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1.
J Orthop Surg Res ; 16(1): 593, 2021 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-34649582

RESUMO

OBJECTIVE: To evaluate the biomechanical influence after percutaneous endoscopic lumbar facetectomy in different diameters on segmental range of motion (ROM) and intradiscal pressure (IDP) of the relevant segments by establishing three dimensional finite element (FE) model. METHODS: An intact L3-5 model was successfully constructed from the CT of a healthy volunteer as Model A (MA). The Model B (MB), Model C (MC) and Model D (MD) were obtained through facetectomy on L4 inferior facet in diameters 7.5 mm, 10 mm and 15 mm on MA for simulation. The ROM and IDP of L3/4 and L4/5 of four models were all compared in forward flexion, backward extension, left and right bending, left and right rotation. RESULTS: Compared with MA, the ROM of L4/5 of MB, MC and MD all increased. MD changed more significantly than MB and MC in backward extension, right bending and right rotation. But that of MB and MC on L3/4 had no prominent change, while MD had a slight increase in backward extension. The IDP of MB and MC on L4/5 in six states was similar to MA, yet MD increased obviously in backward extension, right bending, left and right rotation. The IDP on L3/4 of MB and MC was resemble to MA in six conditions, nevertheless MD increased slightly only in backward extension. CONCLUSION: Compared with the facetectomy in diameters 7.5 mm and 10 mm, the mechanical effect brought by facetectomy in diameter 15 mm on the operating segment changed more significantly, and had a corresponding effect on the adjacent segments.

2.
J Immunother Cancer ; 9(10)2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34615706

RESUMO

BACKGROUND: Triple-negative breast cancers (TNBCs), especially those non-immune-inflamed tumors, have a poor prognosis and limited therapies. Human leukocyte antigen (HLA)-I not only contributes to antitumor immune response and the phenotype of the tumor microenvironment, but also is a negative predictor of outcomes after immunotherapy. However, the importance of HLA functional status in TNBCs remains poorly understood. METHODS: Using the largest original multiomics datasets on TNBCs, we systematically characterized the HLA-Ⅰ status of TNBCs from the perspective of HLA-Ⅰ homogeneity and loss of heterozygosity (LOH). The prognostic significance of HLA-I status was measured. To explain the potential mechanism of prognostic value in HLA-Ⅰ status, the mutational signature, copy number alteration, neoantigen and intratumoral heterogeneity were measured. Furthermore, the correlation between HLA-Ⅰ functional status and the tumor immune microenvironment was analyzed. RESULTS: LOH and homogeneity in HLA-I accounted for 18% and 21% of TNBCs, respectively. HLA-I LOH instead of HLA-I homogeneity was an independent prognostic biomarker in TNBCs. In particular, for patients with non-immune-inflamed tumors, HLA-I LOH indicated a worse prognosis than HLA-I non-LOH. Furthermore, integrated genomic and transcriptomic analysis showed that HLA-I LOH was accompanied by upregulated scores of mutational signature 3 and homologous recombination deficiency scores, which implied the failure of DNA double-strand break repair. Moreover, HLA-I LOH had higher mutation and neoantigen loads and more subclones than HLA-I non-LOH. These results indicated that although HLA-I LOH tumors with failure of DNA double-strand break repair were prone to produce neoantigens, their limited capacity for antigen presentation finally contributed to poor immune selection pressure. CONCLUSION: Our study illustrates the genomic landscape of HLA-I functional status and stresses the prognostic significance of HLA-I LOH in TNBCs. For "cold" tumors in TNBCs, HLA-I LOH indicated a worse prognosis than HLA-I non-LOH.

