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Immunological adjuvants are vaccine components that enhance long-lasting adaptive immune responses to weakly immunogenic antigens. Monophosphoryl lipid A (MPLA) is a potent and safe vaccine adjuvant that initiates an early innate immune response by binding to the Toll-like receptor 4 (TLR4). Importantly, the binding and recognition process is highly dependent on the monomeric state of MPLA. However, current vaccine delivery systems often prioritize improving the loading efficiency of MPLA, while neglecting the need to maintain its monomeric form for optimal immune activation. Here, we introduce a Pickering emulsion-guided MPLA monomeric delivery system (PMMS), which embed MPLA into the oil-water interface to achieve the monomeric loading of MPLA. During interactions with antigen-presenting cells, PMMS functions as a chaperone for MPLA, facilitating efficient recognition by TLR4 regardless of the presence of lipopolysaccharide-binding proteins. At the injection site, PMMS efficiently elicited local immune responses, subsequently promoting the migration of antigen-internalized dendritic cells to the lymph nodes. Within the draining lymph nodes, PMMS enhanced antigen presentation and maturation of dendritic cells. In C57BL/6 mice models, PMMS vaccination provoked potent antigen-specific CD8+ T cell-based immune responses. Additionally, PMMS demonstrated strong anti-tumor effects against E.G7-OVA lymphoma. These data indicate that PMMS provides a straightforward and efficient strategy for delivering monomeric MPLA to achieve robust cellular immune responses and effective cancer immunotherapy.
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mRNA delivery systems, such as lipid nanoparticle (LNP), have made remarkable strides in improving mRNA expression, whereas immune system activation operates on a threshold. Maintaining a delicate balance between antigen expression and dendritic cell (DC) activation is vital for effective immune recognition. Here, a water-in-oil-in-water (w/o/w) Pickering emulsion stabilized with calcium phosphate nanoparticles (CaP-PME) is developed for mRNA delivery in cancer vaccination. CaP-PME efficiently transports mRNA into the cytoplasm, induces pro-inflammatory responses and activates DCs by disrupting intracellular calcium/potassium ions balance. Unlike LNP, CaP-PME demonstrates a preference for DCs, enhancing their activation and migration to lymph nodes. It elicits interferon-γ-mediated CD8+ T cell responses and promotes NK cell proliferation and activation, leading to evident NK cells infiltration and ameliorated tumor microenvironment. The prepared w/o/w Pickering emulsion demonstrates superior anti-tumor effects in E.G7 and B16-OVA tumor models, offering promising prospects as an enhanced mRNA delivery vehicle for cancer vaccinations.
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(1) Background: The research group has developed a new small molecule, 6-Isopropyldithio-2'-deoxyguanosine analogs-YLS004, which has been shown to be the most sensitive in acute T-lymphoblastic leukemia cells. Moreover, it was found that the structure of Nelarabine, a drug used to treat acute T-lymphoblastic leukemia, is highly similar to that of YLS004. Consequently, the structure of YLS004 was altered to produce a new small molecule inhibitor for this study, named YLS010. (2) Results: YLS010 has exhibited potent anti-tumor effects by inducing cell apoptosis and ferroptosis. A dose gradient was designed for in vivo experiments based on tentative estimates of the toxicity dose using acute toxicity in mice and long-term toxicity in rats. The study found that YLS010 at a dose of 8 mg/kg prolonged the survival of late-stage acute T-lymphoblastic leukemia mice in the mouse model study. (3) Conclusions: YLS010 has demonstrated specific killing effects against acute T-lymphoblastic leukemia both in vivo and in vitro. Preclinical studies of YLS010 offer a new opportunity for the treatment of patients with acute T-lymphoblastic leukemia in clinical settings.
