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BACKGROUND: To investigate the optimal B1,rms value of renal amide proton transfer-weighted (APTw) images and the reproducibility of this value, and to explore the utility of APT imaging of renal masses and kidney tissues. METHODS: APTw images with different B1,rms values were repeatedly recorded in 15 healthy volunteers to determine the optimal value. Two 4-point Likert scales (poor [1] to excellent [4]) were used to evaluate contour clarity and artifacts in masses and normal tissues. The APTw values of masses and normal tissues were then compared in evaluable images (contour clarity score > 1, artifacts score > 1). The APTw of malignant masses, normal tissues, and benign masses were calculated and compared with the Mann-Whitney U test. RESULTS: The optimal scanning parameter of B1,rms was 2 µT, and the APTw images had good agreement in the volunteers. Our study of APTw imaging examined 70 renal masses (13 benign, 57 malignant) and 49 normal kidneys (including those from 15 healthy volunteers). The mean APTw value for renal malignant masses (2.28(1.55)) was different from that for benign masses (0.91(1.30)) (P<0.001), renal cortex (1.30 (1.25)) (P<0.001), renal medulla (1.64 (1.33)) (P<0.05), and renal pelvis (5.49 (2.65)) (P<0.001). CONCLUSION: These preliminary data demonstrate that APTw imaging of the kidneys has potential use as an imaging biomarker for the differentiation of normal tissues, malignant masses, and benign masses.
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INTRODUCTION: Chimeric antigen receptor (CAR) T cell therapy has markedly improved the prognosis of patients with diffuse large B-cell lymphoma (DLBCL). The relative positioning of tumor lesions in lymphoma varies among patients, manifesting as either aggregation (clumped together) or dissemination (spread throughout the body). Prognostic significance of factors indicating the relative positioning of tumor lesions in CAR T cell therapy remains underexplored. For aggregation, prior research proposed the tumor volume surface ratio (TVSR), linking it to prognosis in chemotherapy. Regarding dissemination, indicators such as disease stage or extranodal involvement, commonly used in clinical practice, have not demonstrated prognostic significance in CAR T cell therapy. This study aims to analyze current indicators of tumor aggregation or dissemination and introduce a novel indicator to assess the prognostic value of tumor lesions' relative positioning in DLBCL patients undergoing CAR T cell therapy. METHODS: This retrospective study included 42 patients receiving CAR T cell therapy. Lesion image information was obtained from the last PET/CT scan prior to CAR T cell infusion, including total metabolic tumor volume, total tumor surface, diameter of lymphoma masses, and the sites of tumor lesions. We evaluated TVSR and bulky disease as descriptors of tumor aggregation. We refined existing indicators, stage III&IV and >1 site extranodal involvement, to distill a new indicator, termed 'extra stage', to better represent tumor dissemination. The study examined the prognostic significance of tumor aggregation and dissemination. RESULTS: Our findings indicate that TVSR, while prognostically valuable in chemotherapy, lacks practical prognostic value in CAR T cell therapy. Conversely, bulky disease emerged as an optimal prognostic indicator of tumor aggregation. Both bulky disease and extra stage were associated with poor prognosis and exhibiting synergistic prognostic impact in CAR T cell therapy. CONCLUSIONS: Overall, the relative positioning of tumor lesions significantly influences the prognosis of patients with DLBCL receiving CAR T cell therapy. The ideal scenario involves tumors with minimal dissemination and no aggregation.
