and effective for more than a year POS. We also found the varied reactions of different antibodies as time passed: N-IgA rose most rapidly in the early stage of infection, while S2-IgG was present at a high level in the long time of observation. This study described the long traceable antibody response of the COVID-19 and offered hints about targets to screen for postinfectious immunity and for vaccination development of SARS-CoV-2.
Subject(s)
Antibodies, Neutralizing/blood , Antibodies, Viral/blood , COVID-19/immunology , SARS-CoV-2/immunology , Aged , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/diagnosis , Coronavirus Nucleocapsid Proteins/immunology , Female , Follow-Up Studies , Hospitalization , Humans , Immunoglobulin Isotypes/blood , Immunoglobulin Isotypes/immunology , Kinetics , Male , Middle Aged , Models, Theoretical , Phosphoproteins/immunology , Protein Domains/immunology , SARS-CoV-2/isolation & purification , Seroconversion , Spike Glycoprotein, Coronavirus/immunologyABSTRACT
Transmembrane protein 229A (TMEM229A) is a member of the TMEM family that plays an important role in tooth differentiation and development. However, the expression level and biological role of TMEM229A in cancer remains unknown. The present study aimed to investigate the expression level of TMEM229A in nonsmall cell lung cancer (NSCLC), as well as its effect and mechanism on NSCLC progression. Clinical specimens from patients with NSCLC were enrolled from the First People's Hospital of Huzhou (Huzhou, China). TMEM229A expression was detected using reverse transcriptionquantitative PCR (RTqPCR), western blotting and immunohistochemical analysis. The relationship between TMEM229A expression and the survival rate of patients with NSCLC was analyzed using KaplanMeier Plotter datasets. The effects of TMEM229A on cell proliferation, migration and invasion were detected using Cell Counting Kit8, colony formation, soft agar, realtime cellular analysis and Transwell assays. The expression levels of epithelialmesenchymal transition (EMT)related proteins, as well as ERK and AKT phosphorylation were determined via RTqPCR and western blot analysis. The results demonstrated that TMEM229A expression was significantly downregulated in human NSCLC tissues and in several cell lines compared with adjacent normal lung tissues and BEAS2B cells, respectively. Survival analysis of lung adenocarcinoma and squamous cell lung carcinoma cases identified that low TMEM229A expression was associated with a poor prognosis. The in vitro assays indicated that overexpressing TMEM229A significantly inhibited cell proliferation, migration and invasion, while TMEM229A knockdown had the opposite effect. Mechanistically, TMEM229A overexpression effectively increased Ecadherin expression and reduced Ncadherin, snail family transcriptional repressor 1 and MMP2 expression, indicating that EMT was suppressed. In addition, overexpression of TMEM229A reduced the expression levels of phosphorylated (p)ERK and pAKT, and this effect was partially suppressed by the incorporation of specific ERK inhibitor PD98059. Collectively, the results of the present study demonstrated that the effects of TMEM229A on inhibiting cell proliferation, migration and invasion were partially mediated by inactivating the ERK signaling pathway, thereby providing a potential therapeutic target for the treatment of NSCLC.
Subject(s)
Carcinoma, Non-Small-Cell Lung/mortality , Down-Regulation , Lung Neoplasms/mortality , Membrane Proteins/genetics , Membrane Proteins/metabolism , A549 Cells , Adult , Aged , Aged, 80 and over , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/metabolism , Cell Line, Tumor , Cell Movement , Cell Proliferation , Disease Progression , Epithelial-Mesenchymal Transition , Female , Gene Expression Regulation, Neoplastic , Humans , Lung Neoplasms/genetics , Lung Neoplasms/metabolism , MAP Kinase Signaling System , Male , Middle Aged , PrognosisABSTRACT
