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BACKGROUND: Esophageal cancer is a highly aggressive malignancy with limited treatment options and poor prognosis. The identification of novel molecular subtypes and therapeutic targets is crucial for improving clinical outcomes. METHOD: In this study, we investigated the role of R-spondin 2 (RSPO2) in esophageal cancer and its association with mitochondrial metabolism. Using bioinformatics analysis of publicly available datasets, we identified a panel of RSPO2-related mitochondrial metabolism genes and their expression patterns in esophageal cancer. Based on these genes, we stratified esophageal cancer patients into distinct molecular subtypes with different survival rates, immune cell infiltration profiles, and drug sensitivities. RESULTS: Our findings suggest that RSPO2-related mitochondrial metabolism genes may serve as potential therapeutic targets and prognostic markers for esophageal cancer. These genes play an important role in the prognosis, immune cell infiltration and drug sensitivity of esophageal cancer. CONCLUSION: The identified molecular subtypes provide valuable insights into the underlying molecular mechanisms of esophageal cancer and could guide personalized treatment strategies in the future.
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BACKGROUND: The risk of ductal carcinoma in situ (DCIS) identified by biopsy often increases during surgery. Therefore, confirming the DCIS grade preoperatively is necessary for clinical decision-making. PURPOSE: To train a three-classification deep learning (DL) model based on ultrasound (US), combining clinical data, mammography (MG), US, and core needle biopsy (CNB) pathology to predict low-grade DCIS, intermediate-to-high-grade DCIS, and upstaged DCIS. MATERIALS AND METHODS: Data of 733 patients with 754 DCIS cases confirmed by biopsy were retrospectively collected from May 2013 to June 2022 (N1), and other data (N2) were confirmed by biopsy as low-grade DCIS. The lesions were randomly divided into training (n=471), validation (n=142), and test (n = 141) sets to establish the DCIS-Net. Information on the DCIS-Net, clinical (age and sign), US (size, calcifications, type, breast imaging reporting and data system [BI-RADS]), MG (microcalcifications, BI-RADS), and CNB pathology (nuclear grade, architectural features, and immunohistochemistry) were collected. Logistic regression and random forest analyses were conducted to develop Multimodal DCIS-Net to calculate the specificity, sensitivity, accuracy, receiver operating characteristic curve, and area under the curve (AUC). RESULTS: In the test set of N1, the accuracy and AUC of the multimodal DCIS-Net were 0.752-0.766 and 0.859-0.907 in the three-classification task, respectively. The accuracy and AUC for discriminating DCIS from upstaged DCIS were 0.751-0.780 and 0.829-0.861, respectively. In the test set of N2, the accuracy and AUC of discriminating low-grade DCIS from upstaged low-grade DCIS were 0.769-0.987 and 0.818-0.939, respectively. DL was ranked from one to five in the importance of features in the multimodal-DCIS-Net. CONCLUSION: By developing the DCIS-Net and integrating it with multimodal information, diagnosing low-grade DCIS, intermediate-to high-grade DCIS, and upstaged DCIS is possible. It can also be used to distinguish DCIS from upstaged DCIS and low-grade DCIS from upstaged low-grade DCIS, which could pave the way for the DCIS clinical workflow.
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Neoplasias da Mama , Calcinose , Carcinoma Ductal de Mama , Carcinoma Intraductal não Infiltrante , Patologia Cirúrgica , Humanos , Feminino , Carcinoma Intraductal não Infiltrante/diagnóstico por imagem , Carcinoma Intraductal não Infiltrante/cirurgia , Estudos Retrospectivos , Mamografia , Neoplasias da Mama/diagnóstico por imagemRESUMO
BACKGROUND: Serrated polyps are considered the precursor lesions of colorectal cancer through the serrated pathway. In the present study, we aimed to evaluate and discuss the clinical and endoscopic characteristics and management of serrated polyps. METHODS: The data of 220 cases with serrated polyps between September 2018 and November 2021 in Shenzhen People's Hospital were retrospectively analyzed. RESULTS: Of all these cases, 32 were hyperplastic polyps, 36 were traditional serrated adenomas, 126 were sessile serrated lesions, 25 were SSLs with dysplasia, and one was an unclassified serrated adenoma. Although most patients were males aged ≥50 years and most serrated polyps were located in the distal colon and rectum with a size of 6-10 mm and the shape of type 0-Is, there was no significant difference (P > 0.05). Serrated polyps of ≤5 mm in size and type 0-IIa were mostly removed by cold biopsy forceps. Cold snare polypectomy was primarily used for those of 6-10 mm in size. Endoscopic mucosal resection was used for those of 6-20 mm, and endoscopic submucosal dissection was used for those of ≥20 mm (P < 0.05). All complications occurred in SSL patients with or without dysplasia (P < 0.05). CONCLUSIONS: Clinical and endoscopic characteristics were beneficial for distinguishing and diagnosing serrated polyps. In addition, management options were crucial to prevent recurrence and progression. However, the detection rate of serrated polyps was relatively low. Therefore, prospective multicenter studies with large samples are necessary to better assess colorectal serrated polyps.