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Linfoma Difuso de Grandes Células B , Receptores de Antígenos Quiméricos , Humanos , Imunoterapia Adotiva/métodos , Receptores de Antígenos Quiméricos/uso terapêutico , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Estudos Retrospectivos , Prognóstico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Terapia Baseada em Transplante de Células e TecidosRESUMO
BACKGROUND: Conventional magnetic resonance imaging (MRI) has certain limitations in distinguishing between malignant and benign urinary bladder (UB) lesions. Amide proton transfer (APT) imaging may provide more diagnostic information than diffusion-weighted imaging (DWI) to distinguish between malignant and benign UB. PURPOSE: To investigate the potential of APT imaging in the diagnosis of malignant and benign UB lesions and to compare its diagnostic efficacy with that of conventional DWI. STUDY TYPE: Prospective. SUBJECTS: Eighty patients with UB lesions. FIELD STRENGTH/SEQUENCE: A 3.0 T/turbo spin echo (TSE) T1-weighted and T2-weighted imaging, single-shot echo planar DWI, and three-dimensional TSE APT imaging. ASSESSMENT: Patients underwent radical cystectomy or transurethral resection of the bladder lesions within 2 weeks after CT urography and MRI examination. APT signal intensity in UB lesions was quantified by the asymmetric magnetization transfer ratio (MTRasym). MTRasym and apparent diffusion coefficient (ADC) values were measured and compared between malignant and benign UB lesions. STATISTICAL TESTS: Kolmogorov-Smirnov test, Student's t test or Mann-Whitney U test, Spearman rank correlation coefficient, area under the receiver operating characteristic (ROC) curve (AUC), Delong test, and intraclass correlation coefficient (ICC). The significance threshold was set at P < 0.05. RESULTS: Thirty-two patients had pathologically confirmed benign UB lesions, including 2 bladder leiomyomas, 1 submucosal amyloidosis, 1 inflammatory myofibroblastic tumor, and 28 inflammatory lesions, and 48 patients had pathologically confirmed urothelial carcinoma. Urothelial carcinomas showed significantly higher MTRasym values (1.53% [0.74%] vs. 0.85% [0.23%]) and significantly lower ADC values (1.24 ± 0.34 × 10-3 mm2/s vs. 1.43 ± 0.22 × 10-3 mm2/s) than benign UB lesions. The MTRasym value (AUC = 0.928) was significantly better in differentiating urothelial carcinoma from benign UB lesions than the ADC value (AUC = 0.722). DATA CONCLUSION: APT imaging may have value in discriminating malignant from benign UB lesions and has better diagnostic performance than DWI. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 2.
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Imagem de Difusão por Ressonância Magnética , Neoplasias da Bexiga Urinária , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Imagem de Difusão por Ressonância Magnética/métodos , Neoplasias da Bexiga Urinária/diagnóstico por imagem , Idoso , Estudos Prospectivos , Adulto , Bexiga Urinária/diagnóstico por imagem , Bexiga Urinária/patologia , Idoso de 80 Anos ou mais , Imageamento por Ressonância Magnética/métodos , Prótons , Diagnóstico Diferencial , Sensibilidade e Especificidade , Amidas , Reprodutibilidade dos Testes , Curva ROCRESUMO
INTRODUCTION: Renal fibrosis (RF), being the most important pathological change in the progression of CKD, is currently assessed by the evaluation of a biopsy. This present study aimed to apply a novel functional MRI (fMRI) protocol named amide proton transfer (APT) weighting to evaluate RF noninvasively. METHODS: Male Sprague-Dawley (SD) rats were initially subjected to bilateral kidney ischemia/reperfusion injury (IRI), unilateral ureteral obstruction, and sham operation, respectively. All rats underwent APT mapping on the 7th and 14th days after operation. Besides, 26 patients underwent renal biopsy at the Nephrology Department of Shanghai Tongji Hospital between July 2022 and May 2023. Patients underwent APT and apparent diffusion coefficient (ADC) mappings within 1 week before biopsy. MRI results of both patients and rats were calculated by comparing with gold standard histology for fibrosis assessment. RESULTS: In animal models, the cortical APT (cAPT) and medullary APT (mAPT) values were positively correlated with the degree of RF. Compared to the sham group, IRI group showed significantly increased cAPT and mAPT values on the 7th and 14th days after surgery, but no group differences were found in ADC values. Similar results were found in human patients. Cortical/medullary APT values were significantly increased in patients with moderate-to-severe fibrosis than in patients with mild fibrosis. ROC curve analysis indicated that APT value displayed a better diagnostic value for RF. Furthermore, combination of cADC and cAPT improved fibrosis detection by imaging variables alone (p < 0.1). CONCLUSION: APT values had better diagnostic capability at early stage of RF compared to ADC values, and the addition of APT imaging to conventional ADC will significantly improve the diagnostic performance for predicting kidney fibrosis.
