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The parity-time (PT) symmetry of a non-Hermitian Hamiltonian leads to real (complex) energy spectrum when the non-Hermiticity is below (above) a threshold. Recently, it has been demonstrated that the non-Hermitian skin effect generates a new type of PT symmetry, dubbed the non-Bloch PT symmetry, featuring unique properties such as high sensitivity to the boundary condition. Despite its relevance to a wide range of non-Hermitian lattice systems, a general theory is still lacking for this generic phenomenon even in one spatial dimension. Here, we uncover the geometric mechanism of non-Bloch PT symmetry and its breaking. We find that non-Bloch PT symmetry breaking occurs by the formation of cusps in the generalized Brillouin zone (GBZ). Based on this geometric understanding, we propose an exact formula that efficiently determines the breaking threshold. Moreover, we predict a new type of spectral singularities associated with the symmetry breaking, dubbed non-Bloch van Hove singularity, whose physical mechanism fundamentally differs from their Hermitian counterparts. This singularity is experimentally observable in linear responses.
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Large cohorts of samples from multiple batches are usually required for global metabolomic studies to characterize the metabolic state of human disease. As such, it is critical to eliminate systematic variation and truly reveal the biologically associated alterations. In this study, we proposed a reference material-based approach (Ref-M) for data correction by liquid chromatography-mass spectrometry and represented by an analysis of multibatch human serum samples. The reference material was generated by mixing serum from healthy donors and distributed to each extraction batch of subject samples. Pooled quality control samples and isotopic internal standards were then applied in each acquisition batch for data quality control. Finally, each metabolite in subject samples was normalized by its counterpart in the reference serum. We demonstrated that Ref-M significantly enhanced the numbers of efficient features and effectively eliminated the batch variation of 522 serum samples of healthy individuals, benign pulmonary nodules, and lung cancer patients. Twenty differential metabolites were identified to distinguish lung cancer from healthy controls in the training set. The discriminant model was validated in an independent data set with an area under the receiver operating characteristics (ROC) curve (AUC) of 0.853. Another 40 serum samples further tested with Ref-M were achieved an AUC of 0.843 by the established model. Our results showed that the reference material-based approach presents the potential to improve the data comparability and precision for biomarker discovery in large-scale metabolomic studies.
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Neoplasias Pulmonares , Espectrometría de Masas en Tándem , Humanos , Cromatografía Liquida/métodos , Metabolómica/métodos , Metaboloma , Neoplasias Pulmonares/metabolismoRESUMEN
BACKGROUND: Patients with early endometrial carcinoma (EC) have a good prognosis, but it is difficult to distinguish from endometrial polyps (EPs). PURPOSE: To develop and assess magnetic resonance imaging (MRI)-based radiomics models for discriminating Stage I EC from EP in a multicenter setting. MATERIAL AND METHODS: Patients with Stage I EC (n = 202) and EP (n = 99) who underwent preoperative MRI scans were collected in three centers (seven devices). The images from devices 1-3 were utilized for training and validation, and the images from devices 4-7 were utilized for testing, leading to three models. They were evaluated by the area under the receiver operating characteristic curve (AUC) and metrics including accuracy, sensitivity, and specificity. Two radiologists evaluated the endometrial lesions and compared them with the three models. RESULTS: The AUCs of device 1, 2_ada, device 1, 3_ada, and device 2, 3_ada for discriminating Stage I EC from EP were 0.951, 0.912, and 0.896 for the training set, 0.755, 0.928, and 1.000 for the validation set, and 0.883, 0.956, and 0.878 for the external validation set, respectively. The specificity of the three models was higher, but the accuracy and sensitivity were lower than those of radiologists. CONCLUSION: Our MRI-based models showed good potential in differentiating Stage I EC from EP and had been validated in multiple centers. Their specificity was higher than that of radiologists and may be used for computer-aided diagnosis in the future to assist clinical diagnosis.
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Neoplasias Endometriales , Neoplasias Uterinas , Femenino , Humanos , Imagen por Resonancia Magnética/métodos , Neoplasias Endometriales/diagnóstico por imagen , Neoplasias Endometriales/patología , Curva ROC , Estudios RetrospectivosRESUMEN
We unveil an unexpected non-Hermitian phenomenon, dubbed edge burst, in non-Hermitian quantum dynamics. Specifically, in a class of non-Hermitian quantum walk in periodic lattices with open boundary condition, an exceptionally large portion of loss occurs at the system boundary. The physical origin of this edge burst is found to be an interplay between two unique non-Hermitian phenomena: non-Hermitian skin effect and imaginary gap closing. Furthermore, we establish a universal bulk-edge scaling relation underlying the non-Hermitian edge burst. Our predictions are experimentally accessible in various non-Hermitian systems including quantum-optical and cold-atom platforms.
