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Size-control of species via wavelength to selectively synthesize Ag quantum clusters (QCs) was utilized and the synthesis conditions of this system (AgNO3, poly(methacrylic acid) (PMAA) with light) were optimized by changing a variety of parameters. Silver QCs, stabilized by PMAA with different compositions, have been synthesized in aqueous solution by tuning the irradiation monochromatic light wavelengths (300 or 365 nm) and AgNO3/MAA ratio (1 or 2). The novel preparation procedure has demonstrated a new approach to enlarge the population of the Ag QC family and proved the effectiveness of size control to prepare Ag QCs by tuning the light wavelength. Naked Ag QC species Agn (n = 2-9, 11, and 13) in polymer matrices are fully characterized by mass spectrometer, thus providing finger-printing evidence of their presence. Details regarding the photolysis reaction procedure, Ag QC optical properties, and the origins of fluorescence are discussed. Through a combination of results obtained from mass spectroscopy, fluorescence, and time-dependent density functional theory, we can assign the origin of fluorescence from a small silver cluster of Ag2 in organic scaffolds. The kinetics of the photolysis reaction follows first-order kinetics (k = 0.1/h). After thiolphenol (C6H5SH) ligand functionalization of the generated silver clusters in aqueous solution, the low or high resolution mass spectra showed the constant species composites with a molecular formula AgnLn-1 (n = 2-9 and L = C6H5S). More evidence indicated the formation of polymer-wrapped silver clusters. Their antibio property was explored, and we confirmed that they indeed show efficient activity.
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OBJECTIVES: Hepatoid adenocarcinoma of the stomach (HAS) is characterized by histological resemblance to hepatocellular carcinoma and a poor prognosis. The aim of this study is to elucidate the clinicopathological and molecular characteristics of HAS. METHODS: Forty-two patients with HAS who received gastrectomy were enrolled in this study. Based on a panel of 483 cancer-related genes, targeted sequencing of 24 HAS and 22 clinical parameter-matched common gastric cancer (CGC) samples was performed. Prognostic factors for overall survival (OS) and disease-free survival (DFS) were analysed with the Kaplan-Meier method. RESULTS: The most frequently mutated gene in both HAS and CGC was TP53, with a mutation rate of 30%. Additionally, CEBPA, RPTOR, WISP3, MARK1, and CD3EAP were identified as genes with high-frequency mutations in HAS (10-20%). Copy number gains (CNGs) at 20q11.21-13.12 occurred frequently in HAS, nearly 50% of HAS tumours harboured at least one gene with a CNG at 20q11.21-13.12. This CNG tended to be related to more adverse biobehaviour, including poorer differentiation, greater vascular and nerve invasion, and greater liver metastasis. Pathway enrichment analysis revealed that the HIF-1 signalling pathway and signalling pathways regulating stem cell pluripotency were specifically enriched in HAS. The survival analysis showed that a preoperative serum AFP level ≥ 500 ng/ml was significantly associated with poorer OS (p = 0.007) and tended to be associated with poorer DFS (p = 0.05). CONCLUSION: CNGs at 20q11.21-13.12 happened frequently in HAS and tended to be related to more adverse biobehaviour. The preoperative serum AFP level was a sensitive prognostic biomarker for DFS and OS.
