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1.
J Cancer ; 15(13): 4244-4258, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38947404

RESUMEN

Background: While RACGAP1 is identified as a potential oncogene, its specific role in lung adenocarcinoma (LUAD) remains unclear. Methods: First, we conducted a comprehensive analysis of the role of RACGAP1 across 33 types of cancer. Subsequently, we investigated the expression levels of RACGAP1 and its impact on prognosis using data from The Cancer Genome Atlas (TCGA) database. We utilized single-cell sequencing data to explore the tumor-related processes of RACGAP1 in LUAD and validated our findings through experimental verification. Employing a consensus clustering (CC) approach, we subdivided LUAD patients into two subtypes based on RACGAP1 cell cycle-related genes (RrCCGs). These subtypes exhibited significant differences in tumor characteristics, lymph node metastasis, and recurrence. Furthermore, we evaluated the prognostic influence of RrCCGs using univariate Cox regression and least absolute shrinkage and selection operator regression models (LASSO), successfully establishing a prognostic model. Results: RACGAP1 is frequently overexpressed in various tumors and can impact the prognosis of patients with LUAD. Additionally, experimental evidence has demonstrated that low expression of RACGAP1 favors tumor cell apoptosis and restoration of the cell cycle, while high expression promotes invasion and metastasis. Through CC analysis of RrCCGs, patients were classified into two groups, with survival analysis revealing distinct prognoses and stages between the two groups. Furthermore, Cox and LASSO regression successfully constructed a prognostic model with robust predictive capability.

2.
Arch Biochem Biophys ; 759: 110102, 2024 09.
Artículo en Inglés | MEDLINE | ID: mdl-39029644

RESUMEN

Abdominal aortic aneurysm (AAA) is a dangerous condition affecting the aorta. Macrophage pyroptosis, phenotypic transformation, and apoptosis of aortic smooth muscle cells (ASMCs) are pivotal mechanisms in AAA pathogenesis. This study explores how Gasdermin B (GSDMB) regulates macrophage non-canonical pyroptosis and its impact on the phenotypic transformation and apoptosis of ASMCs, thereby unveiling the role of GSDMB in AAA pathogenesis. Immunofluorescence analysis was used to assess the expression levels and localization of GSDMB, cysteinyl aspartate-specific protease-4 (Caspase-4), and N-terminal of cleaved GSDMD (N-GSDMD) in AAA tissues. A cell model that mimics macrophage non-canonical pyroptosis was established by treating THP-1 cells with lipopolysaccharide (LPS). THP-1 cells with reduced or increased GSDMB were generated using small interfering RNA (siRNA) or plasmids. Co-culture experiments involving THP-1 cells and HASMCs were conducted to explore the impact of GSDMB on HASMCs. The mitochondrial reactive oxygen species (mtROS) scavenger Mito-TEMPO lowered mtROS levels in THP-1 cells. Our findings revealed that GSDMB was significantly upregulated in AAA macrophages, which was accompanied by robust non-canonical pyroptosis. THP-1 cells showed non-canonical pyroptosis in response to LPS, which was accompanied by an increase in GSDMB. Further research demonstrated that altering GSDMB, either by knockdown or overexpression, can affect macrophage non-canonical pyroptosis as well as the phenotypic transformation and apoptosis of HASMCs. LPS-induced non-canonical pyroptosis in THP-1 cells was associated with an increase in mtROS, whereas Mito-TEMPO effectively decreased non-canonical pyroptosis and the expression of GSDMB. These findings suggest that GSDMB plays a role in AAA macrophage non-canonical pyroptosis, which influences the phenotypic transformation and apoptosis of HASMCs. The mtROS-Dynamin-Related Protein 1 (Drp1) axis is likely to regulate the GSDMB-mediated non-canonical pyroptosis.


