RESUMEN

Psoriasis, a chronic immune-mediated inflammatory skin disease, is characterized by dysregulated keratinocyte proliferation. The EF-hand calcium binding protein S100A7 has been found to be overexpressed in psoriatic keratinocytes. It is know that S100A7 may interact with Jab1, a cofactor that stabilizes c-Jun. Jab1 is known to downregulate the expression of the cell cycle inhibitor p27Kip1 in some cancer models. In this study, we aimed to investigate the possible interaction between S100A7 and Jab1 and the downstream effects on p27 Kip1 expression in normal human keratinocyte cells transfected with S100A7 CRISPR activation plasmid and in archival psoriatic skin samples. Our results showed that the upregulated S100A7 colocalizes with Jab1 at the nuclear level in transfected cells and psoriatic skin samples. We also showed a differential protein expression of Jab1 between cytoplasmic and nuclear compartments, thus suggesting Jab1 translocation from nucleus to cytoplasm. p27 Kip1 protein expression patterns would imply a translocation from nucleus and a subsequent degradation of this protein. The upregulation of S1007 and its interaction with Jab1 would contribute to the p27 Kip1 -dependent impaired proliferation that characterizes psoriatic skin.

Asunto(s)

Complejo del Señalosoma COP9/metabolismo , Sistemas CRISPR-Cas , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Queratinocitos/metabolismo , Péptido Hidrolasas/metabolismo , Psoriasis/metabolismo , Proteína A7 de Unión a Calcio de la Familia S100/metabolismo , Complejo del Señalosoma COP9/genética , Estudios de Casos y Controles , Núcleo Celular/metabolismo , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/genética , Citoplasma/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Queratinocitos/citología , Péptido Hidrolasas/genética , Psoriasis/genética , Psoriasis/patología , Proteína A7 de Unión a Calcio de la Familia S100/antagonistas & inhibidores , Proteína A7 de Unión a Calcio de la Familia S100/genética

RESUMEN

BACKGROUND: A growing body of evidence shows an increased risk of deep vein thrombosis (DVT) among cancer patients. Novel markers are needed to identify patients prone to develop DVT. The aim of the present study was to determine whether IL-6-174 G > C and MMP-9-1562 C > T polymorphisms may influence the development of DVT in cancer patients. METHODS: Polymorphisms of IL-6 and MMP-9 were analyzed in 320 DNA samples from cancer patients (DVT+ and DVT-) and in 215 healthy donors. IL-6 and MMP-9 plasma levels were also measured by ELISA. RESULTS: Distribution of -174 IL-6 genotype and -1562 MMP-9 were similar between healthy controls and DVT- cancer cases (OR = 0.98 and 1.04, respectively). Different results were obtained by compared healthy controls with DVT+ cancer patients. -174 IL-6 GG polymorphism was associated to DVT (OR = 2.07; 95% CI: 1.30-3.30), as well as -1562 MMP-9 CC polymorphism (OR = 2.60; 95% CI: 1.48-4.57). CONCLUSION: The results of the present study support a model in which the GG and CC genotypes, respectively for IL-6-174 G > C and MMP-9-1562 C > T polymorphisms, are associated with a risk of DVT in cancer patients by inducing the release of IL-6 with subsequent increment of MMP-9. Overall, these findings may contribute to the management of DVT in cancer patients.

Asunto(s)

Predisposición Genética a la Enfermedad , Interleucina-6/genética , Metaloproteinasa 9 de la Matriz/genética , Neoplasias/genética , Polimorfismo de Nucleótido Simple/genética , Trombosis de la Vena/complicaciones , Trombosis de la Vena/genética , Anciano , Estudios de Casos y Controles , Intervalos de Confianza , Femenino , Humanos , Interleucina-6/sangre , Leucocitos Mononucleares/enzimología , Masculino , Metaloproteinasa 9 de la Matriz/sangre , Persona de Mediana Edad , Neoplasias/sangre , Neoplasias/complicaciones , Neoplasias/enzimología , Oportunidad Relativa , Factores de Riesgo , Trombosis de la Vena/sangre , Trombosis de la Vena/enzimología