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Adenocarcinoma/patologia , Gastrectomia/métodos , Neoplasias Hepáticas/epidemiologia , Neoplasias Gástricas/patologia , Adenocarcinoma/genética , Adenocarcinoma/cirurgia , Adulto , Idoso , Biomarcadores Tumorais/sangue , Variações do Número de Cópias de DNA , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , Neoplasias Gástricas/genética , Neoplasias Gástricas/cirurgia , Taxa de Sobrevida , alfa-Fetoproteínas/metabolismoRESUMO
UHRF1 is best known for its positive role in the maintenance of DNMT1-mediated DNA methylation and is implicated in a variety of tumor processes. In this paper, we provided evidence to demonstrate a role of UHRF2 in cell motility and invasion through the regulation of the epithelial-mesenchymal transition (EMT) process by acting as a transcriptional co-regulator of the EMT-transcription factors (TFs). We ectopically expressed UHRF2 in gastric cancer cell lines and performed multidimensional proteomics analyses. Proteome profiling analysis suggested a role of UHRF2 in repression of cell-cell adhesion; analysis of proteome-wide TF DNA binding activities revealed the up-regulation of many EMT-TFs in UHRF2-overexpressing cells. These data suggest that UHRF2 is a regulator of cell motility and the EMT program. Indeed, cell invasion experiments demonstrated that silencing of UHRF2 in aggressive cells impaired their abilities of migration and invasion in vitro Further ChIP-seq identified UHRF2 genomic binding motifs that coincide with several TF binding motifs including EMT-TFs, and the binding of UHRF2 to CDH1 promoter was validated by ChIP-qPCR. Moreover, the interactome analysis with IP-MS uncovered the interaction of UHRF2 with TFs including TCF7L2 and several protein complexes that regulate chromatin remodeling and histone modifications, suggesting that UHRF2 is a transcription co-regulator for TFs such as TCF7L2 to regulate the EMT process. Taken together, our study identified a role of UHRF2 in EMT and tumor metastasis and demonstrated an effective approach to obtain clues of UHRF2 function without prior knowledge through combining evidence from multidimensional proteomics analyses.
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Transição Epitelial-Mesenquimal , Proteômica/métodos , Neoplasias Gástricas/metabolismo , Fatores de Transcrição/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Antígenos CD , Sítios de Ligação , Caderinas/genética , Caderinas/metabolismo , Adesão Celular , Linhagem Celular Tumoral , Movimento Celular , Regulação Neoplásica da Expressão Gênica , Humanos , Regiões Promotoras Genéticas , Proteína 2 Semelhante ao Fator 7 de Transcrição/genética , Proteína 2 Semelhante ao Fator 7 de Transcrição/metabolismo , Fatores de Transcrição/genética , Ubiquitina-Proteína Ligases/química , Regulação para CimaRESUMO
A quantitative description of aerobic waste degradation is important in evaluating landfill waste stability and economic management. This research aimed to develop a coupling model to predict the degree of aerobic waste degradation. On the basis of the first-order kinetic equation and the law of conservation of mass, we first developed the coupling model of aerobic waste degradation that considered temperature, initial moisture content and air injection volume to simulate and predict the chemical oxygen demand in the leachate. Three different laboratory experiments on aerobic waste degradation were simulated to test the model applicability. Parameter sensitivity analyses were conducted to evaluate the reliability of parameters. The coupling model can simulate aerobic waste degradation, and the obtained simulation agreed with the corresponding results of the experiment. Comparison of the experiment and simulation demonstrated that the coupling model is a new approach to predict aerobic waste degradation and can be considered as the basis for selecting the economic air injection volume and appropriate management in the future.
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Análise da Demanda Biológica de Oxigênio , Eliminação de Resíduos , Instalações de Eliminação de Resíduos , Reatores Biológicos , Reprodutibilidade dos Testes , Temperatura , Poluentes Químicos da ÁguaRESUMO
The past decades have witnessed intensive research on the biological effects of graphene-based nanomaterials (GBNs) and the application of GBNs in different fields. The published literature shows that GBNs exhibit inhibitory effects on almost all microorganisms under pure culture conditions, and that this inhibitory effect is influenced by the microbial species, the GBN's physicochemical properties, the GBN's concentration, treatment time, and experimental surroundings. In addition, microorganisms exist in the soil in the form of microbial communities. Considering the complex interactions between different soil components, different microbial communities, and GBNs in the soil environment, the effects of GBNs on soil microbial communities are undoubtedly intertwined. Since bacteria and fungi are major players in terrestrial biogeochemistry, this review focuses on the antibacterial and antifungal performance of GBNs, their antimicrobial mechanisms and influencing factors, as well as the impact of this effect on soil microbial communities. This review will provide a better understanding of the effects of GBNs on microorganisms at both the individual and population scales, thus providing an ecologically safe reference for the release of GBNs to different soil environments.
