RESUMEN
It is known that V-set and immunoglobulin domain containing 1 (VSIG1) is a cell-cell adhesion molecule that can serve as an indicator of better survival in patients with gastric cancer. Its interaction with cytoplasmic thyroid transcription factor 1 (TTF-1) has been hypothesized to characterize gastric-type HCC, but its clinical importance is far from understood. As VSIG1 has also been supposed to be involved in the epithelial-mesenchymal transition (EMT) phenomenon, we checked for the first time in the literature the supposed interaction between VSIG1, TTF-1, and Vimentin (VIM) in HCCs. Immunohistochemical (IHC) stains were performed on 217 paraffin-embedded tissue samples that included tumor cells and normal hepatocytes, which served as positive internal controls. VSIG1 positivity was seen in 113 cases (52.07%). In 71 out of 217 HCCs (32.71%), simultaneous positivity for VSIG1 and TTF-1 was seen, being more specific for G1/G2 carcinomas with a trabecular architecture and a longer OS (p = 0.004). A negative association with VIM was revealed (p < 0.0001). Scirrhous-type HCC proved negative for all three examined markers. The present paper validates the hypothesis of the existence of a gastric-type HCC, which shows a glandular-like architecture and is characterized by double positivity for VSIG1 and TTF-1, vimentin negativity, and a significant OS.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Vimentina , Humanos , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/genética , Masculino , Femenino , Persona de Mediana Edad , Vimentina/metabolismo , Anciano , Adulto , Biomarcadores de Tumor/metabolismo , Transición Epitelial-Mesenquimal/genética , Regulación Neoplásica de la Expresión Génica , Anciano de 80 o más Años , Factor Nuclear Tiroideo 1/metabolismo , Factor Nuclear Tiroideo 1/genética , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , InmunohistoquímicaRESUMEN
Similarly to our healthy organs, the tumor tissue also constitutes an ecosystem. This implies that stromal cells acquire an altered phenotype in tandem with tumor cells, thereby promoting tumor survival. Cancer cells are fueled by abnormal blood vessels, allowing them to develop and proliferate. Tumor-associated fibroblasts adapt their cytokine and chemokine production to the needs of tumor cells and alter the peritumoral stroma by generating more collagen, thereby stiffening the matrix; these processes promote epithelial-mesenchymal transition and tumor cell invasion. Chronic inflammation and the mobilization of pro-tumorigenic inflammatory cells further facilitate tumor expansion. All of these events can impede the effective administration of tumor treatment; so, the successful inhibition of tumorous matrix remodeling could further enhance the success of antitumor therapy. Over the last decade, significant progress has been made with the introduction of novel immunotherapy that targets the inhibitory mechanisms of T cell activation. However, extensive research is also being conducted on the stromal components and other cell types of the tumor microenvironment (TME) that may serve as potential therapeutic targets.
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Neoplasias , Microambiente Tumoral , Humanos , Ecosistema , Neoplasias/metabolismo , Carcinogénesis , InmunoterapiaRESUMEN
Tumors are intricate ecosystems where cancer cells and non-malignant stromal cells, including cancer-associated fibroblasts (CAFs), engage in complex communication. In this study, we investigated the interaction between poorly (HLE) and well-differentiated (HuH7) hepatoma cells and LX2 fibroblasts. We explored various communication channels, including soluble factors, metabolites, extracellular vesicles (EVs), and miRNAs. Co-culture with HLE cells induced LX2 to produce higher levels of laminin ß1, type IV collagen, and CD44, with pronounced syndecan-1 shedding. Conversely, in HuH7/LX2 co-culture, fibronectin, thrombospondin-1, type IV collagen, and cell surface syndecan-1 were dominant matrix components. Integrins α6ß4 and α6ß1 were upregulated in HLE, while α5ß1 and αVß1 were increased in HuH7. HLE-stimulated LX2 produced excess MMP-2 and 9, whereas HuH7-stimulated LX2 produced excess MMP-1. LX2 activated MAPK and Wnt signaling in hepatoma cells, and conversely, hepatoma-derived EVs upregulated MAPK and Wnt in LX2 cells. LX2-derived EVs induced over tenfold upregulation of SPOCK1/testican-1 in hepatoma EV cargo. We also identified liver cancer-specific miRNAs in hepatoma EVs, with potential implications for early diagnosis. In summary, our study reveals tumor type-dependent communication between hepatoma cells and fibroblasts, shedding light on potential implications for tumor progression. However, the clinical relevance of liver cancer-specific miRNAs requires further investigation.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/genética , Sindecano-1 , Colágeno Tipo IV , Ecosistema , Neoplasias Hepáticas/genética , Fibroblastos , Comunicación , ProteoglicanosRESUMEN
