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Alveolar and interstitial macrophages play crucial roles in eradicating pathogens and transformed cells in the lungs. The immune checkpoint CD47, found on normal and malignant cells, interacts with the SIRPα ligand on macrophages, inhibiting phagocytosis, antigen presentation, and promoting immune evasion. In this study, we demonstrated that CD47 is not only a transmembrane protein, but that it is also highly concentrated in extracellular vesicles from lung cancer cell lines and patient plasma. Abundant CD47 was observed in the cytoplasm of lung cancer cells, aligning with our finding that it was packed into extracellular vesicles for physiological and pathological functions. In our clinical cohort, extracellular vesicle CD47 was significantly higher in the patients with early-stage lung cancer, emphasizing innate immunity inactivation in early tumor progression. To validate our hypothesis, we established an orthotopic xenograft model mimicking lung cancer development, which showed increased serum soluble CD47 and elevated IL-10/TNF-α ratio, indicating an immune-suppressive tumor microenvironment. CD47 expression led to reduced tumor-infiltrating macrophages during progression, while there was a post-xenograft increase in tumor-associated macrophages. In conclusion, CD47 is pivotal in early lung cancer progression, with soluble CD47 emerging as a key pathological effector.
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Antígeno CD47 , Progresión de la Enfermedad , Neoplasias Pulmonares , Antígeno CD47/metabolismo , Antígeno CD47/inmunología , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Humanos , Animales , Línea Celular Tumoral , Vesículas Extracelulares/inmunología , Vesículas Extracelulares/metabolismo , Ratones , Escape del Tumor , Evasión Inmune , Microambiente Tumoral/inmunología , Macrófagos/inmunología , Macrófagos/metabolismo , Femenino , Estadificación de NeoplasiasRESUMEN
AIMS: Metabolic syndrome (MetS) is associated with arrhythmias and cardiovascular mortality. Arrhythmogenesis in MetS results from atrial structural and electrical remodelling. The small-conductance Ca2+-activated K+ (SK) currents modulate atrial repolarization and may influence atrial arrhythmogenicity. This study investigated the regulation of SK current perturbed by a high-fat diet (HFD) to mimic MetS. METHODS AND RESULTS: Thirty mice were divided into two groups that were fed with normal chow (CTL) and HFD for 4 months. Electrocardiography and echocardiography were used to detect cardiac electrical and structure remodelling. Atrial action potential duration (APD) and calcium transient duration (CaTD) were measured by optical mapping of Langendorff-perfused mice hearts. Atrial fibrillation (AF) inducibility and duration were assessed by burst pacing. Whole-cell patch clamp was performed in primarily isolated atrial myocytes for SK current density. The SK current density is higher in atrial myocytes from HFD than in CTL mice (P ≤ 0.037). The RNA and protein expression of SK channels are increased in HFD mice (P ≤ 0.041 and P ≤ 0.011, respectively). Action potential duration is shortened in HFD compared with CTL (P ≤ 0.015). The shortening of the atrial APD in HFD is reversed by the application of 100â nM apamin (P ≤ 0.043). Compared with CTL, CaTD is greater in HFD atria (P ≤ 0.029). Calcium transient decay (Tau) is significantly higher in HFD than in CTL (P = 0.001). Both APD and CaTD alternans thresholds were higher in HFD (P ≤ 0.043), along with higher inducibility and longer duration of AF in HFD (P ≤ 0.023). CONCLUSION: Up-regulation of apamin-sensitive SK currents plays a partial role in the atrial arrhythmogenicity of HFD mice.
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Fibrilación Atrial , Calcio , Ratones , Animales , Calcio/metabolismo , Potasio/metabolismo , Apamina/metabolismo , Canales de Potasio de Pequeña Conductancia Activados por el Calcio/genética , Potenciales de Acción/fisiología , Miocitos Cardíacos/metabolismoRESUMEN
Chronic inflammation and cancer stem cells are known risk factors for tumorigenesis. The aetiology of hepatocellular carcinoma (HCC) involves a multistep pathological process that is characterised by chronic inflammation and hepatocyte damage, but the correlation between HCC, inflammation and cancer stem cells remains unclear. In this study, we examined the role of hepatic progenitor cells in a mouse model of chemical-induced hepatocarcinogenesis to elucidate the relationship between inflammation, malignant transformation and cancer stem cells. We used diethylnitrosamine (DEN) to induce liver tumour and scored for H&E and reticulin staining. We also scored for immunohistochemistry staining for OV-6 expression and analysed the statistical correlation between them. DEN progressively induced inflammation at week 7 (40%, 2/5); week 27 (75%, 6/8); week 33 (62.5%, 5/8); and week 50 (100%, 12/12). DEN progressively induced malignant transformation at week 7 (0%, 0/5); week 27 (87.5%, 7/8); week 33 (100%, 8/8); and week 50 (100%, 12/12). The obtained data showed that DEN progressively induced high-levels of OV-6 expression at week 7 (20%, 1/5); week 27 (37.5%, 3/8); week 33 (50%, 4/8); and week 50 (100%, 12/12). DEN-induced inflammation, malignant transformation and high-level OV-6 expression in hamster liver, as shown above, as well as applying Spearman's correlation to the data showed that the expression of OV-6 was significantly correlated to inflammation (p = 0.001) and malignant transformation (p < 0.001). There was a significant correlation between the number of cancer stem cells, inflammation and malignant transformation in a DEN-induced model of hepatic carcinogenesis in the hamster.