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Devising a low-cost and effective strategy to reduce Cd contamination of brown rice is critical to achieve the safe production of rice grain for human consumption. Accordingly, here field experiments were conducted at two sites to evaluate the effects of applying humic acid (HA) to foliage twice, at the booting and full heading stage, on diminishing the translocation of cadmium (Cd) into rice grains. Besides measuring the Cd subcellular distribution in the flag leaf and the polysaccharide composition of the cell wall, the latter's types and concentrations of functional groups were quantitatively analyzed by potentiometric titration and fitted by a surface complexation model. The results demonstrated that applying HA to leaves not only increased the rice yield but also reduced the Cd concentration in brown rice by 35.48-39.74% when using an application rate of just 600 g/ha. The HA treatment augmented Cd fixation in flag leaves, reduced the Cd translocation to rachis and brown rice, and increased the subcellular distribution of Cd in flag leaf cell wall. Furthermore, the Cd concentration in the pectin and hemicellulose 1 of cell wall increased by 33.00% and 25.73%, respectively. Besides those effects, foliar spraying of HA induced a greater abundance of carboxyl, hydroxyl, and amino groups on the cell wall, allowing for more sites to be involved in the binding of Cd, thereby promoting the immobilization of Cd in the flag leaf, and ultimately reducing the remobilization of Cd into the grain. Thus, foliage application of HA may offer a promising and cost-effective tactic for the remediation and continued use of Cd-contaminated paddy soils. CAPSULE: Foliage application of humic acid promoted the deposition of Cd in the cell wall of rice flag leaf, thereby enhancing the immobilization of Cd and ultimately reducing the remobilization of Cd into the grain.
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Oryza , Contaminantes del Suelo , Cadmio/metabolismo , Pared Celular/metabolismo , Grano Comestible/química , Humanos , Sustancias Húmicas/análisis , Oryza/metabolismo , Hojas de la Planta/metabolismo , Suelo/química , Contaminantes del Suelo/análisisRESUMEN
Reactive oxygen species (ROS) homeostasis and mitochondrial metabolism are critical for the survival of cancer cells, including cancer stem cells (CSCs), which often cause drug resistance and cancer relapse. Auranofin is a mono-gold anti-rheumatic drug, and it has been repurposed as an anticancer agent working by the induction of both ROS increase and mitochondrial dysfunction. Hypothetically, increasing auranofin's positive charges via incorporating more gold atoms to enhance its mitochondria-targeting capacity could enhance its anti-cancer efficacy. Hence, in this work, both mono-gold and bi-gold compounds were designed and evaluated to test our hypothesis. The results showed that bi-gold compounds generally suppressed cancer cells proliferation better than their mono-gold counterparts. The most potent compound, BGC2a, substantially inhibited the antioxidant enzyme TrxR and increased the cellular ROS. BGC2a induced cell apoptosis, which could not be reversed by the antioxidant agent vitamin C, implying that the ROS induced by TrxR inhibition might not be the decisive cause of cell death. As expected, a significant proportion of BGC2a accumulated within mitochondria, likely contributing to mitochondrial dysfunction, which was further confirmed by measuring oxygen consumption rate, mitochondrial membrane potential, and ATP production. Moreover, BGC2a inhibited colony formation and reduced stem-like side population (SP) cells of A549. Finally, the compound effectively suppressed the tumor growth of both A549 and PANC-1 xenografts. Our study showed that mitochondrial disturbance may be gold-based compounds' major lethal factor in eradicating cancer cells, providing a new approach to developing potent gold-based anti-cancer drugs by increasing mitochondria-targeting capacity.