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BACKGROUND: Although DHFR gene amplification has long been known as a major mechanism for methotrexate (MTX) resistance in cancer, the early changes and detailed development of the resistance are not yet fully understood. METHODS: We performed genomic, transcriptional and proteomic analyses of human colon cancer cells with sequentially increasing levels of MTX-resistance. RESULTS: The genomic amplification evolved in three phases (pre-amplification, homogenously staining region (HSR) and extrachromosomal DNA (ecDNA)). We confirm that genomic amplification and increased expression of DHFR, with formation of HSRs and especially ecDNAs, is the major driver of resistance. However, DHFR did not play a detectable role in the early phase. In the late phase (ecDNA), increase in FAM151B protein level may also have an important role by decreasing sensitivity to MTX. In addition, although MSH3 and ZFYVE16 may be subject to different posttranscriptional regulations and therefore protein expressions are decreased in ecDNA stages compared to HSR stages, they still play important roles in MTX resistance. CONCLUSION: The study provides a detailed evolutionary trajectory of MTX-resistance and identifies new targets, especially ecDNAs, which could help to prevent drug resistance. It also presents a proof-of-principal approach which could be applied to other cancer drug resistance studies.
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Resistencia a Medicamentos Antineoplásicos , Amplificação de Genes , Metotrexato , Tetra-Hidrofolato Desidrogenase , Humanos , Metotrexato/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Tetra-Hidrofolato Desidrogenase/genética , Tetra-Hidrofolato Desidrogenase/metabolismo , Linhagem Celular Tumoral , Neoplasias do Colo/genética , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Antimetabólitos Antineoplásicos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Genômica/métodosRESUMO
BACKGROUND: Apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 2 (APOBEC2) is associated with nucleotide alterations in the transcripts of tumor-related genes which are contributed to carcinogenesis. Expression and prognosis value of APOBEC2 in stomach adenocarcinoma (STAD) remains unclear. METHODS: The APOBEC2 gene alteration frequency of STAD and APOBEC2 gene expression in STAD and normal tissues were investigated in cBioportal and GEPIA, respectively. We detected expression of APOBEC2, infiltration of CD66b+ tumor-associated neutrophils and CD163+ tumor-associated macrophages in tissue microarrays by immunohistochemistry. APOBEC2 gene expression was explored by western blot and qRT-PCR. Relationships between APOBEC2 and CD66b, CD163, and other clinicopathological characteristics were investigated. Associations among APOBEC2 expression status and patient survival outcome were further analyzed. RESULTS: APOBEC2 gene alteration frequency was 5%, and APOBEC2 gene was downexpressed in STAD compared to normal tissues (P < 0.05). APOBEC2 expression status were associated with the infiltration of CD66b+ TANs, differentiation grade, TNM stage, histological type and gender (all P < 0.05) in STAD. Little or no APOBEC2 expression was detected in STAD and adjacent normal tissues by western blot. We failed to show that APOBEC2 was an independent risk factor for OS (Hazard Ratio 0.816, 95%CI 0.574-1.161, P = 0.259) or DFS (Hazard Ratio 0.821, 95%CI 0.578-1.166, P = 0.270) in STAD by multivariate Cox regression analysis, but APOBEC2 negative subgroup has a worse OS and DFS among patients with adjuvant chemotherapy. CONCLUSIONS: APOBEC2 correlates with CD66b, differentiation grade, TNM stages, histological classification, and gender in STAD. APOBEC2 is not an independent prognostic factor for STAD, our results suggest that patients with positive APOBEC2 can benefit from postoperative chemotherapy, and combination of APOBEC2 and CD66b is helpful to further stratify patients into different groups with distinct prognoses.