3.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 43(4): 590-594, 2021 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-34494531

RESUMO

Objective To investigate the oral health status and awareness of urban children in Lhasa,aiming to provide a data basis for the prevention and treatment of children's caries and the promotion of oral health education. Methods A total of 504 Tibetan students were selected by cluster sampling from 2 primary schools in Chengguan District of Lhasa.All the participants were required to take oral health examination and complete a questionnaire about oral health awareness and behavior. Results The caries prevalence rate and mean decayed-missing-filled tooth(DMFT)of permanent teeth were 75.00% and 2.18±1.91,respectively.The rates of pit and fissure sealant and filling of permanent teeth were 3.77% and 6.81%,respectively.The caries prevalence rate of first permanent molars was 47.62%.The mean DMFT of permanent teeth and caries prevalence rate of first permanent molar were significantly higher in female group(P=0.001 and P=0.007,respectively).The prevalence rate of dental fluorosis was 61.51%,and the detection rate of dental calculus was 71.83%.Multivariate logistic regression analysis showed that prevalence of caries was influenced by many independent factors including gender,oral health awareness,intention of dental intervention,and dental experience. Conclusion High caries prevalence rate,low filling rate,and poor oral hygiene and health awareness were found among the primary school students in Lhasa,which require continuous dentistry investment and oral health education for the local students and their parents.


Assuntos
Cárie Dentária , Saúde Bucal , Criança , Índice CPO , Cárie Dentária/epidemiologia , Feminino , Humanos , Higiene Bucal , Prevalência , Instituições Acadêmicas , Estudantes , Inquéritos e Questionários
5.
Cancer Res ; 2021 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-34408002

RESUMO

Genomic alterations are crucial for the development and progression of human cancers. Copy number gains found in genes encoding metabolic enzymes may induce triple-negative breast cancer (TNBC) adaptation. However, little is known about how metabolic enzymes regulate TNBC metastasis. Using our previously constructed multiomic profiling of a TNBC cohort, we identified decaprenyl diphosphate synthase subunit 1 (PDSS1) as an essential gene for TNBC metastasis. PDSS1 expression was significantly upregulated in TNBC tissues compared to adjacent normal tissues and was positively associated with poor survival among TNBC patients. PDSS1 knockdown inhibited TNBC cell migration, invasion, and distant metastasis. Mechanistically, PDSS1, but not a catalytically inactive mutant, positively regulated the cellular level of coenzyme Q10 (CoQ10) and intracellular calcium levels, thereby inducing CAMK2A phosphorylation, which is essential for STAT3 phosphorylation in the cytoplasm. Phosphorylated STAT3 entered the nucleus, promoting oncogenic STAT3 signaling and TNBC metastasis. STAT3 phosphorylation inhibitors (e.g., Stattic) effectively blocked PDSS1-induced cell migration and invasion in vitro and tumor metastasis in vivo. Taken together, our study highlights the importance of targeting the previously uncharacterized PDSS1/CAMK2A/STAT3 oncogenic signaling axis, expanding the repertoire of precision medicine in TNBC.

6.
Photodiagnosis Photodyn Ther ; 36: 102487, 2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34411738

RESUMO

INTRODUCTION: Delineating the margins of Oral squamous cell carcinoma (OSCC) is a critical step for optimaltumor resection. The aim of this study was to evaluate the accuracy of lesion surgical margin identification using autofluorescence visualization. MATERIALS AND METHODS: Thirty patients with OSCC were included in this study. For each lesion, the fluorescence loss boundary was determined using VELscope before ablative surgical resection (with a 1.5-2cm safety margin) was performed. A total of 126 samples were obtained from 30 surgical specimens, each containing the tissue from the fluorescence loss boundary to surgical margin. The status of each sample was determined by oral pathologists and the staining intensities of Ki-67, E-cadherin, and Vimentin at the fluorescence loss boundary and surgical margin were evaluated by immunohistochemistry. RESULTS: Fluorescence loss regions were identified in all patients. Of the 126 samples collected, HE staining identified 77 normal epithelia (61.1%), 26 mild dysplasia (20.6%), 17 severe dysplasia (13.4%) and 6 carcinomas in situ (4.9%). A significant correlation was found between the differentiation grade of tumor cells and the pathological status of the surgical marginal specimens (P<0.05). Forty-two of the 126 samples were randomly selected for further immunohistochemical staining. No significant differences were seen in Ki-67, E-cadherin, or Vimentin expression at the fluorescence loss boundary or surgical margin, however, the proteins' expression level was positively correlated with the degree of dysplasia (P<0.01). CONCLUSION: Autofluorescence visualization has potential as a simple surgical margin setting device for OSCC and may help delineate the superficial area of OSCC with acceptable accuracy. However, when considering the inherent limitations of this system, we suggest that the approach should only be applied under certain conditions, such as when dealing with superficial, well-differentiated lesions.

