RESUMEN
PURPOSES: This study aimed to evaluate the diagnostic capacity of apparent diffusion coefficient (ADC) in predicting pathological Masaoka and T stages in patients with thymic epithelial tumors (TETs). METHODS: Medical records of 62 patients who were diagnosed with TET and underwent diffusion-weighted imaging (DWI) prior to surgery between August 2017 and July 2021 were retrospectively analyzed. ADC values were calculated from DWI images using b values of 0, 400, and 800 s/mm2. Pathological stages were determined by histological examination of surgical specimens. Cut-off points of ADC values were calculated via receiver operating characteristic (ROC) analysis. RESULTS: Patients had a mean age of 56.3 years. Mean ADC values were negatively correlated with pathological Masaoka and T stages. Higher values of the area under the ROC curve suggested that mean ADC values more accurately predicated pathological T stages than pathological Masaoka stages. The optimal cut-off points of mean ADC were 1.62, 1.31, and 1.48 × 10-3 mm2/sec for distinguishing pathological T2-T4 from pathological T1, pathological T4 from pathological T1-T3, and pathological T3-T4 from pathological T2, respectively. CONCLUSION: ADC seems to more precisely predict pathological T stages, compared to pathological Masaoka stage. The cut-off values of ADC identified may be used to preoperatively predict pathological T stages of TETs.
Asunto(s)
Neoplasias Glandulares y Epiteliales , Neoplasias del Timo , Imagen de Difusión por Resonancia Magnética/métodos , Humanos , Persona de Mediana Edad , Neoplasias Glandulares y Epiteliales/diagnóstico por imagen , Curva ROC , Estudios Retrospectivos , Neoplasias del Timo/diagnóstico por imagen , Neoplasias del Timo/patologíaRESUMEN
BACKGROUND: Oct4, a key stemness transcription factor, is overexpressed in lung cancer. Here, we reveal a novel transcription regulation of long non-coding RNAs (lncRNAs) by Oct4. LncRNAs have emerged as important players in cancer progression. METHODS: Oct4 chromatin-immunoprecipitation (ChIP)-sequencing and several lncRNA databases with literature annotation were integrated to identify Oct4-regulated lncRNAs. Luciferase activity, qRT-PCR and ChIP-PCR assays were conducted to examine transcription regulation of lncRNAs by Oct4. Reconstitution experiments of Oct4 and downstream lncRNAs in cell proliferation, migration and invasion assays were performed to confirm the Oct4-lncRNAs signaling axes in promoting lung cancer cell growth and motility. The expression correlations between Oct4 and lncRNAs were investigated in 124 lung cancer patients using qRT-PCR analysis. The clinical significance of Oct4/lncRNAs signaling axes were further evaluated using multivariate Cox regression and Kaplan-Meier analyses. RESULTS: We confirmed that seven lncRNAs were upregulated by direct binding of Oct4. Among them, nuclear paraspeckle assembly transcript 1 (NEAT1), metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) and urothelial carcinoma-associated 1 (UCA1) were validated as Oct4 transcriptional targets through promoter or enhancer activation. We showed that lung cancer cells overexpressing NEAT1 or MALAT1 and the Oct4-silenced cells reconstituted with NEAT1 or MALAT1 promoted cell proliferation, migration and invasion. In addition, knockdown of NEAT1 or MALAT1 abolished Oct4-mediated lung cancer cell growth and motility. These cell-based results suggested that Oct4/NEAT1 or Oct4/MALAT1 axis promoted oncogenesis. Clinically, Oct4/NEAT1/MALAT1 co-overexpression was an independent factor for prediction of poor outcome in 124 lung cancer patients. CONCLUSIONS: Our study reveals a novel mechanism by which Oct4 transcriptionally activates NEAT1 via promoter and MALAT1 via enhancer binding to promote cell proliferation and motility, and led to lung tumorigenesis and poor prognosis.