Asunto(s)
Aneurisma de la Aorta Abdominal , Macrófagos , Piroptosis , Aneurisma de la Aorta Abdominal/metabolismo , Aneurisma de la Aorta Abdominal/patología , Humanos , Macrófagos/metabolismo , Células THP-1 , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Proteínas de Unión a Fosfato/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Lipopolisacáridos/farmacología , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Caspasas Iniciadoras/metabolismo , Masculino , Proteínas de Neoplasias/metabolismo , Proteínas de Neoplasias/genética , Mitocondrias/metabolismo , Gasderminas
3.
Anal Chim Acta ; 1312: 342778, 2024 Jul 11.
Artículo en Inglés | MEDLINE | ID: mdl-38834257

RESUMEN

BACKGROUND: The technology of capturing circulating tumor cells (CTCs) plays a crucial role in the diagnosis, evaluation of therapeutic efficacy, and prediction of prognosis in lung cancer. However, the presence of complex blood environment often results in severe nonspecific protein adsorption and interferences from blood cells, which negatively impacts the specificity of CTCs capture. There is a great need for development of novel nanomaterials for CTCs capture with prominent anti-nonspecific adsorptions from proteins or blood cells. RESULTS: We present a novel immune magnetic probe Fe3O4@(PEI/AA)4@Apt. The surface of Fe3O4 particles was modified with four layers of PEI/AA composite by layer-by-layer assembly. Furthermore, aptamers targeting epithelial marker EpCAM (SYL3C) and mesenchymal marker CSV (ZY5C) were simultaneously connected on Fe3O4@(PEI/AA)4 to improve the detection of different phenotypic CTCs and reduce false negatives. The results demonstrated that the (PEI/AA)4 coatings not only minimized non-specific protein adsorptions, but also significantly reduced the adsorption rate of red blood cells to a mere 1 %, as a result of which, the Fe3O4@(PEI/AA)4@Apt probe achieved a remarkably high capture efficiency toward CTCs (95.9 %). In the subsequent validation of clinical samples, the probe was also effective in capturing rare CTCs from lung cancer patients. SIGNIFICANCE AND NOVELTY: A (PEI/AA) polymerized composite with controllable layers was fabricated by layer-by-layer self-assembly technique, which displayed remarkable anti-nonspecific adsorption capabilities toward proteins and cells. Importantly, Fe3O4@(PEI/AA)4@Apt probe significantly improved CTCs capture purity in lung cancer patients to 89.36 %. For the first time, this study combined controllable (PEI/AA) layers with magnetic separation to innovatively build a resistant interface that significantly improves the specific capture performances of CTCs, broadening the application of this polymerized composite.


Asunto(s)
Alginatos , Células Neoplásicas Circulantes , Polietileneimina , Humanos , Células Neoplásicas Circulantes/patología , Polietileneimina/química , Alginatos/química , Nanopartículas de Magnetita/química , Neoplasias Pulmonares/patología , Aptámeros de Nucleótidos/química , Adsorción , Propiedades de Superficie , Molécula de Adhesión Celular Epitelial/inmunología
4.
Respir Res ; 25(1): 147, 2024 Mar 30.
Artículo en Inglés | MEDLINE | ID: mdl-38555425

RESUMEN

Inflammation and immune processes underlie pulmonary hypertension progression. Two main different activated phenotypes of macrophages, classically activated M1 macrophages and alternatively activated M2 macrophages, are both involved in inflammatory processes related to pulmonary hypertension. Recent advances suggest that macrophages coordinate interactions among different proinflammatory and anti-inflammatory mediators, and other cellular components such as smooth muscle cells and fibroblasts. In this review, we summarize the current literature on the role of macrophages in the pathogenesis of pulmonary hypertension, including the origin of pulmonary macrophages and their response to triggers of pulmonary hypertension. We then discuss the interactions among macrophages, cytokines, and vascular adventitial fibroblasts in pulmonary hypertension, as well as the potential therapeutic benefits of macrophages in this disease. Identifying the critical role of macrophages in pulmonary hypertension will contribute to a comprehensive understanding of this pathophysiological abnormality, and may provide new perspectives for pulmonary hypertension management.