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Antirreumáticos , Neoplasias , Humanos , Especies Reactivas de Oxígeno/metabolismo , Auranofina/farmacología , Antioxidantes/farmacología , Mitocondrias/metabolismo , Apoptosis , Compuestos de Oro , Ácido Ascórbico/farmacología , Antirreumáticos/farmacología , Adenosina Trifosfato/metabolismo , Proliferación Celular , Línea Celular Tumoral , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismoRESUMEN
BACKGROUND: Breast cancer is the fastest-growing cancer among females and the second leading cause of female death. At present, targeted antibodies combined with hyperthermia locally in tumor has been identified as a potential combination therapy to combat tumors. But in fact, the uniformly deep distribution of photosensitizer in tumor sites is still an urgent problem, which limited the clinical application. We reported an HER2-modified thermosensitive liposome (immunoliposome)-assisted complex by reducing gold nanocluster on the surface (GTSL-CYC-HER2) to obtain a new type of bioplasma resonance structured carrier. The HER2 decoration on the surface enhanced targeting to the breast cancer tumor site and forming irregular, dense, "petal-like" shells of gold nanoclusters. Due to the good photothermal conversion ability under near-infrared light (NIR) irradiation, the thermosensitive liposome released the antitumor Chinese traditional medicine, cyclopamine, accompanied with the degradation of gold clusters into 3-5 nm nanoparticles which can accelerate renal metabolism of the gold clusters. With the help of cyclopamine to degrade the tumor associated matrix, this size-tunable gold wrapped immunoliposome was more likely to penetrate the deeper layers of the tumor, while the presence of gold nanoparticles makes GTSL-CYC-HER2 multimodal imaging feasible. RESULTS: The prepared GTSL-CYC-HER2 had a size of 113.5 nm and displayed excellent colloidal stability, photo-thermal conversion ability and NIR-sensitive drug release. These GTSL-CYC-HER2 were taken up selectively by cancer cells in vitro and accumulated at tumour sites in vivo. As for the in vivo experiments, compared to the other groups, under near-infrared laser irradiation, the temperature of GTSL-CYC-HER2 rises rapidly to the phase transition temperature, and released the cyclopamine locally in the tumor. Then, the released cyclopamine destroyed the stroma of the tumor tissue while killing the tumor cells, which in turn increased the penetration of the liposomes in deep tumor tissues. Moreover, the GTSL-CYC-HER2 enhanced the performance of multimodal computed tomography (CT) and photothermal (PT) imaging and enabled chemo-thermal combination therapy. CONCLUSIONS: This optically controlled biodegradable plasmonic resonance structures not only improves the safety of the inorganic carrier application in vivo, but also greatly improves the anti-tumor efficiency through the visibility of in vivo CT and PT imaging, as well as chemotherapy combined with hyperthermia, and provides a synergistic treatment strategy that can broaden the conventional treatment alone.
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Neoplasias de la Mama/tratamiento farmacológico , Oro/química , Oro/farmacología , Liposomas/química , Liposomas/farmacología , Animales , Neoplasias de la Mama/patología , Línea Celular Tumoral , Terapia Combinada , Sistemas de Liberación de Medicamentos/métodos , Liberación de Fármacos , Femenino , Humanos , Hipertermia Inducida , Rayos Infrarrojos , Nanopartículas del Metal/química , Ratones , Fotoquimioterapia/métodos , Fototerapia , Receptor ErbB-2RESUMEN
An amendment to this paper has been published and can be accessed via the original article.
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BACKGROUND: Cancer cells primarily utilize aerobic glycolysis for energy production, a phenomenon known as the Warburg effect. Increased aerobic glycolysis supports cancer cell survival and rapid proliferation and predicts a poor prognosis in cancer patients. METHODS: Molecular profiles from The Cancer Genome Atlas (TCGA) cohort were used to analyze the prognostic value of glycolysis gene signature in human cancers. Gain- and loss-of-function studies were performed to key drivers implicated in hepatocellular carcinoma (HCC) glycolysis. The molecular mechanisms underlying Osteopontin (OPN)-mediated glycolysis were investigated by real-time qPCR, western blotting, immunohistochemistry, luciferase reporter assay, and xenograft and diethyl-nitrosamine (DEN)-induced HCC mouse models. RESULTS: Increased glycolysis predicts adverse clinical outcome in many types of human cancers, especially HCC. Then, we identified a handful of differentially expressed genes related to HCC glycolysis. Gain- and loss-of-function studies showed that OPN promotes, while SPP2, LECT2, SLC10A1, CYP3A4, HSD17B13, and IYD inhibit HCC cell glycolysis as revealed by glucose utilization, lactate production, and extracellular acidification ratio. These glycolysis-related genes exhibited significant tumor-promoting or tumor suppressive effect on HCC cells and these effects were glycolysis-dependent. Mechanistically, OPN enhanced HCC glycolysis by activating the αvß3-NF-κB signaling. Genetic or pharmacological blockade of OPN-αvß3 axis suppressed HCC glycolysis in xenograft tumor model and hepatocarcinogenesis induced by DEN. CONCLUSIONS: Our findings reveal crucial determinants for controlling the Warburg metabolism in HCC cells and provide a new insight into the oncogenic roles of OPN in HCC. Video Abstract.