7.
mBio ; 12(4): e0223121, 2021 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-34425699

RESUMO

Diaphorobacter sp. strain JS3051 utilizes 2,3-dichloronitrobenzene (23DCNB), a toxic anthropogenic compound, as the sole carbon, nitrogen, and energy source for growth, but the metabolic pathway and its origins are unknown. Here, we establish that a gene cluster (dcb), encoding a Nag-like dioxygenase, is responsible for the initial oxidation of the 23DCNB molecule. The 2,3-dichloronitrobenzene dioxygenase system (DcbAaAbAcAd) catalyzes conversion of 23DCNB to 3,4-dichlorocatechol (34DCC). Site-directed mutagenesis studies indicated that residue 204 of DcbAc is crucial for the substrate specificity of 23DCNB dioxygenase. The presence of glutamic acid at position 204 of 23DCNB dioxygenase is unique among Nag-like dioxygenases. Genetic, biochemical, and structural evidence indicate that the 23DCNB dioxygenase is more closely related to 2-nitrotoluene dioxygenase from Acidovorax sp. strain JS42 than to the 34DCNB dioxygenase from Diaphorobacter sp. strain JS3050, which was isolated from the same site as strain JS3051. A gene cluster (dcc) encoding the enzymes for 34DCC catabolism, homologous to a clc operon in Pseudomonas knackmussii strain B13, is also on the chromosome at a distance of 2.5 Mb from the dcb genes. Heterologously expressed DccA catalyzed ring cleavage of 34DCC with high affinity and catalytic efficiency. This work not only establishes the molecular mechanism for 23DCNB mineralization, but also enhances the understanding of the recent evolution of the catabolic pathways for nitroarenes. IMPORTANCE Because anthropogenic nitroaromatic compounds have entered the biosphere relatively recently, exploration of the recently evolved catabolic pathways can provide clues for adaptive evolutionary mechanisms in bacteria. The concept that nitroarene dioxygenases shared a common ancestor with naphthalene dioxygenase is well established. But their phylogeny and how they evolved in response to novel nitroaromatic compounds are largely unknown. Elucidation of the molecular basis for 23DCNB degradation revealed that the catabolic pathways of two DCNB isomers in different isolates from the same site were derived from different recent origins. Integrating structural models of catalytic subunits and enzymatic activities data provided new insight about how recently modified enzymes were selected depending on the structure of new substrates. This study enhances understanding and prediction of adaptive evolution of catabolic pathways in bacteria in response to new chemicals.

8.
Signal Transduct Target Ther ; 6(1): 312, 2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34417437

RESUMO

Immunotherapies play critical roles in cancer treatment. However, given that only a few patients respond to immune checkpoint blockades and other immunotherapeutic strategies, more novel technologies are needed to decipher the complicated interplay between tumor cells and the components of the tumor immune microenvironment (TIME). Tumor immunomics refers to the integrated study of the TIME using immunogenomics, immunoproteomics, immune-bioinformatics, and other multi-omics data reflecting the immune states of tumors, which has relied on the rapid development of next-generation sequencing. High-throughput genomic and transcriptomic data may be utilized for calculating the abundance of immune cells and predicting tumor antigens, referring to immunogenomics. However, as bulk sequencing represents the average characteristics of a heterogeneous cell population, it fails to distinguish distinct cell subtypes. Single-cell-based technologies enable better dissection of the TIME through precise immune cell subpopulation and spatial architecture investigations. In addition, radiomics and digital pathology-based deep learning models largely contribute to research on cancer immunity. These artificial intelligence technologies have performed well in predicting response to immunotherapy, with profound significance in cancer therapy. In this review, we briefly summarize conventional and state-of-the-art technologies in the field of immunogenomics, single-cell and artificial intelligence, and present prospects for future research.