The identification of novel biomarkers and therapeutic targets in advanced cancer is critical for improving cancer diagnosis and therapeutics. Survivin (SV) is highly expressed predominantly in most cancer cells and tissues but is absent or undetectable in terminally differentiated normal adult tissues. Therefore, it functions as an almost universal tumor antigen. Peptides are short chains of amino acids linked by peptide bonds. To obtain novel SV decamers that are able to induce SV-specific cytotoxic T lymphocytes (CTLs) with a higher cytotoxic efficiency against cancer cells, major histocompatibility complex (MHC) peptide binding algorithms were conducted to predict nine modified SV95 decamers (from SV95-2 to SV95-10) based on the natural SV95-104 peptide sequence of ELTLGEFLKL (here defined as SV95-1). The fluorescent density of each SV95 peptide was determined by a MHC stability assay, followed by the generation of SV95-specific CTLs with each SV95 peptide (from SV95-1 to SV95-10) and human dendritic cells (DCs) loaded with Poly(lactic-co-glycolic) acid (PLGA) nanoparticles encapsulated with SV95 peptide. Finally, IFN-γ ELISpot and CytoTox 96® Non-Radioactive Cytotoxicity Assays were employed to verify their cytotoxic efficiency of the SV95-specific CTLs generated with the corresponding artificial antigen presenting cells (aAPCs) containing SV95 (SV95-1 to SV95-10) peptide. Furthermore, the cytotoxicity of the SV95 specific CTLs generated with nine mutated SV95 peptides was compared to the one generated with natural SV95-1 peptide and TIL2080 cells. The results indicated that the HLA-A2-restricted mutated SV95 epitope decamers (SV95-6 and SV95-7) showed significant higher binding ability compared to natural peptide SV95-1 in MHC stability assay. More importantly, SV95-specific CTLs with higher cytotoxicity were successfully induced with both SV95-6 and SV95-7 peptides, which significantly eliminated target cells (not only SV95-1 peptide pulsed T2 cells, but also both HLA-A2 and SV positive cancer cells) when compared to those generated with natural SV95-1 peptide and TIL2080 cells. These findings suggest that the SV95-6 and SV95-7 peptides are two novel HLA-A2-restricted CTL epitopes and may be useful for the immunotherapy for patients with survivin expressing cancer.
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We investigated the role of microRNA (miR)-9 in modulating chemoresistance in hepatocellular carcinoma (HCC) cells. MiR-9 was overexpressed or knocked down in HCC cell lines. Cell viability, cell proliferation, the expression of EIF5A2 and the epithelial-mesenchymal transition (EMT)-related proteins were examined. HCC cells overexpressing miR-9 were more sensitive to cisplatin; miR-9 knockdown yielded the opposite result. The in vivo nude mouse HCC xenograft tumors yielded the same results. EIF5A2 was identified as a potential target of miR-9, where miR-9 regulated EIF5A2 expression at mRNA and protein level. EIF5A2 knockdown reversed miR-9 inhibition-mediated cisplatin resistance. Altering miR-9 and EIF5A2 expression changed E-cadherin and vimentin expression. Furthermore, EIF5A2 mediated miR-9 EMT pathway regulation, indicating that miR-9 can enhance cisplatin sensitivity by targeting EIF5A2 and inhibiting the EMT pathway. Targeting miR-9 may be useful for overcoming drug resistance in HCC.
Subject(s)
Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/metabolism , Cisplatin/therapeutic use , Liver Neoplasms/drug therapy , Liver Neoplasms/metabolism , MicroRNAs/metabolism , Peptide Initiation Factors/metabolism , RNA-Binding Proteins/metabolism , Animals , Carcinoma, Hepatocellular/genetics , Cell Line, Tumor , Cell Movement/drug effects , Cell Movement/ethics , Cell Proliferation/drug effects , Cell Proliferation/genetics , Epithelial-Mesenchymal Transition/genetics , Epithelial-Mesenchymal Transition/physiology , Female , Gene Expression Regulation, Neoplastic/drug effects , Gene Expression Regulation, Neoplastic/genetics , Humans , Immunohistochemistry , In Situ Nick-End Labeling , Liver Neoplasms/genetics , Mice , Mice, Nude , MicroRNAs/genetics , Peptide Initiation Factors/genetics , RNA, Messenger/genetics , RNA, Messenger/metabolism , RNA-Binding Proteins/genetics , Eukaryotic Translation Initiation Factor 5AABSTRACT
Unfortunately, the original version of this article contained two mistakes.