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In recent years, translational research and pharmacological targeting of epigenetic modifications have become the focus of personalized therapy for patients with pancreatic cancer. Preclinical and clinical trials targeting post-translational modifications have been evaluated as monotherapy or in combination with standard chemotherapy. In this study, we selected 43 genes from seven families of chromatin-modifying enzymes and investigated the influences of epigenetic modifications and their interactions on pancreatic ductal adenocarcinoma (PDAC) using hierarchical clustering analysis. Our analysis also evaluated their effects on treatment modalities and regimens of chemotherapy for PDAC. RNA-seq data for a total of 177 patients with pancreatic cancer, obtained from The Cancer Genome Atlas database, were analyzed. Our results suggested that high-risk patients of survival significant chromatin remodeling-associated gene cluster (gene cluster 2), composed of histone methyltransferases, histone acetyltransferases, histone deacetylases, histone demethylases, and 10-11 translocation family, demonstrated inferior progression-free survival and overall survival in patients with PDAC, especially in men. Our novel biomarker, survival significant chromatin remodeling-associated gene cluster, showed superior prediction performance compared with the conventional TNM system. Overall, these findings suggest that epigenetic modifications and interactions play an important role in the prognosis and therapeutic response of patients with PDAC.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/genética , Cromatina/genética , Ensamble y Desensamble de Cromatina/genética , Análisis por Conglomerados , Histona Acetiltransferasas/genética , Histona Desacetilasas/genética , Histona Desacetilasas/metabolismo , Histona Metiltransferasas/genética , Histonas/metabolismo , Humanos , Masculino , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Pronóstico , Neoplasias PancreáticasRESUMEN
Most patients with oral squamous cell cancer (OSCC) have a locally advanced stage at diagnosis. The treatment strategies are diverse, including surgery, radiotherapy and chemotherapy. Despite multimodality treatment, the response rate is unsatisfactory. DNA repair and genetic instability are highly associated with carcinogenesis and treatment outcomes in oral squamous cell cancer, affecting cell growth and proliferation. Therefore, focusing on DNA repair and genetic instability interactions could be a potential target for improving the outcomes of OSCC patients. DNA polymerase-ß (POLB) is an important enzyme in base excision repair and contributes to gene instability, leading to tumorigenesis and cancer metastasis. The aim of our study was to confirm POLB regulates the growth of OSCC cells through modulation of cell cycle and chromosomal instability. We analyzed a tissue array from 133 OSCC patients and discovered that low POLB expression was associated with advanced tumor stage and poor overall survival. In multivariate Cox proportional hazards regression analysis, low POLB expression and advanced lymph node status were significantly associated with poor survival. By performing in vitro studies on model cell lines, we demonstrated that POLB silencing regulated cell cycles, exacerbated mitotic abnormalities and enhanced cell proliferation. After POLB depletion, OSCC cells showed chromosomal instability and aneuploidy. Thus, POLB is an important maintainer of karyotypic stability in OSCC cells.