RESUMEN

The Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascades are often activated by genetic alterations in upstream signaling molecules such as receptor tyrosine kinases (RTK). Targeting these pathways is often complex and can result in pathway activation depending on the presence of upstream mutations (e.g., Raf inhibitors induce Raf activation in cells with wild type (WT) RAF in the presence of mutant, activated RAS) and rapamycin can induce Akt activation. Targeting with inhibitors directed at two constituents of the same pathway or two different signaling pathways may be a more effective approach. This review will first evaluate potential uses of Raf, MEK, PI3K, Akt and mTOR inhibitors that have been investigated in pre-clinical and clinical investigations and then discuss how cancers can become insensitive to various inhibitors and potential strategies to overcome this resistance.

Asunto(s)

Antineoplásicos/uso terapéutico , Resistencia a Antineoplásicos , Mutación/genética , Neoplasias/tratamiento farmacológico , Línea Celular Tumoral , Quinasas MAP Reguladas por Señal Extracelular/antagonistas & inhibidores , Quinasas MAP Reguladas por Señal Extracelular/genética , Humanos , Quinasas Quinasa Quinasa PAM/antagonistas & inhibidores , Quinasas Quinasa Quinasa PAM/genética , Neoplasias/genética , Neoplasias/patología , Fosfohidrolasa PTEN/antagonistas & inhibidores , Fosfohidrolasa PTEN/genética , Fosfatidilinositol 3-Quinasas/genética , Inhibidores de las Quinasa Fosfoinosítidos-3 , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/genética , Transducción de Señal , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/genética , Proteínas ras/antagonistas & inhibidores , Proteínas ras/genética

RESUMEN

The Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascades are often activated by genetic alterations in upstream signaling molecules such as receptor tyrosine kinases (RTK). Certain components of these pathways, RAS, NF1, BRAF, MEK1, DUSP5, PP2A, PIK3CA, PIK3R1, PIK3R4, PIK3R5, IRS4, AKT, NFKB1, MTOR, PTEN, TSC1, and TSC2 may also be activated/inactivated by mutations or epigenetic silencing. Upstream mutations in one signaling pathway or even in downstream components of the same pathway can alter the sensitivity of the cells to certain small molecule inhibitors. These pathways have profound effects on proliferative, apoptotic and differentiation pathways. Dysregulation of components of these cascades can contribute to: resistance to other pathway inhibitors, chemotherapeutic drug resistance, premature aging as well as other diseases. This review will first describe these pathways and discuss how genetic mutations and epigenetic alterations can result in resistance to various inhibitors.

Asunto(s)

Proteínas Quinasas Activadas por Mitógenos/genética , Mutación , Fosfohidrolasa PTEN/genética , Fosfatidilinositol 3-Quinasas/genética , Proteínas Proto-Oncogénicas c-akt/genética , Serina-Treonina Quinasas TOR/genética , Proteínas ras/genética , Animales , Quinasas MAP Reguladas por Señal Extracelular/genética , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Humanos , Quinasas Quinasa Quinasa PAM/genética , Quinasas Quinasa Quinasa PAM/metabolismo , Sistema de Señalización de MAP Quinasas , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Fosfohidrolasa PTEN/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismo , Quinasas raf/genética , Quinasas raf/metabolismo , Proteínas ras/metabolismo