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Poly(lactic-co-glycolic) acid (PLGA) has been successfully used in drug delivery and biomaterial applications, but very little attention has been directed towards the potential in vivo effects of peptide-loaded PLGA nanoparticles (NPs), specifically the potency of intravenous (IV) STEAP peptide-loaded PLGA-NP (nanovaccine) dosing and whether STEAP-specific CD8+ T cells directly play a key role in tumor inhibition. To address these concerns, syngeneic prostate cancer mouse models were established and treated with either mSTEAP peptide emulsified in incomplete Freund's adjuvant (IFA) via subcutaneous (SC) injection or mSTEAP peptide nanovaccine containing the same amount of peptide via IV or SC injection. Meanwhile, mice were treated with either CD8b mAb followed by nanovaccine treatment, free mSTEAP peptide, or empty PLGA-NPs. Immune responses in these mice were examined using cytotoxicity assays at 14 days after treatment. Tumor size and survival in various treatment groups were measured and monitored. The results demonstrated that mSTEAP peptide nanovaccine resulted in tumor inhibition by eliciting a significantly stronger CD8+ T cell immune response when compared with the controls. Moreover, the survival periods of mice treated with mSTEAP nanovaccine were significantly longer than those of mice treated with mSTEAP peptide emulsified in IFA or the treatment controls. Additionally, it was observed that the peptide nanovaccine was mainly distributed in the mouse liver and lungs after IV injection. These findings suggest that the peptide nanovaccine is a promising immunotherapeutic approach and offers a new opportunity for prostate cancer therapies.
Subject(s)
Antigens, Neoplasm/administration & dosage , CD8-Positive T-Lymphocytes/drug effects , Cancer Vaccines/administration & dosage , Nanoparticles/administration & dosage , Polylactic Acid-Polyglycolic Acid Copolymer/administration & dosage , Prostatic Neoplasms/drug therapy , Animals , Antigens, Neoplasm/pharmacology , CD8-Positive T-Lymphocytes/immunology , Cancer Vaccines/pharmacokinetics , Cell Line, Tumor , Liver/metabolism , Lung/metabolism , Male , Mice, Inbred C57BL , Polylactic Acid-Polyglycolic Acid Copolymer/pharmacokinetics , Prostatic Neoplasms/immunology , Prostatic Neoplasms/metabolismABSTRACT
PURPOSE: A series of microRNAs (miRNAs) have been identified as associated with the survival of patients with non-small-cell lung cancer (NSCLC). The aim of the present study was to explore whether combination of these experimentally validated individual miRNA biomarkers could be used to further increase their prognostic power in NSCLC. PATIENTS AND METHODS: Based on previously validated NSCLC prognostic miRNAs, gene signatures that could discriminate high-risk subgroups with poor clinical outcome in four NSCLC miRNA expression datasets (GSE13937, GSE16025, The Cancer Genome Atlas Lung Adenocarcinoma, and TCGA lung squamous cell carcinoma) were developed using the SurvMicro tool. The potential of the miRNA signature established was validated by quantitative real-time PCR analysis of clinical NSCLC samples, and its prognostic power evaluated using the survivalROC method. RESULTS: We developed two miRNA signatures with prognostic significance for NSCLC, comprising 12- and 7-miRNAs. The 7-miRNA signature (miR-148b, miR-365, miR-32, miR-375, miR-21, miR-125b, and miR-155) was a subset of a 12-miRNA set that retained prognostic power across NSCLC cohorts. Compared with previously established miRNA signatures, our 7-miRNA signature has similar potential, while comprising fewer miRNA components. The prognostic ability of the 7-miRNA signature was validated experimentally in an independent NSCLC cohort using real-time PCR (HR=3.4847, 95% CI=1.3693-8.8680, P=0.0092), and this signature, combined with tumor pathological stage, had superior prognostic ability compared with tumor stage alone. CONCLUSION: Our data indicate that the established 7-miRNA signature is simple, robust, and may have greater clinical prognostic utility for patients with NSCLC.
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miR-132, a microRNA, has been reported to be down-regulated in several human cancers and is related with tumor progression; however, its function in non-small cell lung cancer (NSCLC) progression remains unclear. This study aimed to investigate the putative role of miR-132 in the metastasis of NSCLC. We determined the function of miR-132 in the migration and invasion of a NSCLC cell line in vitro using a miR-132 inhibitor and mimic. Our results showed overexpression of miR-132 significantly inhibited the migration and invasion of NSCLC cells in vitro. We then identified USP9X as a potential target of miR-132, and demonstrated miR-132 could regulate the expression of USP9X at both the mRNA and protein level. miR-132 could directly bind to the 3' untranslated region (3'-UTR) of USP9X. Inhibition of USP9X by its inhibitor WP1130 reduced the migration and invasion of NSCLC cells. Furthermore, USP9X inhibition also reversed the increased migration and invasion mediated by miR-132 inhibition. We found USP9X inhibition up-regulated expression of the epithelial-mesenchymal transition (EMT) marker E-cadherin, but down-regulated vimentin expression. A similar effect was seen with miR-132 overexpression, while the opposite effect occurred with miR-132 knockdown. USP9X inhibition reversed the miR-132 inhibitor-induced vimentin up-regulation and E-cadherin down-regulation. Taken together, these results indicate miR-132 prohibits the migration and invasion of NSCLC cells via targeting USP9X-induced EMT. Our data provides further evidence for the critical role of miR-132 and USP9X in regulating cell invasion and migration of NSCLC.
