Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 89
Filtrar
1.
Br J Cancer ; 2022 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-35017656

RESUMO

BACKGROUND: Immunotherapy has revolutionised the field of cancer therapy and immunology, but has demonstrated limited therapeutic efficacy in high-grade serous ovarian cancer (HGSOC). METHODS: Multi-omics data of 495 TCGA HGSOC tumours and RNA-seq data of 1708 HGSOC tumours were analyzed. Multivariate Cox regression analysis and meta-analyses were used to identify prognostic genes. The immune microenvironment was characterised using the ssGSEA methods for 28 immune cell types. Immunohistochemistry staining of tumour tissues of 14 patients was used to validate the key findings further. RESULTS: A total of 1142 genes were identified as favourable prognostic genes, which are prevailing in immune-related pathways and the infiltration of most immune subpopulations was observed to be associated with a favourable prognosis suggesting that tumour immunogenicity was the most prominent factor associated with improved clinical outcomes and response to chemotherapy of HGSOC. We identified multiple genomic and transcriptomic determinants of immunogenicity, including the copy loss of chromosome 4q and deficiencies of the homologous recombination pathway. Finally, an immunological subtype characterised by increased infiltration of activated CD8 T cells and decreased Tregs was associated with favourable prognosis and improved therapeutic efficacy. CONCLUSIONS: Our study characterised the immunogenomic landscape and refined the immunological classifications of HGSOC. This may improve the selection of patients with HGSOC who are suitable candidates for immunotherapy.

2.
Eur Radiol ; 32(1): 243-253, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34236464

RESUMO

OBJECTIVES: Accurate preoperative differentiation between squamous cell carcinoma (SCC) and non-Hodgkin's lymphoma (NHL) in the palatine tonsil is crucial because of their different treatment. This study aimed to construct and validate a contrast-enhanced CT (CECT)-based radiomics nomogram for preoperative differentiation of SCC and NHL in the palatine tonsil. METHODS: This study enrolled 135 patients with a pathological diagnosis of SCC or NHL from two clinical centers, who were divided into training (n = 94; SCC = 50, NHL = 44) and external validation sets (n = 41; SCC = 22, NHL = 19). A radiomics signature was constructed from radiomics features extracted from routine CECT images and a radiomics score (Rad-score) was calculated. A clinical model was established using demographic features and CT findings. The independent clinical factors and Rad-score were combined to construct a radiomics nomogram. Performance of the clinical model, radiomics signature, and nomogram was assessed using receiver operating characteristics analysis and decision curve analysis. RESULTS: Eleven features were finally selected to construct the radiomics signature. The radiomics nomogram incorporating gender, mean CECT value, and radiomics signature showed better predictive value for differentiating SCC from NHL than the clinical model for training (AUC, 0.919 vs. 0.801, p = 0.004) and validation (AUC, 0.876 vs. 0.703, p = 0.029) sets. Decision curve analysis demonstrated that the radiomics nomogram was more clinically useful than the clinical model. CONCLUSIONS: A CECT-based radiomics nomogram was constructed incorporating gender, mean CECT value, and radiomics signature. This nomogram showed favorable predictive efficacy for differentiating SCC from NHL in the palatine tonsil, and might be useful for clinical decision-making. KEY POINTS: • Differential diagnosis between SCC and NHL in the palatine tonsil is difficult by conventional imaging modalities. • A radiomics nomogram integrated with the radiomics signature, gender, and mean contrast-enhanced CT value facilitates differentiation of SCC from NHL with improved diagnostic efficacy.


Assuntos
Carcinoma de Células Escamosas , Linfoma não Hodgkin , Carcinoma de Células Escamosas/diagnóstico por imagem , Diferenciação Celular , Humanos , Linfoma não Hodgkin/diagnóstico por imagem , Nomogramas , Tonsila Palatina , Tomografia Computadorizada por Raios X
3.
Nat Commun ; 12(1): 6071, 2021 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-34663807

RESUMO

In contrast to the curative effect of allogenic stem cell transplantation in acute myeloid leukemia via T cell activity, only modest responses are achieved with checkpoint-blockade therapy, which might be explained by T cell phenotypes and T cell receptor (TCR) repertoires. Here, we show by paired single-cell RNA analysis and TCR repertoire profiling of bone marrow cells in relapsed/refractory acute myeloid leukemia patients pre/post azacytidine+nivolumab treatment that the disease-related T cell subsets are highly heterogeneous, and their abundance changes following PD-1 blockade-based treatment. TCR repertoires expand and primarily emerge from CD8+ cells in patients responding to treatment or having a stable disease, while TCR repertoires contract in therapy-resistant patients. Trajectory analysis reveals a continuum of CD8+ T cell phenotypes, characterized by differential expression of granzyme B and a bone marrow-residing memory CD8+ T cell subset, in which a population with stem-like properties expressing granzyme K is enriched in responders. Chromosome 7/7q loss, on the other hand, is a cancer-intrinsic genomic marker of PD-1 blockade resistance in AML. In summary, our study reveals that adaptive T cell plasticity and genomic alterations determine responses to PD-1 blockade in acute myeloid leukemia.