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Aneuploidia , Biomarcadores de Tumor/metabolismo , Carcinoma de Células Escamosas/mortalidad , ADN Polimerasa beta/metabolismo , Neoplasias de la Boca/mortalidad , Biomarcadores de Tumor/genética , Carcinoma de Células Escamosas/enzimología , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/secundario , Proliferación Celular , ADN Polimerasa beta/antagonistas & inhibidores , ADN Polimerasa beta/genética , Femenino , Estudios de Seguimiento , Humanos , Metástasis Linfática , Masculino , Persona de Mediana Edad , Mitosis , Neoplasias de la Boca/enzimología , Neoplasias de la Boca/genética , Neoplasias de la Boca/patología , Pronóstico , Tasa de Supervivencia , Células Tumorales CultivadasRESUMEN
Iron overload is related to leukemia transformation in myelodysplastic syndrome (MDS) patients. Siderophores help to transport iron. Type 2-hydroxybutyrate dehydrogenase (BDH2) is a rate-limiting factor in the biogenesis of siderophores. Using qRT-PCR, we analyze BDH2mRNA expression in the bone marrow (BM) of 187 MDS patients, 119 de novo acute myeloid leukemia (AML) patients, and 43 lymphoma patients with normal BM. Elevated BDH2mRNA expression in BM is observed in MDS patients (n = 187 vs. 43, normal BM; P = 0.009), and this is related to ferritin levels. Patients with higher BDH2 expression show a greater risk of leukemia progression (15.25% vs. 3.77%, lower expression; P = 0.017) and shorter leukemia-free-survival (medium LFS, 9 years vs. 7 years; P = 0.024), as do patients with a ferritin level ≥350 ng/mL. Additionally, we investigate the mechanisms related to the prognostic ability of BDH2 by using BDH2-KD THP1. The cell cycle analysis, surface markers, and special stain studies indicate that BDH2-KD induces differentiation and decreases the growth rate of THP1 cells, which is associated with the retardation of the cell cycle. Moreover, many genes, including genes related to mitochondrial catabolism, oncogenes, tumor suppressor genes, and genes related to cell differentiation and proliferation influence BDH2-KD THP1 cells. Herein, we demonstrate that BDH2 is involved in cell cycle arrest and the inhibition of differentiation in malignant cells. Furthermore, the high BDH2 expression in MDS patients could be suggestive of a poor prognostic factor. This study provides a foundation for further research on the roles of BDH2 and iron metabolism in the pathogenesis of MDS.
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Médula Ósea/patología , Regulación de la Expresión Génica/genética , Hidroxibutirato Deshidrogenasa/fisiología , Leucemia Mieloide Aguda/enzimología , Síndromes Mielodisplásicos/enzimología , Preleucemia/enzimología , Adulto , Anciano , Anciano de 80 o más Años , Apoptosis/genética , Médula Ósea/metabolismo , Puntos de Control del Ciclo Celular/genética , Diferenciación Celular/genética , Femenino , Ferritinas/sangre , Regulación Leucémica de la Expresión Génica , Humanos , Hidroxibutirato Deshidrogenasa/biosíntesis , Hidroxibutirato Deshidrogenasa/genética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Lipocalina 2/biosíntesis , Lipocalina 2/genética , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/sangre , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/patología , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/sangre , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/fisiología , Preleucemia/genética , Preleucemia/patología , Pronóstico , Supervivencia sin Progresión , Interferencia de ARN , ARN Mensajero/biosíntesis , ARN Neoplásico/biosíntesis , ARN Interferente Pequeño/genética , Células THP-1 , Adulto JovenRESUMEN
Triple-negative breast cancer (TNBC) is a subtype of cancer with aggressive behaviors (high recurrence and metastasis rate) and poor prognosis. Therefore, studying the determining factors that lead to malignant TNBCs is necessary to develop personalized therapy and improve survival rates. In this study, we first analyzed levels of chromodomain helicase DNA binding protein 4 (CHD4) in 60 TNBC patients by immunohistochemical staining. We then clarified the role of CHD4 in TNBC and non-TNBC cell lines. Our clinical data indicated that higher CHD4 expression is positively correlated with metastatic stage, tumor recurrence, and survival status. Consistent with the clinical analytical data, our in vitro data also indicated that high level of CHD4 is positively correlated with malignant behaviors in TNBC cells, such as cell motility and mortality. For further analyses, we found that E-cadherin, N-cadherin and fibronetin are involved in CHD4-mediated epithelial-mesenchymal transition (EMT). Silencing of CHD4 also increased drug sensitivity to cisplatin and PARP1 inhibitor, especially in TNBC cells. Altogether, our findings showed that CHD4 is not only a potential prognostic biomarker for TNBC patient survival, but is also a powerful candidate in the development of new anti-cancer agents in TNBC.