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Microplastic pollution has exhibited a global distribution, including seas, lakes, rivers, and terrestrial environment in recent years. However, little attention was paid on the atmospheric environment, though the fact that plastic debris can escape as wind-blown debris was previously reported. Thus, characteristics of microplastics in the atmospheric fallout from Dongguan city were preliminarily studied. Microplastics of three different polymers, i.e., PE, PP, and PS, were identified. Diverse shapes of microplastics including fiber, foam, fragment, and film were found, and fiber was the dominant shape of the microplastics. SEM images illustrated that adhering particles, grooves, pits, fractures, and flakes were the common patterns of degradation. The concentrations of non-fibrous microplastics and fibers ranged from 175 to 313 particles/m2/day in the atmospheric fallout. Thus, dust emission and deposition between atmosphere, land surface, and aquatic environment were associated with the transportation of microplastics.
Subject(s)
Environmental Pollution/analysis , Plastics/analysis , Waste Products/analysis , Atmosphere , China , Lakes , Oceans and Seas , Rivers , WindABSTRACT
Peptide recognition through the MHC class I molecule by cytotoxic T lymphocytes (CTLs) leads to the killing of cancer cells. A potential challenge for T-cell immunotherapy is that dendritic cells (DCs) are exposed to the MHC class I-peptide complex for an insufficient amount of time. To improve tumour antigen presentation to T cells and thereby initiate a more effective T-cell response, we generated artificial antigen-presenting cells (aAPCs) by incubating human immature DCs (imDCs) with poly(lactic-co-glycolic) acid nanoparticles (PLGA-NPs) encapsulating tumour antigenic peptides, followed by maturation with lipopolysaccharide. Tumour antigen-specific CTLs were then induced using either peptide-loaded mature DCs (mDCs) or aAPCs, and their activities were analysed using both ELISpot and cytotoxicity assays. We found that the aAPCs induced significantly stronger tumour antigen-specific CTL responses than the controls, which included both mDCs and aAPCs loaded with empty nanoparticles. Moreover, frozen CTLs that were generated by exposure to aAPCs retained the capability to eradicate HLA-A2-positive tumour antigen-bearing cancer cells. These results indicated that aAPCs are superior to DCs when inducing the CTL response because the former are capable of continuously presenting tumour antigens to T cells in a sustained manner. The development of aAPCs with PLGA-NPs encapsulating tumour antigenic peptides is a promising approach for the generation of effective CTL responses in vitro and warrants further assessments in clinical trials.
Subject(s)
Antigen Presentation , Cancer Vaccines/pharmacology , Cytotoxicity, Immunologic/drug effects , Dendritic Cells/drug effects , Inhibitor of Apoptosis Proteins/pharmacology , Lactic Acid/chemistry , Lipopolysaccharides/pharmacology , MART-1 Antigen/pharmacology , Nanoparticles , Neoplasms/therapy , Peptide Fragments/pharmacology , Polyglycolic Acid/chemistry , T-Lymphocytes, Cytotoxic/drug effects , Cancer Vaccines/chemistry , Cancer Vaccines/immunology , Cell Survival/drug effects , Delayed-Action Preparations , Dendritic Cells/immunology , Dendritic Cells/metabolism , Drug Compounding , Drug Liberation , Humans , Inhibitor of Apoptosis Proteins/chemistry , Inhibitor of Apoptosis Proteins/immunology , Kinetics , Lipopolysaccharides/immunology , MART-1 Antigen/chemistry , MART-1 Antigen/immunology , MCF-7 Cells , Neoplasms/immunology , Neoplasms/metabolism , Neoplasms/pathology , Peptide Fragments/chemistry , Peptide Fragments/immunology , Polylactic Acid-Polyglycolic Acid Copolymer , Solubility , Survivin , T-Lymphocytes, Cytotoxic/immunology , T-Lymphocytes, Cytotoxic/metabolismABSTRACT
Cisplatin-based combination chemotherapy significantly improves the survival outcomes in non-small cell lung carcinomas (NSCLCs), but drug resistance commonly contributes to disease progression and relapse. Recently, accumulating evidence has indicated that deubiquitinases (DUBs) are involved in regulating tumor cell proliferation, apoptosis, and chemoresistance. We designed this study to investigate the role of WP1130, a DUB inhibitor, in regulating cisplatin cytotoxicity in NSCLCs. After being combined with WP1130, cisplatin sensitivity was significantly increased in A549 and HCC827 cells with decreased p53 expression, inhibiting their proliferation, but not in p53-deficient NCI-H1299 cells. The synergistic cytotoxicity of the cisplatin and WP1130 co-treatment was abolished in p53-knockdown cells. Western blotting verified the decreased p53 expression in A549 and HCC827 cells treated with cisplatin and WP1130. The administration of MG132, a proteasome inhibitor, or knockdown of ubiquitin-specific peptidase 9, X-linked (USP9X) both eliminated the effect of WP1130 in decreasing p53 expression. Taken together, our findings confirm that the inclusion of WP1130 is potentially contributes to better therapeutic effects of cisplatin-based chemotherapy of NSCLCs in a manner dependent on the USP9X-p53 ubiquitination-mediated degradation pathway.