9.
Andrologia ; 53(9): e14122, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34319588

RESUMO

Radical prostatectomy, radiotherapy and active surveillance are three widely used treatment options for patients with low-risk prostate cancer, but the relative effects are controversial. We searched PubMed, Embase and Web of Science until June 2020, focusing on the studies comparing the effect of radical prostatectomy, radiotherapy and active surveillance in patients with low-risk prostate cancer. Through the random-effects model, dichotomous data were extracted and summarised by odds ratio with a 95% confidence interval. Twenty-two studies containing 185,363 participants were pooled for the comprehensive comparison. The Bayesian mixed network estimate demonstrated the cancer-specific mortality of radical prostatectomy was significantly lower than active surveillance (OR, 0.46; 95% CI 0.34-0.64) and external beam radiation therapy (OR, 0.66; 95% CI 0.46-0.96), but not brachytherapy (OR, 0.63; 95% CI 0.41-1.03). The brachytherapy demonstrated the best treatment ranking probability results in terms of all-cause mortality, while no significant difference was observed when compared with other three treatment modalities. Brachytherapy and radical prostatectomy were associated with a similar risk of cancer-specific mortality, and both of them were significantly superior to active surveillance and external beam radiation therapy; nevertheless, there was no significant difference among the aforementioned treatment methods in all-cause mortality.


Assuntos
Braquiterapia , Neoplasias da Próstata , Teorema de Bayes , Humanos , Masculino , Metanálise em Rede , Prostatectomia , Neoplasias da Próstata/radioterapia , Neoplasias da Próstata/cirurgia
10.
J Immunother Cancer ; 9(7)2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34321275

RESUMO

BACKGROUND: Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer and lacks definite treatment targets. Tumor immune microenvironment (TIME) heterogeneity has a profound impact on the immunotherapy response. Tumors with non-inflamed TIME derive limited benefit from immunotherapy. However, what drives the formation of the non-inflamed TIME in TNBC remains unclear. METHODS: Using our multiomics database of TNBC, we conducted an analysis to explore the key genomic events driving the formation of the non-inflamed TIME in TNBC. In vitro and in vivo studies further revealed potential mechanisms and the efficacy of combination treatment with immunotherapy. RESULTS: With transcriptomic and genomic data, we systematically analyzed the TIME of TNBC and revealed that the classical basal-like subtype of TNBC consisted of two distinct microenvironment phenotypes, defined as the 'inflamed' and 'non-inflamed' subtypes. We performed further screening and demonstrated that MYC amplification and overexpression led to low immune infiltration and cytolytic activity in TIME. Mechanistically, MYC bound to DNMT1 promoter and activated DNMT1 transcription in TNBC cells, thus suppressing the Cyclic GMP-AMP synthase (cGAS)-STING pathway via an epigenetic regulatory way. In MYC-overexpressing TNBC, decitabine, an Food and Drug Administration (FDA)-approved DNA methyltransferase inhibitor, converted tumors from non-inflamed to inflamed tumors by enhancing T cell infiltration. Furthermore, the combination of decitabine with programmed cell death protein 1 (PD-1) inhibitor reversed T cell exhaustion and improved T cell function in mouse models, which elicited potent antitumor activity in MYC-overexpressing TNBC. CONCLUSIONS: Our work elucidates that the classic oncogene MYC induces immune evasion by repressing innate immunity. Furthermore, we provide a rationale for combining DNA methyltransferase inhibition with immunotherapy for the treatment of MYC-overexpressing TNBC.