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Cadherinas/metabolismo , Complejo Desacetilasa y Remodelación del Nucleosoma Mi-2/metabolismo , Neoplasias de la Mama Triple Negativas/metabolismo , Antineoplásicos/farmacología , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Cisplatino/farmacología , Transición Epitelial-Mesenquimal/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Metástasis de la Neoplasia , Neoplasias de la Mama Triple Negativas/tratamiento farmacológicoRESUMEN
Anaplastic variant (av) of diffuse large B-cell lymphoma (DLBCL) is morphologically defined in the 2017 World Health Organization classification, but still an enigmatic disease in its clinicopathologic distinctiveness, posing the differential diagnostic problem from gray zone lymphoma (GZL) and classic Hodgkin lymphoma (cHL). Thirty-one cases previously diagnosed as avDLBCL were reassessed. Of these, 27 (87%) and 4 (13%) were node-based and extranodal diseases, respectively. They were further reclassified into nodal avDLBCL (n = 18), nodal CD30+ DLBCL with T-cell/histiocyte-rich large B-cell lymphoma-like features (CD30+ DLBCL-THRLBCL) (n = 6), GZL with features intermediate between DLBCL and cHL (n = 3) and CD30+ extranodal DLBCL, NOS (n = 4). The nodal avDLBCL cases had a sheet-like proliferation of large cells and/or Hodgkin/Reed-Sternberg (HRS)-like cells in 12 (67%) notably with a sinusoidal pattern in 16 (89%). They showed an expression of CD20 and/or CD79a in all and CD30 in 15 of 18. All of them were negative for PD-L1 on tumor cells, although HRS-like cells showed negativity or partial loss of other B-cell markers to varying degrees. The present study highlighted the distinctiveness of the nodal avDLBCL with sinusoidal pattern, but without neoplastic PD-L1 expression, which provide refined diagnostic criteria for a more precise pathologic and clinical characterization of this disease.
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Biomarcadores de Tumor/metabolismo , Enfermedad de Hodgkin/patología , Linfoma de Células B Grandes Difuso/patología , Anciano , Anciano de 80 o más Años , Antígenos CD20/metabolismo , Antígenos CD79/metabolismo , Capilares/metabolismo , Capilares/patología , Femenino , Enfermedad de Hodgkin/diagnóstico , Enfermedad de Hodgkin/metabolismo , Humanos , Antígeno Ki-1/metabolismo , Linfoma de Células B Grandes Difuso/diagnóstico , Linfoma de Células B Grandes Difuso/metabolismo , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Primary lymphomas of the gastrointestinal tract are rare, accounting for only 1 to 4% of malignancies arising in the stomach, small intestine, or colon. The stomach is the most common extranodal site of lymphoma and gastric mucosa-associated lymphoid tissue (MALT) lymphoma accounts for 40% of primary gastric lymphoma. Gastric MALT lymphoma reaches its peak incidence between 50 to 60 years of age, therefore, it is rarely encountered in pediatric population. The presenting symptoms of gastric MALT lymphoma are usually nonspecific and primary perforation of gastric MALT lymphoma is uncommon. CASE PRESENTATION: A 12 year-old female presented with iron deficient anemia developed gastric perforation. Emergency laparoscopic repair of the perforation was performed and tissue pathology showed gastric MALT lymphoma infiltration. Helicobacter pylori eradication and radiotherapy were sequentially performed. Complete remission was achieved at two months after radiotherapy. To our best knowledge, she is the youngest patient with gastric MALT lymphoma reported in the literature. CONCLUSION: Iron deficient anemia is a common presenting manifestation of malignancies in adulthood. In pediatric population, iron deficient anemia is usually caused by nutritional deficient or blood loss. In this case report, we present a teenaged female without previous gastric ulcer history who presented with a rare gastric tumor and an uncommon primary perforation. Even if there is an uncertainty about the exact diagnosis prior to the surgery, the strategy of stomach-preserving therapy by laparoscopy for primary perforation was successful and provided a good quality of life.
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Linfoma de Células B de la Zona Marginal/complicaciones , Perforación Espontánea/etiología , Gastropatías/etiología , Neoplasias Gástricas/complicaciones , Anemia Ferropénica/etiología , Antibacterianos/uso terapéutico , Niño , Femenino , Infecciones por Helicobacter/complicaciones , Infecciones por Helicobacter/tratamiento farmacológico , Helicobacter pylori , Humanos , Laparoscopía , Linfoma de Células B de la Zona Marginal/radioterapia , Perforación Espontánea/cirugía , Gastropatías/cirugía , Neoplasias Gástricas/radioterapiaRESUMEN
Gastrointestinal stromal tumor (GIST) is a type of KIT-driven cancer. KIT gene mutations are found in approximately 80% of GISTs, and most of these mutations occur in exon 9 and exon 11. Imatinib has been successfully used as a first-line treatment for advanced GIST, with a significant improvement in progression-free survival (PFS) and overall survival. However, disease progression might develop due to primary or secondary resistance to imatinib. Sunitinib and regorafenib have been approved as second- and third-line treatments for advanced GIST patients, with median PFS values of 6.8 and 4.8 months, respectively. However, these relatively modest improvements in PFS underscore the need for more effective KIT inhibitors. BPR1J373 is a multitargeted kinase inhibitor that has been shown to inhibit the proliferation of KIT-driven acute myeloid leukemia cells in vitro and in vivo. In this study, we found that BPR1J373 inhibited proliferation and induced apoptosis by targeting KIT in GIST cells with KIT gene mutations. BPR1J373 also induced cell cycle arrest and senescent change in KIT-mutant GIST48 cells, probably by targeting aurora kinase A. In the KIT-null COS-1 cell-based system, BPR1J373 effectively inhibited KIT with single or double mutations of KIT developed in GIST. The antiproliferative effect was also consistently evident in GIST430 tumor-grafted mice. The results suggest that BPR1J373 could be a potential anticancer drug for GIST and deserves further investigation for clinical applications.