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Adenoma , Pólipos do Colo , Neoplasias Colorretais , Masculino , Humanos , Feminino , Pólipos do Colo/diagnóstico , Pólipos do Colo/cirurgia , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/cirurgia , Neoplasias Colorretais/patologia , Colonoscopia , Estudos Prospectivos , Estudos Retrospectivos , Adenoma/diagnóstico , Adenoma/cirurgia , Adenoma/patologia , HiperplasiaRESUMO
A 57-year-old female was found a 12 mm × 10 mm submucosal lesion in the rectum with a smooth mucosa and telangiectasia The lesion was considered as a neuroendocrine tumor, and removed by endoscopic submucosal dissection (ESD) It was finally diagnosed with mucosa-associated lymphoid tissue (MALT) lymphoma with negative margin by pathological examination and histopathological test. MALT lymphoma in the rectum is rare and difficult to diagnose without histopathological test. In this case, the characteristic of this case is telangiectasia on the surface of lesion. Therefore, our findings suggested small lesion in rectum but big in impact.
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Cuproptosis is a recently described copper-dependent cell death pathway. Consequently, there are still few studies on lung adenocarcinoma (LUAD)-related cuproptosis, and we aimed to deepen in this matter. In this study, data from 503 patients with lung cancer from the TCGA-LUAD cohort data collection and 11 LUAD single-cells from GSE131907 as well as from 10 genes associated with cuproptosis were analyzed. The AUCell R package was used to determine the copper-dependent cell death pathway activity for each cell subpopulation, calculate the CellChat score, and display cell communication for each cell subpopulation. The PROGENy score was calculated to show the scores of tumor-related pathways in different cell populations. GO and KEGG analyses were used to calculate pathway activity. Univariate COX and random forest analyses were used to screen prognosis-associated genes and construct models. The ssGSEA and xCell algorithms were used to calculate the immunocyte infiltration score. Based on data from the GDSC database, the drug sensitivity score was calculated using oncoPredict. Finally, in vitro experiments were performed to determine the role of TLE1, the most important gene in the prognostic model. The 11 LUAD single-cell samples were classified into 8 different cell populations, from which epithelial cells showed the highest copper-dependent cell death pathway activity. Epithelial cell subsets were significantly positively correlated with MAKP, hypoxia, and other pathways. In addition, cell subgroup communication showed highly active collagen and APP pathways. Using the Findmark algorithm, differentially expressed genes (DEGs) between epithelial and other cell types were identified. Combined with the bulk data in the TCGA-LUAD database, DEGs were enriched in pathways such as EGFR tyrosine kinase inhibitor resistance, Hippo signaling pathway, and tight junction. Subsequently, we selected 4 genes (out of 112) with prognostic significance, ANKRD29, RHOV, TLE1, and NPAS2, and used them to construct a prognostic model. The high- and low-risk groups, distinguished by the median risk score, showed significantly different prognoses. Finally, we chose TLE1 as a biomarker based on the relative importance score in the prognostic model. In vitro experiments showed that TLE1 promotes tumor proliferation and migration and inhibits apoptosis.