Assuntos
Inibidores de Checkpoint Imunológico/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T/efeitos dos fármacos , Idoso , Idoso de 80 Anos ou mais , Azacitidina/uso terapêutico , Medula Óssea/efeitos dos fármacos , Medula Óssea/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Deleção Cromossômica , Cromossomos Humanos Par 7/genética , Resistencia a Medicamentos Antineoplásicos/genética , Granzimas/metabolismo , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/imunologia , Pessoa de Meia-Idade , Nivolumabe/uso terapêutico , Receptores de Antígenos de Linfócitos T/genética , Análise de Célula Única , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Transcriptoma/efeitos dos fármacos
4.
Nat Commun ; 12(1): 5606, 2021 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-34556668

RESUMO

Immune checkpoint therapy (ICT) provides substantial clinical benefits to cancer patients, but a large proportion of cancers do not respond to ICT. To date, the genomic underpinnings of primary resistance to ICT remain elusive. Here, we performed immunogenomic analysis of data from TCGA and clinical trials of anti-PD-1/PD-L1 therapy, with a particular focus on homozygous deletion of 9p21.3 (9p21 loss), one of the most frequent genomic defects occurring in ~13% of all cancers. We demonstrate that 9p21 loss confers "cold" tumor-immune phenotypes, characterized by reduced abundance of tumor-infiltrating leukocytes (TILs), particularly, T/B/NK cells, altered spatial TILs patterns, diminished immune cell trafficking/activation, decreased rate of PD-L1 positivity, along with activation of immunosuppressive signaling. Notably, patients with 9p21 loss exhibited significantly lower response rates to ICT and worse outcomes, which were corroborated in eight ICT trials of >1,000 patients. Further, 9p21 loss synergizes with PD-L1/TMB for patient stratification. A "response score" was derived by incorporating 9p21 loss, PD-L1 expression and TMB levels in pre-treatment tumors, which outperforms PD-L1, TMB, and their combination in identifying patients with high likelihood of achieving sustained response from otherwise non-responders. Moreover, we describe potential druggable targets in 9p21-loss tumors, which could be exploited to design rational therapeutic interventions.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 9/genética , Resistencia a Medicamentos Antineoplásicos/imunologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Microambiente Tumoral/imunologia , Antígeno B7-H1/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/imunologia , Resistencia a Medicamentos Antineoplásicos/genética , Homozigoto , Humanos , Tolerância Imunológica , Imunoterapia , Linfócitos do Interstício Tumoral/imunologia , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/mortalidade , Prognóstico , Transdução de Sinais/imunologia
5.
Eur Radiol ; 2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34448928

RESUMO

OBJECTIVES: To evaluate the performance of a deep learning radiomic nomogram (DLRN) model at predicting tumor relapse in patients with soft tissue sarcomas (STS) who underwent surgical resection. METHODS: In total, 282 patients who underwent MRI and resection for STS at three independent centers were retrospectively enrolled. In addition, 113 of the 282 patients received additional contrast-enhanced MRI scans. We separated the participants into a development cohort and an external test cohort. The development cohort consisted of patients from one center and the external test cohort consisted of patients from two other centers. Two MRI-based DLRNs for prediction of tumor relapse after resection of STS were established. We universally tested the DLRNs and compared them with other prediction models constructed by using widespread adopted predictors (i.e., staging systems and Ki67) instead of radiomics features. RESULTS: The DLRN1 model incorporated plain MRI-based radiomics signature into the clinical data, and the DLRN2 model integrated radiomics signature extracted from plain and contrast-enhanced MRI with the clinical predictors. Across both study sets, the two MRI-based DLRNs had relatively better prognostic capability (C index ≥ 0.721 and median AUC ≥ 0.746; p < 0.05 compared with most other models and predictors) and less opportunity for prediction error (integrated Brier score ≤ 0.159). The decision curve analysis indicates that the DLRNs have greater benefits than staging systems, Ki67, and other models. We selected appropriate cutoff values for the DLRNs to divide STS recurrence into three risk strata (low, medium, and high) and calculated those groups' cumulative risk rates. CONCLUSION: The DLRNs were shown to be a reliable and externally validated tool for predicting STS recurrence by comparing with other prediction models. KEY POINTS: • The prediction of a high recurrence rate of STS before emergence of local recurrence can help to determine whether more active treatment should be implemented. • Two MRI-based DLRNs for prediction of tumor relapse were shown to be a reliable and externally validated tool for predicting STS recurrence. • We used the DLRNs to divide STS recurrence into three risk strata (low, medium, and high) to facilitate more targeted postoperative management in the clinic.