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Fibrose , Rim , Imageamento por Ressonância Magnética , Ratos Sprague-Dawley , Masculino , Animais , Fibrose/diagnóstico por imagem , Humanos , Ratos , Pessoa de Meia-Idade , Rim/diagnóstico por imagem , Rim/patologia , Imageamento por Ressonância Magnética/métodos , Traumatismo por Reperfusão/diagnóstico por imagem , Feminino , Adulto , Amidas , Prótons , Nefropatias/diagnóstico por imagem , Nefropatias/patologia , Nefropatias/diagnóstico , Idoso , Insuficiência Renal Crônica/diagnóstico por imagem , Insuficiência Renal Crônica/patologia , Obstrução Ureteral/diagnóstico por imagem , Modelos Animais de DoençasRESUMO
OBJECTIVE: To investigate the potential of amide proton transfer-weighted (APTw) MRI in identifying benign and malignant renal tumors and to evaluate whether APTw MRI can add diagnostic value to diffusion-weighted imaging (DWI). MATERIALS AND METHODS: Participants with renal tumor underwent preoperative multiparametric MRI, including APTw MRI and DWI. The APTw and apparent diffusion coefficient (ADC) of malignant tumors and benign tumors were calculated independently by two radiologists and compared. The value of the mean APTw and the mean ADC for differentiating malignant and benign tumors was evaluated by receiver operating characteristic analysis. RESULTS: In total, 65 participants (mean age, 59 years ±14; 41 men) were evaluated: 54 with malignant and 11 with benign renal tumors. Malignant renal tumors showed higher mean APTw values [2.03% (1.63) vs 1.00% (1.60); P < 0.01] and lower mean ADC values (1.22 × 10-3 mm2/s ± 0.37 vs 1.51 × 10-3 mm2/s ± 0.37; P < 0.05) than benign renal tumors. The area under the receiver operating characteristic curve (AUC) of APTw, ADC and the combination of them for the identification of benign and malignant renal tumors was 0.78(95% CI: 0.66, 0.87; P < 0.001),0.70(95% CI: 0.54, 0.86; P < 0.05) and 0.79 (95% CI: 0.67, 0.88; P < 0.001). The optimal cutoff value for mean APTw was 2.14% (sensitivity, 74%; specificity, 73%). There was no difference between these three parameters for differentiating malignant from benign renal tumors (P > 0.05). CONCLUSION: The APTw MRI has the potential use as an imaging biomarker for renal malignant and benign tumors.
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Neoplasias Renais , Prótons , Masculino , Humanos , Pessoa de Meia-Idade , Amidas , Imagem de Difusão por Ressonância Magnética/métodos , Imageamento por Ressonância Magnética , Neoplasias Renais/diagnóstico por imagem , Diagnóstico Diferencial , Sensibilidade e Especificidade , Estudos RetrospectivosRESUMO
Multidrug resistance (MDR) is one of the major factors causing failure of non-small-cell lung cancer (NSCLC) chemotherapy. Real-time and accurate differentiation between drug-resistant and sensitive NSCLC is of primary importance for guiding the subsequent treatments and improving the therapeutic outcome. However, there is no effective method to provide such an accurate differentiation. This study creates an innovative strategy of integrating H2 O2 -responsive nanoprobes with the quantitative T1 -mapping magnetic resonance imaging (MRI) technique to achieve an accurate differential diagnosis between drug-resistant and sensitive NSCLC in light of differences in H2 O2 content in the tumor microenvironment (TME). The result demonstrates that the synthesized MIL-53(Fe)@MnO2 nanocomposites possess an excellent capability of shortening the cancer longitudinal relaxation time (T1 ) when meeting H2 O2 in TME. T1 -mapping MRI could sensitively detect this T1 variation (about 2.6-fold that of T1-weighted imaging (T1 WI)) to accurately differentiate the H2 O2 content between drug-resistant and sensitive NSCLC. In addition, the quantitative data provided by the T1 -mapping MRI dedicates correct comparison across imaging tests and is more reliable than T1 WI, thus giving it a chance for precise assessment of the anti-cancer effect. This innovative strategy of merging TME adaptable nanoprobes with the quantitative MRI technique provides a new approach for the precise diagnosis of multidrug-resistant NSCLC.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/patologia , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/patologia , Meios de Contraste , Compostos de Manganês , Diagnóstico Diferencial , Óxidos , Imageamento por Ressonância Magnética/métodos , Microambiente TumoralRESUMO