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Claudin18.2 (CLDN18.2) is highly expressed with the development of various malignant tumors, especially gastrointestinal cancers, and is emerging as a new target for cancer treatment. Satricabtagene autoleucel (satri-cel)/CT041 is an autologous chimeric antigen receptor (CAR) T cell targeting CLDN18.2, and the interim results of the CT041-CG4006 trial were reported in June 2022. Here we present the final results of this single-arm, open-label, phase 1 trial, which evaluated the safety and efficacy of satri-cel in patients with CLDN18.2-positive advanced gastrointestinal cancers. This trial included a dose-escalation stage (n = 15) and a dose-expansion stage in four different cohorts (total n = 83): cohort 1, satri-cel monotherapy in 61 patients with standard chemotherapy-refractory gastrointestinal cancers; cohort 2, satri-cel plus anti-PD-1 therapy in 15 patients with standard chemotherapy-refractory gastrointestinal cancers; cohort 3, satri-cel as sequential treatment after first-line therapy in five patients with gastrointestinal cancers; and cohort 4, satri-cel monotherapy in two patients with anti-CLDN18.2 monoclonal antibody-refractory gastric cancer. The primary endpoint was safety; secondary endpoints included efficacy, pharmacokinetics and immunogenicity. A total of 98 patients received satri-cel infusion, among whom 89 were dosed with 2.5 × 108, six with 3.75 × 108 and three with 5.0 × 108 CAR T cells. Median follow-up was 32.4 months (95% confidence interval (CI): 27.3, 36.5) since apheresis. No dose-limiting toxicities, treatment-related deaths or immune effector cell-associated neurotoxicity syndrome were reported. Cytokine release syndrome occurred in 96.9% of patients, all classified as grade 1-2. Gastric mucosal injuries were identified in eight (8.2%) patients. The overall response rate and disease control rate in all 98 patients were 38.8% and 91.8%, respectively, and the median progression-free survival and overall survival were 4.4 months (95% CI: 3.7, 6.6) and 8.8 months (95% CI: 7.1, 10.2), respectively. Satri-cel demonstrates therapeutic potential with a manageable safety profile in patients with CLDN18.2-positive advanced gastrointestinal cancer. ClinicalTrials.gov identifier: NCT03874897 .
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Claudinas , Neoplasias Gastrointestinais , Imunoterapia Adotiva , Receptores de Antígenos Quiméricos , Humanos , Masculino , Neoplasias Gastrointestinais/imunologia , Neoplasias Gastrointestinais/terapia , Neoplasias Gastrointestinais/patologia , Feminino , Pessoa de Meia-Idade , Idoso , Adulto , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Receptores de Antígenos Quiméricos/imunologia , Claudinas/imunologia , Resultado do Tratamento , Linfócitos T/imunologia , Linfócitos T/transplanteRESUMO
BACKGROUND: Obesity is a global public health threat. Chromium picolinate (CrP) is advocated in the medical literature for the reduction of bodyweight, and preparations are sold as slimming aids in the USA and Europe, and on the Internet. OBJECTIVES: To assess the effects of CrP supplementation in overweight or obese people. SEARCH METHODS: We searched The Cochrane Library, MEDLINE, EMBASE, ISI Web of Knowledge, the Chinese Biomedical Literature Database, the China Journal Full text Database and the Chinese Scientific Journals Full text Database (all databases to December 2012), as well as other sources (including databases of ongoing trials, clinical trials registers and reference lists). SELECTION CRITERIA: We included trials if they were randomised controlled trials (RCT) of CrP supplementation in people who were overweight or obese.We excluded studies including children, pregnant women or individuals with serious medical conditions. DATA COLLECTION AND ANALYSIS: Two authors independently screened titles and abstracts for relevance. Screening for inclusion, data extraction and 'Risk of bias'assessment were carried out by one author and checked by a second. We assessed the risk of bias by evaluating the domains selection,performance, attrition, detection and reporting bias. We performed a meta-analysis of included trials using Review Manager 5. MAIN RESULTS: We evaluated nine RCTs involving a total of 622 participants. The RCTs were conducted in the community setting, with interventions mainly delivered by health professionals, and had a short- to medium-term follow up (up to 24 weeks). Three RCTs compared CrPplus resistance or weight training with placebo plus resistance or weight training, the other RCTs compared CrP alone versus placebo.We focused this review on investigating which dose of CrP would prove most effective versus placebo and therefore assessed the results