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Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Mutación , Inhibidores de Proteínas Quinasas/administración & dosificación , Proteínas Proto-Oncogénicas c-kit/genética , Pirimidinas/administración & dosificación , Animales , Puntos de Control del Ciclo Celular , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Femenino , Tumores del Estroma Gastrointestinal/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Masculino , Ratones , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , Transducción de Señal/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Cell migration is a critical process during development, tissue repair, and cancer metastasis. It requires complex processes of cell adhesion, cytoskeletal dynamics, and force generation. Lis1 plays an important role in the migration of neurons, fibroblasts and other cell types, and is essential for normal development of the cerebral cortex. Mutations in human LIS1 gene cause classical lissencephaly (smooth brain), resulting from defects in neuronal migration. However, how Lis1 may affect force generation in migrating cells is still not fully understood. Using traction force microscopy (TFM) with live cell imaging to measure cellular traction force in migrating NIH3T3 cells, we showed that Lis1 knockdown (KD) by RNA interference (RNAi) caused reductions in cell migration and traction force against the extracellular matrix (ECM). Immunostaining of cytoskeletal components in Lis1 KD cells showed disorganization of microtubules and actin filaments. Interestingly, focal adhesions at the cell periphery were significantly reduced. These results suggest that Lis1 is important for cellular traction force generation through the regulation of cytoskeleton organization and focal adhesion formation in migrating cells.
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1-Alquil-2-acetilglicerofosfocolina Esterasa/metabolismo , Movimiento Celular , Citoesqueleto/metabolismo , Fibroblastos/citología , Proteínas Asociadas a Microtúbulos/metabolismo , 1-Alquil-2-acetilglicerofosfocolina Esterasa/genética , Animales , Fenómenos Biomecánicos , Fibroblastos/metabolismo , Adhesiones Focales/metabolismo , Ratones , Proteínas Asociadas a Microtúbulos/genética , Células 3T3 NIH , Interferencia de ARNRESUMEN
BACKGROUND: Patients with advanced gastric cancer (GC) may ultimately die because GC mostly leads to synchronous or metachronous metastasis. However, colonic metastasis of GC is extremely rare. According to a PubMed search of papers published from May 1968 to March 2017, only 21 patients with GC (10 patients from 10 case reports and 11 patients from a retrospective study) have been found to have colonic metastasis. In this report, we present two cases of synchronous and metachronous colonic metastases of advanced GC. CASE PRESENTATION: Two patients with advanced GC received a diagnosis of colonic metastasis based on colonoscopic findings and computed tomography images, and the diagnosis was confirmed through pathological immunohistochemical analysis. Herein, we describe the management and outcomes of these metastases. CONCLUSIONS: Submucosal swelling and segmental bowel wall thickening observed through colonoscopy in patients with advanced GC might indicate colonic metastasis.
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Neoplasias del Colon/secundario , Neoplasias Primarias Múltiples/secundario , Neoplasias Primarias Secundarias/secundario , Neoplasias Gástricas/patología , Anciano , Neoplasias del Colon/cirugía , Humanos , Masculino , Neoplasias Primarias Múltiples/cirugía , Neoplasias Primarias Secundarias/cirugía , Pronóstico , Neoplasias Gástricas/cirugíaRESUMEN
The paper presents a novel and economic manufacturing process for microlens arrays (MLAs). This process uses micromilling machining, PDMS casting, and hybrid bonding between a glass substrate and PDMS membrane to create a microfluidic chip which is used for manufacturing MLAs on a PDMS substrates. MLAs of various diameters were fabricated for experiments, including 1000 µm, 500 µm, and 200 µm. The sag height of the MLAs is easily adjusted by controlling the pressure inside the microchannel to deform the PDMS membrane. Multiple experiments were conducted to characterize the performance of MLAs, the results of which demonstrate: (1) this fabrication process is able to manufacture MLAs with various dimensions and the diameter of an MLAs is determined by the size of micromilling bit and cutting path; (2) the sag height and curvature of MLAs can be controlled by the PDMS membrane thickness and the hydraulic pressure inside the microchannel; (3) an optical system was built to investigate the uniformity of MLAs and the experiment results showed uniform focal length of MLAs; (4) the resulting MLAs magnify tiny objects and significantly enhance the fluorescence signal emitted from the microchannel.