6.
Cancer Discov ; 2021 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-34429321

RESUMO

Clonal hematopoiesis is a prevalent age-related condition associated with greatly increased risk of hematologic disease; mutations in DNA methyltransferase 3A (DNMT3A) are the most common driver of this state. DNMT3A variants occur across the gene with some particularly associated with malignancy, but the functional relevance and mechanisms of pathogenesis of the majority of mutations is unknown. Here, we systematically investigated the methyltransferase activity and protein stability of 253 disease-associated DNMT3A mutations, finding that 74% were loss-of-function mutations. Half of these variants exhibited reduced protein stability and, as a class, correlated with greater clonal expansion and AML development. We investigated the mechanisms underlying the instability using a CRISPR screen and uncovered regulated destruction of DNMT3A mediated by the DCAF8 E3 ubiquitin ligase adaptor. We establish a new paradigm to classify novel variants that has prognostic and potential therapeutic significance for patients with hematologic disease.

7.
Cancer Discov ; 11(10): 2506-2523, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33972311

RESUMO

Little is known of the geospatial architecture of individual cell populations in lung adenocarcinoma (LUAD) evolution. Here, we perform single-cell RNA sequencing of 186,916 cells from five early-stage LUADs and 14 multiregion normal lung tissues of defined spatial proximities from the tumors. We show that cellular lineages, states, and transcriptomic features geospatially evolve across normal regions to LUADs. LUADs also exhibit pronounced intratumor cell heterogeneity within single sites and transcriptional lineage-plasticity programs. T regulatory cell phenotypes are increased in normal tissues with proximity to LUAD, in contrast to diminished signatures and fractions of cytotoxic CD8+ T cells, antigen-presenting macrophages, and inflammatory dendritic cells. We further find that the LUAD ligand-receptor interactome harbors increased expression of epithelial CD24, which mediates protumor phenotypes. These data provide a spatial atlas of LUAD evolution, and a resource for identification of targets for its treatment. SIGNIFICANCE: The geospatial ecosystem of the peripheral lung and early-stage LUAD is not known. Our multiregion single-cell sequencing analyses unravel cell populations, states, and phenotypes in the spatial and ecologic evolution of LUAD from the lung that comprise high-potential targets for early interception.This article is highlighted in the In This Issue feature, p. 2355.

8.
Nat Commun ; 12(1): 2877, 2021 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-34001881

RESUMO

The mechanisms driving therapeutic resistance and poor outcomes of mantle cell lymphoma (MCL) are incompletely understood. We characterize the cellular and molecular heterogeneity within and across patients and delineate the dynamic evolution of tumor and immune cell compartments at single cell resolution in longitudinal specimens from ibrutinib-sensitive patients and non-responders. Temporal activation of multiple cancer hallmark pathways and acquisition of 17q are observed in a refractory MCL. Multi-platform validation is performed at genomic and cellular levels in PDX models and larger patient cohorts. We demonstrate that due to 17q gain, BIRC5/survivin expression is upregulated in resistant MCL tumor cells and targeting BIRC5 results in marked tumor inhibition in preclinical models. In addition, we discover notable differences in the tumor microenvironment including progressive dampening of CD8+ T cells and aberrant cell-to-cell communication networks in refractory MCLs. This study reveals diverse and dynamic tumor and immune programs underlying therapy resistance in MCL.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Perfilação da Expressão Gênica/métodos , Heterogeneidade Genética , Linfoma de Célula do Manto/genética , Análise de Célula Única/métodos , Microambiente Tumoral/genética , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/genética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Humanos , Imidazóis/farmacologia , Linfoma de Célula do Manto/diagnóstico por imagem , Linfoma de Célula do Manto/tratamento farmacológico , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Naftoquinonas/farmacologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Análise de Sequência de RNA/métodos , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
9.
Front Oncol ; 11: 659905, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34012922