Asunto(s)
Hipertensión Pulmonar , Humanos , Hipertensión Pulmonar/etiología , Macrófagos , Macrófagos Alveolares/patología , Inflamación/complicaciones , Citocinas
6.
Am J Cancer Res ; 13(3): 1038-1048, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37034202

RESUMEN

This study aimed to develop and validate a prognostic nomogram that combines clinical and sociodemographic factors of patients with newly diagnosed multiple myeloma (MM). A total of 257 newly diagnosed patients with MM from two independent medical centers in China were included in this retrospective cohort study. Univariate and multivariate Cox regression models were used to identify independent risk factors and to construct the nomogram. The predictive ability of the nomogram was evaluated using the areas under the curve (AUCs) and calibration curves. K-fold cross-validation was employed for internal validation of the nomogram performance. Moreover, a stratification system to determine risk level was generated based on the nomogram. Hemoglobulin, creatinine, rurality, and marital status were significantly associated with overall survival (OS) and were incorporated into the nomogram for OS prediction. The prognostic nomogram showed good discrimination and accuracy, and its predictive capability was superior to the International Staging System. The AUC values predicting the 1-, 3-, and 5-year OS probabilities of the nomogram were 0.775, 0.755, and 0.754, respectively. Subsequently, patients were classified into high- and low-risk subgroups based on the median total points of the nomogram; this risk stratification clearly distinguished between high- and low-risk MM patients with significantly different clinical outcomes (median OS: 27 months vs. 84 months). We established a novel prognostic prediction model by comprehensively incorporating clinical and sociodemographic variables, which can effectively predict the survival outcomes in patients with MM.

7.
Biomaterials ; 297: 122108, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-37037180

RESUMEN

The combination of cancer cell-activated fluorescence and the advantages of both type I and type II photodynamic therapy (PDT) capabilities to achieve a synergistic therapeutic effect in a complex tumor environment is highly desirable. Herein, we report an approach by means of tumor intracellular hypochlorite (ClO-) to turn on fluorescence integrated with type I and II ROS generation for imaging-guided PDT. The resultant PTZSPy functions as a type II photosensitizer with mitochondria-targeting capability. In the presence of ClO-, PTZSPy is transformed into its oxidized counterpart SPTZSPy, turns on an orange-red fluorescence and triggers the type I ROS generation ability. Biological studies revealed that PTZSPy can accurately distinguishes tumor cells from normal cells, dynamically monitors the cell ablation process and be utilized for theranostics in MCF-7 tumor-bearing nude mice in vivo. This work provides an innovative strategy exploiting the highly abundant ClO- in tumor cells for the type I and II ROS two-pronged and imaging-guided PDT.


Asunto(s)
Nanopartículas , Fotoquimioterapia , Ratones , Animales , Ácido Hipocloroso , Fluorescencia , Ratones Desnudos , Línea Celular Tumoral , Fármacos Fotosensibilizantes/uso terapéutico
8.
BMC Cancer ; 23(1): 111, 2023 Jan 31.
Artículo en Inglés | MEDLINE | ID: mdl-36721273