The DNA-encoded library (DEL) is a powerful hit-generation tool in drug discovery. This study describes a new DEL with a privileged scaffold quinazolin-4(3H)-one developed by a robust DNA-compatible multicomponent reaction and a series of novel glutathione S-transferase (GST) inhibitors that were identified through affinity-mediated DEL selection. A novel inhibitor 16 was subsequently verified with an inhibitory potency value of 1.55 ± 0.02 µM against SjGST and 2.02 ± 0.20 µM against hGSTM2. Further optimization was carried out via various structure-activity relationship studies. And especially, the co-crystal structure of the compound 16 with the SjGST was unveiled, which clearly demonstrated its binding mode was quite different from the known GSH-like compounds. This new type of probe is likely to play a different role compared with the GSH, which may provide new opportunities to discover more potent GST inhibitors.
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Inibidores Enzimáticos , Glutationa Transferase , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Relação Estrutura-AtividadeRESUMO
Accurately evaluating tumor responses to immunotherapy is clinically relevant. However, non-invasive, real-time visualization techniques to evaluate tumor immunotherapy are still lacking. Herein, a smart responsive fluorescence-MR dual-modal nanoprobe, QM(GP)-MZF(CP), is reported that can be targeted for cleavage by the cytotoxic T cell activation marker granzyme B and the apoptosis-related marker cysteine-aspartic acid-specific protease 3 (Caspase-3). The probe uses quinoline-malononitrile (QM), an aggregation-induced emission luminogen, and Mn-Zn ferrite magnetic nanoparticles (MZF-MNPs), a T2-weighted imaging (T2WI) contrast agent, as imaging molecules that are linked with the substrate peptides specific to granzyme B and Caspase-3. Therefore, both granzyme B and Caspase-3 can target and cleave the substrate peptides in QM(GP)-MZF(CP). Via aggregation-induced fluorescence imaging of QM and the aggregation-induced T2WI-enhanced imaging effect of MZF-MNPs, the status of T cells after tumor immunotherapy and the subsequent triggering of tumor cell apoptosis can be determined to identify tumor responsiveness to immunotherapy and thereby evaluate the effectiveness of this therapy in the early stages of treatment.
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Neoplasias , Humanos , Fluorescência , Caspase 3 , Granzimas , Neoplasias/diagnóstico por imagem , Neoplasias/terapia , Imageamento por Ressonância Magnética , ImunoterapiaRESUMO
A novel series of benzamide derivatives were successively designed and synthesized prepared from the pyridazinone scaffold. Among them, (S)-17b, demonstrated potent inhibitory activity in vitro toward human class I HDAC isoforms and human myelodysplastic syndrome (SKM-1) cell line. Also, (S)-17b strongly increased the intracellular level of acetyl-histone H3 and P21 simultaneously and effectively induced G1 cell cycle arrest and apoptosis. Through oral dosing in SKM-1 xenograft models, (S)-17b exhibited excellent in vivo antitumor activity. In addition, compound (S)-17b showed better antitumor efficacy on mouse models with intact immune system than those with thymus deficiencies. Furthermore, this compound displayed a favorable pharmacokinetic profile in ICR mice and SD rat, respectively, minimal metabolic property differences among hepatocytes from five species, and a low inhibition upon the human ether-a-go-go (hERG) channel with an IC50 value of 34.6 µΜ. This novel compound (S)-17b may serve as a new drug candidate for further investigation.