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Desaminases APOBEC , Adenocarcinoma , Neoplasias Gástricas , Humanos , Adenocarcinoma/patologia , Desaminases APOBEC/metabolismo , Proteínas Musculares , Neutrófilos/patologia , Nucleotídeos/metabolismo , Prognóstico , Modelos de Riscos Proporcionais , Neoplasias Gástricas/metabolismoRESUMO
BACKGROUND: It has been demonstrated that circularRNA (circRNAs) plays a critical role in various cancers. While the potential molecular mechanism of circRNAs in the progression of colorectal cancer (CRC) remains uncertain. METHODS: Differentially expressed circRNAs were identified by RNA sequencing. RT-qPCR detected the expression of circ_0009092, miR-665, and NLK in CRC tissues and cells. Functions of circ_0009092 on tumor cell proliferation, migration, and invasion were investigated by a series of in vitro assays. The underlying mechanism of circ_0009092 was explored by bioinformatics analysis, RNA immunoprecipitation (RIP) and luciferase assays. A co-culture assay in vitro was performed to detect the affection of circ_0009092 on macrophage recruitment in the tumor microenvironment (TME). A xenograft mouse model was used to explore the effect of circ_0009092 on tumor growth. RESULTS: Circ_0009092 was downregulated in CRCand predicted a good prognosis. Overexpression of circ_0009092 reduced tumor cell EMT, proliferation, migration, and invasion in vitro and in vivo. Mechanistically, circ_0009092 elevated the NLK expression via sponging miR-665 and suppressed the Wnt/ß-catenin signaling pathway. EIF4EA3 induced circ_0009092 expression in CRC cells. In addition, NLK regulates phosphorylation and O-GlcNAcylation of STAT3 by binding to STAT3, thereby inhibiting CCL2 expression, in which it inhibits macrophage recruitment in the tumor microenvironment (TME). CONCLUSION: EIF4A3 suppressed circ_0009092 biogenesis, whichinhibits CRC progression by sponging miR-665 to downregulate NLK. Circ_0009092/miR-665/NLK suppressed tumor EMT, proliferation, migration, and invasion by acting on the Wnt/ß-catenin signaling pathway. NLK directly interacted with STAT3 and decreased the CCL2 expression, inhibiting the recruitment of tumor-associated macrophages (TAMs) in the TME. Our study provided novel insights into the roles of circ_0009092 as a novel promising prognostic and therapeutic target in CRC.
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Neoplasias Colorretais , MicroRNAs , Humanos , Animais , Camundongos , RNA Circular/genética , RNA Circular/metabolismo , Macrófagos Associados a Tumor/metabolismo , Microambiente Tumoral/genética , Linhagem Celular Tumoral , Neoplasias Colorretais/patologia , MicroRNAs/genética , MicroRNAs/metabolismo , Via de Sinalização Wnt , Proliferação de Células/genética , Proteínas Serina-Treonina Quinases/metabolismo , Fator de Iniciação 4A em Eucariotos/metabolismo , RNA Helicases DEAD-box/metabolismoRESUMO
Extrachromosomal DNAs (ecDNAs), also known as double minutes (DMs), can induce a fast increase in gene copy numbers and promote the development of cancer, including drug resistance. MutS homolog 3 (MSH3), a key protein in mismatch repair, has been indicated to participate in the regulation of DNA doublestrand break (DSB) repair, which has been reported to be associated with the formation of ecDNAs. However, it remains unclear whether MSH3 can influence drug resistance via ecDNAs in cancer. In the present study, high MSH3 expression was observed in methotrexate (MTX)resistant HT29 cells [DM and homogeneously staining region (HSR)containing cells] compared with parental HT29 cells. Additionally, decreased amounts of ecDNAs, HSRs and amplified genes locating on ecDNAs and HSRs were detected following depletion of MSH3 and this could be reversed by overexpressing MSH3 in DMcontaining cells. No corresponding changes were found in HSRcontaining cells. The present study further verified the involvement of MSH3regulated DNA DSB repair pathways in the formation of ecDNAs by detecting the expression of core proteins and pathway activity. Furthermore, expulsion of ecDNAs/HSRs was detected and increased frequencies of micronuclei/nuclear buds with dihydrofolate reductase (DHFR) signals were observed in MSH3depleted DMcontaining cells. Finally, changes in MSH3 expression could affect DHFR amplificationderived DHFR expression and cell sensitivity to MTX, suggesting that MSH3 may influence cancer drug resistance by altering the amount of ecDNAs. In conclusion, the present study revealed a novel mechanism involving MSH3 in the regulation of ecDNAs by DSB repair, which will have clinical value in the treatment of ecDNAbased drug resistance in cancer.