11.
Curr Pharm Teach Learn ; 13(8): 945-952, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34294258

RESUMO

INTRODUCTION: In order to gain exposure to hospital practice earlier in the education of doctor of pharmacy students, a recent curricular change by the faculty of pharmacy prioritized institutional sites for year two early practice experiences (EPE2s). The goal of this study was to assess whether year two student pharmacists were adequately equipped by the faculty to apply clinical concepts when providing direct patient care in an institutional setting. METHODS: At the study institution, four students rated the relevancy of clinical concepts covered in five pharmacotherapy courses to their EPE2 practice using a relevance score tool. Students self-evaluated their ability-to-practice (AP) these concepts at the start and end of the rotation using an AP score tool. RESULTS: The students determined that all pharmacotherapy courses covered at least one clinical concept that was occasionally seen and applied to practice at the study institution, except for dermatology/ears, eyes, nose, and throat. All AP scores for relevant clinical concepts improved post-rotation except for dyslipidemia, which remained unchanged. CONCLUSIONS: The year two students who participated in the pilot study had sufficient knowledge to apply pharmacotherapy concepts when performing supervised direct patient care at the study institution.

12.
J Immunother Cancer ; 9(7)2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34281987

RESUMO

PURPOSE: Regulatory T cells (Tregs) heavily infiltrate triple-negative breast cancer (TNBC), and their accumulation is affected by the metabolic reprogramming in cancer cells. In the present study, we sought to identify cancer cell-intrinsic metabolic modulators correlating with Tregs infiltration in TNBC. EXPERIMENTAL DESIGN: Using the RNA-sequencing data from our institute (n=360) and the Molecular Taxonomy of Breast Cancer International Consortium TNBC cohort (n=320), we calculated the abundance of Tregs in each sample and evaluated the correlation between gene expression levels and Tregs infiltration. Then, in vivo and in vitro experiments were performed to verify the correlation and explore the underlying mechanism. RESULTS: We revealed that GTP cyclohydrolase 1 (GCH1) expression was positively correlated with Tregs infiltration and high GCH1 expression was associated with reduced overall survival in TNBC. In vivo and in vitro experiments showed that GCH1 increased Tregs infiltration, decreased apoptosis, and elevated the programmed cell death-1 (PD-1)-positive fraction. Metabolomics analysis indicated that GCH1 overexpression reprogrammed tryptophan metabolism, resulting in L-5-hydroxytryptophan (5-HTP) accumulation in the cytoplasm accompanied by kynurenine accumulation and tryptophan reduction in the supernatant. Subsequently, aryl hydrocarbon receptor, activated by 5-HTP, bound to the promoter of indoleamine 2,3-dioxygenase 1 (IDO1) and thus enhanced the transcription of IDO1. Furthermore, the inhibition of GCH1 by 2,4-diamino-6-hydroxypyrimidine (DAHP) decreased IDO1 expression, attenuated tumor growth, and enhanced the tumor response to PD-1 blockade immunotherapy. CONCLUSIONS: Tumor-cell-intrinsic GCH1 induced immunosuppression through metabolic reprogramming and IDO1 upregulation in TNBC. Inhibition of GCH1 by DAHP serves as a potential immunometabolic strategy in TNBC.

13.
J Hematol Oncol ; 14(1): 98, 2021 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-34172088

RESUMO

Tumors are not only aggregates of malignant cells but also well-organized complex ecosystems. The immunological components within tumors, termed the tumor immune microenvironment (TIME), have long been shown to be strongly related to tumor development, recurrence and metastasis. However, conventional studies that underestimate the potential value of the spatial architecture of the TIME are unable to completely elucidate its complexity. As innovative high-flux and high-dimensional technologies emerge, researchers can more feasibly and accurately detect and depict the spatial architecture of the TIME. These findings have improved our understanding of the complexity and role of the TIME in tumor biology. In this review, we first epitomized some representative emerging technologies in the study of the spatial architecture of the TIME and categorized the description methods used to characterize these structures. Then, we determined the functions of the spatial architecture of the TIME in tumor biology and the effects of the gradient of extracellular nonspecific chemicals (ENSCs) on the TIME. We also discussed the potential clinical value of our understanding of the spatial architectures of the TIME, as well as current limitations and future prospects in this novel field. This review will bring spatial architectures of the TIME, an emerging dimension of tumor ecosystem research, to the attention of more researchers and promote its application in tumor research and clinical practice.