Subject(s)
Carcinoma, Non-Small-Cell Lung/genetics , Cisplatin/pharmacology , Cyanoacrylates/pharmacology , Drug Resistance, Neoplasm/drug effects , Drug Resistance, Neoplasm/genetics , Lung Neoplasms/genetics , Pyridines/pharmacology , Tumor Suppressor Protein p53/genetics , Animals , Apoptosis/drug effects , Carcinoma, Non-Small-Cell Lung/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Transformation, Neoplastic/drug effects , Disease Models, Animal , Gene Expression Regulation, Neoplastic/drug effects , Humans , Lung Neoplasms/metabolism , Mice , Proteolysis , Tumor Suppressor Protein p53/metabolism , Ubiquitination , Xenograft Model Antitumor AssaysABSTRACT
While large quantities of studies on microplastics in the marine environment have been widely carried out, few were available in the freshwater environment. The occurrence and characteristics, including composition, abundance, surface texture and interaction with heavy metals, of microplastics in the surface sediments from Beijiang River littoral zone were investigated. The concentrations of microplastics ranged from 178 ± 69 to 544 ± 107 items/kg sediment. SEM images illustrated that pits, fractures, flakes and adhering particles were the common patterns of degradation. Chemical weathering of microplastics was also observed and confirmed by µ-FTIR. EDS spectra displayed difference in the elemental types of metals on the different surface sites of individual microplastic, indicating that some metals carried by microplastics were not inherent but were derived from the environment. The content of metals (Ni, Cd, Pb, Cu, Zn and Ti) in microplastics after ultrasonic cleaning has been analyzed by ICP-MS. Based on data from the long-term sorption of metals by microplastics and a comparison of metal burden between microplastics, macroplastics and fresh plastic products, we suggested that the majority of heavy metals carried by microplastics were derived from inherent load.
Subject(s)
Geologic Sediments/chemistry , Metals, Heavy/metabolism , Plastics/chemistry , Rivers/chemistry , Water Pollutants, Chemical/chemistry , Water Pollutants, Chemical/metabolism , China , Environmental MonitoringABSTRACT
BACKGROUND: Esophageal reconstruction with colon interposition is an alternative solution for the esophageal cancer patients who have partial gastrectomy. The aim of this study was to investigate the therapeutic effects of colon interposition among the esophageal carcinoma patients with partial gastrectomy. MATERIALS AND METHODS: Under institutional review board approval, 32 esophageal carcinoma patients with a history of partial gastrectomy were included in this study. All the patients had been diagnosed and confirmed squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma by histopathological examination. Surgical approaches, complications and therapeutic results were analyzed in the current study. RESULTS: Thirty-two esophageal carcinoma patients (29 men, 3 women, median age 63.2 years) were included in this study. Isoperistaltic colon interposition was carried out on 14 patients; their 1-year and 2-year survival rate was 92.9% and 78.6%, respectively. Antiperistaltic colon interposition was carried out on 18 patients; their 1-year and 2-year survival rate was 88.9% and 77.8%, respectively. In which, cervical anastomotic leakage was observed on six patients. CONCLUSION: Colon interposition is an ideal surgical approach for the esophageal carcinoma patients who had partial gastrectomy. Isoperistaltic colon interposition is preferred, but antiperistaltic colon interposition has the advantage that a longer colon can be used.