RESUMEN

BACKGROUND: Functioning and non-functioning adrenocortical adenoma are two subtypes of benign adrenal adenoma, and their differential diagnosis is crucial. Current diagnostic procedures use an invasive method, adrenal venous sampling, for endocrinologic assessment. METHODS: This study proposes establishing an accurate differential model for subtyping adrenal adenoma using computed tomography (CT) radiomic features and machine learning (ML) methods. Dataset 1 (289 patients with adrenal adenoma) was collected to develop the models, and Dataset 2 (54 patients) was utilized for external validation. Cuboids containing the lesion were cropped from the non-contrast, arterial, and venous phase CT images, and 1,967 features were extracted from each cuboid. Ten discriminative features were selected from each phase or the combined phases. Random forest, support vector machine, logistic regression (LR), Gradient Boosting Machine, and eXtreme Gradient Boosting were used to establish prediction models. RESULTS: The highest accuracies were 72.7%, 72.7%, and 76.1% in the arterial, venous, and non-contrast phases, respectively, when using radiomic features alone with the ML classifier of LR. When features from the three CT phases were combined, the accuracy of LR reached 83.0%. After adding clinical information, the area under the receiver operating characteristic curve increased for all the machine learning methods except for LR. In Dataset 2, the accuracy of LR was the highest, reaching 77.8%. CONCLUSION: The radiomic features of the lesion in three-phase CT images can potentially suggest the functioning or non-functioning nature of adrenal adenoma. The resulting radiomic models can be a non-invasive, low-cost, and rapid method of minimizing unnecessary testing in asymptomatic patients with incidentally discovered adrenal adenoma.


Asunto(s)
Adenoma , Adenoma Corticosuprarrenal , Humanos , Adenoma Corticosuprarrenal/diagnóstico por imagen , Arterias , Aprendizaje Automático , Tomografía Computarizada por Rayos X , Adenoma/diagnóstico por imagen
9.
Nanoscale ; 15(8): 3872-3883, 2023 Feb 23.
Artículo en Inglés | MEDLINE | ID: mdl-36722904

RESUMEN

A single epithelial cell adhesion molecule (EpCAM) for circulating tumor cell (CTCs) isolation has been proved to be low in efficiency as it fails to recognize EpCAM-negative CTCs. Meanwhile, the current immunocytochemical (ICC) identification strategy for the captured cells is tedious and time-consuming. To address these issues, we designed a dual-labeled fluorescent immunomagnetic nanoprobe (BP-Fe3O4-AuNR/Apt), by loading magnetic Fe3O4 nanoparticles and gold nanorods (AuNRs) onto black phosphorus (BP) nanosheets and then linking them with Cy3-labeled EpCAM and Texas red-labeled tyrosine protein kinase 7 (PTK7) aptamers, which created a high-performance bio-interface for efficient, heterogeneous CTC capture and rapid self-identification with high accuracy. As few as 5 CTCs could be captured from 1.0 mL PBS, mixed cell solution and lysed blood. What's more, the presence of BP and AuNRs on this capturing interface also allowed us to preliminarily investigate the potential photothermal therapeutic effect of the probe toward CTC elimination. The applicability of the probe was further demonstrated in gastric cancer patients. By detecting the number of CTCs in the blood of gastric cancer patients, the correlations between the CTC number and the disease stage, as well as distant metastasis were systematically explored.


Asunto(s)
Células Neoplásicas Circulantes , Neoplasias Gástricas , Humanos , Células Neoplásicas Circulantes/metabolismo , Molécula de Adhesión Celular Epitelial/metabolismo , Línea Celular Tumoral , Moléculas de Adhesión Celular , Proteínas Tirosina Quinasas Receptoras
10.
IUBMB Life ; 75(2): 137-148, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36177774

RESUMEN

N6-methyladenosine (m6A) regulators play an important role in tumorigenesis; however, their role in multiple myeloma (MM) remains unknown. This study aimed to create an m6A RNA regulators prognostic signature for MM patients. We integrated data from the Multiple Myeloma Research Foundation CoMMpass Study and the Genotype-Tissue Expression database to analyze gene expression profiles of 21 m6A regulators. Consistent clustering analysis was used to identify the clusters of patients with MM having different clinical outcomes. Gene distribution was analyzed using principal component analysis. Next, we generated an mRNA gene signature of m6A regulators using a multivariate logistic regression model with least absolute shrinkage and selection operator. The expressions of m6A regulators, except FMR1, were significantly different in MM samples compared with those in normal samples. The KIAA1429, HNRNPC, FTO, and WTAP expression levels were dramatically downregulated in tumor samples, whereas those of other signatures were remarkably upregulated. Three clusters of patients with MM were identified, and significant differences were found in terms of overall survival (p = .024). A prognostic two-gene signature (KIAA1429 and HNRNPA2B1) was constructed, which had a good prognostic significance using the ROC method (AUC = 0.792). Moreover, the risk score correlated with the infiltration immune cells. In addition, KEGG pathway analysis showed that 16 pathways were dramatically enriched. The m6A signature might be a novel biomarker for predicting the prognosis of patients with MM (p = .002). Our study is the first to explore the potential application value of m6A in MM. These findings may enhance the understanding of the functional organization of m6A in MM and provide new insights into the treatment of MM patients.