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Neoplasias Colorretais , Metotrexato , Humanos , Metotrexato/farmacologia , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Reparo do DNA , Aberrações Cromossômicas , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , DNA , Proteína 3 Homóloga a MutS/genética , Proteína 3 Homóloga a MutS/metabolismoRESUMO
Peritoneal metastasis (PM) is a frequent manifestation of advanced abdominal malignancies. Accurately assessing the extent of PM before surgery is essential for patients to receive optimal treatment. Therefore, we propose to construct a deep learning (DL) model based on enhanced computed tomography (CT) images to stage PM preoperatively in patients. All 168 patients with PM underwent contrast-enhanced abdominal CT before either open surgery or laparoscopic exploration, and peritoneal cancer index (PCI) was used to evaluate patients during the surgical procedure. DL features were extracted from portal venous-phase abdominal CT scans and subjected to feature selection using the Spearman correlation coefficient and LASSO. The performance of models for preoperative staging was assessed in the validation cohort and compared against models based on clinical and radiomics (Rad) signature. The DenseNet121-SVM model demonstrated strong patient discrimination in both the training and validation cohorts, achieving AUC was 0.996 in training and 0.951 validation cohort, which were both higher than those of the Clinic model and Rad model. Decision curve analysis (DCA) showed that patients could potentially benefit more from treatment using the DL-SVM model, and calibration curves demonstrated good agreement with actual outcomes. The DL model based on portal venous-phase abdominal CT accurately predicts the extent of PM in patients before surgery, which can help maximize the benefits of treatment and optimize the patient's treatment plan.
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Aprendizado Profundo , Neoplasias Peritoneais , Humanos , Neoplasias Peritoneais/diagnóstico por imagem , Neoplasias Peritoneais/cirurgia , Peritônio/diagnóstico por imagem , Peritônio/cirurgia , Tomografia Computadorizada por Raios X , Estudos RetrospectivosRESUMO
Background: Nicotinamide N-methyltransferase (NNMT) and Dickkopf-1 (DKK1) play an important role in the development of breast cancer, and the purpose of this study was designed to examine the clinical and prognostic significance of NNMT and DKK1 in breast cancer. Methods: The GEPIA2 database was used to evaluate the expression and survival of NNMT mRNA and DKK1 mRNA of breast cancer. Then an immunohistochemical study was carried out on 374 cases of breast tissue to identify the protein expression and significance of NNMT and DKK1. Next, the prognostic significance of DKK1 in breast cancer was explored by COX and Kaplan-Meier models. Results: Protein NNMT expression was correlated with lymph node metastasis and histological grade (P < .05) while protein DKK1 expression was related to tumor size, pT stage, histological grade, and Ki-67 (P < .05). Protein DKK1 was related to disease-specific survival (DSS), and low DKK1 expression indicated a poor prognosis of breast cancer patients (P < .05). Combined expression of protein NNMT and protein DKK1 predicted different prognosis of DSS (P < .05). Conclusions: Nicotinamide N-methyltransferase and DKK1 were linked to breast cancer malignancy and invasion. Breast cancer patients with low DKK1 expression had a worse prognosis. Oncotypes of NNMT and DKK1 expression predicted patient outcomes.
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OBJECTIVE: To explore the rapid evaluation of the early pathogen of severe Chlamydophila psittaci pneumonia by bedside diagnostic bronchoscopy, so as to start effective anti-infection treatment before the results of macrogenome next generation sequencing (mNGS) test. METHODS: The clinical data of three patients with severe Chlamydophila psittaci pneumonia who were successfully treated in the First Affiliated Hospital of Xinjiang Medical University, the First People's Hospital of Aksu District, and the First Division Hospital of Xinjiang Production and Construction Corps from October 2020 to June 2021 were retrospectively analyzed, including the rapid assessment of early pathogens by bedside diagnostic bronchoscopy and the use of antibiotics to start anti-infection treatment. These patients were successfully treated. RESULTS: The three patients were male, aged 63, 45 and 58 years old, respectively. Before the onset of the penumonia, they had a clear medical history of bird exposure. The clinical manifestations mainly included fever, dry cough, shortness of breath and dyspnea. One case had abdominal pain and lethargy. The results of laboratory examination indicated that the peripheral blood white blood cell count (WBC) of two patients were high [(10.2-11.9)×109/L], the percentage of neutrophils increased (85.2%-94.6%) and the percentage of lymphocytes decreased (3.2%-7.7%) in all 3 patients after admission to hospital and entering into intensive care unit (ICU). The procalcitonin (PCT) of 3 patients increased after admission, and still increased when entering ICU (0.3-4.8 ng/L), so did C-reactive protein (CRP, 58.0-162.0 mg/L) and erythrocyte sedimentation rate (ESR, 36.0-90.0 mm/1 h). After admission, serum alanine