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Carcinoma Hepatocelular/genética , Glucólisis/genética , Neoplasias Hepáticas/genética , Animales , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Proliferación Celular/genética , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Integrina alfaVbeta3/metabolismo , Neoplasias Hepáticas/patología , Masculino , Ratones Endogámicos BALB C , Ratones Desnudos , FN-kappa B/metabolismo , Osteopontina/metabolismo , Pronóstico , Transducción de Señal , Efecto Warburg en OncologíaRESUMEN
[This corrects the article DOI: 10.1371/journal.pbio.1001326.].
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BACKGROUND: Cancer stem cells (CSCs) are thought to play an important role in tumor recurrence and drug resistance, and present a major challenge in cancer therapy. The tumor microenvironment such as growth factors, nutrients and oxygen affect CSC generation and proliferation by providing the necessary energy sources and growth signals. The side population (SP) analysis has been used to detect the stem-like cancer cell populations based on their high expression of ABCG2 that exports Hoechst-33342 and certain cytotoxic drugs from the cells. The purpose of this research is to investigate the effect of a main nutrient molecule, glutamine, on SP cells and the possible underlying mechanism(s). METHODS: Biochemical assays and flow cytometric analysis were used to evaluate the effect of glutamine on stem-like side population cells in vitro. Molecular analyses including RNAi interfering, qRT-PCR, and immunoblotting were employed to investigate the molecular signaling in response to glutamine deprivation and its influence on tumor formation capacity in vivo. RESULTS: We show that glutamine supports the maintenance of the stem cell phenotype by promoting glutathione synthesis and thus maintaining redox balance for SP cells. A deprivation of glutamine in the culture medium significantly reduced the proportion of SP cells. L-asparaginase, an enzyme that catalyzes the hydrolysis of asparagine and glutamine to aspartic acid and glutamate, respectively, mimics the effect of glutamine withdrawal and also diminished the proportion of SP cells. Mechanistically, glutamine deprivation increases intracellular ROS levels, leading to down-regulation of the ß-catenin pathway. CONCLUSION: Glutamine plays a significant role in maintaining the stemness of cancer cells by a redox-mediated mechanism mediated by ß-catenin. Inhibition of glutamine metabolism or deprivation of glutamine by L-asparaginase may be a new strategy to eliminate CSCs and overcome drug resistance.
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Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Glutamina/farmacología , Proteínas de Neoplasias/metabolismo , Neoplasias/patología , Células Madre Neoplásicas/efectos de los fármacos , Vía de Señalización Wnt/efectos de los fármacos , Células A549 , Animales , Asparaginasa/genética , Asparaginasa/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Resistencia a Antineoplásicos , Glutatión/metabolismo , Humanos , Ratones , Neoplasias/genética , Neoplasias/metabolismo , Células Madre Neoplásicas/metabolismo , Oxidación-Reducción/efectos de los fármacos , Células de Población Lateral/efectos de los fármacos , Células de Población Lateral/metabolismoRESUMEN
In our current work, acetyl chloride-mediated synthesis of phenethyl isothiocyanate (PEITC) derivatives proves to be convenient and provides the expected products at good to excellent yields. Biological evaluation and structure-activity relationship analysis found that the novel compound 7 showed the best anticancer activity against human cancer cell line Panc1 and HGC27 compared with PEITC. Compounds 6 and 7 induced more apoptosis in pancreatic cancer cells but less toxicity in non-cancer cells. Further biological study demonstrated that 7 substantially increased intracellular reactive oxygen species (ROS) and depleted glutathione (GSH), leading to an oxidative stress to kill cancer cell.