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The network of stemness genes and oncogenes in human patient-specific reprogrammed cancer stem cells (CSCs) remains elusive, especially in liver cancer. HepG2-derived induced pluripotent stem cell-like cells (HepG2-iPS-like cells) were generated by introducing Yamanaka factors and the knockdown vector shTP53. They exhibited features of stemness and a higher tumorigenesis after xenograft transplantation compared with HepG2 cells. The cancerous mass of severe combined immunodeficiency (SCID) mice derived from one colony was dissected and cultured to establish reprogrammed HepG2-derived CSC-like cells (designated rG2-DC-1C). A single colony exhibited 42% occurrence of tumors with higher proliferation capacities. rG2-DC-1C showed continuous expression of the OCT4 stemness gene and of representative tumor markers, potentiated chemoresistance characteristics, and invasion activities. The sphere-colony formation ability and the invasion activity of rG2-DC-1C were also higher than those of HepG2 cells. Moreover, the expression of the OCT4 gene and the c-JUN oncogene, but not of c-MYC, was significantly elevated in rG2-DC-1C, whereas no c-JUN expression was observed in HepG2 cells. The positive-feedback regulation via OCT4-mediated transactivation of the c-JUN promoter and the c-JUN-mediated transactivation of the OCT4 promoter were crucial for promoting cancer development and maintaining cancer stemness in rG2-DC-1C. Increased expression of OCT4 and c-JUN was detected in the early stage of human liver cancer. Therefore, the positive feedback regulation of OCT4 and c-JUN, resulting in the continuous expression of oncogenes such as c-JUN, seems to play a critical role in the determination of the cell fate decision from iPS cells to CSCs in liver cancer. Stem Cells 2016;34:2613-2624.
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Retroalimentación Fisiológica , Regulación Neoplásica de la Expresión Génica , Proteínas Quinasas JNK Activadas por Mitógenos/genética , Neoplasias Hepáticas/genética , Células Madre Neoplásicas/metabolismo , Factor 3 de Transcripción de Unión a Octámeros/genética , Anciano , Animales , Antineoplásicos/farmacología , Diferenciación Celular , Reprogramación Celular , Cisplatino/farmacología , Doxorrubicina/farmacología , Resistencia a Antineoplásicos/genética , Femenino , Fluorouracilo/farmacología , Células Hep G2 , Humanos , Células Madre Pluripotentes Inducidas/efectos de los fármacos , Células Madre Pluripotentes Inducidas/metabolismo , Células Madre Pluripotentes Inducidas/patología , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Masculino , Ratones , Ratones SCID , Persona de Mediana Edad , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/patología , Factor 3 de Transcripción de Unión a Octámeros/metabolismo , Transducción de Señal , Esferoides Celulares/efectos de los fármacos , Esferoides Celulares/metabolismo , Esferoides Celulares/patología , Activación Transcripcional , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Heat shock protein 90 (Hsp90) is a molecular chaperone that facilitates the correct folding and functionality of its client protein. Numerous Hsp90-client proteins are involved in cancer development. Thus, Hsp90 inhibitors have potential applications as anti-cancer drugs. We previously discovered that Hsp90α expression increased in breast cancer stem cells (BCSCs), which can initiate tumorigenesis and metastasis and resist treatment. In the present study, we further demonstrated that 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), an inhibitor of Hsp90, could suppress the self-renewal of BCSCs by downregulating B lymphoma Mo-MLV insertion region 1 homolog (BMI1), a polycomb family member with oncogenic activity in breast cancer. Through immunoprecipitation analysis, we found that BMI1 did not interact with Hsp90α and that the downregulation of BMI1 by 17-DMAG was mediated by the inhibition of c-Myc and enhancement of zeste homolog 2 (EZH2) expression. The transcriptional and BMI1 promoter-binding activities of c-Myc in BCSCs were inhibited by 17-DMAG treatment. The overexpression of EZH2 attenuated the inhibitory effect of 17-DMAG on BMI1 and c-Myc expression. Furthermore, Hsp90α could be co-immunoprecipitated with c-Myc and EZH2 and bind to the BMI1 promoter. Treatment with 17-DMAG decreased the nuclear expression of EZH2 and c-Myc but not that of Hsp90α. In conclusion, our data suggested that Hsp90α could positively regulate the self-renewal of BCSCs by facilitating the nuclear translocation of c-Myc and EZH2 to maintain BMI1 expression.