according to CrP dose. However, in order to find out if CrP works in general, we also analysed the effect of all pooled CrP doses versus placebo on body weight only.Across all CrP doses investigated (200 µg, 400 µg, 500 µg, 1000 µg) we noted an effect on body weight in favour of CrP of debatable clinical relevance after 12 to 16 weeks of treatment: mean difference (MD) -1.1 kg (95% CI -1.7 to -0.4); P = 0.001; 392 participants;6 trials; low-quality evidence (GRADE)). No firm evidence and no dose gradient could be established when comparing different doses of CrP with placebo for various weight loss measures (body weight, body mass index, percentage body fat composition, change in waist circumference).Only three studies provided information on adverse events (low-quality evidence (GRADE)). There were two serious adverse events and study dropouts in participants taking 1000 µg CrP, and one serious adverse event in an individual taking 400 µg CrP. Two participants receiving placebo discontinued due to adverse events; one event was reported as serious. No study reported on all-cause mortality,morbidity, health-related quality of life or socioeconomic effects. AUTHORS' CONCLUSIONS: We found no current, reliable evidence to inform firm decisions about the efficacy and safety of CrP supplements in overweight or obese adults.
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Suplementos Nutricionais , Obesidade/tratamento farmacológico , Ácidos Picolínicos/administração & dosagem , Adulto , Humanos , Sobrepeso/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto , Treinamento Resistido , Levantamento de Peso , Redução de PesoRESUMO
The poly(methacrylic acid) (PMAA) polymer stabilized silver nanoclusters Agn (n = 2-9), synthesized in aqueous solution by the selected light wavelength irradiation photolysis approach, have been functionalized with thiol and amine ligands and successfully transferred from aqueous to organic media. Low- or high-resolution positive mass spectra showed constant species composites with the molecular formula AgnLn-1 [n = 2 to â¼9, L = butylmercaptan (C4H9S), thiolphenol (C6H5S), or dodecanethiol (C12H25S)] and proved that the molecules consist of deprotonated sulfur ligands in each species with one positive charge. Fourier transform infrared and X-ray photoelectron spectroscopy are consistent, indicating deprotonated sulfur, while silver has a zero valence value. The composition of the functionalized silver clusters is in agreement with that observed from polymer-wrapped "naked" silver clusters, which strongly indicates their real existence. For the silver cluster amine systems (heptylamine, dodecylamine, and oleylamine), only "naked" silver cluster species were detected from mass spectroscopy, similar to the polymer-wrapped case, indicating they are not stable enough in the gas phase. The development of a new antibacterial mask material is very important. The dodecylamine-capping silver nanoclusters were selected by coating the coffee filter surface to conduct antibacterial tests with Staphylococcus aureus and Escherichia coli, demonstrating very efficient antimicrobial properties even with organic capping ligands. Experiments also show that they work on mask material. One nanowire assembly with polystyrene and dodecylamine-capping silver nanoclusters was prepared, showing uniform nanofibers generated via the electrospray technique.
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The application of immunotherapy in gastrointestinal (GI) cancers remains challenging because of the limited response rate and emerging therapeutic resistance. Combining clinical cohorts, multi-omics study, and functional/molecular experiments, it is found that ANO1 amplification or high-expression predicts poor outcomes and resistance to immunotherapy for GI cancer patients. Knocking-down or inhibiting ANO1 suppresses the growth/metastasis/invasion of multiple GI cancer cell lines, cell-derived xenograft, and patient-derived xenograft models. ANO1 contributes to an immune-suppressive tumor microenvironment and induces acquired resistance to anti-PD-1 immunotherapy, while ANO1 knockdown or inhibition enhances immunotherapeutic effectiveness and overcomes resistance to immunotherapy. Mechanistically, through inhibiting cancer ferroptosis in a PI3K-Akt signaling-dependent manner, ANO1 enhances tumor progression and facilitates cancer-associated fibroblast recruitment by promoting TGF-ß release, thus crippling CD8+ T cell-mediated anti-tumor immunity and generating resistance to immunotherapy. This work highlights ANO1's role in mediating tumor immune microenvironment remodeling and immunotherapeutic resistance, and introduces ANO1 as a promising target for GI cancers' precision treatment.