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Lymph node metastasis (LNM) of colorectal cancer (CRC) is an important factor for both prognosis and treatment. Given the deficiencies of conventional tests, we aim to discover novel DNA methylation markers to efficiently identify LNM status of CRC. In this study, genome-wide methylation sequencing was performed in a cohort (n=30) using fresh CRC tissue to discover differentially methylated markers. These markers were subsequently validated with fluorescence quantitative PCR in a cohort (n=221), and the optimal marker was compared to conventional diagnostic methods. Meanwhile, immunohistochemistry was used to verify the effectiveness of the antibody corresponding to this marker in a cohort (n=56). LBX2 achieved an AUC of 0.87, specificity of 87.3%, sensitivity of 75.7%, and accuracy of 81.9%, which outperformed conventional methods including imaging (CT, PET-CT) with an AUC of 0.52, CA199 with an AUC of 0.58, CEA with an AUC of 0.56. LBX2 was also superior to clinicopathological indicators including the depth of tumor invasion and lymphatic invasion with an AUC of 0.61and 0.63 respectively. Moreover, the AUC of LBX2 antibody was 0.84, which was also better than these conventional methods. In conclusion, A novel methylation marker LBX2 could be used as a simple, cost-effective, and reliable diagnostic method for LNM of CRC.
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Primary cardiac lymphomas (PCLs) are extremely rare and affect the heart. Patients with PCLs usually have delayed diagnosis and treatment. As a consequence, their prognosis is quite unfavorable, and their median survival is approximately 7 months. Herein, we report a 64-year-old man who underwent liver transplantation, presented with chest pain and exertional dyspnea, developed a huge cardiac mass within 2 months and passed away on day 3 of hospitalization. Histological examination revealed diffuse large B-cell lymphoma (DLBCL), which is a rare cardiac tumor with a poor prognosis. In this case, DLBCL was only detected postmortem. The extension of the mass and its relationship with the heart were explored with non-invasive cardiac imaging. Despite the rarity of DLBCL, it should be considered in the differential diagnosis of cardiac tumors.
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BACKGROUND AND AIMS: Ulcerative colitis (UC) is a heterogeneous disorder with complex pathogenesis. Therefore, in the present study, we aimed to assess genome-wide DNA methylation changes associated explicitly with the pathogenesis of UC. METHODS: DNA methylation changes were identified by comparing UC tissues with healthy controls (HCs) from the GEO databases. The candidate genes were obtained and verified in clinical samples. Moreover, the underlying molecular mechanism related to Zbtb7b in the pathogenesis of UC was explored using the dextran sodium sulfate (DSS)-induced colitis model. RESULTS: Bioinformatic analysis from GEO databases confirmed that Zbtb7b, known as Th-inducing POZ-Kruppel factor (ThPOK), was demethylated in UC tissues. Then, we demonstrated that Zbtb7b was in a hypo-methylation pattern through the DSS-induced colitis model (P = 0.0357), whereas the expression of Zbtb7b at the mRNA and protein levels was significantly up-regulated in the inflamed colonic tissues of UC patients (qRT-PCR, WB, IHC: P < 0.0001, P = 0.0079, P < 0.0001) and DSS-induced colitis model (qRT-PCR, WB, IHC: P < 0.0001, P = 0.0045, P = 0.0004). Moreover, the expression of Zbtb7b was positively associated with the degree of UC activity. Mechanically, over-expression of Zbtb7b might activate the maturation of CD4+T cells (FCM, IF: P = 0.0240, P = 0.0003) and repress the differentiation of double-positive CD4+CD8+T (DP CD4+CD8+T) cells (FCM, IF: P = 0.0247, P = 0.0118), contributing to the production of inflammatory cytokines, such as TNF-α (P = 0.0005, P = 0.0005), IL-17 (P = 0.0014, P = 0.0381), and IFN-γ (P = 0.0016, P = 0.0042), in the serum and colonic tissue of DSS-induced colitis model. CONCLUSIONS: Epigenetic DNA hypo-methylation of Zbtb7b activated the maturation of CD4+T cells and repressed the differentiation of DP CD4+CD8+ T cells, resulting in the production of inflammatory cytokines and colonic inflammation in UC. Therefore, Zbtb7b might be a diagnostic and therapeutic biomarker for UC, and hypo-methylation might affect the biological function of Zbtb7b.