RESUMO

Objectives: To investigate the efficacy of multi-parametric MRI-based radiomics nomograms for preoperative distinction between benign and malignant sinonasal tumors. Methods: Data of 244 patients with sinonasal tumor (training set, n=192; test set, n=52) who had undergone pre-contrast MRI, and 101 patients who underwent post-contrast MRI (training set, n=74; test set, n=27) were retrospectively analyzed. Independent predictors of malignancy were identified and their performance were evaluated. Seven radiomics signatures (RSs) using maximum relevance minimum redundancy (mRMR), and the least absolute shrinkage selection operator (LASSO) algorithm were established. The radiomics nomograms, comprising the clinical model and the RS algorithms were built: one based on pre-contrast MRI (RNWOC); the other based on pre-contrast and post-contrast MRI (RNWC). The performances of the models were evaluated with area under the curve (AUC), calibration, and decision curve analysis (DCA) respectively. Results: The efficacy of the clinical model (AUC=0.81) of RNWC was higher than that of the model (AUC=0.76) of RNWOC in the test set. There was no significant difference in the AUC of radiomic algorithms in the test set. The RS-T1T2 (AUC=0.74) and RS-T1T2T1C (RSWC, AUC=0.81) achieved a good distinction efficacy in the test set. The RNWC and the RNWOC showed excellent distinction (AUC=0.89 and 0.82 respectively) in the test set. The DCA of the nomograms showed better clinical usefulness than the clinical models and radiomics signatures. Conclusions: The radiomics nomograms combining the clinical model and RS can be accurately, safely and efficiently used to distinguish between benign and malignant sinonasal tumors.

10.
Phys Rev E ; 103(2-1): 022126, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33735955

RESUMO

By means of extensive Monte Carlo simulation, we study extended-range site percolation on square and simple cubic lattices with various combinations of nearest neighbors up to the eighth nearest neighbors for the square lattice and the ninth nearest neighbors for the simple cubic lattice. We find precise thresholds for 23 systems using a single-cluster growth algorithm. Site percolation on lattices with compact neighborhoods of connected sites can be mapped to problems of lattice percolation of extended objects of a given shape, such as disks and spheres, and the thresholds can be related to the continuum thresholds η_{c} for objects of those shapes. This mapping implies zp_{c}∼4η_{c}=4.51235 in two dimensions and zp_{c}∼8η_{c}=2.7351 in three dimensions for large z for circular and spherical neighborhoods, respectively, where z is the coordination number. Fitting our data for compact neighborhoods to the form p_{c}=c/(z+b) we find good agreement with this prediction, c=2^{d}η_{c}, with the constant b representing a finite-z correction term. We also examined results from other studies using this fitting formula. A good fit of the large but finite-z behavior can also be made using the formula p_{c}=1-exp(-2^{d}η_{c}/z), a generalization of a formula of Koza, Kondrat, and Suszcaynski [J. Stat. Mech.: Theor. Exp. (2014) P110051742-546810.1088/1742-5468/2014/11/P11005]. We also study power-law fits which are applicable for the range of values of z considered here.

11.
J Magn Reson Imaging ; 53(6): 1683-1696, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33604955

RESUMO

BACKGROUND: Preoperative prediction of soft tissue sarcoma (STS) grade is important for treatment decisions. Therefore, formulation an STS grade model is strongly needed. PURPOSE: To develop and test an magnetic resonance imaging (MRI)-based radiomics nomogram for predicting the grade of STS (low-grade vs. high grade). STUDY TYPE: Retrospective POPULATION: One hundred and eighty patients with STS confirmed by pathologic results at two independent institutions were enrolled (training set, N = 109; external validation set, N = 71). FIELD STRENGTH/SEQUENCE: Unenhanced T1-weighted (T1WI) and fat-suppressed T2-weighted images (FS-T2WI) were acquired at 1.5 T and 3.0 T. ASSESSMENT: Clinical-MRI characteristics included age, gender, tumor-node-metastasis (TNM) stage, American Joint Committee on Cancer (AJCC) stage, progression-free survival (PFS), and MRI morphological features (ie, margin). Radiomics feature extraction were performed on T1WI and FS-T2WI images by minimum redundancy maximum relevance (MRMR) method and least absolute shrinkage and selection operator (LASSO) algorithm. The selected features constructed three radiomics signatures models (RS-T1, RS-FST2, and RS-Combined). Univariate and multivariate logistic regression analysis were applied for screening significant risk factors. Radiomics nomogram was constructed by incorporating the radiomics signature and risk factors. STATISTICAL TESTS: Clinical-MRI characteristics were performed by a univariate analysis. Model performances (discrimination, calibration, and clinical usefulness) were validated in the external validation set. The RS-T1 model, RS-FST2 model, and RS-Combined model had an area under curves (AUCs) of 0.645, 0.641, and 0.829, respectively, in the external validation set. The radiomics nomogram, incorporating significant risk factors and the RS-Combined model had AUCs of 0.916 (95%CI, 0.866-0.966, training set) and 0.879 (95%CI, 0.791-0.967, external validation set), and demonstrated good calibration and good clinical utility. DATA CONCLUSION: The proposed noninvasive MRI-based radiomics models showed good performance in differentiating low-grade from high-grade STSs. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY STAGE: 2.