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Antineoplásicos , Inibidores de Histona Desacetilases , Camundongos , Humanos , Ratos , Animais , Inibidores de Histona Desacetilases/uso terapêutico , Inibidores de Histona Desacetilases/farmacocinética , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacocinética , Ratos Sprague-Dawley , Camundongos Endogâmicos ICR , Modelos Animais de Doenças , Benzamidas/farmacologia , Proliferação de Células , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Apoptose , Relação Estrutura-AtividadeRESUMO
PURPOSE: To assess the ability of amide proton transfer (APT) imaging, in comparison with diffusion-weighted imaging (DWI), to differentiate low-grade from high-grade bladder tumors and predict the aggressiveness of bladder cancer (BCa). METHODS: Forty-eight patients diagnosed with BCa confirmed by histopathological findings who underwent magnetic resonance (MR) imaging, including APT imaging and DWI (b = 0, 1000 sec/mm2), were enrolled in this study. The asymmetric magnetization transfer ratio (MTRasym) was defined as the magnetization transfer asymmetry at 3.5 ppm. MTRasym and apparent diffusion coefficients (ADCs) were compared between the low- and high-grade groups and between non-muscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC) in terms of the areas under the receiver operating characteristic curves (AUCs). RESULTS: The MTRasym values were significantly higher in patients with high-grade bladder tumors than in those with low-grade tumors (1.61 % [0.76 %], 1.12 ± 0.3 %; P = 0.000) and in MIBC than in NMIBC (2.53 ± 0.67 %, 1.38 % [0.35 %]; P = 0.000). The AUCs of MTRasym were significantly larger than those of ADC for differentiating MIBC from NMIBC (0.973, 0.771; P = 0.016). Adding APT imaging to DWI significantly improved the diagnostic accuracy for differentiating MIBC from NMIBC versus DWI alone (0.985, 0.876; P = 0.013). CONCLUSIONS: APT imaging can predict tumor grade and aggressiveness in BCa. The diagnostic performance of APT imaging in predicting tumor aggressiveness was better than that of DWI, and adding APT imaging to DWI significantly improved the diagnostic accuracy of predicting tumor aggressiveness versus DWI alone.
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Prótons , Neoplasias da Bexiga Urinária , Humanos , Amidas , Imagem de Difusão por Ressonância Magnética/métodos , Neoplasias da Bexiga Urinária/diagnóstico por imagem , Neoplasias da Bexiga Urinária/patologia , Imageamento por Ressonância Magnética/métodosRESUMO
Novel pyrrolopyridone BET degraders were designed and synthesized based on the binding mode between the pyrrolopyridone BET inhibitor with the BRD4 protein. The potent degraders on MV-4-11 cells were discovered through structure-activity relationship study. Modification of warhead on pyrrolopyridone BET degraders significantly regulates BRD4 isoform (long and short) protein degradation, which induces differential cell cycle arrest and apoptosis on MV-4-11 cells. Docking study revealed that the fine structural modification of BET degraders may bind with the BD domain of BRD4 protein to engage various surface areas that bind with CRBN.
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Antineoplásicos , Proteínas Nucleares , Antineoplásicos/farmacologia , Proteínas de Ciclo Celular , Proteínas Nucleares/metabolismo , Relação Estrutura-Atividade , Fatores de Transcrição/metabolismoRESUMO
Macrophage cell membrane-camouflaged nanocarriers can effectively reduce immune cell clearance and actively target tumors. In this study, a macrophage cell membrane-camouflaged mesoporous silica nanorod (MSNR)-based antitumor drug carrier equipped with a cationic polymer layer was developed. As drug carriers, these MSNRs were loaded with the thermosensitive phase change material L-menthol (LM), the chemotherapy drug doxorubicin (DOX) and the fluorescent molecule indocyanine green (ICG). The rod-like shape of the MSNRs was shown to enhance the penetration of the drug carriers to tumors. In the weakly acidic tumor microenvironment, the cationic polymer exhibited a proton sponge effect to trigger macrophage cell membrane coating detachment, promoting tumor cell uptake. Following nanocarrier uptake, ICG is heated by near-infrared (NIR) irradiation to make LM undergo a phase transition to release DOX and generate a synergistic effect of thermochemotherapy which kills tumor cells and inhibits tumor growth together with reactive oxygen species (ROS) produced by ICG. Overall, this nanohybrid drug delivery system demonstrates an intelligent cascade response, leads to tissue-cell specific targeting and improves drug release accuracy, thus proving to be an effective cancer therapy.