transaminase (ALT) increased in 2 cases (136.7 U/L, 220.5 U/L), so did aspartate transaminase (AST) in 2 cases (249.6 U/L, 164.2 U/L). ALT (162.2-267.9 U/L) and AST (189.8-223.2 U/L) increased in 3 patients when they entered ICU. The level of serum creatinine (SCr) of 3 patients were normal after admission and entering ICU. The chest computed tomography (CT) findings of 3 patients were acute interstitial pneumonia, bronchopneumonia and lung consolidation, of which 2 cases were accompanied by a small amount of pleural effusion, and 1 case was accompanied by more regular small air sacs. Multiple lung lobes were involved, but mainly one lung lobe. The oxygenation index (PaO2/FiO2) of the 3 patients admitting to ICU were 100.0, 57.5 and 105.4 mmHg (1 mmHg ≈ 0.133 kPa), respectively, which met with the diagnostic criteria of moderate and severe acute respiratory distress syndrome (ARDS). All three patients received endotracheal intubation and mechanical ventilation. Under the bedside bronchoscope, the bronchial mucosa of 3 patients were obviously congested and edematous, without purulent secretion, and there was 1 case with mucosal hemorrhage. Three patients underwent bedside diagnostic bronchoscopy, and the evaluation result of the pathogen was that it might be atypical pathogen infection, so they were given moxifloxacin, cisromet and doxycycline intravenously, respectively, and combined with carbapenem antibiotics intravenously. After 3 days, the detection results of mNGS in bronchoalveolar lavage fluid (BALF) showed that only Chlamydia psittaci was infected. At this time, the condition was significantly improved, and PaO2/FiO2 was significantly increased. Therefore, the antibiotic treatment scheme remained unchanged, and mNGS only served to verify the initial diagnosis. Two patients were extubated on the 7th and 12th day of admission to the ICU, respectively, while one patient was extubated on the 16th day of admission to the ICU due to nosocomial infection. All 3 patients were transferred to the respiratory ward after the condition was stable. CONCLUSIONS: The bedside diagnostic bronchoscopy based on clinical characteristics is conducive to not only the rapid assessment of the early pathogens of severe Chlamydia psittaci pneumonia, but also effective anti-infection treatment before the returning of mNGS test results, which can make up for the lag and uncertainty of the mNGS test results.
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Chlamydophila psittaci , Pneumonia , Animais , Humanos , Masculino , Pessoa de Meia-Idade , Antibacterianos , Aspartato Aminotransferases , Broncoscopia , Hospitalização , Estudos RetrospectivosRESUMO
Farnesoid X receptor (FXR) is a nuclear receptor known to play protective roles in anti-hepatocarcinogenesis and regulation of the basal metabolism of glucose, lipids, and bile acids. FXR expression is low or absent in HBV-associated hepatocarcinogenesis. Full-length HBx and HBx C-terminal truncation are frequently found in clinical HCC samples and play distinct roles in hepatocarcinogenesis by interacting with FXR or FXR signaling. However, the impact of C-terminal truncated HBx on the progression of hepatocarcinogenesis in the absence of FXR is unclear. In this study, we found that one known FXR binding protein, a C-terminal truncated X protein (HBx C40) enhanced obviously and promoted tumor cell proliferation and migration by altering cell cycle distribution and inducing apoptosis in the absence of FXR. HBx C40 enhanced the growth of FXR-deficient tumors in vivo. In addition, RNA-sequencing analysis showed that HBx C40 overexpression could affect energy metabolism. Overexpressed HSPB8 aggravated the metabolic reprogramming induced by down-regulating glucose metabolism-associated hexokinase 2 genes in HBx C40-induced hepatocarcinogenesis. Overall, our study suggests that C-terminal truncated HBx C40 synergizes with FXR deficiency by altering cell cycle distribution as well as disturbing glucose metabolism to promote HCC development.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinogênese/genética , Carcinoma Hepatocelular/metabolismo , Ciclo Celular/genética , Proliferação de Células/genética , Transformação Celular Neoplásica , Vírus da Hepatite B/genética , Neoplasias Hepáticas/metabolismo , Transativadores/genética , Transativadores/metabolismo , Proteínas Virais Reguladoras e AcessóriasRESUMO
The molecular mechanism underlying gastric cancer (GC) peritoneal metastasis (PM) remains unclear. Here, we identified LINC00924 as a GC PM-related lncRNA through Microarray sequencing. LINC00924 was highly expressed in GC, and its high expression is associated with a broad range of PM. Via RNA sequencing, RNA pulldown assay, mass spectrometry, Seahorse, Lipidomics, spheroid formation and cell viability assays, we found that LINC00924 promoted fatty acid (FA) oxidation (FAO) and FA uptake, which was essential for matrix-detached GC cell survival and spheroid formation. Regarding the mechanism, LINC00924 regulated the alternative splicing (AS) of Mnk2 pre-mRNA by binding to hnRNPC. Specifically, LINC00924 enhanced the binding of hnRNPC to Mnk2 pre-mRNA at e14a, thus downregulating Mnk2a splicing and regulating the p38 MAPK/PPARα signaling pathway. Collectively, our results demonstrate that LINC00924 plays a role in promoting GC PM and could serve as a drug target.