RESUMEN

NECL-5 is involved in regulating cell-cell junctions, in cooperation with cadherins, integrins and platelet-derived growth factor receptor, that are essential for intercellular communication. Its role in malignant transformation was previously described. It has been reported that transformation of melanocytes is associated with altered expression of adhesion molecules suggesting the potential involment of NECL-5 in melanoma development and prognosis. To shed light on this issue, the expression and the role of NECL-5 in melanoma tissues was investigated by bioinformatic and molecular approaches. NECL-5 was up-regulated both at the mRNA and the protein levels in WM35, M14 and A375 cell lines compared with normal melanocytes. A subsequent analysis in primary and metastatic melanoma specimens confirmed "in vitro" findings. NECL-5 overexpression was observed in 53 of 59 (89.8%) and 12 of 12 (100%), primary melanoma and melanoma metastasis, respectively; while, low expression of NECL-5 was detected in 12 of 20 (60%) benign nevi. A significant correlation of NECL-5 overexpression was observed with most of known negative melanoma prognostic factors, including lymph-node involvement (P = 0.009) and thickness (P = 0.004). Intriguingly, by analyzing the large series of melanoma samples in the Xu dataset, we identified the transcription factor YY1 among genes positively correlated with NECL-5 (r = 0.5). The concordant computational and experimental data of the present study indicate that the extent of NECL-5 expression correlates with melanoma progression.

Asunto(s)

Moléculas de Adhesión Celular/metabolismo , Melanoma/metabolismo , Receptores Virales/genética , Receptores Virales/metabolismo , Neoplasias Cutáneas/metabolismo , Factor de Transcripción YY1/biosíntesis , Biomarcadores de Tumor/biosíntesis , Adhesión Celular , Moléculas de Adhesión Celular/biosíntesis , Línea Celular Tumoral , Movimiento Celular/genética , Transformación Celular Neoplásica/metabolismo , Progresión de la Enfermedad , Femenino , Humanos , Uniones Intercelulares , Masculino , Melanocitos/metabolismo , Persona de Mediana Edad , Interferencia de ARN , ARN Mensajero/biosíntesis , ARN Interferente Pequeño

RESUMEN

Over the past few years, significant advances have occurred in both our understanding of the complexity of signal transduction pathways as well as the isolation of specific inhibitors which target key components in those pathways. Furthermore critical information is being accrued regarding how genetic mutations can affect the sensitivity of various types of patients to targeted therapy. Finally, genetic mechanisms responsible for the development of resistance after targeted therapy are being discovered which may allow the creation of alternative therapies to overcome resistance. This review will discuss some of the highlights over the past few years on the roles of key signaling pathways in various diseases, the targeting of signal transduction pathways and the genetic mechanisms governing sensitivity and resistance to targeted therapies.

Asunto(s)

Antineoplásicos/uso terapéutico , Terapia Molecular Dirigida , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Transducción de Señal/efectos de los fármacos , Animales , Diseño de Fármacos , Resistencia a Antineoplásicos , Regulación Neoplásica de la Expresión Génica , Humanos , Mutación , Neoplasias/enzimología , Neoplasias/genética , Neoplasias/patología , Transducción de Señal/genética

RESUMEN

Dysregulated signaling through the Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways is often the result of genetic alterations in critical components in these pathways or upstream activators. Unrestricted cellular proliferation and decreased sensitivity to apoptotic-inducing agents are typically associated with activation of these pro-survival pathways. This review discusses the functions these pathways have in normal and neoplastic tissue growth and how they contribute to resistance to apoptotic stimuli. Crosstalk and commonly identified mutations that occur within these pathways that contribute to abnormal activation and cancer growth will also be addressed. Finally the recently described roles of these pathways in cancer stem cells, cellular senescence and aging will be evaluated. Controlling the expression of these pathways could ameliorate human health.

Asunto(s)

Envejecimiento/metabolismo , Neoplasias/metabolismo , Transducción de Señal/fisiología , Envejecimiento/efectos de los fármacos , Envejecimiento/genética , Animales , Apoptosis , Proliferación Celular , Senescencia Celular , Femenino , Humanos , Sistema de Señalización de MAP Quinasas , Masculino , Ratones , Modelos Biológicos , Mutación , Neoplasias/genética , Neoplasias/terapia , Fosfohidrolasa PTEN , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Serina-Treonina Quinasas TOR/metabolismo , Quinasas raf/metabolismo