14.
Org Lett ; 23(13): 5186-5191, 2021 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-34125538

RESUMO

Access to 1,3-conjugated enynes with defined stereoselectivity is highly desirable and challenging. Herein, we report a facile synthesis of stereodefined 1,3-conjugated enynes via Ni-catalyzed intermolecular cross-alkylalkynylation of alkynes with unsaturated carbonyl compounds and alkynes or alkynyl silicates. The operational simple protocol proceeds at room temperature and tolerates a wide range of functional groups, providing an attractive alternative to carbonyl-tethered trisubstituted conjugated 1,3-enynes from easily accessible starting materials.

15.
J Cell Mol Med ; 25(12): 5782-5798, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33982381

RESUMO

Sepsis is a life-threatening organ dysfunction syndrome, and liver is a susceptible target organ in sepsis, because the activation of inflammatory pathways contributes to septic liver injury. Oxidative stress has been documented to participate in septic liver injury, because it not only directly induces oxidative genotoxicity, but also exacerbates inflammatory pathways to potentiate damage of liver. Therefore, to ameliorate oxidative stress is promising for protecting liver in sepsis. Wogonin is the compound extracted from the medicinal plant Scutellaria baicalensis Geogi and was found to exert therapeutic effects in multiple inflammatory diseases via alleviation of oxidative stress. However, whether wogonin is able to mitigate septic liver injury remains unknown. Herein, we firstly proved that wogonin treatment could improve survival of mice with lipopolysaccharide (LPS)- or caecal ligation and puncture (CLP)-induced sepsis, together with restoration of reduced body temperature and respiratory rate, and suppression of several pro-inflammatory cytokines in circulation. Then, we found that wogonin effectively alleviated liver injury via potentiation of the anti-oxidative capacity. To be specific, wogonin activated Nrf2 thereby promoting expressions of anti-oxidative enzymes including NQO-1, GST, HO-1, SOD1 and SOD2 in hepatocytes. Moreover, wogonin-induced Nrf2 activation could suppress NF-κB-regulated up-regulation of pro-inflammatory cytokines. Ultimately, we provided in vivo evidence that wogonin activated Nrf2 signalling, potentiated anti-oxidative enzymes and inhibited NF-κB-regulated pro-inflammatory signalling. Taken together, this study demonstrates that wogonin can be the potential therapeutic agent for alleviating liver injury in sepsis by simultaneously ameliorating oxidative stress and inflammatory response through the activation of Nrf2.


Assuntos
Modelos Animais de Doenças , Flavanonas/farmacologia , Falência Hepática Aguda/tratamento farmacológico , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo , Sepse/complicações , Animais , Lipopolissacarídeos/toxicidade , Falência Hepática Aguda/etiologia , Falência Hepática Aguda/metabolismo , Falência Hepática Aguda/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2/genética , NF-kappa B/genética , Transdução de Sinais
16.
Eur Radiol ; 31(11): 8160-8167, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33956178

RESUMO

OBJECTIVE: To compare the performance of a deep learning (DL)-based method for diagnosing pulmonary nodules compared with radiologists' diagnostic approach in computed tomography (CT) of the chest. MATERIALS AND METHODS: A total of 150 pathologically confirmed pulmonary nodules (60% malignant) assessed and reported by radiologists were included. CT images were processed by the proposed DL-based method to generate the probability of malignancy (0-100%), and the nodules were divided into the groups of benign (0-39.9%), indeterminate (40.0-59.9%), and malignant (60.0-100%). Taking the pathological results as the gold standard, we compared the diagnostic performance of the proposed DL-based method with the radiologists' diagnostic approach using the McNemar-Bowker test. RESULTS: There was a statistically significant difference between the diagnosis results of the proposed DL-based method and the radiologists' diagnostic approach (p < 0.001). Moreover, there was no statistically significant difference in the composition of the diagnosis results between the proposed DL-based method and the radiologists' diagnostic approach (all p > 0.05). The difference in diagnostic accuracy between the proposed DL-based method (70%) and radiologists' diagnostic performance (64%) was not statistically significant (p = 0.243). CONCLUSIONS: The proposed DL-based method achieved an accuracy comparable with the radiologists' diagnostic approach in clinical practice. Furthermore, its advantage in improving diagnostic certainty may raise the radiologists' confidence in diagnosing pulmonary nodules and may help clinical management. Therefore, the proposed DL-based method showed great potential in a certain clinical application. KEY POINTS: • Deep learning-based method for diagnosing the pulmonary nodules in computed tomography provides a higher diagnostic certainty.