Assuntos
Sarcoma , Neoplasias de Tecidos Moles , Humanos , Imageamento por Ressonância Magnética , Nomogramas , Estudos Retrospectivos , Sarcoma/diagnóstico por imagem , Neoplasias de Tecidos Moles/diagnóstico por imagem
12.
Cancer Imaging ; 21(1): 20, 2021 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-33549151

RESUMO

BACKGROUND: We sought to evaluate the performance of a computed tomography (CT)-based radiomics nomogram we devised in distinguishing benign from malignant bone tumours. METHODS: Two hundred and six patients with bone tumours were spilt into two groups: a training set (n = 155) and a validation set (n = 51). A feature extraction process based on 3D Slicer software was used to extract the radiomics features from unenhanced CT images, and least absolute shrinkage and selection operator logistic regression was used to calculate the radiomic score to generate a radiomics signature. A clinical model comprised demographics and CT features. A radiomics nomogram combined with the clinical model and the radiomics signature was constructed. The performance of the three models was comprehensively evaluated from three aspects: identification ability, accuracy, and clinical value, allowing for generation of an optimal prediction model. RESULTS: The radiomics nomogram comprised clinical and radiomics signature features. The nomogram model displayed good performance in training and validation sets with areas under the curve of 0.917 and 0.823, respectively. The areas under the curve, decision curve analysis, and net reclassification improvement showed that the radiomics nomogram model could obtain better diagnostic performance than the clinical model and achieve greater clinical net benefits than the clinical and radiomics signature models alone. CONCLUSIONS: We constructed a combined nomogram comprising a clinical model and radiomics signature as a noninvasive preoperative prediction method to distinguish between benign and malignant bone tumours and assist treatment planning.


Assuntos
Neoplasias Ósseas/diagnóstico por imagem , Neoplasias Ósseas/diagnóstico , Nomogramas , Tomografia Computadorizada por Raios X/métodos , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
13.
Nat Med ; 27(1): 141-151, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33398161

RESUMO

Intratumoral heterogeneity (ITH) is a fundamental property of cancer; however, the origins of ITH remain poorly understood. We performed single-cell transcriptome profiling of peritoneal carcinomatosis (PC) from 15 patients with gastric adenocarcinoma (GAC), constructed a map of 45,048 PC cells, profiled the transcriptome states of tumor cell populations, incisively explored ITH of malignant PC cells and identified significant correlates with patient survival. The links between tumor cell lineage/state compositions and ITH were illustrated at transcriptomic, genotypic, molecular and phenotypic levels. We uncovered the diversity in tumor cell lineage/state compositions in PC specimens and defined it as a key contributor to ITH. Single-cell analysis of ITH classified PC specimens into two subtypes that were prognostically independent of clinical variables, and a 12-gene prognostic signature was derived and validated in multiple large-scale GAC cohorts. The prognostic signature appears fundamental to GAC carcinogenesis and progression and could be practical for patient stratification.


Assuntos
Adenocarcinoma/secundário , Neoplasias Gástricas/patologia , Adenocarcinoma/genética , Adenocarcinoma/patologia , Adulto , Idoso , Linhagem da Célula/genética , Cromossomos Humanos Par 17/genética , Estudos de Coortes , Variações do Número de Cópias de DNA , Feminino , Perfilação da Expressão Gênica , Variação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Peritoneais/genética , Neoplasias Peritoneais/patologia , Neoplasias Peritoneais/secundário , Prognóstico , RNA-Seq , Análise de Célula Única , Neoplasias Gástricas/genética
14.
Theranostics ; 11(5): 2442-2459, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33500735