RESUMEN

The Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascades are often activated by genetic alterations in upstream signaling molecules such as receptor tyrosine kinases (RTK). Integral components of these pathways, Ras, B-Raf, PI3K, and PTEN are also activated/inactivated by mutations. These pathways have profound effects on proliferative, apoptotic and differentiation pathways. Dysregulation of these pathways can contribute to chemotherapeutic drug resistance, proliferation of cancer initiating cells (CICs) and premature aging. This review will evaluate more recently described potential uses of MEK, PI3K, Akt and mTOR inhibitors in the proliferation of malignant cells, suppression of CICs, cellular senescence and prevention of aging. Ras/Raf/MEK/ERK and Ras/PI3K/PTEN/Akt/mTOR pathways play key roles in the regulation of normal and malignant cell growth. Inhibitors targeting these pathways have many potential uses from suppression of cancer, proliferative diseases as well as aging.

Asunto(s)

Quinasas MAP Reguladas por Señal Extracelular/antagonistas & inhibidores , Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Fosfohidrolasa PTEN/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Quinasas raf/antagonistas & inhibidores , Proteínas ras/antagonistas & inhibidores , Línea Celular Tumoral , Transformación Celular Neoplásica/metabolismo , Transformación Celular Neoplásica/patología , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/enzimología , Fosfohidrolasa PTEN/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Quinasas raf/metabolismo , Proteínas ras/metabolismo

RESUMEN

The addition of anti-CD20 monoclonal antibody (rituximab) to chemotherapy has significantly improved survival in B-cell lymphoma. However, a substantial number of patients relapse after treatment with rituximab. Understanding of anti-CD20 antibody molecular function may facilitate the development of pharmacologic strategies to overcome resistance. Cell death have been demonstrated to be caused by rituximab binding to CD20 throughout direct and indirect mechanisms. The direct mechanism comprises growth inhibition, induction of apoptosis and sensitization of cells to chemotherapy. While, the indirect mechanisms to Rituximab include complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC). However, these mechanisms are still poorly understood. To shed light on this issue, we have analyzed the most significant results showing the role of Rituximab as a signal-inducing antibody and as a chemosensitizing agent through negative regulation of major survival pathways. Mechanisms of resistance to Rituximab are also discussed. Additionally, studies here reported show that, cellular targets are modified after treatment with Rituximab and may become useful for novel therapeutic strategies in the treatment of patients resistant to standard therapy.

Asunto(s)

Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Antígenos CD20/inmunología , Resistencia a Antineoplásicos/inmunología , Anticuerpos Monoclonales de Origen Murino/inmunología , Citotoxicidad Celular Dependiente de Anticuerpos/inmunología , Antígenos CD20/metabolismo , Apoptosis/efectos de los fármacos , Vía Clásica del Complemento/inmunología , Humanos , Linfoma de Células B/tratamiento farmacológico , Linfoma no Hodgkin/tratamiento farmacológico , FN-kappa B/antagonistas & inhibidores , Inhibidores de las Quinasa Fosfoinosítidos-3 , Proteínas Proto-Oncogénicas c-akt , Rituximab , Factor de Transcripción STAT3/antagonistas & inhibidores , Proteína bcl-X/antagonistas & inhibidores , Receptor fas/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Familia-src Quinasas/metabolismo