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Antineoplásicos , Membrana Celular , Sistemas de Liberação de Medicamentos/métodos , Macrófagos/citologia , Nanotubos/química , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Membrana Celular/química , Membrana Celular/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/química , Doxorrubicina/farmacocinética , Doxorrubicina/farmacologia , Humanos , Verde de Indocianina/química , Raios Infravermelhos , Neoplasias/metabolismo , Fotoquimioterapia , Terapia Fototérmica , Silício/químicaRESUMO
Purpose: Accurate prediction of the progression to severe stroke in initially diagnosed nonsevere patients with acute-subacute anterior circulation nonlacuna ischemic infarction (ASACNLII) is important in making clinical decision. This study aimed to apply a machine learning method to predict if the initially diagnosed nonsevere patients with ASACNLII would progress to severe stroke by using diffusion-weighted images and clinical information on admission. Methods: This retrospective study enrolled 344 patients with ASACNLII from June 2017 to August 2020 on admission, and 108 cases progressed to severe stroke during hospitalization within 3-21 days. The entire data were randomized into a training set (n = 271) and an independent test set (n = 73). A U-Net neural network was employed for automatic segmentation and volume measurement of the ischemic lesions. Predictive models were developed and used for evaluating the progression to severe stroke using different feature sets (the volume data, the clinical data, and the combination) and machine learning methods (random forest, support vector machine, and logistic regression). Results: The U-Net showed high correlation with manual segmentation in terms of Dice coefficient of 0.806 and R 2 value of the volume measurements of 0.960 in the test set. The random forest classifier of the volume + clinical combination achieved the best area under the receiver operating characteristic curve of 0.8358 (95% CI 0.7321-0.9269), and the accuracy, sensitivity, and specificity were 0.7780 (0.7397-0.7945), 0.7695 (0.6102-0.9074), and 0.8686 (0.6923-1.0), respectively. The Shapley additive explanation diagram showed the volume variable as the most important predictor. Conclusion: The U-Net was fully automatic and showed a high correlation with manual segmentation. An integrated approach combining clinical variables and stroke lesion volumes that were derived from the advanced machine learning algorithms had high accuracy in predicting the progression to severe stroke in ASACNLII patients.
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Single-cell analysis is critical to revealing cell-to-cell heterogeneity that would otherwise be lost in ensemble analysis. Detailed lipidome characterization for single cells is still far from mature, especially when considering the highly complex structural diversity of lipids and the limited sample amounts available from a single cell. We report the development of a general strategy enabling single-cell lipidomic analysis with high structural specificity. Cell fixation is applied to retain lipids in the cell during batch treatments prior to single-cell analysis. In addition to tandem mass spectrometry analysis revealing the class and fatty acyl-chain for lipids, batch photochemical derivatization and single-cell droplet treatment are performed to identify the C=C locations and sn-positions of lipids, respectively. Electro-migration combined with droplet-assisted electrospray ionization enables single-cell mass spectrometry analysis with easy operation but high efficiency in sample usage. Four subtypes of human breast cancer cells are correctly classified through quantitative analysis of lipid C=C location or sn-position isomers in ~160 cells. Most importantly, the single-cell deep lipidomics strategy successfully discriminates gefitinib-resistant cells from a population of wild-type human lung cancer cells (HCC827), highlighting its unique capability to promote precision medicine.