Lung cancer is one of the most commonly diagnosed cancer types. Studying the molecular changes that occur in lung cancer is important to understand tumor formation and identify new therapeutic targets and early markers of the disease to decrease mortality. Glycosaminoglycan chains play important roles in various signaling events in the tumor microenvironment. Therefore, we have determined the quantity and sulfation characteristics of chondroitin sulfate and heparan sulfate in formalin-fixed paraffin-embedded human lung tissue samples belonging to different lung cancer types as well as tumor adjacent normal areas. Glycosaminoglycan disaccharide analysis was performed using HPLC-MS following on-surface lyase digestion. Significant changes were identified predominantly in the case of chondroitin sulfate; for example, the total amount was higher in tumor tissue compared to the adjacent normal tissue. We also observed differences in the degree of sulfation and relative proportions of individual chondroitin sulfate disaccharides between lung cancer types and adjacent normal tissue. Furthermore, the differences in the 6-O-/4-O-sulfation ratio of chondroitin sulfate were different between the lung cancer types. Our pilot study revealed that further investigation of the role of chondroitin sulfate chains and enzymes involved in their biosynthesis is an important aspect of lung cancer research.
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Glicosaminoglicanos , Neoplasias Pulmonares , Humanos , Sulfatos de Condroitina , Proyectos Piloto , Heparitina Sulfato , Disacáridos , Microambiente TumoralRESUMEN
SPOCK1, 2, and 3 are considered matricellular proteoglycans without a structural role. Their functions are only partly elucidated. SPOCK1 was detected in the brain as a member of the neural synapses, then in the neuromuscular junctions. It plays a role in the regulation of the blood-brain barrier. Its best-characterized activity was its oncogenic potential discovered in 2012. Its deleterious effect on tumor progression was detected on 36 different types of tumors by the end of 2020. However, its mode of action is still not completely understood. Furthermore, even less was discovered about its physiological function. The fact that it was found to localize in the mitochondria and interfered with the lipid metabolism indicated that the full discovery of SPOCK1 is still waiting for us.
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Carcinogénesis , Proteoglicanos , Línea Celular Tumoral , Humanos , Proteoglicanos/genética , Proteoglicanos/metabolismoRESUMEN
Syndecan-1 (SDC-1) is a heparan sulfate (HS)/chondroitin sulfate proteoglycan (PG) of the cell surface and the extracellular matrix (ECM), which regulates a broad spectrum of physiological and pathological processes such as cell proliferation, migration, inflammation, matrix remodeling, wound healing, and tumorigenesis. Syndecan-1 represents the major PG of the liver, expressed by hepatocytes and cholangiocytes, and its elevated expression is a characteristic feature of liver diseases. The highest syndecan-1 expression is found in liver cirrhosis and in hepatocellular carcinoma (HCC) developed in cirrhotic livers. In addition, as being a hepatitis C receptor, hepatitis C virus (HCV)-infected livers produce extremely large amounts of syndecan-1. The serum levels of the cleaved (shedded) extracellular domain have clinical significance, as their increased concentration reflects on poor prognosis in cirrhosis as well as in cancer. In vivo experiments confirmed that syndecan-1 protects against early stages of fibrogenesis mainly by enhanced clearance of transforming growth factor ß1 (TGFß1) and thrombospondin-1 (THBS1) via circulation, and against hepatocarcinogenesis by interfering with several signaling pathways and enhancing cell cycle blockade. In addition, syndecan-1 is capable to hinder lipid metabolism and ribosomal biogenesis in induced cancer models. These observations together with its participation in the uptake of viruses (e.g., HCV and SARS-CoV-2) indicate that syndecan-1 is a central player in liver pathologies.