RESUMEN

Survival strategies adopted by tumor cells in response to a hypoxic stress include activation of hypoxia-inducible factor 1 (HIF-1) and autophagy. However, the importance and the function of each molecular response is not well defined. In the present study, we investigated invasiveness, migration, matrix metalloproteinases (MMPs) activity, and cell survival of MDA-MB-231 cells under normoxia, hypoxia, and hypoxia/reoxygenation (H/R). Moreover, to assess the importance of hypoxia and autophagy on the parameters studied, cells were either left untreated or treated with Chetomin (a selective inhibitor of HIF-1alpha) or trifluoperazine (TFP, an activator of autophagy). We found that hypoxia and H/R stimulated invasiveness and migration of MDA-MB-231 cells with an increased MMP-2 activity. Chetomin and TFP differently regulated the cellular behavior under the oxygenation conditions studied. In fact, Chetomin was most effective in inhibiting cell invasion, MMPs activity, and cell survival under hypoxia but not normoxia or H/R. By contrast, TFP inhibition of cell invasion, migration, and cell survival was independent from oxygenation conditions. TFP-induced autophagy was inhibited by light chain protein 3 (LC3) silencing or 3-methyladenine (3MA) treatment. In fact, LC3-silenced cells were able to invade in the presence of TFP without any GATE16 processing and p62 degradation. Immunofluorescence assay showed that LC3 silencing inhibited TFP-induced autophagosome formation. However, we also showed that both TPF treatment and LC3 silencing caused cytoskeleton impairments suggesting a possible interaction between LC3 and cytoskeleton components. In conclusion, our study shows that hypoxia and autophagy by acting on common (HIF-1alpha) or separate (MMPs, cytoskeleton) targets differently regulate cell invasion, MMPs activity, and survival.

Asunto(s)

Autofagia/fisiología , Invasividad Neoplásica/fisiopatología , Neoplasias/metabolismo , Neoplasias/fisiopatología , Adenina/análogos & derivados , Adenina/farmacología , Autofagia/efectos de los fármacos , Hipoxia de la Célula/fisiología , Línea Celular Tumoral , Ensayos de Migración Celular , Movimiento Celular/fisiología , Supervivencia Celular/fisiología , Citoesqueleto/metabolismo , Disulfuros/farmacología , Antagonistas de Dopamina/farmacología , Matriz Extracelular/enzimología , Femenino , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/antagonistas & inhibidores , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Alcaloides Indólicos/farmacología , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasas de la Matriz/metabolismo , Proteínas Asociadas a Microtúbulos/genética , Consumo de Oxígeno/fisiología , Fagosomas/efectos de los fármacos , Fagosomas/metabolismo , Interferencia de ARN , Trifluoperazina/farmacología

RESUMEN

PURPOSE: Prostate cancer remains the second most frequent cause of tumor-related deaths in the Western world. Additional markers for the identification of prostate cancer development and progression are needed. Osteopontin (OPN), which activates matrix metalloproteinases (MMP), is considered a prognostic biomarker in several cancers. "In silico" and experimental approaches were used to determine whether OPN-mediated MMP activation may be a signal of prostate cancer progression. EXPERIMENTAL DESIGN: Pearson correlation coefficients were computed for each OPN/MMP pair across seven publicly available prostate cancer gene expression data sets. Using Gene Set Enrichment Analysis, 101 cancer-related gene sets were analyzed for association with OPN and MMP-9 expression. OPN, MMP-9, MMP-2 tissue inhibitor of metalloproteinase-1 plasma levels, and MMP gelatinase activity were measured by ELISA and zymography in 96 and 92 patients with prostate cancer and benign prostatic hyperplasia, respectively, and 125 age-matched healthy men. RESULTS: Computational analyses identified a significant correlation only between MMP-9 and OPN, and showed significant enrichment scores in "cell proliferation", "genes constituting the phosphoinositide-3-kinase predictor", "proliferation signature", and "tumor metastasis" gene sets in association with both OPN and MMP-9. Plasma analyses revealed a significant increase in OPN and MMP-9 levels and activity in patients with prostate cancer in association with clinical variables (prostate-specific antigen > 4 ng/mL and Gleason score > 7). Significant correlation between OPN and MMP-9 levels were also observed. Mean plasma levels of OPN and MMP-9 decreased in patients with prostate cancer within 6 months after prostatectomy. CONCLUSIONS: The concordant computational and experimental data indicate that the extent of OPN pathway activation correlates with prostate cancer progression.