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Lipidômica/métodos , Lipídeos/análise , Análise de Célula Única/métodos , Espectrometria de Massas em Tandem/métodos , Linhagem Celular Tumoral , Ésteres do Colesterol/análise , Ésteres do Colesterol/química , Diglicerídeos/análise , Diglicerídeos/química , Ácidos Graxos/análise , Ácidos Graxos/química , Humanos , Isomerismo , Lipídeos/química , Células MCF-7 , Estrutura Molecular , Reprodutibilidade dos Testes , Triglicerídeos/análise , Triglicerídeos/químicaRESUMO
Chemotherapy-induced neutropenia, a symptom of neutrophil depletion, makes cancer patients highly susceptible to invasive fungal infection with substantial morbidity and mortality. To address the cryptococcal brain infection in this condition, this study attempts to arm neutrophils (NEs) with antibiotics to potentiate the antifungal capability of NEs. To allow effective integration, amphotericin B, a potent antibiotic, is assembled with albumin nanoparticles through hydrophobic and hydrogen-bond interactions to form AmB@BSA nanoparticles (A-NPs). The nutrient composition (albumin) and virus-like size (~40 nm) facilitate efficient uptake of A-NPs by NEs to construct the antibiotics-armed NEs. It is demonstrated that the armed NEs can maintain the intrinsic biological functions of NEs, such as cell viability and capacity of migration to an inflammatory site. In a neutropenic mouse model of brain fungal infection, the treatment with the armed NEs allows for preventing fungal invasion more effectively than that with the native NEs, without the apparent systemic toxicity. Such a synergistic anti-infection system maximizes the antifungal effects by taking advantage of NEs and antibiotics. It provides a potential NEs-mediated therapeutic approach for treating fungal infection caused by chemotherapy-induced neutropenia.
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Antineoplásicos , Micoses , Neutropenia , Animais , Antibacterianos/uso terapêutico , Antifúngicos/uso terapêutico , Antineoplásicos/uso terapêutico , Braço , Encéfalo , Humanos , Camundongos , Micoses/tratamento farmacológico , Neutropenia/induzido quimicamente , Neutropenia/tratamento farmacológico , NeutrófilosRESUMO
BACKGROUND: Accumulating evidence has revealed that circular RNAs (circRNAs), as novel noncoding RNAs, play critical roles in carcinogenesis and tumor progression. However, the functions and molecular mechanisms of circRNAs in clear cell renal cell carcinoma (ccRCC) are largely unknown. METHODS: The expression and functions of circAGAP1 were identified in clinical samples, ccRCC cells and in vivo animal models. The molecular mechanism of circAGAP1 was investigated by fluorescence in situ hybridization, RNA immunoprecipitation and luciferase assays. RESULTS: circAGAP1 (circ0058792) expression was significantly upregulated in ccRCC tissues compared to adjacent nontumor tissues. Moreover, the expression of circAGAP1 was closely related to the tumor size, nuclear grade and clinical stage of ccRCC in patients. Mechanistic studies demonstrated that cytoplasmic circAGAP1 targeted miR-15-5p in an RNA-induced silencing complex. Additionally, miR-15-5p expression was downregulated in ccRCC. Luciferase reporter assays showed that E2F transcription factor 3 (E2F3) was a target of miR-15-5p, and upregulated E2F3 expression was positively correlated with circAGAP1 in ccRCC. Furthermore, the tumor-promoting functions of circAGAP1 could be alleviated by miR-15-5p mimics in vitro and in vivo. CONCLUSION: Our results clarify that circAGAP1 exerts its oncogenic functions as a competitive endogenous RNA (ceRNA) by sponging miR-15-5p, which promotes E2F3 expression. Targeting circAGAP1 might be a new attractive therapeutic strategy in ccRCC.