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Carcinoma Hepatocelular , Hepatitis C , Neoplasias Hepáticas , Hígado , Sindecano-1 , Humanos , Hígado/fisiopatología , Proteoglicanos/metabolismo , Sindecano-1/genética , Sindecano-1/metabolismoRESUMEN
Hyaluronan (HA) is a component of the extracellular matrix (ECM) it is the main non-sulfated glycosaminoglycan able to modulate cell behavior in the healthy and tumor context. Sulfated hyaluronan (sHA) is a biomaterial derived from chemical modifications of HA, since this molecule is not naturally sulfated. The HA sulfation modifies several properties of the native molecule, acquiring antitumor properties in different cancers. In this study, we evaluated the action of sHA of ~30-60 kDa with different degrees of sulfation (0.7 sHA1 and 2.5 sHA3) on tumor cells of a breast, lung, and colorectal cancer model and its action on other cells of the tumor microenvironment, such as endothelial and monocytes/macrophage cells. Our data showed that in breast and lung tumor cells, sHA3 is able to modulate cell viability, cytotoxicity, and proliferation, but no effects were observed on colorectal cancer cells. In 3D cultures of breast and lung cancer cells, sHA3 diminished the size of the tumorsphere and modulated total HA levels. In these tumor models, treatment of monocytes/macrophages with sHA3 showed a downregulation of the expression of angiogenic factors. We also observed a decrease in endothelial cell migration and modulation of the hyaluronan-binding protein TSG-6. In the breast in vivo xenograft model, monocytes/macrophages preincubated with sHA1 or sHA3 decreased tumor vasculature, TSG-6 and HA levels. Besides, in silico analysis showed an association of TSG-6, HAS2, and IL-8 with biological processes implicated in the progression of the tumor. Taken together, our data indicate that sHA in a breast and lung tumor context is able to induce an antiangiogenic action on tumor cells as well as in monocytes/macrophages (Mo/MØ) by modulation of endothelial migration, angiogenic factors, and vessel formation.
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Neoplasias Colorrectales , Neoplasias Pulmonares , Materiales Biocompatibles , Neoplasias Colorrectales/tratamiento farmacológico , Humanos , Receptores de Hialuranos , Ácido Hialurónico/química , Ácido Hialurónico/farmacología , Interleucina-8 , Pulmón , Neoplasias Pulmonares/tratamiento farmacológico , Macrófagos , Monocitos , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/genética , Sulfatos/química , Sulfatos/farmacología , Microambiente TumoralRESUMEN
Chronic liver diseases have both high incidence and mortality rates; therefore, a deeper understanding of the underlying molecular mechanisms is essential. We have determined the content and sulfation pattern of chondroitin sulfate (CS) and heparan sulfate (HS) in human hepatocellular carcinoma and cirrhotic liver tissues, considering the etiology of the diseases. A variety of pathological conditions such as alcoholic liver disease, hepatitis B and C virus infections, and primary sclerosing cholangitis were studied. Major differences were observed in the total abundance and sulfation pattern of CS and HS chains. For example, the 6-O-sulfation of CS is fundamentally different regarding etiologies of cirrhosis, and a 2-threefold increase in HS N-sulfation/O-sulfation ratio was observed in hepatocellular carcinoma compared to cirrhotic tissues.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Sulfatos de Condroitina , Glicosaminoglicanos/metabolismo , Heparitina Sulfato , Humanos , Cirrosis Hepática , Proyectos PilotoRESUMEN
Proteoglycan macromolecules play key roles in several physiological processes (e.g., adhesion, proliferation, migration, invasion, angiogenesis, and apoptosis), all of which are important for placentation and healthy pregnancy. However, their precise roles in human reproduction have not been clarified. To fill this gap, herein, we provide an overview of the proteoglycans' expression and role in the placenta, in trophoblast development, and in pregnancy complications (pre-eclampsia, fetal growth restriction), highlighting one of the most important members of this family, syndecan-1 (SDC1). Microarray data analysis showed that of 34 placentally expressed proteoglycans, SDC1 production is markedly the highest in the placenta and that SDC1 is the most upregulated gene during trophoblast differentiation into the syncytiotrophoblast. Furthermore, placental transcriptomic data identified dysregulated proteoglycan genes in pre-eclampsia and in fetal growth restriction, including SDC1, which is supported by the lower concentration of syndecan-1 in maternal blood in these syndromes. Overall, our clinical and in vitro studies, data analyses, and literature search pointed out that proteoglycans, as important components of the placenta, may regulate various stages of placental development and participate in the maintenance of a healthy pregnancy. Moreover, syndecan-1 may serve as a useful marker of syncytialization and a prognostic marker of adverse pregnancy outcomes. Further studies are warranted to explore the role of proteoglycans in healthy and complicated pregnancies, which may help in diagnostic or therapeutic developments.