Asunto(s)
Mieloma Múltiple , Humanos , Mieloma Múltiple/genética , Pronóstico , Adenosina/genética , Carcinogénesis , Biomarcadores de Tumor/genética , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato
11.
ACS Sens ; 8(1): 187-196, 2023 01 27.
Artículo en Inglés | MEDLINE | ID: mdl-36562728

RESUMEN

The rarity of circulating tumor cells (CTCs) poses a great challenge to their clinical application as reliable "liquid biopsy" markers for cancer diagnosis. Meanwhile, the epithelial-mesenchymal transition (EMT) led to a reduced efficiency in capturing cells with lost or downregulated epithelial cell adhesion molecule (EpCAM) expressions. In this study, we proposed an integrated, highly efficient strategy for heterogeneous CTC capture and portable detection from the blood of non-small-cell lung cancer (NSCLC) patients. First, the cellulose wrinkled hydrogel with excellent biocompatibility and high specific area was employed as the biointerface to capture heterogeneous CTCs with an improved capture efficiency in virtue of dual targeting against epithelial and mesenchymal ones. Meanwhile, the strategy of glucometer readout was introduced for the quantification of captured CTCs on the same hydrogel interface by a detection probe, Au-G-MSN-Apt, which was fabricated via entrapping glucose into the amino group functionalized mesoporous silica nanoparticle (MSN) framework sealed by l-cysteine modified gold nanoparticles (AuNPs) and then linked with dual aptamers of EpCAM and Vimentin. The number of captured CTCs on the hydrogel could be reflected according to the portable glucose meter (PGM) readings. Moreover, it was found that the captured cells maintained a higher viability on the hydrogel and could be in situ recultured without releasing from the substrate. Finally, this integrated strategy was successfully applied to inspect the correlations between the number of heterogeneous CTCs in the blood of NSCLC patients with disease stage and whether there was distant metastasis.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Nanopartículas del Metal , Células Neoplásicas Circulantes , Humanos , Células Neoplásicas Circulantes/metabolismo , Neoplasias Pulmonares/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Molécula de Adhesión Celular Epitelial/metabolismo , Oro , Hidrogeles , Oligonucleótidos , Glucosa
12.
Front Public Health ; 10: 958325, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36324453

RESUMEN

Background: This study aimed to develop reliable nomogram-based predictive models that could guide prognostic stratification and individualized treatments in patients with multiple myeloma (MM). Methods: Clinical information of 560 patients was extracted from the MM dataset of the MicroArray Quality Control (MAQC)-II project. The patients were divided into a development cohort (n = 350) and an internal validation cohort (n = 210) according to the therapeutic regimens received. Univariate and multivariate Cox regression analyses were performed to identify independent prognostic factors for nomogram construction. Nomogram performance was assessed using concordance indices, the area under the curve, calibration curves, and decision curve analysis. The nomograms were also validated in an external cohort of 56 patients newly diagnosed with MM at Nanjing Drum Tower Hospital from May 2016 to June 2019. Results: Lactate dehydrogenase (LDH), albumin, and cytogenetic abnormalities were incorporated into the nomogram to predict overall survival (OS), whereas LDH, ß2-microglobulin, and cytogenetic abnormalities were incorporated into the nomogram to predict event-free survival (EFS). The nomograms showed good predictive performances in the development, internal validation, and external validation cohorts. Additionally, we observed a superior prognostic predictive ability in nomograms compared to that of the International Staging System. According to the prognostic nomograms, risk stratification was applied to divide the patients into two risk groups. The OS and EFS rates of low-risk patients were significantly better than those of high-risk patients, suggesting a greater function of the nomogram models for risk stratification. Conclusion: Two simple-to-use prognostic models were established and validated. The proposed nomograms have potential clinical applications in predicting OS and EFS for patients with MM.