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Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Colite Ulcerativa , Proteínas de Ligação a DNA , Epigênese Genética , Fatores de Transcrição , Animais , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Colite/induzido quimicamente , Colite/genética , Colite Ulcerativa/genética , Colo/patologia , Citocinas/metabolismo , Metilação de DNA , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Sulfato de Dextrana/efeitos adversos , Sulfato de Dextrana/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the colonic mucosa. Environmental factors, genetics, intestinal microbiota, and the immune system are all involved in the pathophysiology of IBD. Lately, accumulating evidence has shown that abnormal epigenetic changes in DNA methylation, histone markers, and non-coding RNA expression greatly contribute to the development of the entire disease. Epigenetics regulates many functions, such as maintaining the homeostasis of the intestinal epithelium and regulating the immune system of the immune cells. In the present study, we systematically summarized the latest advances in epigenetic modification of IBD and how epigenetics reveals new mechanisms of IBD. Our present review provided new insights into the pathophysiology of IBD. Moreover, exploring the patterns of DNA methylation and histone modification through epigenetics can not only be used as biomarkers of IBD but also as a new target for therapeutic intervention in IBD patients.
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BACKGROUND: Lymph node metastasis (LNM) is an important factor for both treatment and prognosis of early gastric cancer (EGC). Current methods are insufficient to evaluate LNM in EGC due to suboptimal accuracy. Herein, we aim to identify methylation signatures for LNM of EGC, facilitate precision diagnosis, and guide treatment modalities. METHODS: For marker discovery, genome-wide methylation sequencing was performed in a cohort (marker discovery) using 47 fresh frozen (FF) tissue samples. The identified signatures were subsequently characterized for model development using formalin-fixed paraffin-embedded (FFPE) samples by qPCR assay in a second cohort (model development cohort, n = 302, training set: n = 151, test set: n = 151). The performance of the established model was further validated using FFPE samples in a third cohorts (validation cohort, n = 130) and compared with image-based diagnostics, conventional clinicopathology-based model (conventional model), and current standard workups. RESULTS: Fifty LNM-specific methylation signatures were identified de novo and technically validated. A derived 3-marker methylation model for LNM diagnosis was established that achieved an AUC of 0.87 and 0.88, corresponding to the specificity of 80.9% and 85.7%, sensitivity of 80.6% and 78.1%, and accuracy of 80.8% and 83.8% in the test set of model development cohort and validation cohort, respectively. Notably, this methylation model outperformed computed tomography (CT)-based imaging with a superior AUC (0.88 vs. 0.57, p < 0.0001) and individual clinicopathological features in the validation cohort. The model integrated with clinicopathological features demonstrated further enhanced AUCs of 0.89 in the same cohort. The 3-marker methylation model and integrated model reduced 39.4% and 41.5% overtreatment as compared to standard workups, respectively. CONCLUSIONS: A novel 3-marker methylation model was established and validated that shows diagnostic potential to identify LNM in EGC patients and thus reduce unnecessary gastrectomy in EGC.
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Metilação de DNA/genética , Detecção Precoce de Câncer/estatística & dados numéricos , Metástase Linfática/fisiopatologia , Neoplasias Gástricas/genética , Fatores de Tempo , Idoso , Metilação de DNA/fisiologia , Detecção Precoce de Câncer/métodos , Feminino , Gastrectomia/métodos , Gastrectomia/estatística & dados numéricos , Humanos , Metástase Linfática/genética , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Neoplasias Gástricas/fisiopatologiaRESUMO
Background: At present, only a small fraction of patients with cancer benefit from treatment with immune checkpoint inhibitors, the reasons for which are not fully understood. Monitoring molecular and immunologic changes during treatment with immune checkpoint inhibitors would help to identify potential biomarkers and mechanisms associated with resistance and guide subsequent treatment. Methods: The authors report on a patient previously treated for lung squamous cell carcinoma who received atezolizumab-based therapy for 24 months. Results & Conclusion: Analysis of samples before and after atezolizumab treatment suggested that genetic mutations in EGFR exon 20 insertion, phosphatase and PTEN and NOTCH1 as well as changes in tumor immune microenvironment may be associated with acquired resistance to immune checkpoint inhibitor therapy.