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Preeclampsia , Complicaciones del Embarazo , Femenino , Retardo del Crecimiento Fetal/genética , Retardo del Crecimiento Fetal/metabolismo , Humanos , Placenta/metabolismo , Preeclampsia/genética , Preeclampsia/metabolismo , Embarazo , Complicaciones del Embarazo/genética , Complicaciones del Embarazo/metabolismo , Proteoglicanos/genética , Proteoglicanos/metabolismo , Sindecano-1/genética , Sindecano-1/metabolismoRESUMEN
The tumor microenvironment plays a determining role in cancer development through a plethora of interactions between the extracellular matrix and tumor cells. Decorin is a prototype member of the SLRP family found in a variety of tissues and is expressed in the stroma of various forms of cancer. Decorin has gained recognition for its essential roles in inflammation, fibrotic disorders, and cancer, and due to its antitumor properties, it has been proposed to act as a "guardian from the matrix." Initially identified as a natural inhibitor of transforming growth factor-ß, soluble decorin is emerging as a pan-RTK inhibitor targeting a multitude of RTKs, including EGFR, Met, IGF-IR, VEGFR2, and PDGFR. Besides initiating signaling, decorin/RTK interaction can induce caveosomal internalization and receptor degradation. Decorin also triggers cell cycle arrest and apoptosis and evokes antimetastatic and antiangiogenic processes. In addition, as a novel regulatory mechanism, decorin was shown to induce conserved catabolic processes, such as endothelial cell autophagy and tumor cell mitophagy. Therefore, decorin is a promising candidate for combatting cancer, especially the cancer types heavily dependent on RTK signaling.
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Decorina , Neoplasias/metabolismo , Microambiente Tumoral , Autofagia , Decorina/metabolismo , Humanos , Proteínas Tirosina Quinasas Receptoras/metabolismo , Transducción de SeñalRESUMEN
Zinc finger protein 554 (ZNF554), a member of the Krüppel-associated box domain zinc finger protein subfamily, is predominantly expressed in the brain and placenta in humans. Recently, we unveiled that ZNF554 regulates trophoblast invasion during placentation and its decreased expression leads to the early pathogenesis of preeclampsia. Since ZNF proteins are immensely implicated in the development of several tumors including malignant tumors of the brain, here we explored the pathological role of ZNF554 in gliomas. We examined the expression of ZNF554 at mRNA and protein levels in normal brain and gliomas, and then we searched for genome-wide transcriptomic changes in U87 glioblastoma cells transiently overexpressing ZNF554. Immunohistochemistry of brain tissues in our cohort (n = 62) and analysis of large TCGA RNA-Seq data (n = 687) of control, oligodendroglioma, and astrocytoma tissues both revealed decreased expression of ZNF554 towards higher glioma grades. Furthermore, low ZNF554 expression was associated with shorter survival of grade III and IV astrocytoma patients. Overexpression of ZNF554 in U87 cells resulted in differential expression, mostly downregulation of 899 genes. The "PI3K-Akt signaling pathway", known to be activated during glioma development, was the most impacted among 116 dysregulated pathways. Most affected pathways were cancer-related and/or immune-related. Congruently, cell proliferation was decreased and cell cycle was arrested in ZNF554-transfected glioma cells. These data collectively suggest that ZNF554 is a potential tumor suppressor and its decreased expression may lead to the loss of oncogene suppression, activation of tumor pathways, and shorter survival of patients with malignant glioma.
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Neoplasias Encefálicas/genética , Regulación Neoplásica de la Expresión Génica , Glioma/genética , Factores de Transcripción de Tipo Kruppel/genética , Transducción de Señal , Adolescente , Adulto , Anciano , Neoplasias Encefálicas/patología , Puntos de Control del Ciclo Celular/genética , Línea Celular Tumoral , Proliferación Celular/genética , Femenino , Genoma Humano , Glioma/patología , Humanos , Factores de Transcripción de Tipo Kruppel/metabolismo , Masculino , Persona de Mediana Edad , ARN Mensajero/genética , ARN Mensajero/metabolismo , Análisis de Supervivencia , Adulto JovenRESUMEN
Background: Predictive biomarkers for immunotherapy in lung cancer are intensively investigated; however, correlations between PD-L1/PD-1 expressions and clinical features or histopathological tumor characteristics determined on hematoxylin and eosin stained sections have not extensively been studied. Material and methods: We determined PD-L1 expression of tumor cells (TC) and immune cells (IC), and PD-1 expression of IC by immunohistochemistry in 268 lung adenocarcinoma (LADC) patients, and correlated the data with smoking, COPD, tumor grade, necrosis, lepidic growth pattern, vascular invasion, density of stromal IC, and EGFR/KRAS status of the tumors. Results: There was a positive correlation between PD-L1 expression of TC and IC, as well as PD-L1 and PD-1 expression of IC. Tumor necrosis was associated with higher PD-L1 expression of TC and PD-1 expression of IC. A negative correlation was observed between lepidic growth pattern and PD-L1 expression of TC and PD-L1/PD-1 expression of IC. EGFR mutation seemed to negatively correlate with PD-1 expression of IC, but this tendency could not be verified when applying corrections for multiple comparisons. No significant effect of the KRAS mutation on any of the studied variables could be established. Conclusion: Here we first demonstrate that the presence of necrosis correlates with higher PD-L1 expression of TC and PD-1 expression of IC in LADC. Further studies are required to determine the predictive value of this observation in LADC patients receiving immunotherapy.