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Fibroblastos Associados a Câncer , Ferroptose , Neoplasias Gastrointestinais , Humanos , Fibroblastos Associados a Câncer/metabolismo , Fosfatidilinositol 3-Quinases , Proliferação de Células , Proteínas de Neoplasias/metabolismo , Imunoterapia , Microambiente Tumoral , Anoctamina-1/metabolismoRESUMO
Diffuse-type gastric cancer (DGC) and intestinal-type gastric cancer (IGC) are the major histological types of gastric cancer (GC). The molecular mechanism underlying DGC and IGC differences are poorly understood. In this research, we carry out multilevel proteomic analyses, including proteome, phospho-proteome, and transcription factor (TF) activity profiles, of 196 cases covering DGC and IGC in Chinese patients. Integrative proteogenomic analysis reveals ARIDIA mutation associated with opposite prognostic effects between DGC and IGC, via diverse influences on their corresponding proteomes. Systematical comparison and consensus clustering analysis identify three subtypes of DGC and IGC, respectively, based on distinct patterns of the cell cycle, extracellular matrix organization, and immune response-related proteins expression. TF activity-based subtypes demonstrate that the disease progressions of DGC and IGC were regulated by SWI/SNF and NFKB complexes. Furthermore, inferred immune cell infiltration and immune clustering show Th1/Th2 ratio is an indicator for immunotherapeutic effectiveness, which is validated in an independent GC anti-PD1 therapeutic patient group. Our multilevel proteomic analyses enable a more comprehensive understanding of GC and can further advance the precision medicine.
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Neoplasias Gástricas , Humanos , Neoplasias Gástricas/patologia , Proteômica , Proteoma/genética , MutaçãoRESUMO
Tuberculosis is a chronic and lethal infectious disease caused by Mycobacterium tuberculosis. In previous decades, most studies in this area focused on the pathogenesis and drug targets for disease treatments. However, the emergence of drug-resistant strains has increased the difficulty of clinical trials over time. Now, more post-translational modified proteins in Mycobacterium tuberculosis have been discovered. Evidence suggests that these proteins have the ability to influence tuberculosis drug resistance. Hence, this paper systematically summarizes updated research on the impacts of protein acylation and phosphorylation on the acquisition of drug resistance in Mycobacterium tuberculosis through acylation and phosphorylation protein regulating processes. This provides us with a better understanding of the mechanism of antituberculosis drugs and may contribute to a reduction the harm that tuberculosis brings to society, as well as aiding in the discovery of new drug targets and therapeutic regimen adjustments in the future.
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Numerous reports of graphene-family nanomaterials (GFNs) promoting plant growth have opened up a wide range of promising potential applications in agroforestry. However, several toxicity studies have raised growing concerns about the biosafety of GFNs. Although these studies have provided clues about the role of GFNs from different perspectives (such as plant physiology, biochemistry, cytology, and molecular biology), the mechanisms by which GFNs affect plant growth remain poorly understood. In particular, a systematic collection of data regarding differentially expressed genes in response to GFN treatment has not been conducted. We summarize here the fate and biological effects of GFNs in plants. We propose that soil environments may be conducive to the positive effects of GFNs but may be detrimental to the absorption of GFNs. Alterations in plant physiology, biochemistry, cytological structure, and gene expression in response to GFN treatment are discussed. Coincidentally, many changes from the morphological to biochemical scales, which are caused by GFNs treatment, such as affecting root growth, disrupting cell membrane structure, and altering antioxidant systems and hormone concentrations, can all be mapped to gene expression level. This review provides a comprehensive understanding of the effects of GFNs on plant growth to promote their safe and efficient use.