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Antineoplásicos/farmacología , Isotiocianatos/farmacología , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Glutatión/metabolismo , Humanos , Isotiocianatos/química , Estructura Molecular , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Although cyclic diaryliodonium species have the potential to act as valuable synthons for cascade transformations, they still remain largely unexplored. The regioselectivity associated with unsymmetrical cyclic diaryliodonium species has previously been known to pose a challenge. A regioselective relayed alkynylation and olefination of unsymmetrical cyclic diaryliodonium species has been achieved by installation of a directing amido group. These relayed transformations were delayed until an oxazole ring had formed, delivering a series of unique fluorescent benzoxazoles. Moreover, some of these synthetic benzoxazoles showed apparent inhibitory activity against malignant cancer cells. Further confocal visualization revealed that benzoxazoles targeted cell nuclei. These findings might provide a novel structural scaffold to develop desirable anticancer agents.
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Benzoxazoles/química , Benzoxazoles/toxicidad , Cobre/química , Colorantes Fluorescentes/química , Colorantes Fluorescentes/toxicidad , Compuestos Onio/química , Paladio/química , Catálisis , Estructura Molecular , EstereoisomerismoRESUMEN
Elevated aerobic glycolysis in cancer cells (the Warburg effect) may be attributed to respiration injury or mitochondrial dysfunction, but the underlying mechanisms and therapeutic significance remain elusive. Here we report that induction of mitochondrial respiratory defect by tetracycline-controlled expression of a dominant negative form of DNA polymerase γ causes a metabolic shift from oxidative phosphorylation to glycolysis and increases ROS generation. We show that upregulation of NOX is critical to support the elevated glycolysis by providing additional NAD+. The upregulation of NOX is also consistently observed in cancer cells with compromised mitochondria due to the activation of oncogenic Ras or loss of p53, and in primary pancreatic cancer tissues. Suppression of NOX by chemical inhibition or genetic knockdown of gene expression selectively impacts cancer cells with mitochondrial dysfunction, leading to a decrease in cellular glycolysis, a loss of cell viability, and inhibition of cancer growth in vivo. Our study reveals a previously unrecognized function of NOX in cancer metabolism and suggests that NOX is a potential novel target for cancer treatment.
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Glucólisis , Mitocondrias/patología , NADPH Oxidasas/metabolismo , Neoplasias Pancreáticas/enzimología , Animales , Supervivencia Celular , Activación Enzimática , Técnicas de Silenciamiento del Gen , Genes Relacionados con las Neoplasias , Células HEK293 , Humanos , Ratones , Ratones Desnudos , Mitocondrias/enzimología , Mitocondrias/metabolismo , NADPH Oxidasa 1 , NADPH Oxidasas/genética , Fosforilación Oxidativa , Neoplasias Pancreáticas/patología , Plásmidos/genética , Plásmidos/metabolismo , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , ARN Interferente Pequeño/uso terapéutico , Especies Reactivas de Oxígeno/metabolismo , Superóxido Dismutasa/metabolismo , Superóxido Dismutasa-1 , Tetraciclina/farmacología , Transfección , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Cyclic diaryliodoniums remain unexplored compared to linear iodoniums. In our current work, internal alkynes were for the first time applied to react with cyclic iodoniums, catalyzed by Pd, resulting in a [4 + 2] benzannulation. Our work offers a new strategy to synthesize multi-substituted phenanthrene derivatives which are not easily accessed by conventional methods.
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Alquinos/química , Compuestos Onio/química , Compuestos Organometálicos/química , Paladio/química , Fenantrenos/síntesis química , Catálisis , Ciclización , Estructura Molecular , Fenantrenos/químicaRESUMEN
INTRODUCTION: Oncogenic activation of the K-ras gene occurs in >90% of pancreatic ductal carcinoma and plays a critical role in the pathogenesis of this malignancy. Increase of reactive oxygen species (ROS) has also been observed in a wide spectrum of cancers. This study aimed to investigate the mechanistic association between K-ras-induced transformation and increased ROS stress and its therapeutic implications in pancreatic cancer. METHODS: ROS level, NADPH oxidase (NOX) activity and expression, and cell invasion were examined in human pancreatic duct epithelial E6E7 cells transfected with K-ras (G12V) compared with parental E6E7 cells. The cytotoxic effect and antitumor effect of capsaicin, a NOX inhibitor, were also tested in vitro and in vivo. RESULTS: K-ras transfection caused activation of the membrane-associated redox enzyme NOX and elevated ROS generation through the phosphatidylinositol 3'-kinase (PI3K) pathway. Importantly, capsaicin preferentially inhibited the enzyme activity of NOX and induced severe ROS accumulation in K-ras-transformed cells compared with parental E6E7 cells. Furthermore, capsaicin effectively inhibited cell proliferation, prevented invasiveness of K-ras-transformed pancreatic cancer cells, and caused minimum toxicity to parental E6E7 cells. In vivo, capsaicin exhibited antitumor activity against pancreatic cancer and showed oxidative damage to the xenograft tumor cells. CONCLUSIONS: K-ras oncogenic signaling causes increased ROS stress through NOX, and abnormal ROS stress can selectively kill tumor cells by using NOX inhibitors. Our study provides a basis for developing a novel therapeutic strategy to effectively kill K-ras-transformed cells through a redox-mediated mechanism.