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Adenocarcinoma del Pulmón/patología , Antígeno B7-H1/metabolismo , Biomarcadores de Tumor/metabolismo , Neoplasias Pulmonares/patología , Pulmón/patología , Receptor de Muerte Celular Programada 1/metabolismo , Adenocarcinoma del Pulmón/inmunología , Adenocarcinoma del Pulmón/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Pulmón/citología , Pulmón/cirugía , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/cirugía , Masculino , Persona de Mediana Edad , Necrosis , NeumonectomíaRESUMEN
Urachal cancer (UrC) is a rare but aggressive malignancy often diagnosed in advanced stages requiring systemic treatment. Although cytotoxic chemotherapy is of limited effectiveness, prospective clinical studies can hardly be conducted. Targeted therapeutic treatment approaches and potentially immunotherapy based on a biological rationale may provide an alternative strategy. We therefore subjected 70 urachal adenocarcinomas to targeted next-generation sequencing, conducted in situ and immunohistochemical analyses (including PD-L1 and DNA mismatch repair proteins [MMR]) and evaluated the microsatellite instability (MSI) status. The analytical findings were correlated with clinicopathological and outcome data and Kaplan-Meier and univariable/multivariable Cox regression analyses were performed. The patients had a mean age of 50 years, 66% were male and a 5-year overall survival (OS) of 58% and recurrence-free survival (RFS) of 45% was detected. Sequence variations were observed in TP53 (66%), KRAS (21%), BRAF (4%), PIK3CA (4%), FGFR1 (1%), MET (1%), NRAS (1%), and PDGFRA (1%). Gene amplifications were found in EGFR (5%), ERBB2 (2%), and MET (2%). We detected no evidence of MMR-deficiency (MMR-d)/MSI-high (MSI-h), whereas 10 of 63 cases (16%) expressed PD-L1. Therefore, anti-PD-1/PD-L1 immunotherapy approaches might be tested in UrC. Importantly, we found aberrations in intracellular signal transduction pathways (RAS/RAF/PI3K) in 31% of UrCs with potential implications for anti-EGFR therapy. Less frequent potentially actionable genetic alterations were additionally detected in ERBB2 (HER2), MET, FGFR1, and PDGFRA. The molecular profile strengthens the notion that UrC is a distinct entity on the genomic level with closer resemblance to colorectal than to bladder cancer.
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Adenocarcinoma/genética , Adenocarcinoma/patología , Biomarcadores de Tumor/genética , Regulación Neoplásica de la Expresión Génica , Inestabilidad de Microsatélites , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/patología , Adenocarcinoma Mucinoso/genética , Adenocarcinoma Mucinoso/patología , Adulto , Anciano , Carcinoma de Células en Anillo de Sello/genética , Carcinoma de Células en Anillo de Sello/patología , Femenino , Estudios de Seguimiento , Amplificación de Genes , Perfilación de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Mutación , Pronóstico , Adulto JovenRESUMEN
BACKGROUND: Diethylnitrosamine is a well known carcinogen that induces cancers of various organs in mice and rats. Using FVB/N mouse strain, here we show that diethylnitrosamine induces primarily lung adenocarcinomas with modest tumor development in the liver, offering a new model to study chemical carcinogenesis in the lung. METHODS: Animals were exposed to a single high dose of diethylnitrosamine, and more than 70% of the mice developed lung cancer. To obtain a new transplantable tumor line, pieces of primary tumors were inoculated and maintained subcutaneously in the same mouse strain. We used immunohistochemistry to characterize the tumor for main lung adenocarcinoma markers. We searched for mutations in KRAS exon 2 and EGFR exon 19, 21 with Sanger sequencing. We also compared the normal lung tissue with the diethylnitrosamine induced primary adenocarcinoma, and with the subcutaneously maintained adenocarcinoma using Western blot technique for main cell cycle markers and to identify the main pathways. RESULTS: Primary and subcutaneous tumors express cytokeratin-7 and thyroid transcription factor-1, markers characteristic to lung adenocarcinoma. In addition, no mutations were found in the hot spot regions of KRAS and EGFR genes. We found high mTOR activation, but the level of p-Akt Ser473 and p-Akt Thr308 decreased in the tumorous samples. CONCLUSIONS: We established a new lung adenocarcinoma model using FVB/N mouse strain and diethylnitrosamine. We believe that this new model system would be highly useful in lung cancer research.