Asunto(s)
Mieloma Múltiple , Nomogramas , Humanos , Pronóstico , Supervivencia sin Progresión , Mieloma Múltiple/diagnóstico , Aberraciones Cromosómicas
13.
Anal Chem ; 94(44): 15240-15249, 2022 11 08.
Artículo en Inglés | MEDLINE | ID: mdl-36279553

RESUMEN

Circulating tumor cells (CTC) have been represented by different phenotypes due to the epithelial-mesenchymal transition (EMT), which are epithelial CTC (E-CTC), mesenchymal CTC (M-CTC), and mixed (epithelial, mesenchymal) CTC (EM-CTC). Limited work has systematically discussed the associations of CTC number, especially proportions of E-CTC, M-CTC, and EM-CTC in total CTC, with colorectal cancer (CRC) progressions via a simple method with high performances. To achieve this goal, this paper presents the fabrication of a novel anti-nonspecific adsorption immunomagnetic platform called Fe3O4@SiO2@PTMAO@Aptamer, which was obtained by modifying polymeric trimethylamine N-oxide (PTMAO) on magnetic Fe3O4@SiO2, which was then linked with dual aptamers of an epithelial cellular adhesion molecule (EpCAM) and cell surface vimentin (CSV), targeting different CTC phenotypes. Results demonstrated that the abundant coating of PTMAO on Fe3O4@SiO2 improved the anti-nonspecific adsorption and noncell adhesion abilities of the immunomagnetic particles and could capture heterogeneous CTC with higher efficiency within 10 min. These excellent performances of Fe3O4@SiO2@PTMAO@Aptamer allowed us to inspect the correlations of numbers of E-CTC, M-CTC, EM-CTC, or proportions of them in total CTC with clinical information on CRC patients in detail. Our data innovatively and clearly revealed that the captured CTC, especially M-CTC proportion, displayed more close associations with progression, diagnosis, surgery, and chemotherapeutic effects for CRC patients. Overall, we believe that our approach will bring a new understanding of CTC-based liquid biopsy for cancer diagnosis and treatment.


Asunto(s)
Neoplasias Colorrectales , Células Neoplásicas Circulantes , Humanos , Células Neoplásicas Circulantes/patología , Adsorción , Dióxido de Silicio , Transición Epitelial-Mesenquimal/genética , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/patología , Biomarcadores de Tumor , Molécula de Adhesión Celular Epitelial
14.
J Thorac Dis ; 14(8): 2927-2942, 2022 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-36071766