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Neoplasias Peritoneais , RNA Longo não Codificante , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/genética , Processamento Alternativo/genética , Ácidos Graxos , Precursores de RNA , Proteínas Serina-Treonina Quinases/genética , RNA Longo não Codificante/genética , Ribonucleoproteínas Nucleares Heterogêneas Grupo CRESUMO
Hypoxic microenvironment and metabolic dysregulation of tumor impairs the therapeutic efficacy of chemotherapeutic drugs, resulting in drug resistance and tumor metastasis, which has always been a challenge for the treatment of solid tumors, including renal cell carcinoma (RCC). Herein, starting from the evaluation of methionine metabolism in RCC cells, we demonstrated that the increased methionine accumulation in RCC cells was mediated by L-type amino acid transporter 1 (LAT1) under hypoxia. Glutathione (GSH), as a methionine metabolite, would attenuate the therapeutic efficacy of oxaliplatin through chemical chelation. Reducing methionine uptake by LAT1 inhibitor JPH203 significantly enhanced the sensitivity of RCC cells to oxaliplatin by reducing GSH production in vitro and in vivo. Therefore, we proposed an effective and stable therapeutic strategy based on the combination of oxaliplatin and LAT1 inhibitor, which is expected to solve the resistance of RCC to platinum-based drugs under hypoxia to a certain extent, providing a meaningful insight into the development of new therapeutic strategies and RCC treatment.
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While research on cancer vaccines has made great strides in the field of immunotherapy, the targeted delivery of multiple effective components (rational-tailored antigens and adjuvants) remains a challenge. Here, we utilized the unique hierarchical structures of Pickering emulsions (particles, oil core, and water-oil interface) to develop mannosylated (M) Pickering emulsions (PE) that target antigen presenting cells and synergistically deliver antigenic peptides and the TLR9 agonist CpG (C) as an enhanced cancer vaccine (MPE-C). We chemically linked mannose residues to PLGA/PLAG-PEG nanoparticles and produced a dense array of mannose on the nanopatterned surface of Pickering emulsions, allowing for increased cellular targeting. Together with the inherent deformability of the oily core, MPE-C increased the droplet-cellular contact area and provoked the cellular recognition of mannose and CpG for enhanced immune activation. We found that MPE-C attracted a large number of APCs to the local site of administration, evidently increasing cellular uptake and activation. Additionally, we observed increased antigen-specific cellular immune responses, with potent anti-tumor effects against both E.G7-OVA and B16-MUCI tumors. Furthermore, MPE-C combined with PD-1 antibodies produced a significant tumor regression, resulting in synergistic increases in anti-tumor effects. Thus, through the strategic loading of mannose, antigens, and CpG, Pickering emulsions could serve as a targeted delivery platform for enhanced multicomponent cancer vaccines.