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Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Proteínas HSP90 de Choque Térmico/metabolismo , Células Madre Neoplásicas/metabolismo , Complejo Represivo Polycomb 1/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Benzoquinonas/farmacología , Neoplasias de la Mama/patología , Línea Celular Tumoral , Autorrenovación de las Células/genética , Proteína Potenciadora del Homólogo Zeste 2/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Lactamas Macrocíclicas/farmacología , Unión Proteica , Transporte de Proteínas , Proteínas Proto-Oncogénicas c-myc/genética , Transcripción GenéticaRESUMEN
Triple negative breast cancer (TNBC) displays higher risk of recurrence and distant metastasis. Due to absence of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2), TNBC lacks clinically established targeted therapies. Therefore, understanding of the mechanism underlying the aggressive behaviors of TNBC is required for the design of individualized strategies and the elongation of overall survival duration. Here, we supported a positive correlation between ß1 integrin and malignant behaviors such as cell migration, invasion, and drug resistance. We found that silencing of ß1 integrin inhibited cell migration, invasion, and increased the sensitivity to anti-cancer drug. In contrast, activation of ß1 integrin increased cell migration, invasion, and decreased the sensitivity to anti-cancer drug. Furthermore, we found that silencing of ß1 integrin abolished Focal adhesion kinese (FAK) mediated cell survival. Overexpression of FAK could restore cisplatin-induced apoptosis in ß1 integrin-depleted cells. Consistent to in vitro data, ß1 integrin expression was also positively correlated with FAK (p = 0.031) in clinical tissue. More importantly, ß1 integrin expression was significantly correlated with patient outcome. In summary, our study indicated that ß1 integrin could regulate TNBC cells migration, invasion, drug sensitivity, and be a potential prognostic biomarker in TNBC patient survival.
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Biomarcadores de Tumor/metabolismo , Integrina beta1/metabolismo , Neoplasias de la Mama Triple Negativas/metabolismo , Apoptosis , Biomarcadores de Tumor/genética , Línea Celular Tumoral , Movimiento Celular , Supervivencia Celular , Femenino , Proteína-Tirosina Quinasas de Adhesión Focal/genética , Proteína-Tirosina Quinasas de Adhesión Focal/metabolismo , Humanos , Integrina beta1/genética , Neoplasias de la Mama Triple Negativas/patologíaRESUMEN
BACKGROUND AND AIM: The clinical utility of our designed primary culture method in patients with hepatocellular carcinoma was investigated. METHODS: Specimens obtained from ultrasound-guided fine-needle aspiration of 108 hepatocellular carcinoma patients were cultured. The associations of the cellular proliferative speeds with cancer invasiveness and 1-year survivals were analyzed. RESULTS: Successful cultures were achieved in 105 patients (97.2%). Ten hepatocellular carcinoma and nine cancer-associated fibroblast cell lines were established. The cells obtained from patients with American Joint Committee on Cancer TNM staging ≥ IIIB upon entering the study had higher proportion of rapidly proliferative cancer cells than those from patients with staging ≤ IIIA (P < 0.005). For Barcelona Clinic Liver Cancer classification A or B patients receiving palliative transcatheter chemoembolization, patients with rapidly proliferative cancer-associated fibroblasts showed higher incidence of cancer-related death than patients with other proliferative patterns (P = 0.0385). The influence of the presence of rapidly proliferative cancer cells on survivals in this group could not be calculated due to a very small number of this kind of patients (9.5%). For Barcelona Clinic Liver Cancer classification C patients receiving non-curative treatment, the incidence of rapidly proliferative cancer cells was 45.2%. Patients with rapidly proliferative cancer cells showed higher incidence of cancer-related death than patients with other proliferative patterns in patients receiving chemoembolization (P = 0.0452) and in patients receiving conservative treatment (P = 0.0206). CONCLUSION: Our method can provide cells from individual patient for researches and predict outcomes in patients receiving non-curative treatment of hepatocellular carcinoma.