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Adenocarcinoma/patología , Modelos Animales de Enfermedad , Neoplasias Pulmonares/patología , Pulmón/patología , Adenocarcinoma/inducido químicamente , Adenocarcinoma/genética , Animales , Secuencia de Bases , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Dietilnitrosamina , Receptores ErbB/genética , Femenino , Humanos , Queratina-7/metabolismo , Pulmón/metabolismo , Neoplasias Pulmonares/inducido químicamente , Neoplasias Pulmonares/genética , Masculino , Ratones , Mutación , Proteínas Proto-Oncogénicas p21(ras)/genética , Factor Nuclear Tiroideo 1/metabolismoRESUMEN
BACKGROUND: The introduction of targeted treatments for subsets of non-small cell lung cancer (NSCLC) has highlighted the importance of accurate molecular diagnosis to determine if an actionable genetic alteration is present. Few data are available for Central and Eastern Europe (CEE) on mutation rates, testing rates, and compliance with testing guidelines. METHODS: A questionnaire about molecular testing and NSCLC management was distributed to relevant specialists in nine CEE countries, and pathologists were asked to provide the results of EGFR and ALK testing over a 1-year period. RESULTS: A very high proportion of lung cancer cases are confirmed histologically/cytologically (75-100%), and molecular testing of NSCLC samples has been established in all evaluated CEE countries in 2014. Most countries follow national or international guidelines on which patients to test for EGFR mutations and ALK rearrangements. In most centers at that time, testing was undertaken on request of the clinician rather than on the preferred reflex basis. Immunohistochemistry, followed by fluorescent in situ hybridization confirmation of positive cases, has been widely adopted for ALK testing in the region. Limited reimbursement is a significant barrier to molecular testing in the region and a disincentive to reflex testing. Multidisciplinary tumor boards are established in most of the countries and centers, with 75-100% of cases being discussed at a multidisciplinary tumor board at specialized centers. CONCLUSIONS: Molecular testing is established throughout the CEE region, but improved and unbiased reimbursement remains a major challenge for the future. Increasing the number of patients reviewed by multidisciplinary boards outside of major centers and access to targeted therapy based on the result of molecular testing are other major challenges.
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Biomarcadores de Tumor/genética , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Reordenamiento Génico , Pruebas Genéticas/métodos , Neoplasias Pulmonares/diagnóstico , Mutación , Carcinoma de Pulmón de Células no Pequeñas/epidemiología , Carcinoma de Pulmón de Células no Pequeñas/genética , Europa (Continente)/epidemiología , Humanos , Neoplasias Pulmonares/epidemiología , Neoplasias Pulmonares/genética , PronósticoRESUMEN
Authors report on a case of a male patient of systemic mastocytosis that was associated with extensive cutaneous lesions. Chronic diarrhoea worsening his quality of life was well managed by the administration of antihistamines. The pleural fluid recurrence soon after drainage has been controlled by the administration of alpha interferon. 40 years after the onset of the first skin signs progression has been manifested in the development of "B" (bone marrow infiltration rate >30%, dysmyelopoiesis, serum tryptase >20 µg/L, hepato- and splenomegaly) and "C" symptoms (liver function test abnormalities, cytopenia, malabsorption, osteoporosis). The patient died at age of 87. The authors' aim was to attract attention on this rare disease and emphasize that symptomatic therapy with antihistamines and drugs available based on customised rights by the National Health Insurance Fund might provide good quality of life. Orv Hetil. 2018; 159(5): 192-196.