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Vacinas Anticâncer , Nanopartículas , Adjuvantes Imunológicos/farmacologia , Emulsões/química , Imunidade Celular , Nanopartículas/químicaRESUMO
The performance of the integrated process of coagulation and ozonation with ceramic membrane filtration was evaluated for the treatment of shale gas hydraulic fracturing flowback wastewater (HFFW). The removal efficiencies of carbon oxygen demand (CODCr ), dissolved organic carbon (DOC), petroleum oils, and turbidity in effluent by the combined process were 87.1%, 72.2%, 94.3%, and 99.6%, respectively. Compared with sole membrane filtration, the transmembrane pressure (TMP) of ceramic membrane filtration was reduced by >99% with the integrated process. The coagulation and ozonation can effectively remove the organics with high molecular weights in the cake layer of ceramic membrane. To the best of our knowledge, this work proposed the combined process of coagulation, ozonation, and flat-sheet ceramic membrane filtration for the treatment of HFFW for the first time. The water quality of the effluent met the discharge standard (Comprehensive Wastewater Discharge Standard GB8978-1996). The findings can provide an important technical foundation for the innovation of integrated equipment for HFFW treatment. PRACTITIONER POINTS: An integrated process combining coagulation and ozonation with flat-sheet ceramic membrane ultrafiltration for the treatment of shale gas wastewater. The water quality of this integrated process met the discharge standard. Coagulation and ozonation effectively alleviated the membrane fouling related to organics with high molecular weights. A new avenue for on-site treatment of shale gas wastewater and an alternative of the current centralized wastewater management.
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Fraturamento Hidráulico , Ozônio , Purificação da Água , Cerâmica , Filtração , Laboratórios , Membranas Artificiais , Gás Natural , Águas ResiduáriasRESUMO
A major challenge in vaccine delivery is to achieve robust lymph-node (LN) accumulation, which can capitalize on concentrated immunocytes and cytokines in LNs to stimulate the onset and persistence of adaptive immune responses. Previous attempts at developing vaccine delivery systems have focused on the sizes, charges, or surface ligands but not on their deformability. In fact, the LN homing of antigen-presenting cells depends on deformability to pass through the cellular gaps. Herein, the deformability of albumin-stabilized emulsions is engineered. Owing to self-adaptive deformability, the droplets (≈330 nm) can attach to and deform between cells and adjust their sizes to pass through the endothelial gaps (20-100 nm), favoring direct LN transfer (intercellular pathway). Additionally, owing to relatively large sizes, some emulsions can be retained at the administration sites for potent antigen uptake and activation of APCs as well as LN-targeted delivery of vaccines (intracellular pathway). Compared with solid particles, the dual LN transfer strategy evidently enhances antigen accumulation and activation of LN drainage, potently stimulates cellular immune responses, and increases the survival rate of tumor-bearing mice. Thus, the deformability of albumin-stabilized droplets may offer an efficient strategy for potent LN targeting and enhanced vaccinations.
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Células Apresentadoras de Antígenos , Imunidade Celular , Vacinação , Animais , Emulsões , Linfonodos , Camundongos , VacinasAssuntos
COVID-19 , Leucemia-Linfoma Linfoblástico de Células Precursoras , SARS-CoV-2/metabolismo , COVID-19/sangue , COVID-19/diagnóstico , COVID-19/terapia , Pré-Escolar , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapiaRESUMO
BACKGROUND: Determining the status of lymph node (LN) metastasis in rectal cancer patients preoperatively is crucial for the treatment option. However, the diagnostic accuracy of current imaging methods is low. PURPOSE: To develop and test a model for predicting metastatic LNs of rectal cancer patients based on clinical data and MR images to improve the diagnosis of metastatic LNs. STUDY TYPE: Retrospective. SUBJECTS: In all, 341 patients with histologically confirmed rectal cancer were divided into one training set (120 cases) and three validation sets (69, 103, 49 cases). FIELD STRENGTH/SEQUENCE: 3.0T, axial and sagittal T2 -weighted turbo spin echo and diffusion-weighted imaging (b = 0 s/mm2 , 800 s/mm2 ) ASSESSMENT: In the training dataset, univariate logistic regression was used to identify the clinical factors (age, gender, and tumor markers) and MR data that correlated with LN metastasis. Then we developed a prediction model with these factors by multiple logistic regression analysis. The accuracy of the model was verified using three validation sets and compared with the traditional MRI method. STATISTICAL TESTS: Univariate and multivariate logistic regression. The area under the curve (AUC) value was used to quantify the diagnostic accuracy of the model. RESULTS: Eight factors (CEA, CA199, ADCmean, mriT stage, mriN stage, CRM, EMVI, and differentiation degree) were significantly associated with LN metastasis in rectal cancer patients (P<0.1). In the training set (120) and the three validation sets (69, 103, 49), the AUC values of the model were much higher than the diagnosis by MR alone (training set, 0.902 vs. 0.580; first validation set, 0.789 vs. 0.743; second validation set, 0.774 vs. 0.573; third validation set, 0.761 vs. 0.524). DATA CONCLUSION: For the diagnosis of metastatic LNs in rectal cancer patients, our proposed logistic regression model, combining clinical and MR data, demonstrated higher diagnostic efficiency than MRI alone. LEVEL OF EVIDENCE: 4 TECHNICAL EFFICACY STAGE: 2.