Asunto(s)
Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Factor 3 de Transcripción de Unión a Octámeros/genética , ARN Largo no Codificante/genética , Anciano , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Inmunoprecipitación de Cromatina , Elementos de Facilitación Genéticos , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Factor 3 de Transcripción de Unión a Octámeros/metabolismo , Pronóstico , Regiones Promotoras Genéticas , ARN Largo no Codificante/metabolismo , Transcripción GenéticaRESUMEN
Development of new inhibitors targeting histone deacetylases (HDACs) with improved efficacy for solid tumor therapy is urgently needed. Here, we report the development of a novel HDAC inhibitor TMU-35435 and verify it as a single agent and in combination treatment with DNA demethylation reagent 5-aza-2'-deoxycytidine (5-aza-dC) in lung cancer preclinical models. TMU-35435 exerted cancer-specific cytotoxicity via mitochondria-mediated apoptosis. Expression microarrays revealed a unique TMU-35435-induced gene networks enriched in biological processes, including "negative regulation of cell proliferation" and "Wnt receptor signaling pathway" compared to FDA-approved HDAC inhibitor SAHA. TMU-35435 inhibited tumor growth with good pharmacokinetic properties and safety features in lung orthotopic and subcutaneously implanted xenograft models. TMU-35435 and 5-aza-dC showed synergistic antitumor effects through reactivation of tumor suppressor genes and those genes encoding negative regulators of Wnt signaling pathway in vitro and in vivo. Some genes showed additive inhibition of DNA methylation upon TMU-35435 and 5-aza-dC combined treatment. Our findings suggested that TMU-35435 is a potential HDAC inhibitor for lung cancer treatment as a single agent and in combination with 5-aza-dC.
Asunto(s)
Amidas/química , Biomarcadores de Tumor/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Metilación de ADN/efectos de los fármacos , Inhibidores de Histona Desacetilasas/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Vía de Señalización Wnt/efectos de los fármacos , Acetilación , Animales , Apoptosis/efectos de los fármacos , Azacitidina/análogos & derivados , Azacitidina/farmacología , Western Blotting , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Decitabina , Sinergismo Farmacológico , Quimioterapia Combinada , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Histonas/metabolismo , Humanos , Técnicas para Inmunoenzimas , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: The risks attributed to drug-herb interactions, even when known, are often ignored or underestimated, especially for those involving anti-clotting drugs and Chinese medicines. The aim of this study was to structurally search and evaluate the existing evidence-based data associated with potential drug interactions between anticoagulant/antiplatelet drugs and Chinese herbal medicines (CHMs) and evaluate the documented mechanisms, consequences, and/or severity of interactions. METHODOLOGY AND FINDINGS: Information related to anticoagulant/antiplatelet drug-CHM interactions was retrieved from eight interaction-based textbooks, four web resources and available primary biomedical literature. The primary literature searches were conducted in English and/or Chinese from January 2000 through December 2011 using the secondary databases (e.g., PubMed, Airiti Library, China Journal full-text database). The search terms included the corresponding medical subject headings and key words. Herbs or natural products not used as a single entity CHM or in Chinese Medicinal Prescriptions were excluded from further review. The corresponding mechanisms and severity ratings of interactions were retrieved using MicroMedex®, Lexicomp® and Natural Medicines Comprehensive Database®. Finally, we found 90 single entity CHMs contributed to 306 documented drug-CHM interactions. A total of 194 (63.4%) interactions were verified for its evidence describing possible mechanisms and severity. Of them, 155 interactions (79.9%) were attributable to pharmacodynamic interactions, and almost all were rated as moderate to severe interactions. The major consequences of these interactions were increased bleeding risks due to the additive anticoagulant or antiplatelet effects of the CHMs, specifically danshen, dong quai, ginger, ginkgo, licorice, and turmeric. CONCLUSIONS/SIGNIFICANCE: Conventional anticoagulants and antiplatelet drugs were documented to have harmful interactions with some commonly used single entity CHMs. For those patients who are taking conventional anti-clotting medications with CHMs for cardiovascular or cerebrovascular diseases, the potential risks of increased bleeding due to drug-CHM interactions should not be ignored.