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Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/terapia , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/terapia , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Hepatocelular/clasificación , Carcinoma Hepatocelular/mortalidad , Proliferación Celular , Supervivencia Celular , Quimioembolización Terapéutica , Femenino , Estudios de Seguimiento , Predicción , Humanos , Neoplasias Hepáticas/clasificación , Neoplasias Hepáticas/mortalidad , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Cuidados Paliativos , Resultado del Tratamiento , Células Tumorales CultivadasRESUMEN
Laryngeal schwannomas are rare, benign neurogenic tumors. They normally present as a slow-growing, encapsulated, submucosal mass in the supraglottic region. We describe a 20-year-old female presenting with a 2-year history of hoarseness and progressive worsening dyspnea. Fiberoptic laryngoscopy and computed tomography revealed a round, low-density submucosal mass at right false cord and arytenoepiglottic regions with glottic extension. Microlaryngoscopic biopsy and debulking for this solid tumor were performed without tracheostomy. Schwannoma was confirmed by histopathological study. However, rapidly worsening stridor occurred 2 weeks after the surgery. Fiberoptic laryngoscopy showed an exophytic tumor occupying the right hemilarynx with airway compromise. Definite complete excision of the tumor was performed by right vertical hemilaryngectomy. At 5-month follow-up, the laryngeal wound was clear without signs of recurrence. Rapid occurrence of airway obstruction after debulking and biopsy was demonstrated in this case. Vertical hemilaryngectomy was inevitable to cure this potentially life-threatening laryngeal schwannoma in this young female with postoperative serviceable voice.
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Neoplasias Laríngeas/patología , Enfermedades Pulmonares Obstructivas/patología , Neurilemoma/patología , Adulto , Femenino , Ronquera , Humanos , Neoplasias Laríngeas/complicaciones , Neoplasias Laríngeas/cirugía , Laringectomía , Enfermedades Pulmonares Obstructivas/etiología , Enfermedades Pulmonares Obstructivas/cirugía , Neurilemoma/complicaciones , Neurilemoma/cirugía , Pronóstico , Tomografía Computarizada por Rayos X , Adulto JovenRESUMEN
BACKGROUND: Focal hypermethylation in promoter regions of tumor suppressor genes against the background of global hypomethylation is a landmark of carcinogenesis. This study aimed to investigate the methylation status of retinoic acid receptor beta2 (RARß2) and long interspersed nuclear elements (LINE-1) in different stages of esophageal squamous cell carcinoma (ESCC). METHOD: The tumor and adjacent normal esophageal tissues from 125 male ESCC patients who underwent primary surgery were analyzed for the methylation status of RARß2 promoter and LINE-1 through methylation-specific polymerase chain reaction and pyrosequencing. RESULTS: RARß2 hypermethylation was detected in 20% of the tumor samples, but not in the normal counterparts. The methylation frequency of LINE-1 was significantly lower in the tumor than in the normal parts (median: 67.7% vs. 80%, P < 0.0005). Ninety-eight patients (78.4%) had both RARß2 hypermethylation and LINE-1 hypomethylation or either one. There was a trend toward higher risk of advanced T stage (P for trend = 0.05) or lymph node metastasis (P for trend = 0.02) when more adverse gene methylation profiles were present. CONCLUSION: Methylation status of RARß2 and LINE-1 was related to the development and possibly the severity of ESCC.
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Carcinoma de Células Escamosas/genética , Metilación de ADN , Neoplasias Esofágicas/genética , Receptores de Ácido Retinoico/genética , Biomarcadores de Tumor/genética , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/terapia , Quimioradioterapia , Quimioterapia Adyuvante , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/terapia , Humanos , Elementos de Nucleótido Esparcido Largo/genética , Metástasis Linfática , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Radioterapia AdyuvanteRESUMEN
BACKGROUND/AIM: Patients diagnosed with advanced metastatic colorectal cancer (CRC) confront a bleak prognosis characterized by low survival rates. Anoikis, the programmed apoptosis resistance exhibited by metastatic cancer cells, is a crucial factor in this scenario. MATERIALS AND METHODS: We employed bulk flow cytometry and RT-qPCR assays, conducted in vivo experiments with mice and zebrafish, and analyzed patient tissues to examine the effects of the B cell-specific Moloney murine leukemia virus insertion site 1 (Bmi1)-midkine (MDK) axis on the cellular response to anoikis. Bmi1 is pivotal in tumorigenesis. This study elucidated the involvement of Bmi1 in conferring anoikis resistance in CRC and explored its downstream targets associated with metastasis. RESULTS: Elevated levels of Bmi1 expression correlated with distant metastasis in CRC. Suppression of Bmi1 significantly diminished the metastatic potential of CRC cells. Inhibition of Bmi1 led to an increase in the proportion of apoptotic SW620 cells detached from the matrix. This effect was further enhanced by the addition of irinotecan, a topoisomerase I inhibitor. Furthermore, Bmi1 was found to synergize with MDK in modulating CRC viability, with consistent expression patterns observed in in vivo models and clinical tissue specimens. In summary, Bmi1 acted as a regulator of CRC metastatic capability by conferring anoikis resistance. Additionally, it collaborated with MDK to facilitate invasion and distant metastasis. CONCLUSION: Targeting Bmi1 may offer a promising adjunctive therapeutic strategy when administering traditional chemotherapy regimens to patients with advanced CRC.