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Capsaicina , Transformación Celular Neoplásica , Genes ras , NADPH Oxidasas , Neoplasias Pancreáticas , Especies Reactivas de Oxígeno , Carcinoma Ductal Pancreático , Proliferación Celular , Células Epiteliales , Humanos , Fosfatidilinositol 3-Quinasas , Transducción de Señal , TransfecciónRESUMEN
OBJECTIVES: Accurate axillary evaluation plays an important role in prognosis and treatment planning for breast cancer. This study aimed to develop and validate a dynamic contrast-enhanced (DCE)-MRI-based radiomics model for preoperative evaluation of axillary lymph node (ALN) status in early-stage breast cancer. METHODS: A total of 410 patients with pathologically confirmed early-stage invasive breast cancer (training cohort, N = 286; validation cohort, N = 124) from June 2018 to August 2022 were retrospectively recruited. Radiomics features were derived from the second phase of DCE-MRI images for each patient. ALN status-related features were obtained, and a radiomics signature was constructed using SelectKBest and least absolute shrinkage and selection operator regression. Logistic regression was applied to build a combined model and corresponding nomogram incorporating the radiomics score (Rad-score) with clinical predictors. The predictive performance of the nomogram was evaluated using receiver operator characteristic (ROC) curve analysis and calibration curves. RESULTS: Fourteen radiomic features were selected to construct the radiomics signature. The Rad-score, MRI-reported ALN status, BI-RADS category, and tumour size were independent predictors of ALN status and were incorporated into the combined model. The nomogram showed good calibration and favourable performance for discriminating metastatic ALNs (N + (≥1)) from non-metastatic ALNs (N0) and metastatic ALNs with heavy burden (N + (≥3)) from low burden (N + (1-2)), with the area under the ROC curve values of 0.877 and 0.879 in the training cohort and 0.859 and 0.881 in the validation cohort, respectively. CONCLUSIONS: The DCE-MRI-based radiomics nomogram could serve as a potential non-invasive technique for accurate preoperative evaluation of ALN burden, thereby assisting physicians in the personalized axillary treatment for early-stage breast cancer patients. ADVANCES IN KNOWLEDGE: This study developed a potential surrogate of preoperative accurate evaluation of ALN status, which is non-invasive and easy-to-use.
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Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/patología , Estudios Retrospectivos , Metástasis Linfática/diagnóstico por imagen , Metástasis Linfática/patología , Estudios de Factibilidad , Radiómica , Ganglios Linfáticos/diagnóstico por imagen , Ganglios Linfáticos/patología , Nomogramas , Imagen por Resonancia Magnética/métodosRESUMEN
Mutations in isocitrate dehydrogenases (IDH) are oncogenic events due to the generation of oncogenic metabolite 2-hydroxyglutarate. However, the role of wild-type IDH in cancer development remains elusive. Here we show that wild-type IDH2 is highly expressed in triple negative breast cancer (TNBC) cells and promotes their proliferation in vitro and tumor growth in vivo. Genetic silencing or pharmacological inhibition of wt-IDH2 causes a significant increase in α-ketoglutarate (α-KG), indicating a suppression of reductive tricarboxylic acid (TCA) cycle. The aberrant accumulation of α-KG due to IDH2 abrogation inhibits mitochondrial ATP synthesis and promotes HIF-1α degradation, leading to suppression of glycolysis. Such metabolic double-hit results in ATP depletion and suppression of tumor growth, and renders TNBC cells more sensitive to doxorubicin treatment. Our study reveals a metabolic property of TNBC cells with active utilization of glutamine via reductive TCA metabolism, and suggests that wild-type IDH2 plays an important role in this metabolic process and could be a potential therapeutic target for TNBC.