RESUMO

Cancer growth is usually accompanied by metastasis which kills most cancer patients. Here we aim to study the effect of cisplatin at different doses on breast cancer growth and metastasis. Methods: We used cisplatin to treat breast cancer cells, then detected the migration of cells and the changes of epithelial-mesenchymal transition (EMT) markers by migration assay, Western blot, and immunofluorescent staining. Next, we analyzed the changes of RNA expression of genes by RNA-seq and confirmed the binding of activating transcription factor 3 (ATF3) to cytoskeleton related genes by ChIP-seq. Thereafter, we combined cisplatin and paclitaxel in a neoadjuvant setting to treat xenograft mouse models. Furthermore, we analyzed the association of disease prognosis with cytoskeletal genes and ATF3 by clinical data analysis. Results: When administered at a higher dose (6 mg/kg), cisplatin inhibits both cancer growth and metastasis, yet with strong side effects, whereas a lower dose (2 mg/kg) cisplatin blocks cancer metastasis without obvious killing effects. Cisplatin inhibits cancer metastasis through blocking early steps of EMT. It antagonizes transforming growth factor beta (TGFß) signaling through suppressing transcription of many genes involved in cytoskeleton reorganization and filopodia formation which occur early in EMT and are responsible for cancer metastasis. Mechanistically, TGFß and fibronectin-1 (FN1) constitute a positive reciprocal regulation loop that is critical for activating TGFß/SMAD3 signaling, which is repressed by cisplatin induced expression of ATF3. Furthermore, neoadjuvant administration of cisplatin at 2 mg/kg in conjunction with paclitaxel inhibits cancer growth and blocks metastasis without causing obvious side effects by inhibiting colonization of cancer cells in the target organs. Conclusion: Thus, cisplatin prevents breast cancer metastasis through blocking early EMT, and the combination of cisplatin and paclitaxel represents a promising therapy for killing breast cancer and blocking tumor metastasis.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias da Mama/tratamento farmacológico , Movimento Celular , Transição Epitelial-Mesenquimal , Neoplasias Pulmonares/tratamento farmacológico , Animais , Apoptose , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células , Cisplatino/administração & dosagem , Feminino , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Camundongos , Camundongos Nus , Paclitaxel/administração & dosagem , Transdução de Sinais , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
15.
J Magn Reson Imaging ; 53(1): 141-151, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32776393

RESUMO

BACKGROUND: Preoperative discrimination between malignant and benign sinonasal tumors is important for treatment plan selection. PURPOSE: To build and validate a radiomic nomogram for preoperative discrimination between malignant and benign sinonasal tumors. STUDY TYPE: Retrospective. POPULATION: In all, 197 patients with histopathologically confirmed 84 benign and 113 malignant sinonasal tumors. FIELD STRENGTH/SEQUENCES: Fast-spin-echo (FSE) T1 -weighted and fat-suppressed FSE T2 -weighted imaging on a 1.5T and 3.0T MRI. ASSESSMENT: T1 and fat-suppressed T2 -weighted images were selected for feature extraction. The least absolute shrinkage selection operator (LASSO) algorithm was applied to establish a radiomic score. Multivariate logistic regression analysis was applied to determine independent risk factors, and the radiomic score was combined to build a radiomic nomogram. The nomogram was assessed in a training dataset (n = 138/3.0T MRI) and tested in a validation dataset (n = 59/1.5T MRI). STATISTICAL TESTS: Independent t-test or Wilcoxon's test, chi-square-test, or Fisher's-test, univariate analysis, LASSO, multivariate logistic regression analysis, area under the curve (AUC), Hosmer-Lemeshow test, decision curve, and the Delong test. RESULTS: In the validation dataset, the radiomic nomogram could differentiate benign from malignant sinonasal tumors with an AUC of 0.91. There was no significant difference in AUC between the combined radiomic score and radiomic nomogram (P > 0.05), and the radiomic nomogram showed a relatively higher AUC than the combined radiomic score. There was a significant difference in AUC between each two of the following models (the radiomic nomogram vs. the clinical model, all P < 0.001; the combined radiomic score vs. the clinical model, P = 0.0252 and 0.0035, respectively, in the training and validation datasets). The radiomic nomogram outperformed the radiomic scores and clinical model. DATA CONCLUSION: The radiomic nomogram combining the clinical model and radiomic score is a simple, effective, and reliable method for patient risk stratification. LEVEL OF EVIDENCE: 4 TECHNICAL EFFICACY STAGE: 2.