Asunto(s)

Activación Enzimática/fisiología , Metaloproteinasa 9 de la Matriz/metabolismo , Osteopontina/metabolismo , Neoplasias de la Próstata/metabolismo , Transducción de Señal/fisiología , Anciano , Progresión de la Enfermedad , Ensayo de Inmunoadsorción Enzimática , Expresión Génica , Perfilación de la Expresión Génica , Humanos , Inmunohistoquímica , Masculino , Metaloproteinasa 9 de la Matriz/genética , Persona de Mediana Edad , Osteopontina/genética , Neoplasias de la Próstata/genética

RESUMEN

Increased plasma levels of several acute phase proteins, such as C-reactive protein (CRP), have been documented among different patients with chronic renal failure (CRF). The aim of the present study was to determine whether pentraxin-3 (PTX3) is a reliable marker of inflammation in CRF. Plasma samples and monocytes were taken from 43 patients before and after undergoing haemodialysis (HD), from 45 uraemic patients (UR) without HD treatment and from 25 healthy controls. Plasma and monocyte samples were analyzed by ELISA for levels of PTX3, tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and interleukin-6 (IL-6); all of these protein levels were higher in CRF patients with respect to the controls. After HD, plasma PTX3 and cytokine levels increased. Inter- and intra-individual variations in CRP were observed in HD patients, while PTX3 plasma levels were stable. Release of PTX3, TNF-alpha, IL-1beta and IL-6 by unstimulated monocytes from patients, before and after HD, was higher with respect to UR patients and controls. After lipopolysaccharide stimulation, all values were higher in patients before HD than those in UR patients, but lower when compared to those in the controls. In contrast, no changes were observed after HD. A significant correlation among plasma PTX3 versus fibrinogen, TNF-alpha and IL-1beta was observed in HD and UR patients. Collectively, these data suggest that PTX3 protein may represent an additional and stable marker of inflammation in CRF.

Asunto(s)

Proteína C-Reactiva/metabolismo , Citocinas/metabolismo , Mediadores de Inflamación/metabolismo , Fallo Renal Crónico/patología , Componente Amiloide P Sérico/metabolismo , Anciano , Separación Celular , Citocinas/sangre , Femenino , Fibrinógeno/metabolismo , Humanos , Inflamación , Mediadores de Inflamación/sangre , Lipopolisacáridos/farmacología , Masculino , Monocitos/efectos de los fármacos , Monocitos/metabolismo , Diálisis Renal , Fracciones Subcelulares/efectos de los fármacos , Factores de Tiempo , Uremia/sangre

RESUMEN

Peripheral arterial disease (PAD) affects about 5% of the elderly population in the western world. It has been reported that PAD is associated with elevated plasma levels of the inflammatory markers. The goal of this review is to describe which proinflammatory molecules may play a role in PAD development, C-reactive protein, fibrinogen, pro-inflammatory cytokines, adhesion molecules and matrix metalloproteinases have been reported to be involved. High serum levels of both C-reactive protein and fibrinogen have been shown to be significantly associated with increasing severity of PAD. Among cytokines, IL-6 is one of the most studied in PAD. IL-6 is well recognized for its role in the acute phase inflammatory response which is characterized by production of a variety of hepatic proteins termed acute phase proteins. It has been shown that increased serum concentrations of several markers of the acute response, including IL-6, are elevated in patients with type 2 diabetes. These patients have a two-fold risk of PAD compared to those without type 2 diabetes. The G(-174)C IL-6 polymorphism has been suggested to influence IL-6 release, and its possible influence on PAD development among individuals with type 2 diabetes is discussed in this review. Further study of these molecules is justified as they appear to be involved in the development of PAD.

Asunto(s)

Mediadores de Inflamación/sangre , Enfermedades Vasculares Periféricas/sangre , Proteína C-Reactiva/metabolismo , Moléculas de Adhesión Celular/sangre , Citocinas/sangre , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/genética , Fibrinógeno/metabolismo , Humanos , Interleucina-6/sangre , Interleucina-6/genética , Metaloproteinasas de la Matriz/sangre , Modelos Biológicos , Enfermedades Vasculares Periféricas/etiología , Enfermedades Vasculares Periféricas/genética , Polimorfismo de Nucleótido Simple