RESUMEN

Background: Left ventricular hypertrophy (LVH) is common in hypertension patients. Hypertension is a recognized risk factor of acute aortic dissection. This study aimed to explore the prognostic value of LVH in predicting postoperative outcomes in acute type A aortic dissection (ATAAD) patients. Methods: This was a single-central retrospectively designed study. One hundred and ninety-three ATAAD patients who underwent surgical repair at Renmin Hospital of Wuhan University from January 2018 to November 2021 were enrolled. Patients were divided based on their left ventricular mass index (LVMI). We compared their baseline characteristics, perioperative data, and in-hospital outcome. Then nomogram models were developed based on logistic regression to predict the postoperative outcomes. Results: LVH presented in 28.5% (55 in 193) patients. LVH group had a higher proportion of female patients compared with the non-LVH group (32.7% vs. 17.4%, P=0.03). Decreased left ventricular ejection fraction and cardiac tamponade were more prevalent in patients with LVH. LVH group had a higher risk of postoperative composite major outcomes (CMO) and operative mortality. Based on multivariable logistic regression, LVH/LVMI, Penn classification, hyperlipidemia, emergency surgery and cardiopulmonary bypass duration were applied to develop nomogram models for predicting postoperative CMO. The area under curve was 0.825 (95% CI: 0.749-0.900) for Model LVH and 0.841 (95% CI: 0.776-0.905) for Model LVMI. Nomogram models for predicting postoperative cardiac were developed based on LVH/LVMI and cardiopulmonary bypass duration. The area under curves for the models involving LVH or LVMI were 0.782 (95% CI: 0.640-0.923) and 0.795 (95% CI: 0.643-0.947), respectively. Conclusions: LVH and increased LVMI was associated with increased risk of postoperative CMO and cardiac events in ATAAD patients. The nomogram models based on LVH or LVMI might help predict postoperative CMO. Future research would be necessary to investigate prognostic value of LVH for long-term outcomes in ATAAD patients.

15.
Front Oncol ; 12: 915835, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36003781

RESUMEN

Purpose: This study aims to evaluate the ability of peritumoral, intratumoral, or combined computed tomography (CT) radiomic features to predict chemotherapy response in non-small cell lung cancer (NSCLC). Methods: After excluding subjects with incomplete data or other types of treatments, 272 (Dataset 1) and 43 (Dataset 2, external validation) NSCLC patients who were only treated with chemotherapy as the first-line treatment were enrolled between 2015 and 2019. All patients were divided into response and nonresponse based on the response evaluation criteria in solid tumors, version 1.1. By using 3D slicer and morphological operations in python, the intra- and peritumoral regions of lung tumors were segmented from pre-treatment CT images (unenhanced) and confirmed by two experienced radiologists. Then radiomic features (the first order, texture, shape, et al.) were extracted from the above regions of interest. The models were trained and tested in Dataset 1 and further validated in Dataset 2. The performance of models was compared using the area under curve (AUC), confusion matrix, accuracy, precision, recall, and F1-score. Results: The radiomic model using features from the peritumoral region of 0-3 mm outperformed that using features from 3-6, 6-9, 9-12 mm peritumoral region, and intratumoral region (AUC: 0.95 versus 0.87, 0.86, 0.85, and 0.88). By the fusion of features from 0-3 and 3-6 mm peritumoral regions, the logistic regression model achieved the best performance, with an AUC of 0.97. This model achieved an AUC of 0.85 in the external cohort. Moreover, among the 20 selected features, seven features differed significantly between the two groups (p < 0.05). Conclusions: CT radiomic features from both the peri- and intratumoral regions can predict chemotherapy response in NSCLC using machine learning models. Combined features from two peritumoral regions yielded better predictions.

16.
Exp Cell Res ; 400(2): 112494, 2021 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-33515593

RESUMEN

Bortezomib (Bort), a chemotherapeutic agent, is widely used for the clinical treatment of cancers. However, Bort-induced peripheral neurotoxicity (BIPN) significantly restricts its clinical application, which is difficult to deal with since the underlying mechanisms of BIPN are unclear. Here, we showed that Bort activates mTORC1 pathway leading to dorsal root ganglion (DRG) neuronal apoptosis. Inhibition of mTORC1 with rapamycin or knockdown of raptor, regulatory-associated protein of mTORC1, with shRNA dramatically rescued the cells from Bort-caused apoptosis. In addition, we found that Bort-activated mTORC1 pathway was attributed to Bort elevation of reactive oxygen species (ROS). This is supported by the evidence that using ROS scavenger N-acetyl cysteine (NAC) significantly alleviated Bort-activated mTORC1 pathway. Furthermore, we revealed that upregulation of NOX2 contributed to Bort-elicited ROS overproduction, leading to mTORC1 pathway-dependent apoptosis in DRG neurons. Inhibition of NOX2 with apocynin remarkably diminished Bort-induced overgeneration of ROS, activation of mTORC1 pathway and apoptosis in the cells. Taken together, these results indicate that Bort activation of mTORC1 pathway mediated by NOX2-drived ROS leads to apoptotic death in DRG neurons. Our findings highlight that manipulation of intracellular ROS level or NOX2 or mTORC1 activity may be exploited for prevention of BIPN.