Assuntos
Neoplasias , Nomogramas , Área Sob a Curva , Humanos , Imageamento por Ressonância Magnética , Estudos Retrospectivos
16.
Artigo em Inglês | MEDLINE | ID: mdl-32712057

RESUMO

OBJECTIVE: The aim of this study was to investigate computed tomography (CT) and magnetic resonance imaging (MRI) findings in adenoid cystic carcinoma (ACC) in the maxillary sinus and their correlations with the tubular, cribriform, and solid histopathologic types of ACC. STUDY DESIGN: Twenty cases of histopathologically proven ACC in the maxillary sinus were retrospectively reviewed. CT and MRI findings were correlated with histopathologic results. RESULTS: On CT, significant differences were discovered among the 3 histopathologic ACC types in range, size, shape, margins, type of bone destruction, and time intensity curve (TIC) (P ≤ .018). Tubular lesions were limited in range, were smaller than the other types, produced small cystic patterns with well-defined margins, and caused a cribriform pattern of bone destruction. All tumors demonstrated heterogeneous intensity signal on T1- and T2-weighted images (T1WI and T2WI) and appeared as hypo- or isointense small cystic lesions on T1WI and hyperintense on T2WI (n = 6). Postcontrast MRI revealed marked heterogeneous enhancement for all lesions. The TIC showed a rapidly enhancing and slow washout pattern in all tubular lesions and a rapidly enhancing and rapid washout pattern in solid tumors. CONCLUSIONS: Different histologic patterns of ACCs have distinctive radiologic features, which can facilitate accurate preoperative diagnosis.


Assuntos
Carcinoma Adenoide Cístico , Carcinoma Adenoide Cístico/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Seio Maxilar/diagnóstico por imagem , Estudos Retrospectivos , Tomografia Computadorizada por Raios X
17.
Acta Radiol ; 62(10): 1397-1403, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33086861

RESUMO

BACKGROUND: Assessment of optic nerve sheath diameter (ONSD) is a non-invasive measure of intracranial pressure (ICP). However, it is not clear whether healthy individuals exhibit ONSD variation or whether factors other than ICP affect the ONSD. PURPOSE: To investigate whether ONSD was correlated with age, sex, height, weight, eyeball transverse diameter (ETD), or body mass index (BMI), and to develop a new diagnostic model to increase the diagnostic accuracy of intracranial hypertension (IH). MATERIAL AND METHODS: A total of 145 relatively healthy adults and 40 patients with acute IH who underwent high-resolution magnetic resonance imaging (MRI) were enrolled in this study. Linear regression analyses were used to determine the relationship between ONSD and these variables. If correlations were identified, an index ONSDΔ removing variables effects was calculated. ROC analysis was used to assess the IH predictive value of ONSDΔ in terms of sensitivity and specificity. RESULTS: In relatively healthy adults, there was a correlation between ONSD and BMI (P = 0.002), which can be presented as an index ONSDΔ. The ONSDΔ model better predicted IH than the ONSD model (P = 0.035), with a sensitivity of 70.00%, a specificity of 71.72%, and an AUC of 0.755. CONCLUSION: A correlation between ONSD and body mass index (BMI) was found using high-resolution MRI. This result indicates that the effects of BMI should be considered along with the ONSD during ICP monitoring. Meanwhile, the index ONSDΔ was better than the ONSD in predicting IH and could be used to obtain a more precise estimation of ICP.


Assuntos
Hipertensão Intracraniana/diagnóstico , Imageamento por Ressonância Magnética/métodos , Nervo Óptico/diagnóstico por imagem , China , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Estudos Retrospectivos , Sensibilidade e Especificidade
18.
Eur Radiol ; 31(5): 2886-2895, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33123791

RESUMO

OBJECTIVES: Preoperative differentiation between benign lymphoepithelial lesion (BLEL) and mucosa-associated lymphoid tissue lymphoma (MALToma) in the parotid gland is important for treatment decisions. The purpose of this study was to develop and validate a CT-based radiomics nomogram combining radiomics signature and clinical factors for the preoperative differentiation of BLEL from MALToma in the parotid gland. METHODS: A total of 101 patients with BLEL (n = 46) or MALToma (n = 55) were divided into a training set (n = 70) and validation set (n = 31). Radiomics features were extracted from non-contrast CT images, a radiomics signature was constructed, and a radiomics score (Rad-score) was calculated. Demographics and CT findings were assessed to build a clinical factor model. A radiomics nomogram combining the Rad-score and independent clinical factors was constructed using multivariate logistic regression analysis. The performance levels of the nomogram, radiomics signature, and clinical model were evaluated and validated on the training and validation datasets, and then compared among the three models. RESULTS: Seven features were used to build the radiomics signature. The radiomics nomogram incorporating the clinical factors and radiomics signature showed favorable predictive value for differentiating parotid BLEL from MALToma, with AUCs of 0.983 and 0.950 for the training set and validation set, respectively. Decision curve analysis showed that the nomogram outperformed the clinical factor model in terms of clinical usefulness. CONCLUSIONS: The CT-based radiomics nomogram incorporating the Rad-score and clinical factors showed favorable predictive efficacy for differentiating BLEL from MALToma in the parotid gland, and may help in the clinical decision-making process. KEY POINTS: • Differential diagnosis between BLEL and MALToma in parotid gland is rather difficult by conventional imaging modalities. • A radiomics nomogram integrated with the radiomics signature, demographics, and CT findings facilitates differentiation of BLEL from MALToma with improved diagnostic efficacy.