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Linfonodos , Neoplasias Retais , Humanos , Linfonodos/diagnóstico por imagem , Metástase Linfática , Imageamento por Ressonância Magnética , Neoplasias Retais/diagnóstico por imagem , Estudos RetrospectivosRESUMO
Cancer vaccines have opened a new paradigm for safe and effective antitumor therapy, but they still suffer from shortcomings such as insufficient immunogenicity and immune tolerance, which seldom makes them the first choice in clinic. In fact, similar to providing a high-end product, a robust antitumor effect depends on the inherent supply chain, which attains, processes, and presents tumor-associated antigens via antigen presenting cells to T cells, which then leads to lysis of the cancer cells to release more antigens to complete the supply chain. Under these circumstances, the failure of cancer vaccines can be treated as a blockade or chain rupture. Thus, for effective tumor treatment, the key is to rationally design logistic systems to restore the supply chain.Under these circumstances, this Account summarizes our recent attempts to exploit the immunogenic trait of synthetic particles to enhance the distribution, presentation, and immune activations of the whole priming process in cancer vaccines: (1) Raw material (tumor antigen/signals) procurement: We illustrated the efforts to deliver antigens to antigen presenting cells (APCs) and draining lymph nodes for potent internalizations, and put more emphasis on the structural effect of sizes, charges, shapes, and assembly strategies for the antigen depot, lymph node transfer, and APC endocytosis. (2) Manufacture of cytotoxic T lymphocytes (CTLs) via APC recognition and presentation: We centered on exploiting the softness of two-dimensional graphene and Pickering emulsions to dynamically potentiate the immune recognition, and demonstrating the recent advances in lysosome escape strategies for enhanced antigen cross-presentations. (3) Marketing the accumulations of CTLs and the reversal of an immunosuppressive microenvironment within the tumor: We demonstrated the previous attempts to inherently cultivate the tumor tropism of the T cells via the multiantigenic repertoire and discussed the advances and challenges of combinatory cancer vaccines with an immune checkpoint blockade to reinforce the antitumor efficacy. Collectively, this Account aims to illustrate the potential of the particulate cancer vaccines to recapitalize the inherent host immune responses for the maximum antitumor effect. And by integrating the antitumor supply chain, optimized synthetic particles may shed light on the development of safe and effective particulate cancer vaccines.
Assuntos
Vacinas Anticâncer/administração & dosagem , Neoplasias/prevenção & controle , Animais , Células Apresentadoras de Antígenos/citologia , Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/metabolismo , Antígenos de Neoplasias/química , Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/química , Vacinas Anticâncer/imunologia , Linhagem Celular Tumoral , Endocitose , Humanos , Interleucina-6/metabolismo , Camundongos , Nanopartículas/química , Neoplasias/imunologia , Neoplasias/mortalidade , Polímeros/química , Taxa de Sobrevida , Linfócitos T Citotóxicos/citologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/metabolismoRESUMO
Memory is no longer a privilege of adaptive immunity. Innate immune cells can exhibit a long-term immune activation after infection or vaccination, which is called "trained immunity." In addition to defense against mycobacterial infection, BCG-induced trained immunity can also exert nonspecific protection, which is regulated by metabolic rewiring and epigenetic reprograming. Enhanced glycolysis and glutamine-driven tricarboxylic acid cycle have been proven to be important metabolic pathways for trained immunity induced by BCG, which is dependent on Akt/mTOR pathway.