Lay abstract The authors aimed to figure out potential biomarkers and mechanisms associated with immune checkpoint inhibitor resistance by monitoring changes during treatment in a lung squamous cell cancer patient. Interestingly, EGFR exon 20 insertion, decreased PTEN copy number and NOTCH1 mutation as well as changes in CD8+ T cells and macrophages were observed after disease progression. Thus, the authors suggest that these changes may be associated with atezolizumab resistance.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/imunologia , Biomarcadores/sangue , Carcinoma de Células Escamosas/imunologia , Humanos , Inibidores de Checkpoint Imunológico/imunologia , Neoplasias Pulmonares/imunologia , Masculino , Resultado do TratamentoRESUMO
Synaptotagmins (SYTs), constitute a family of 17 membrane-trafficking protein, palying crucial roles in the development and progression of human cancers. However, only very few studies have investigated the expression profile and prognostic values of SYTs family members in gastric cancer (GC). Therefore, we comprehensively evaluated the expression, methylation, prognosis and immune significance of SYTs family members through bioinformatics analysis from the online databases in GC. The expressions of SYT4, SYT9, and SYT14 were up-regulated, and negatively associated with their methylation levels in GC. Both the over-expression of SYT4, SYT9 and SYT14 and their hypomethylation levels contributed to an unsatisfactory overall survival (OS) and progression-free survival (PFS) in GC. Moreover, the low expressions of several methylation cg sites (cg02795029, cg07581146, cg15149095, cg19922137, cg25371503, cg26158959, cg02269161, cg03226737, cg08185661, cg16437728, cg22723056 and cg24678137) were significantly correlated with an unfavorable OS and PFS in GC. Furthermore, the expression of SYT4, SYT9 and SYT14 played a pivotal role in immune cells infiltration in GC. Collectively, our current finding suggested that SYT4, SYT9 and SYT14 might be potent prognostic indictors and promising immunotherapeutic targets for GC patients.
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Metilação de DNA/genética , Neoplasias Gástricas , Sinaptotagminas/genética , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/mortalidade , Sinaptotagminas/química , Sinaptotagminas/metabolismo , Transcriptoma/genéticaRESUMO
BACKGROUND: Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide. Early detection of CRC can significantly reduce its mortality rate. Current method of CRC diagnosis relies on the invasive endoscopy. Non-invasive assays including fecal occult blood testing (FOBT) and fecal immunological test (FIT) are compromised by low sensitivity and specificity, especially at early stages. Thus, a non-invasive and accurate approach for CRC screening would be highly desirable. RESULTS: A new qPCR-based assay combining the simultaneous detection of the DNA methylation status of ten candidate genes was used to examine plasma samples from 56 normal controls, 6 hyperplastic polys, 9 non-advanced adenomas (NAAs), 22 advanced adenomas (AAs) and 175 CRC patients, using 10 ng of cfDNA. We further built a logistic regression model for CRC diagnosis. We tested ten candidate methylation markers including twist1, vav3-as1, fbn1, c9orf50, sfmbt2, kcnq5, fam72c, itga4, kcnj12 and znf132. All markers showed moderate diagnostic performance with AUCs ranging from 0.726 to 0.815. Moreover, a 4-marker model, comprised of two previously reported markers (c9orf50 and twist1) and two novel ones (kcnj12 and znf132), demonstrated high performance for detecting colorectal cancer in an independent validation set (N = 69) with an overall AUC of 0.911 [95% confidence interval (CI) 0.834-0.988], sensitivity of 0.800 [95% CI 0.667-0.933] and specificity of 0.971 [95% CI 0.914-1.000]. The stage-stratified sensitivity of the model was 0.455 [95% CI 0.227-0.682], 0.667 [95% CI 0.289-1.000], 0.800 [95% CI 0.449-1.000], 0.800 [95% CI 0.449-1.000] and 0.842 [95% CI 0.678-1.000] for advanced adenoma and CRC stage I-IV, respectively. CONCLUSION: kcnj12 and znf132 are two novel methylation biomarkers for CRC diagnosis. The 4-marker methylation model provides a new non-invasive choice for CRC screening and interception.