Assuntos
Nomogramas , Glândula Parótida , Diagnóstico Diferencial , Humanos , Estudos Retrospectivos , Tomografia Computadorizada por Raios X
19.
Gut ; 70(11): 2055-2065, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33334899

RESUMO

OBJECTIVE: Prognosis of patients with advanced oesophagogastric adenocarcinoma (mEGAC) is poor and molecular determinants of shorter or longer overall survivors are lacking. Our objective was to identify molecular features and develop a prognostic model by profiling the genomic features of patients with mEGAC with widely varying outcomes. DESIGN: We profiled 40 untreated mEGACs (20 shorter survivors <13 months and 20 longer survivors >36 months) with whole-exome sequencing (WES) and RNA sequencing and performed an integrated analysis of exome, transcriptome, immune profile and pathological phenotypes to identify the molecular determinants, developing an integrated model for prognosis and comparison with The Cancer Genome Atlas (TCGA) cohorts. RESULTS: KMT2C alterations were exclusively observed in shorter survivors together with high level of intratumour heterogeneity and complex clonal architectures, whereas the APOBEC mutational signatures were significantly enriched in longer survivors. Notably, the loss of heterozygosity in chromosome 4 (Chr4) was associated with shorter survival and 'cold' immune phenotype characterised by decreased B, CD8, natural killer cells and interferon-gamma responses. Unsupervised transcriptomic clustering revealed a shorter survivor subtype with distinct expression features (eg, upregulated druggable targets JAK2, MAP3K13 and MECOM). An integrated model was then built based on clinical variables and the identified molecular determinants, which significantly segregated shorter and longer survivors. All the above features and the integrated model have been validated independently in multiple TCGA cohorts. CONCLUSION: This study discovered novel molecular features prognosticating overall survival in patients with mEGAC and identified potential novel targets in shorter survivors.

20.
Front Neurosci ; 15: 795539, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34975391

RESUMO

Background: Prediction and early diagnosis of Parkinson's disease (PD) and Parkinson's disease with depression (PDD) are essential for the clinical management of PD. Objectives: The present study aimed to develop a plasma Family with sequence similarity 19, member A5 (FAM19A5) and MRI-based radiomics nomogram to predict PD and PDD. Methods: The study involved 176 PD patients and 181 healthy controls (HC). Sandwich enzyme-linked immunosorbent assay (ELISA) was used to measure FAM19A5 concentration in the plasma samples collected from all participants. For enrolled subjects, MRI data were collected from 164 individuals (82 in the PD group and 82 in the HC group). The bilateral amygdala, head of the caudate nucleus, putamen, and substantia nigra, and red nucleus were manually labeled on the MR images. Radiomics features of the labeled regions were extracted. Further, machine learning methods were applied to shrink the feature size and build a predictive radiomics signature. The resulting radiomics signature was combined with plasma FAM19A5 concentration and other risk factors to establish logistic regression models for the prediction of PD and PDD. Results: The plasma FAM19A5 levels (2.456 ± 0.517) were recorded to be significantly higher in the PD group as compared to the HC group (2.23 ± 0.457) (P < 0.001). Importantly, the plasma FAM19A5 levels were also significantly higher in the PDD subgroup (2.577 ± 0.408) as compared to the non-depressive subgroup (2.406 ± 0.549) (P = 0.045 < 0.05). The model based on the combination of plasma FAM19A5 and radiomics signature showed excellent predictive validity for PD and PDD, with AUCs of 0.913 (95% CI: 0.861-0.955) and 0.937 (95% CI: 0.845-0.970), respectively. Conclusion: Altogether, the present study reported the development of nomograms incorporating radiomics signature, plasma FAM19A5, and clinical risk factors, which might serve as potential tools for early prediction of PD and PDD in clinical settings.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...