Asunto(s)
Apoptosis , Bortezomib/farmacología , Ganglios Espinales/patología , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , NADPH Oxidasa 2/metabolismo , Neuronas/patología , Especies Reactivas de Oxígeno/metabolismo , Animales , Antineoplásicos/farmacología , Ganglios Espinales/efectos de los fármacos , Ganglios Espinales/metabolismo , Regulación de la Expresión Génica , Masculino , Diana Mecanicista del Complejo 1 de la Rapamicina/genética , NADPH Oxidasa 2/genética , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Ratas , Ratas Sprague-Dawley , Transducción de Señal
17.
Int J Nanomedicine ; 15: 521-536, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32021192

RESUMEN

INTRODUCTION: The myelodysplastic syndromes (MDS) are a very heterogeneous group of myeloid disorders characterized by peripheral blood cytopenias and increase risk of transformation to acute myeloid leukemia (AML). Daunorubicin (DNR) is an indispensable drug for the treatment of MDS and AML. However, its side effects including cardiac toxicity and bone marrow suppression severely limit clinical application. Many researches reported high expression of CD123 antigen on high-risk MDS cells, so we constructed a novel drug delivery system comprising daunorubicin-loaded CdTe QDs conjugated with anti-CD123 mAbs (DNR-CdTe-CD123) to develop targeted combination chemotherapy for MDS. METHODS: CdTe conjugated antiCD123 through amide bond, co-loaded with DNR with electrostatic bonding. Then, we determined characterization and release rate of DNR-CdTe-CD123. The therapeutic effect and side effect of drug delivery system were evaluated through in vitro and in vivo experiments. RESULTS: CdTe showed appropriate diameter and good dispersibility and DNR was loaded into CdTes with high encapsulation efficiency and drug loading. The maximum drug loading and encapsulation efficiency were 42.08 ± 0.64% and 74.52 ± 1.81%, respectively, at DNR concentration of 0.2mg/mL and anti-CD123 mAbs volume of 5ul (100ug/mL). Flow cytometry (FCM) showed that CD123 antigen was highly expressed on MUTZ-1 cells, and its expression rate was 72.89 ± 10.67%. In vitro experiments showed that the inhibition rate and apoptosis rate of MUTZ-1 cells treated with DNR-CdTe-CD123 were higher than those in the other groups (P<0.05). Compared with the other groups, the level of apoptosis-related protein (P53, cleaved caspase-9, Bax and cleaved caspase-3) were upregulated in DNR-CdTe-CD123 group (P<0.05). In vivo experiments, DNR-CdTe-CD123 can effectively inhibit the tumor growth of MDS-bearing nude mice and reduce the side effects of DNR on myocardial cells. CONCLUSION: The system of DNR-CdTe-CD123 enhances the therapeutic effects and reduce the side effects of DNR, thus providing a novel platform for MDS treatment.


Asunto(s)
Compuestos de Cadmio/química , Daunorrubicina/administración & dosificación , Sistemas de Liberación de Medicamentos/métodos , Síndromes Mielodisplásicos/tratamiento farmacológico , Telurio/química , Animales , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/farmacología , Apoptosis/efectos de los fármacos , Caspasa 3/metabolismo , Daunorrubicina/farmacología , Humanos , Subunidad alfa del Receptor de Interleucina-3/inmunología , Ratones Endogámicos BALB C , Ratones Desnudos , Síndromes Mielodisplásicos/patología , Puntos Cuánticos/química , Pruebas de Toxicidad , Ensayos Antitumor por Modelo de Xenoinjerto
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