RESUMEN

Psoriasis is a common cutaneous disorder characterized by abnormal epidermal differentiation, proliferation and inflammation mediated by dermal infiltrates, such as T cells, neutrophils, dendritic cells and macrophages. There are renewed interest in the role of components of the innate immune system. Cytokines such as tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL)-6, and -1beta involved in pathogenic phenomena in psoriasis are known as inducers of the acute phase response. Among the large group of acute phase reactants, C-reactive protein (CRP) and fibrinogen are of special interest in psoriasis. The PTX-3, a long pentraxin sharing similarities with the classical short proteins. Thus, considering the numerous biological roles of inflammatory cytokines and their relationship with inflammatory markers, such as CRP and fibrinogen we have investigated the role of PTX3 in psoriasis. To this aim PTX3, TNF-alpha, IL-6 and IL-1beta in plasma and in monocytic cultures by enzyme linked immunosorbent assay (ELISA) in 44 patients including severe and mild psoriasis were measured. An increased production of PTX3, both in supernatant of purified monocytes and in plasma from patients with severe psoriasis, was found. The significant correlation, between cellular production and plasma levels of PTX3 in psoriasis was found as a sign of cellular activation by monocytes/macrophages that first infiltrate the psoriatic lesion. In severe psoriasis, a significant correlation between psoriasis area and severity index (PASI) score and TNF-alpha and IL-6 levels in both supernatant of monocytes and plasma was found. In contrast, no correlation was found for IL-1beta. By immunohistochemistry and immunofluorescence, a strong PTX3 staining in fibroblasts, endothelial cells and monocytes/macrophages in severe psoriatic lesional skin was detected. Finally, a positive correlation between PTX3 and disease activity of psoriasis was observed as PASI score was elevated. These findings suggest that PTX3 could be used as a further marker of disease activity of psoriasis.

Asunto(s)

Biomarcadores/sangre , Proteína C-Reactiva/análisis , Inflamación/diagnóstico , Psoriasis/diagnóstico , Componente Amiloide P Sérico/análisis , Adulto , Artritis Psoriásica/sangre , Artritis Psoriásica/inmunología , Células Cultivadas , Progresión de la Enfermedad , Femenino , Fibrinógeno/análisis , Técnica del Anticuerpo Fluorescente , Humanos , Inmunohistoquímica , Técnicas In Vitro , Inflamación/sangre , Inflamación/inmunología , Mediadores de Inflamación/sangre , Interleucina-1/sangre , Interleucina-6/sangre , Masculino , Persona de Mediana Edad , Monocitos/metabolismo , Psoriasis/sangre , Psoriasis/inmunología , Proyectos de Investigación , Estadística como Asunto , Factor de Necrosis Tumoral alfa/análisis

RESUMEN

Basal cell carcinoma (BCC) is the most common skin cancer, and its incidence is increasing. It was proposed that the RAS oncogene significantly contributes to skin cancer development. Numerous BRAF mutations have been detected in melanoma biopsy specimens and cell lines. For the first time, in the present study, tumor biopsy specimens from 78 patients with BCC were screened for BRAF mutation within exons 11 and 15. Our results indicate that the BRAF gene does not appear to be frequently mutated in nonmelanoma skin tumors such as BCC. These data suggest that other gene alterations may cause tumor development.

Asunto(s)

Carcinoma Basocelular/genética , Proteínas Proto-Oncogénicas B-raf/genética , Neoplasias Cutáneas/genética , Biopsia , Carcinoma Basocelular/patología , Análisis Mutacional de ADN , Femenino , Humanos , Masculino , Mutación , Neoplasias Cutáneas/patología