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Neoplasias Colorretais/sangue , Neoplasias Colorretais/genética , Metilação de DNA/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sensibilidade e Especificidade , Adulto JovemRESUMO
Background: Amino-terminal enhancer of split (AES) has been identified as a tumor and metastasis suppressor in some cancers including colorectal cancer (CRC), but very little is known about the regulation of AES expression. Methods: Bioinformatics analysis was used to investigate the expression patterns of AES, CK1δ and CK1ε. The co-immunoprecipitation, GST pull-down, Western Blot, real-time PCR and immunohistochemistry were performed to study the mechanism underlying the regulation of AES expression by CK1δ/ε. The biological function was assessed by in vitro colony formation, transwell, sphere formation, tumor organoids, in vivo tumor metastasis model and patient-derived colorectal tumor xenografts (PDTX) model. Results: A strong inverse relationship was observed between the expression of AES and the expression of CK1δ/ε. Mechanically, AES could interact with CK1δ/ε and SKP2 using its Q domain. SKP2 mediated the ubiquitination and degradation of AES in a CK1δ/ε-dependent manner. CK1δ/ε phosphorylated AES at Ser121 and accelerated the SKP2-mediated ubiquitination and degradation of AES. In colon cancer cells, CK1δ/ε antagonized the effect of wild-type AES but not that of its mutant (S121A) on Wnt and Notch signaling, leading to an increase in the expression of Wnt target genes and Notch target genes. By downregulating the expression of AES, CK1δ/ε enhanced anchorage-independent growth, migration, invasion and sphere formation in colon cancer cells. CK1δ/ε also promoted the growth of APCmin/+ colorectal tumor organoids and liver metastasis in colon cancer mouse models through the regulation of AES degradation. Furthermore, CK1 inhibitor SR3029 treatment suppressed tumor growth via stabilizing AES in APCmin/+ colorectal tumor organoids and patient-derived colorectal tumor xenografts (PDTX). Conclusions: Our results revealed that the CK1δ/ε-AES axis is important for CRC tumorigenesis and metastasis, and targeted inhibition of this axis may be a potential therapeutic strategy for CRC.
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Carcinogênese/genética , Caseína Quinase 1 épsilon/genética , Caseína Quinase Idelta/genética , Proteínas Correpressoras/genética , Neoplasias Colorretais/genética , Linhagem Celular , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Neoplasias Colorretais/patologia , Regulação para Baixo/genética , Regulação Neoplásica da Expressão Gênica/genética , Células HCT116 , Células HEK293 , Humanos , Organoides/patologia , Fosforilação/genética , Ubiquitinação/genética , Via de Sinalização Wnt/genéticaRESUMO
Colorectal cancer (CRC) is the second leading malignancy worldwide. Accurate screening is pivotal to early CRC detection, yet current screening modality involves invasive colonoscopy while non-invasive FIT tests have limited sensitivity. We applied a DNA methylation assay to identify biomarkers for early-stage CRC detection, risk stratification and precancerous lesion screening at tissue level. A model of biomarkers SFMBT2, ITGA4, THBD and ZNF304 showed 96.1% sensitivity and 87.0% specificity in CRC detection, with 100.0% sensitivity for advanced precancerous lesion and stage I CRC. Performances were further validated with TCGA data set, which showed a consistent AUC of 0.99 and exhibited specificity against other cancer types. KCNJ12, VAV3-AS1 and EVC were further identified for stage stratification (stage 0-I versus stage II-IV), with AUC of 0.87, 83.0% sensitivity and 71.2% specificity. Additionally, dual markers of NEUROD1 and FAM72C showed 83.2% sensitivity and 77.4% specificity in differing non-advanced precancerous lesions from inflammatory bowel diseases.