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Mastocitosis Cutánea/patología , Mastocitosis Sistémica/patología , Enfermedades Raras/patología , Anciano de 80 o más Años , Progresión de la Enfermedad , Resultado Fatal , Humanos , MasculinoRESUMEN
BACKGROUND: Previously, drug-based synchronization procedures were used for characterizing the cell cycle dependent transcriptional program. However, these synchronization methods result in growth imbalance and alteration of the cell cycle machinery. DNA content-based fluorescence activated cell sorting (FACS) is able to sort the different cell cycle phases without perturbing the cell cycle. MiRNAs are key transcriptional regulators of the cell cycle, however, their expression dynamics during cell cycle has not been explored. METHODS: Following an optimized FACS, a complex initiative of high throughput platforms (microarray, Taqman Low Density Array, small RNA sequencing) were performed to study gene and miRNA expression profiles of cell cycle sorted human cells originating from different tissues. Validation of high throughput data was performed using quantitative real time PCR. Protein expression was detected by Western blot. Complex statistics and pathway analysis were also applied. RESULTS: Beyond confirming the previously described cell cycle transcriptional program, cell cycle dependently expressed genes showed a higher expression independently from the cell cycle phase and a lower amplitude of dynamic changes in cancer cells as compared to untransformed fibroblasts. Contrary to mRNA changes, miRNA expression was stable throughout the cell cycle. CONCLUSIONS: Cell cycle sorting is a synchronization-free method for the proper analysis of cell cycle dynamics. Altered dynamic expression of universal cell cycle genes in cancer cells reflects the transformed cell cycle machinery. Stable miRNA expression during cell cycle progression may suggest that dynamical miRNA-dependent regulation may be of less importance in short term regulations during the cell cycle.
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Ciclo Celular/genética , Citometría de Flujo , Regulación de la Expresión Génica , MicroARNs/química , MicroARNs/genética , Análisis de Secuencia de ARN , Línea Celular Transformada , Línea Celular Tumoral , Análisis por Conglomerados , Perfilación de la Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Especificidad de Órganos/genética , TranscriptomaRESUMEN
BACKGROUND: PSA-screening detects many cases of clinically non-aggressive prostate cancer (PC) leading to significant overtreatment. Therefore, pre-operatively available prognostic biomarkers are needed to help therapy decisions. Syndecan-1 (SDC1) is a promising prognostic tissue marker in several cancers including PC but serum levels of shedded SDC1-ectodomain (sSDC1) have not been assessed in PC. METHODS: A total of 150 patients with PC were included in this study (n = 99 serum samples, n = 103 paraffin-embedded samples (FFPE), n = 52 overlap). SDC1 protein expression and cellular localization was evaluated by immunohistochemistry (IHC), while sSDC1 serum concentrations were measured by ELISA. Serum sSDC1 levels were compared to those of MMP7, which is known to be a protease involved in SDC1 ectodomain-shedding. Clinico-pathological and follow-up data were collected and correlated with SDC1 tissue and serum levels. Disease (PC)-specific (DSS) and overall-survival (OS) were primary endpoints. RESULTS: Median follow-up was 167 months in the serum- and 146 months in the FFPE-group. SDC1-reactivity was higher in non-neoplastic prostate glands compared to PC. In addition, cytoplasmatic, but not membranous SDC1 expression was enhanced in PC patients with higher Gleason-score >6 PC (P = 0.016). Soluble SDC1-levels were higher in patients with Gleason-score >6 (P = 0.043) and metastatic disease (P = 0.022) as well as in patients with progressed disease treated with palliative transurethral resection (P = 0.002). In addition, sSDC1 levels were associated with higher MMP7 serum concentration (P = 0.005). In univariable analyses, only sSDC1-levels exhibited a trend to unfavorable DSS (P = 0.077). In a multivariable pre-operative model, high pre-operative sSDC1-level (>123 ng/ml) proved to be an independent marker of adverse OS (P = 0.048) and DSS (P = 0.020). CONCLUSIONS: The present study does not confirm the prognostic relevance of SDC1-IHC. The significant higher sSDC1 serum levels in advanced cases of PC, suggest that SDC1 shedding might be involved in PC progression. Additionally, high sSDC1-level proved to be an independent factor of adverse OS and DSS in a multivariable pre-operative model, making evaluation of sSDC1-levels a promising tool for pre-operative risk-stratification and/or therapy monitoring. Prostate 76:977-985, 2016. © 2016 Wiley Periodicals, Inc.