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Carcinoma de Células Renais/metabolismo , Proteínas Ativadoras de GTPase/genética , MicroRNAs/metabolismo , RNA Circular/metabolismo , Animais , Apoptose/fisiologia , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Progressão da Doença , Regulação para Baixo , Camundongos , Camundongos Nus , MicroRNAs/genética , RNA Circular/genética , Regulação para CimaRESUMO
According to the binding mode of ABBV-744 with bromodomains and the cape space of HDAC, the novel selective HDAC/BRD4 dual inhibitors were designed and synthesized by the pharmacophore fusion strategy. Evaluating the biomolecular activities through SARs exploration identified three kinds of selective dual inhibitors 41c (HDAC1/BRD4), 43a (pan-HDAC/BRD4) and 43d (HDAC6/BRD4(BD2)), whose target-related cellular activities in MV-4-11 cells were also confirmed. Significantly, the selective dual inhibitor 41c (HDAC1/BRD4) exhibited synergistic effects against MV-4-11 cells, which strongly induced G0/G1 cell cycle arrest and apoptosis, and the first HDAC6/BRD4(BD2) dual inhibitor was found. This study provides support for selective HDAC/BRD4 dual inhibitors as epigenetic probes based on pyrrolopyridone core for the future biological evaluation in different cancer cell lines.
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Antineoplásicos/química , Antineoplásicos/farmacologia , Proteínas de Ciclo Celular/antagonistas & inibidores , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/farmacologia , Fatores de Transcrição/antagonistas & inibidores , Apoptose/efeitos dos fármacos , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Desenho de Fármacos , Descoberta de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Epigênese Genética/efeitos dos fármacos , Humanos , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/farmacologia , Modelos Moleculares , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/metabolismo , Piridinas/química , Piridinas/farmacologia , Piridonas/química , Piridonas/farmacologia , Pirróis/química , Pirróis/farmacologia , Fatores de Transcrição/metabolismoRESUMO
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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High-dose radiation activates caspases in tumor cells to produce abundant DNA fragments for DNA sensing in antigen-presenting cells, but the intrinsic DNA sensing in tumor cells after radiation is rather limited. Here we demonstrate that irradiated tumor cells hijack caspase 9 signaling to suppress intrinsic DNA sensing. Instead of apoptotic genomic DNA, tumor-derived mitochondrial DNA triggers intrinsic DNA sensing. Specifically, loss of mitochondrial DNA sensing in Casp9-/- tumors abolishes the enhanced therapeutic effect of radiation. We demonstrated that combining emricasan, a pan-caspase inhibitor, with radiation generates synergistic therapeutic effects. Moreover, loss of CASP9 signaling in tumor cells led to adaptive resistance by upregulating programmed death-ligand 1 (PD-L1) and resulted in tumor relapse. Additional anti-PD-L1 blockade can further overcome this acquired immune resistance. Therefore, combining radiation with a caspase inhibitor and anti-PD-L1 can effectively control tumors by sequentially blocking both intrinsic and extrinsic inhibitory signaling.
Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Caspase 9/metabolismo , Inibidores de Caspase/uso terapêutico , Quimiorradioterapia/métodos , Neoplasias Colorretais/terapia , Ácidos Pentanoicos/uso terapêutico , Animais , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Caspase 9/genética , Linhagem Celular Tumoral , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transplante de Neoplasias , Transdução de Sinais , Regulação para CimaRESUMO
The lack of sufficient functional tumor-infiltrating lymphocytes in the tumor microenvironment (TME) is one of the primary indications for the poor prognosis of patients with cancer. In this study, we developed an Erbitux-based IL-21 tumor-targeting fusion protein (Erb-IL21) to prolong the half-life and improve the antitumor efficacy of IL-21. Compared with Erb-IL2, Erb-IL21 demonstrated much lower toxicity in vivo. Mechanistically, Erb-IL21 selectively expanded functional cytotoxic T lymphocytes but not dysfunctional CD8+ T cells in the TME. We observed that the IL-21-mediated antitumor effect largely depended on the existing intratumoral CD8+ T cells, instead of newly migrated CD8+ T cells. Furthermore, Erb-IL21 overcame checkpoint blockade resistance in mice with advanced tumors. Our study reveals that Erb-IL21 can target IL-21 to tumors and maximize the antitumor potential of checkpoint blockade by expending a subset of tumor antigen-specific CD8+ T cells to achieve effective tumor control.