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Neoplasias Colorretais/diagnóstico , Metilação de DNA , Adolescente , Adulto , Idoso , Biomarcadores Tumorais/metabolismo , Criança , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Progressão da Doença , Feminino , Humanos , Doenças Inflamatórias Intestinais/diagnóstico , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Lesões Pré-Cancerosas/diagnóstico , Adulto JovemRESUMO
Lymphovascular invasion (LVI) and perineural invasion (PNI) are 2 important pathologic parameters and need to be accurately assessed in multiple malignancies. Integrin ß4, a member of the integrin family, has been reported to be positively expressed in vascular endothelia, peripheral nerves, and a collection of epithelia. However, little is known about the effectiveness of ß4 immunostaining on the recognition of LVI and PNI. Herein, we explored the applicability of ß4 immunostaining in stomach, thyroid, and breast cancers. Parallel immunostaining of D2-40, CD34, and S-100 was performed as controls for lymphatic endothelia, vascular endothelia, and neural fibers, respectively. The results demonstrated that ß4 concurrently stained the lymphatic and vascular endothelia, and the peripheral nerves. Both LVI and PNI were clearly and accurately outlined by ß4 immunostaining. ß4 was also expressed in the majority of tumor cells, enabling recognition of LVI and PNI encroached by small tumor clusters. In contrast to D2-40 and CD34, ß4 staining was not observed in stromal cells, and therefore it facilitated differentiation between the shrinkage cleft and LVI. According to our results, ß4 staining strikingly increased the diagnostic accuracy and interobserver concordance for LVI and PNI compared with hematoxylin and eosin staining alone. Finally, the applicability of ß4 was confirmed in 9 other types of malignancies, including cancers of the colon, prostate, esophagus, lung, kidney, uterus, tongue, bladder, and liver. Collectively, ß4 is a reliable marker for synchronous detection and diagnosis of LVI and PNI.
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Biomarcadores Tumorais/análise , Vasos Sanguíneos/química , Integrina beta4/análise , Vasos Linfáticos/química , Neoplasias/química , Nervos Periféricos/química , Vasos Sanguíneos/patologia , Feminino , Humanos , Imuno-Histoquímica , Vasos Linfáticos/patologia , Masculino , Invasividade Neoplásica , Neoplasias/patologia , Variações Dependentes do Observador , Nervos Periféricos/patologia , Valor Preditivo dos Testes , Reprodutibilidade dos TestesRESUMO
This paper aims to investigate the function of structural maintenance of chromosome 4 (SMC4) in the progression of hepatocellular carcinoma (HCC) under hypoxic condition. In this study, we found that suppression of SMC4 could inhibit proliferation and migration of HCC cells through inducing G1 phase arrest and affecting process of epithelial-mesenchymal transition (EMT) under hypoxic condition. Moreover, we demonstrated that SMC4 was transcriptionally regulated by hypoxia-inducible factor-1 (HIF-1) under hypoxic condition. As SMC has been shown to be a target gene of miR-219, we observed that miR-219 was downregulated under hypoxic condition and suppression of HIF-1a could lead to the upregulation of miR-219. We also proved that miR-219 could affect the proliferation and migration of HCC cells under hypoxic condition. In conclusion, our study demonstrated a novel HIF-1-miR-219-SMC4 regulatory pathway under hypoxic condition in HCC cells.
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Adenosina Trifosfatases/metabolismo , Carcinoma Hepatocelular/metabolismo , Movimento Celular , Proliferação de Células , Proteínas Cromossômicas não Histona/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Hepáticas/metabolismo , MicroRNAs/metabolismo , Proteínas de Neoplasias/metabolismo , RNA Neoplásico/metabolismo , Transdução de Sinais , Adenosina Trifosfatases/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Hipóxia Celular/genética , Linhagem Celular Tumoral , Proteínas Cromossômicas não Histona/genética , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , MicroRNAs/genética , Proteínas de Neoplasias/genética , RNA Neoplásico/genéticaRESUMO
PURPOSE: To develop and validate an interpretable and repeatable machine learning model approach to predict molecular subtypes of breast cancer from clinical metainformation together with mammography and MRI images. METHODS: We retrospectively assessed 363 breast cancer cases (Luminal A 151, Luminal B 96, HER2 76, and BLBC 40). Eighty-two features defined in the BI-RADS lexicon were visually described. A decision tree model with the Chi-squared automatic interaction detector (CHAID) algorithm was applied for feature selection and classification. A 10-fold cross-validation was performed to investigate the performance (i.e., accuracy, positive predictive value, sensitivity, and F1-score) of the decision tree model. RESULTS: Seven of the 82 variables were derived from the decision tree-based feature selection and used as features for the classification of molecular subtypes including mass margin calcification on mammography, mass margin types of kinetic curves in the delayed phase, mass internal enhancement characteristics, non-mass enhancement distribution on MRI, and breastfeeding history. The decision tree model accuracy was 74.1%. For each molecular subtype group, Luminal A achieved a sensitivity, positive predictive value, and F1-score of 79.47%, 75.47%, and 77.42%, respectively; Luminal B showed a sensitivity, positive predictive value, and F1-score of 64.58%, 55.86%, and 59.90%, respectively; HER2 had a sensitivity, positive predictive value, and F1-scores of 81.58%, 95.38%, and 87.94%, respectively; BLBC showed sensitivity, positive predictive value, and F1-scores of 62.50%, 89.29%, and 73.53%, respectively. CONCLUSIONS: We applied a complete "white box" machine learning method to predict the molecular subtype of breast cancer based on the BI-RADS feature description in a multi-modal setting. By combining BI-RADS features in both mammography and MRI, the prediction accuracy is boosted and robust. The proposed method can be easily applied widely regardless of variability of imaging vendors and settings because of the applicability and acceptance of the BI-RADS.