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Acquired Trastuzumab resistance is a complicated and disastrous event for HER2-positive gastric cancer (GC). In this study, we successfully established a GC PDX model with Trastuzumab sensitivity (176P) and induced a homologous model with acquired Trastuzumab resistance (176R), then comprehensively delineated the landscape of Trastuzumab resistance mechanisms using single-cell transcriptome sequencing, as well as protein profiling and genomic variation analysis. According to multi-omics study, different gene expression profiles, rather than genetic changes, contributed to acquired Trastuzumab resistance. The mechanisms underlying acquired Trastuzumab resistance present great complexity as multiple molecules and pathways were involved, including ERBB family, MAPK, PI3K/AKT, JAK/STAT, and cell cycle pathways. Through phenotypical and molecular validation, we found that Trastuzumab combined with HER3-targeted antibody or MEK inhibitor demonstrated excellent antitumor activity and good tolerance, which may serve as promising strategies for overcoming acquired Trastuzumab resistance.
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Without treatment, familial adenomatous polyposis (FAP) patients will inevitably develop colorectal cancer (CRC) during lifetime. Yet, surgical trauma is a high risk of desmoid tumor (DT), one of the main causes of death in FAP patients. So far, the timing for colectomy is primarily based on the clinician's experience and the patient's preference; most patients undergo surgery at mid-20's. In this study, we analyzed the germline mutation distribution in 35 FAP patients from different families, 16 of them diagnosed with DTs. We also investigated the association between the molecular alterations and the clinicopathological features. Capture-based targeted sequencing using a panel of 520 genes was performed on tumor tissue and paired normal mucosa or white blood cells from 18 FAP probands who were initially diagnosed with CRC. Of all 35 FAP patients, 30 (85.7%) of them harbored germline APC mutations scattered from codon 161 to 1578. The mutations in the 16 DT patients scattered from codon 457 to 1578. All three patients with the mutation at the 3' of 1444 codon were diagnosed with DT. The percentage of high-risk DT (stage III or IV) harboring mutations at the 5' of 1062 or 1062-1578 was 14.3% and 77.8%, respectively, and all three patients with 3' of 1399 codon mutation had high risk. In addition, by using public database, we compared 140 FAP patients with DT to all 1880 FAP patients on the Leiden Open Variation Database and found that the odd ratio of DT in codon 159 to 495 was 0.34, while in codon 1310 to 2011 was 2.36. Compared to sporadic CRCs, the somatic spectrum of FAP CRCs was similar to the early onset CRCs, with higher TP53 (94.1%) and lower somatic APC mutations (65.7%), but the KRAS mutation rate was the highest (58.5%). One of the 18 FAP CRCs was identified as microsatellite instability-high (MSI-H), with tumor mutation burden (TMB) of 115.65 mut/Mb. Given that no TP53 mutations were detected in the low- and high-grade adenomas, ctDNA TP53 sequencing might be used for the close monitoring before FAP colectomy. In conclusion, except mutations at the 5' end of APC (5' to 495), all FAP patients need to consider the risk of DT after colectomy. The chance of life-threating DTs was higher in patients with 3' 1062 codon mutation and peaked in patients with 3' 1399 codon mutation. Scheduled monitoring of TP53 ctDNA is proposed to be a novel tool for optimizing the operation time.
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Despite success in hematologic malignancies, the treatment landscape of chimeric antigen receptor (CAR) T cell therapy for solid tumors remains limited. Claudin18.2 (CLDN18.2)-redirected CAR T cells showed promising efficacy against gastric cancer (GC) in a preclinical study. Here we report the interim analysis results of an ongoing, open-label, single-arm, phase 1 clinical trial of CLDN18.2-targeted CAR T cells (CT041) in patients with previously treated, CLDN18.2-positive digestive system cancers ( NCT03874897 ). The primary objective was safety after CT041 infusion; secondary objectives included CT041 efficacy, pharmacokinetics and immunogenicity. We treated 37 patients with one of three CT041 doses: 2.5 × 108, 3.75 × 108 or 5.0 × 108 cells. All patients experienced a grade 3 or higher hematologic toxicity. Grade 1 or 2 cytokine release syndrome (CRS) occurred in 94.6% of patients. No grade 3 or higher CRS or neurotoxicities, treatment-related deaths or dose-limiting toxicities were reported. The overall response rate (ORR) and disease control rate (DCR) reached 48.6% and 73.0%, respectively. The 6-month duration of response rate was 44.8%. In patients with GC, the ORR and DCR reached 57.1% and 75.0%, respectively, and the 6-month overall survival rate was 81.2%. These initial results suggest that CT041 has promising efficacy with an acceptable safety profile in patients with heavily pretreated, CLDN18.2-positive digestive system cancers, particularly in those with GC.