17.
BMC Cancer ; 21(1): 568, 2021 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-34006255

RESUMO

BACKGROUND: Triple-negative breast cancer (TNBC) is a heterogeneous disease and we have previously shown that rapid relapse of TNBC is associated with distinct sociodemographic features. We hypothesized that rapid versus late relapse in TNBC is also defined by distinct clinical and genomic features of primary tumors. METHODS: Using three publicly-available datasets, we identified 453 patients diagnosed with primary TNBC with adequate follow-up to be characterized as 'rapid relapse' (rrTNBC; distant relapse or death ≤2 years of diagnosis), 'late relapse' (lrTNBC; > 2 years) or 'no relapse' (nrTNBC: > 5 years no relapse/death). We explored basic clinical and primary tumor multi-omic data, including whole transcriptome (n = 453), and whole genome copy number and mutation data for 171 cancer-related genes (n = 317). Association of rapid relapse with clinical and genomic features were assessed using Pearson chi-squared tests, t-tests, ANOVA, and Fisher exact tests. We evaluated logistic regression models of clinical features with subtype versus two models that integrated significant genomic features. RESULTS: Relative to nrTNBC, both rrTNBC and lrTNBC had significantly lower immune signatures and immune signatures were highly correlated to anti-tumor CD8 T-cell, M1 macrophage, and gamma-delta T-cell CIBERSORT inferred immune subsets. Intriguingly, lrTNBCs were enriched for luminal signatures. There was no difference in tumor mutation burden or percent genome altered across groups. Logistic regression mModels that incorporate genomic features significantly outperformed standard clinical/subtype models in training (n = 63 patients), testing (n = 63) and independent validation (n = 34) cohorts, although performance of all models were overall modest. CONCLUSIONS: We identify clinical and genomic features associated with rapid relapse TNBC for further study of this aggressive TNBC subset.


Assuntos
Biomarcadores Tumorais/genética , Mastectomia , Terapia Neoadjuvante/estatística & dados numéricos , Recidiva Local de Neoplasia/genética , Neoplasias de Mama Triplo Negativas/terapia , Adulto , Quimioterapia Adjuvante/estatística & dados numéricos , Variações do Número de Cópias de DNA , Conjuntos de Dados como Assunto , Intervalo Livre de Doença , Feminino , Seguimentos , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Modelos Logísticos , Pessoa de Meia-Idade , Modelos Genéticos , Mutação , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/prevenção & controle , Prognóstico , Medição de Risco/métodos , Medição de Risco/estatística & dados numéricos , Fatores de Tempo , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/mortalidade
18.
Stem Cell Res Ther ; 12(1): 254, 2021 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-33926537