Assuntos
Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/metabolismo , Aprendizado de Máquina , Imagem Multimodal , Adulto , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Estudos RetrospectivosRESUMO
PURPOSE: The purpose of this study was to compare the diagnostic value of Young's modulus (E) and shear modulus (G) in the differential diagnosis of benign and malignant breast masses using sound touch elastography (STE) and to explore the relationship between G and E in breast lesions. METHODS: A total of 96 consecutive women with 110 pathologically confirmed breast masses were included. All masses were detected by conventional and STE ultrasound. Emean, Emax, Emin, ESD, Gmean, Gmax, Gmin, and GSD were determined and evaluated for evidence of significant differences between benign and malignant breast masses. Receiver operator characteristics were used to compare the diagnostic efficacy of E and G and to determine the G cutoff value that would aid in the differential diagnosis of breast cancer. RESULTS: Emean, Emax, ESD, Gmean, Gmax, and GSD in cases of malignant breast masses were significantly higher than those in cases of benign masses (P < 0.05). There was no significant difference between Emin and Gmin (P = 0.565). In applying the Emean, Emax, ESD, Gmean, Gmax, and GSD to the receiver operator characteristics: (1) the area under the curve (AUC) of Gmean and Gmax is greater than the AUC of Emean and Emax, and the AUC of ESD is equal to the AUC of GSD. (2) The sensitivity and specificity were highest when the Gmean was 10.14 kPa. They were 84.1% and 80.3% respectively. (3) The sensitivity and specificity were highest when the Gmax was 52.20 kPa. They were 88.6% and 87.9% respectively. CONCLUSIONS: These preliminary results of STE evaluation of breast masses suggest that the diagnostic value of G is greater than E. Furthermore, STE is a valuable tool in the differential diagnosis of breast lesions.
Assuntos
Neoplasias da Mama/diagnóstico por imagem , Técnicas de Imagem por Elasticidade/métodos , Ultrassonografia Mamária/métodos , Mama/diagnóstico por imagem , Diagnóstico Diferencial , Módulo de Elasticidade , Feminino , Humanos , Reprodutibilidade dos Testes , Estudos Retrospectivos , Sensibilidade e EspecificidadeRESUMO
To evaluate the value of ultrasonography in the diagnosis of anterior cruciate ligament injury (ACL injury) by conducting a systematic review and meta-analysis. A literature search was carried out in the Cochrane Library, Embase, Pubmed databases and included studies prior to April 2017. Based on inclusion and exclusion criteria, studies evaluating ultrasound to diagnose ACL injury were selected. MRI, arthroscopy and clinical-follow were considered the reference standards. The diagnostic accuracy of ultrasound was assessed using a combination of sensitivity, specificity, likelihood ratio (LR), post-test probability, diagnostic odds ratio (DOR) and by summarizing the area under the receiver operating characteristic (SROC) curve. A total of 4 studies involving 246 patients were eventually included in the analysis. In these four studies, the combined sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, post-test probability and DOR were 90.0% (95% CI: 77-96), 97% (95% CI: 90-99), 31.08 (95% CI: 8.75-110.41), 0.11 (95% CI: 0.05-0.24), 89% (3%) and 288.81 (95% CI: 78.51-1062.48), respectively. The area under the SROC curve was 0.98 (95% CI: 0.97-0.99). Our meta-analysis showed that ultrasound can play an important role in the diagnosis of ACL injury. Because of its high sensitivity, high specificity and high diagnostic ability, ultrasound should be a part of the standard diagnostic work-up of an ACL injury.