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Imunoterapia Adotiva , Neoplasias Gástricas , Claudinas , Síndrome da Liberação de Citocina , Humanos , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Neoplasias Gástricas/terapia , Linfócitos TRESUMO
BACKGROUND: The potential correlation between KIT secondary mutations and Imatinib-resistance in gastrointestinal stromal tumor (GIST) has been hinted, yet their specific linkage and underlying mechanisms remained unelucidated, also the development of substitute strategies dealing with this resistance was urgently needed. METHODS: In this study, we explored the distribution of the most prevalent forms of KIT mutation in Chinese GIST patients, after that, we established cell lines that was overexpressed with mutant KIT, and by performing RNA sequencing, immunoblotting and cell viability, we analyzed their functional and mechanistic relevance with Imatinib-resistance in GIST cell lines. Additionally, we evaluated the tumor inhibition efficacy of four regimens in Imatinib-resistant GIST cell lines and patient-derived xenograft (PDX) models. RESULTS: We found that KIT exon 13-V654A and exon 17-N822K were the most common secondary mutations in GIST with primary exon 11 mutations. These two secondary mutations induced Imatinib resistance by activating PI3K-Akt signaling pathway, while PI3K-Akt inhibition rescued the resistance. By assessing the feasibility of other four tyrosine kinase inhibitor (TKIs, Sunitinib/Regorafenib/Avapritinib/Ripretinib) against Imatinib-resistant GIST, we found that Sunitinib was more suitable for KIT exon 13 secondary mutations, the rest were more effective for KIT exon 17 secondary mutations, while all four TKIs displayed efficacy for KIT exon 9 mutations, emphasizing their clinical applications against Imatinib resistance. CONCLUSIONS: We demonstrated the mechanism by which KIT secondary mutations on exon 13/17 cause Imatinib resistance to GIST, and validated that several novel TKIs were valuable therapeutic options against Imatinib-resistance for both secondary- and primary-KIT mutations.
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Solid-state NMR analysis on wurtzite alloyed CdSe1-xSx crystalline nanoparticles and nanobelts provides evidence that the 113Cd NMR chemical shift is not affected by the varying sizes of nanoparticles, but is sensitive to the S/Se anion molar ratios. A linear correlation is observed between 113Cd NMR chemical shifts and the sulfur component for the alloyed CdSe1-xSx (0
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RhoA is a member of the RHO family GTPases and is associated with essential functions in gastric cancer. In this study, we identified a gastric cancer biomarker, termed the "regulation of RhoA activity panel" (RRAP). Patients with gastric cancer from The Cancer Genome Atlas database were divided into training (N=160) and validation (N=155) cohorts. A cohort of 109 Chinese gastric cancer patients was utilized as an independent validation. Patients with mutated RRAP showed significantly better overall survival than patients with wild type RRAP. We also analyzed the association between RRAP and the migration capacity, immune-related signatures, and the tumor microenvironment. RRAP-mutant tumors had a significantly lower degree of lymph node metastasis and lower activities of migration-related pathways. These tumors also showed significantly increased immune cell infiltration and cytotoxic activity. Furthermore, two independent patient cohorts who received immune checkpoint blockade therapy were assessed for RRAP mutant status. As expected, for both immunotherapy cohorts, higher response rates to immune checkpoint blockade therapy were observed in patients with RRAP-mutant tumors than in patients with wild type RRAP tumors. Overall, this study indicates that the RRAP gene set is a potential biomarker for gastric cancer prognosis and therapeutic selection.