Asunto(s)
Neoplasias de la Próstata/sangre , Sindecano-1/sangre , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/sangre , Supervivencia sin Enfermedad , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Pronóstico , Próstata/química , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata/química , Neoplasias de la Próstata/patología , Sindecano-1/análisisRESUMEN
Native and designer cationic antimicrobial peptides are increasingly acknowledged as host defense molecules rather than true antimicrobials. Due to their ability to activate the innate immune system, these structures are used to treat uninfected and bacterially-infected wounds, including those harboring Acinetobacter baumannii. Previously we documented that when administered intramuscularly or topically in liquid formulations, the proline-rich host defense peptide dimer A3-APO accelerates uninfected wound re-epithelization and eliminates systemic and local A. baumannii, methicillin-resistant Staphylococcus aureus and other pathogen load from infected lesions better than conventional antibiotics. In the current study we sought to produce and characterize a novel delivery system, suitable for immediate and convenient application in non-hospital environments. The APO monomer was incorporated into polyvinyl alcohol nanofibers and the complex was polymerized into a solid patch dressing. Mice were subjected to skin abrasion where the wounds were either left uninfected or were inoculated with a near lethal dose of multidrug resistant A. baumannii strain. Analyzed after 3 days, APO monomer-containing patches improved wound appearance significantly better than polymer patches without antibiotics. When compared to colistin, the APO patches accelerated wound healing, and statistically significantly reduced wound size and wound bacterial load. The in vivo antimicrobial effect was more extensive than after intramuscular administration of the peptide drug, by using only one tenth of the active pharmaceutical ingredient. These data suggest that the APO monomer-impregnated nanofiber dressing can be developed as an economical first-line treatment option to skin injuries in general and battlefield burn and blast injuries in particular.
Asunto(s)
Infecciones por Acinetobacter/tratamiento farmacológico , Acinetobacter baumannii/efectos de los fármacos , Péptidos Catiónicos Antimicrobianos/administración & dosificación , Portadores de Fármacos/química , Nanofibras/química , Alcohol Polivinílico/química , Piel/microbiología , Infecciones por Acinetobacter/microbiología , Acinetobacter baumannii/crecimiento & desarrollo , Animales , Péptidos Catiónicos Antimicrobianos/química , Química Farmacéutica , Sistemas de Liberación de Medicamentos , Humanos , Ratones , Ratones Endogámicos C57BL , Piel/lesionesRESUMEN
BACKGROUND: BRCA mutation-associated (BRCAmut) breast cancer represents a heterogeneous group displaying certain molecular features. Claudin-low breast cancers (CLBC) overlap with characteristics of BRCAmut tumors; therefore, we have investigated whether these are identical subtypes. METHODS: Using public gene expression data, CLDN, CDH1, 9-cell line claudin-low predictor (9CLCLP) and PAM50 expression was evaluated in BRCAmut and BRCA wild-type (BRCAwt) breast cancer cases focusing on their possible overlap with the CLBC subtype. A separate formalin-fixed, paraffin-embedded (FFPE) cohort of 22 BRCAmut and 19 BRCAwt tumor tissues was used for immunohistochemical examination of AR, CD24, CD44, CK5/6, claudin-1, -3, -4 and -7, E-cadherin, EGFR, estrogen receptor (ER), EZH2, HER2, Ki67, p53, progesterone receptor (PgR) and vimentin expression. RESULTS: In the data sets, CLDN1 (ROC = 0.785, p < 0.001), CDH1 (ROC = 0.785, p < 0.001), CLDN7 (ROC = 0.723, p < 0.001), CLDN3 (ROC = 0.696, p = 0.020) and CLDN4 (ROC = 0.685, p = 0.027) were expressed at higher level in BRCAmut than BRCAwt tumor tissue. The PAM50 subtype differed from the assigned immunohistochemistry (IHC)-based subtype in 30%. Based on accessible 9CLCLP predictor genes, BRCAmut breast cancer does not display the claudin-low phenotype. Utilizing FFPE samples, claudins were evidently expressed in both BRCAmut and BRCAwt cases. However, at the protein level, only claudin-3 expression was higher in BRCAmut tumors, while claudin-1, -4 and -7 and E-cadherin expression was lower compared to BRCAwt cases. A CD24low/CD44high phenotype was found in BRCAmut tumors upon comparison with BRCAwt cases (p < 0.001 and p = 0.001, respectively). CONCLUSIONS: There is a prominent correlation between the genes under focus herein and BRCA mutation status. BRCAmut tumors bear stem cell characteristics displaying a distinct cell adhesion molecule profile characterized by high expression of CDH1 and CLDN4 according to public gene expression data set analysis, and higher claudin-3 expression as detected by IHC; thus, BRCAmut breast carcinomas are not identical with the previously identified claudin-low subtype of breast cancer.