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Proliferación Celular , Ciclo del Ácido Cítrico , Isocitrato Deshidrogenasa , Ácidos Cetoglutáricos , Neoplasias de la Mama Triple Negativas , Isocitrato Deshidrogenasa/genética , Isocitrato Deshidrogenasa/metabolismo , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/patología , Humanos , Femenino , Animales , Línea Celular Tumoral , Ciclo del Ácido Cítrico/efectos de los fármacos , Ácidos Cetoglutáricos/metabolismo , Ratones , Proliferación Celular/efectos de los fármacos , Glucólisis/efectos de los fármacos , Adenosina Trifosfato/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Glutamina/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto , MutaciónRESUMEN
Since the survival of lymphoma patients who experience disease progression or relapse remains very poor, new therapeutic approaches and effective drugs are urgently needed. Here we show that auranofin (AF), an anti-rheumatoid drug thought to inhibit thioredoxin reductases (TXNRDs) as its mechanism of action, exhibited potent activity against multiple cancer types, especially effective against B cell lymphoma. Surprisingly, a knockdown of TXNRD1 and TXNRD2 did not cause significant cytotoxicity, suggesting that abrogation of TXNRD enzyme per se was insufficient to cause cancer cell death. Further mechanistic study showed that the interaction of AF with TXNRD could convert this antioxidant enzyme to a ROS-generating molecule via disrupting its electron transport, leading to a leak of electrons that interact with molecular oxygen to form superoxide. AF also suppressed energy metabolism by inhibiting both mitochondria complex II and the glycolytic enzyme GAPDH, leading to a significant depletion of ATP and inhibition of cancer growth in vitro and in vivo. Importantly, we found that the AF-mediated ROS stress could induce PD-L1 expression, revealing an unwanted effect of AF in causing immune suppression. We further showed that a combination of AF with anti-PD-1 antibody could enhance the anticancer activity in a syngeneic immune-competent mouse B-cell lymphoma model. Our study suggests that AF could be a potential drug for lymphoma treatment, and its combination with immune checkpoint inhibitors would be a logical strategy to increase the therapeutic activity.
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Artritis Reumatoide , Auranofina , Metabolismo Energético , Especies Reactivas de Oxígeno , Auranofina/farmacología , Auranofina/uso terapéutico , Animales , Especies Reactivas de Oxígeno/metabolismo , Humanos , Ratones , Metabolismo Energético/efectos de los fármacos , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/metabolismo , Línea Celular Tumoral , Tiorredoxina Reductasa 1/metabolismo , Tiorredoxina Reductasa 1/antagonistas & inhibidores , Tiorredoxina Reductasa 1/genética , Antirreumáticos/farmacología , Antirreumáticos/uso terapéutico , Tiorredoxina Reductasa 2/metabolismo , Tiorredoxina Reductasa 2/genética , Linfoma/tratamiento farmacológico , Linfoma/metabolismo , Linfoma/patología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
RATIONALE AND OBJECTIVES: This study aimed to develop and validate a dual-energy CT (DECT)-based model for preoperative prediction of the number of central lymph node metastases (CLNMs) in clinically node-negative (cN0) papillary thyroid carcinoma (PTC) patients. MATERIALS AND METHODS: Between January 2016 and January 2021, 490 patients who underwent lobectomy or thyroidectomy, CLN dissection, and preoperative DECT examinations were enrolled and randomly allocated into the training (N = 345) and validation cohorts (N = 145). The patients' clinical characteristics and quantitative DECT parameters obtained on primary tumors were collected. Independent predictors of> 5 CLNMs were identified and integrated to construct a DECT-based prediction model, for which the area under the curve (AUC), calibration, and clinical usefulness were assessed. Risk group stratification was performed to distinguish patients with different recurrence risks. RESULTS: More than 5 CLNMs were found in 75 (15.3%) cN0 PTC patients. Age, tumor size, normalized iodine concentration (NIC), normalized effective atomic number (nZeff) and the slope of the spectral Hounsfield unit curve (λHu) in the arterial phase were independently associated with> 5 CLNMs. The DECT-based nomogram that incorporated predictors demonstrated favorable performance in both cohorts (AUC: 0.842 and 0.848) and significantly outperformed the clinical model (AUC: 0.688 and 0.694). The nomogram showed good calibration and added clinical benefit for predicting> 5 CLNMs. The KaplanMeier curves for recurrence-free survival showed that the high- and low-risk groups stratified by the nomogram were significantly different. CONCLUSION: The nomogram based on DECT parameters and clinical factors could facilitate preoperative prediction of the number of CLNMs in cN0 PTC patients.