RESUMO

BACKGROUND: Stem cells that have undergone long-term ex vivo expansion are most likely functionally compromised (namely cellular senescence) in terms of their stem cell properties and therapeutic potential. Due to its ability to attenuate cellular senescence, melatonin (MLT) has been proposed as an adjuvant in long-term cell expansion protocols, but the mechanism underlying MLT-induced cell rejuvenation remains largely unknown. METHODS: Human periodontal ligament stem cells (PDLSCs) were isolated and cultured ex vivo for up to 15 passages, and cells from passages 2, 7, and 15 (P2, P7, and P15) were used to investigate cellular senescence and autophagy change in response to long-term expansion and indeed the following MLT treatment. Next, we examined whether MLT could induce cell rejuvenation by restoring the autophagic processes of damaged cells and explored the underlying signaling pathways. In this context, cellular senescence was indicated by senescence-associated ß-galactosidase (SA-ß-gal) activity and by the expression of senescence-related proteins, including p53, p21, p16, and γ-H2AX. In parallel, cell autophagic processes were evaluated by examining autophagic vesicles (by transmission electronic microscopy), autophagic flux (by assessing mRFP-GFP-LC3-transfected cells), and autophagy-associated proteins (by Western blot assay of Atg7, Beclin-1, LC3-II, and p62). RESULTS: We found that long-term in vitro passaging led to cell senescence along with impaired autophagy. As expected, MLT supplementation not only restored cells to a younger state but also restored autophagy in senescent cells. Additionally, we demonstrated that autophagy inhibitors could block MLT-induced cell rejuvenation. When the underlying signaling pathways involved were investigated, we found that the MLT receptor (MT) mediated MLT-related autophagy restoration by regulating the PI3K/AKT/mTOR signaling pathway. CONCLUSIONS: The present study suggests that MLT may attenuate long-term expansion-caused cellular senescence by restoring autophagy, most likely via the PI3K/AKT/mTOR signaling pathway in an MT-dependent manner. This is the first report identifying the involvement of MT-dependent PI3K/AKT/mTOR signaling in MLT-induced autophagy alteration, indicating a potential of autophagy-restoring agents such as MLT to be used in the development of optimized clinical-scale cell production protocols.


Assuntos
Melatonina , Autofagia , Senescência Celular , Humanos , Melatonina/farmacologia , Ligamento Periodontal , Fosfatidilinositol 3-Quinases/genética , Rejuvenescimento , Células-Tronco
19.
Cell Signal ; 82: 109968, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33675939

RESUMO

While atypical expression of special AT-rich sequence-binding protein 2 (SATB2) has been approved associated with tumor progression, metastasis and unfavourable prognosis in various carcinomas. However, in oral squamous cell carcinoma (OSCC), both the expressive state and associated functions of SATB2's are still undefined. Here we show that, in clinical samples from a retrospective cohort of 58 OSCC patients, high expression of SATB2 is associated with poor prognosis of OSCC patients. In this study, we investigated SATB2 is highly expressed in OSCC tissues and cell lines, which can promote OSCC cells' proliferation, migration, invasion and tumor growth. According to sequencing results based on previous literature, we identified NOX4 is a bona fide downstream target of SATB2, when it was knockdown, OSCC's proliferation can be partially suppressed. Furthermore, NOX4 knockdown inhibits tumorigenicity, which can be rescued partially by ectopic expression of SATB2 in HNSCC cell line, and vice versa. Collectively, our findings not only indicate overexpression of SATB2 triggers the proliferative, migratory and invasive mechanisms which are important in the malignant phenotype of OSCC, but also identify NOX4 as the downstream gene for SATB2. These findings indicate that SATB2 may play a key role in OSCC tumorigenicity and may be a future target for the development of new therapeutic regimens.

20.
Mol Ther ; 29(7): 2350-2365, 2021 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-33677091

RESUMO

An emerging view regarding cancer metabolism is that it is heterogeneous and context-specific, but it remains to be elucidated in breast cancers. In this study, we characterized the energy-related metabolic features of breast cancers through integrative analyses of multiple datasets with genomics, transcriptomics, metabolomics, and single-cell transcriptome profiling. Energy-related metabolic signatures were used to stratify breast tumors into two prognostic clusters: cluster 1 exhibits high glycolytic activity and decreased survival rate, and the signatures of cluster 2 are enriched in fatty acid oxidation and glutaminolysis. The intertumoral metabolic heterogeneity was reflected by the clustering among three independent large cohorts, and the complexity was further verified at the metabolite level. In addition, we found that the metabolic status of malignant cells rather than that of nonmalignant cells is the major contributor at the single-cell resolution, and its interactions with factors derived from the tumor microenvironment are unanticipated. Notably, among various immune cells and their clusters with distinguishable metabolic features, those with immunosuppressive function presented higher metabolic activities. Collectively, we uncovered the heterogeneity in energy metabolism using a classifier with prognostic and therapeutic value. Single-cell transcriptome profiling provided novel metabolic insights that could ultimately tailor therapeutic strategies based on patient- or cell type-specific cancer metabolism.

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