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Carcinoma/genética , Regulação Neoplásica da Expressão Gênica/genética , Neoplasias Gástricas/genética , Microambiente Tumoral/genética , Proteína rhoA de Ligação ao GTP/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma/imunologia , Carcinoma/patologia , Movimento Celular/genética , Estudos de Coortes , Inibidor de Quinase Dependente de Ciclina p27/genética , Feminino , Proteínas Ativadoras de GTPase/genética , Proteínas da Membrana Plasmática de Transporte de Glicina/genética , Fatores de Troca do Nucleotídeo Guanina/genética , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Mutação , Proteínas Oncogênicas/genética , Prognóstico , Modelos de Riscos Proporcionais , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas c-bcr/genética , Proteínas Proto-Oncogênicas c-vav/genética , Fatores de Troca de Nucleotídeo Guanina Rho/genética , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/patologia , Microambiente Tumoral/imunologia , Proteínas Supressoras de Tumor/genética , Proteína cdc42 de Ligação ao GTP/genética , Proteína rhoA de Ligação ao GTP/metabolismoRESUMO
BACKGROUND: As the most abundant epigenetic modification on mRNAs and long non-coding RNAs, N6-methyladenosine (m6A) modification extensively exists in mammalian cells. Controlled by writers (methyltransferases), readers (signal transducers), and erasers (demethylases), m6A influences mRNA structure, maturation, and stability, thus negatively regulating protein expression in a post-translational manner. Nevertheless, current understanding of m6A's roles in tumorigenesis, especially in gastric cancer (GC) remains to be unveiled. In this study, we assessed m6A's clinicopathological relevance to GC and explored the underlying mechanisms. METHODS: By referring to a proteomics-based GC cohort we previously generated and the TCGA-GC cohort, we merged expressions of canonical m6A writers (METTL3/METTL14), readers (YTHDF1/YTHDF2/YTHDF3), and erasers (ALKBH5/FTO), respectively, as W, R, and E signatures to represent m6A modification. We stratified patients according to these signatures to decipher m6A's associations with crucial mutations, prognosis, and clinical indexes. m6A's biological functions in GC were predicted by gene set enrichment analysis (GSEA) and validated by in vitro experiments. RESULTS: We discovered that W and R were potential tumor suppressive signatures, while E was a potential oncogenic signature in GC. According to W/R/E stratifications, patients with low m6A-indications were accompanied with higher mutations of specific genes (CDH1, AR, GLI3, SETBP1, RHOA, MUC6, and TP53) and also demonstrated adverse clinical outcomes. GSEA suggested that reduced m6A was correlated with oncogenic signaling and phenotypes. Through in vitro experiments, we proved that m6A suppression (represented by METTL14 knockdown) promoted GC cell proliferation and invasiveness through activating Wnt and PI3K-Akt signaling, while m6A elevation (represented by FTO knockdown) reversed these phenotypical and molecular changes. m6A may also be involved in interferon signaling and immune responses of GC. CONCLUSIONS: Our work demonstrated that low-m6A signatures predicted adverse clinicopathological features of GC, while the reduction of RNA m6A methylation activated oncogenic Wnt/PI3K-Akt signaling and promoted malignant phenotypes of GC cells.
Assuntos
Adenosina/análogos & derivados , Proteômica/métodos , Neoplasias Gástricas/mortalidade , Via de Sinalização Wnt , Adenosina/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Epigênese Genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Mutação , Fenótipo , Fosfatidilinositol 3-Quinases/metabolismo , Prognóstico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Análise de SobrevidaRESUMO
The diffuse-type gastric cancer (DGC) constitutes a subgroup of gastric cancer with poor prognosis and no effective molecular therapies. Here, we report a phosphoproteomic landscape of DGC derived from 83 tumors together with their nearby tissues. Based on phosphorylation, DGC could be classified into three molecular subtypes with distinct overall survival (OS) and chemosensitivity. We identified 16 kinases whose activities were associated with poor OS. These activated kinases covered several cancer hallmark pathways, with the MTOR signaling network being the most frequently activated. We proposed a patient-specific strategy based on the hierarchy of clinically actionable kinases for prioritization of kinases for further clinical evaluation. Our global data analysis indicates that in addition to finding activated kinase pathways in DGC, large-scale phosphoproteomics could be used to classify DGCs into subtypes that are associated with distinct clinical outcomes as well as nomination of kinase targets that may be inhibited for cancer treatments.