RESUMEN

Hepatitis C virus (HCV) causes hepatitis, liver cirrhosis and hepatocellular carcinoma, and may also induce type II mixed cryoglobulinemia syndrome (MC), a disease characterized by clonal B-cell lymphoproliferations that can evolve into non-Hodgkin's lymphoma (NHL). Interleukin-1 (IL-1) is a cytokine that plays an important role in initiating the cascade of events of immunoinflammatory responses through costimulation of T lymphocytes, B-cell proliferation, induction of adhesion molecules and stimulation of the production of other inflammatory cytokines. The role of IL-1 in immunoinflammatory responses is highlighted by the presence of endogenous regulators (IL-1 receptor antagonist, soluble receptors type 1 and II, human IL-1 accessory protein) that, when secreted into the blood stream may serve as endogenous regulators of IL-1 action. The aim of this study was to evaluate whether abnormalities in the blood levels of IL-1beta IL-1 receptor antagonist, soluble IL-1 receptor type II and human IL-1 accessory protein in HCV+ patients are associated with development of MC and/or NHL. Relative to healthy controls, we observed: i) an increase in the circulating levels of IL-1beta in HCV+ patients simultaneously affected by NHL; ii) increased levels of IL-1 accessory protein in patients singly infected by HCV; iii) increase of IL-1 receptor antagonist in HCV+ patients and in those affected also by NHL with or without MC; iv) a homogeneous increase of sIL-1R type II in all the subgroup of patients. These data indicate that an attempt to increased circulating levels of IL-1 inhibitors occurs at different extent in the course of HCV infection as well as in its progression to NHL and/or MC.

Asunto(s)

Crioglobulinemia/sangre , Hepatitis C Crónica/sangre , Interleucina-1/sangre , Linfoma de Células B/sangre , Receptores de Interleucina-1/sangre , Sialoglicoproteínas/sangre , Estudios de Casos y Controles , Crioglobulinemia/virología , Femenino , Genotipo , Hepacivirus/aislamiento & purificación , Hepatitis C Crónica/virología , Humanos , Proteína Antagonista del Receptor de Interleucina 1 , Proteína Accesoria del Receptor de Interleucina-1 , Leucocitos Mononucleares/virología , Linfoma de Células B/complicaciones , Linfoma de Células B/virología , Masculino , Persona de Mediana Edad , ARN Viral/sangre , Receptores Tipo II de Interleucina-1

RESUMEN

Numerous BRAF mutations have been detected in melanoma biopsy specimens and cell lines. In contrast, several studies report lack of BRAF mutations in uveal melanoma including primary and metastatic choroidal and ciliary body melanomas. To our knowledge, for the first time, here we report a case of choroidal melanoma harboring the BRAF mutation (V600E). The activation of RAF/MEK/ERK pathway, although independent of BRAF mutation, was reported in uveal melanoma. The presence of V600E mutation indicates that the RAF/MEK/ERK pathway, in addition to cutaneous melanoma progression, may play a role in the choroidal melanoma development.

Asunto(s)

Neoplasias de la Coroides/genética , Melanoma/genética , Proteínas Proto-Oncogénicas B-raf/genética , Neoplasias de la Coroides/enzimología , Neoplasias de la Coroides/patología , Análisis Mutacional de ADN , Exones/genética , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Femenino , Humanos , Melanoma/enzimología , Melanoma/patología , Persona de Mediana Edad , Mutación , Fosfatidilinositol 3-Quinasas/genética , Quinasas raf/metabolismo

RESUMEN

Hepatitis C virus (HCV) infection is associated with chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Recent evidences have also suggested that HCV infection contributes to development of autoimmune disorders and B-cell nonHodgkin's lymphoma (NHL). Mechanisms by which HCV infection promotes B-cell NHL development remain unclear. Increased serum osteopontin (OPN) levels have been associated with several autoimmune diseases as well as a variety of cancers. However, the association between OPN and B-cell NHL or HCV-associated B-cell proliferation has not previously been reported. In the present study, we determined whether serum OPN differences were associated with HCV infection, type II mixed cryglobulinemia (MC) syndrome and B-cell NHL. Serum OPN levels were measured by capture enzyme-linked immunosorbent assay. Our results show that high serum OPN levels are associated with B-cell NHL and HCV infection. Interestingly, highest serum OPN concentrations were found among HCV-infected patients with concomitant type II MC syndrome with and without B-cell NHL. These data indicate that OPN is involved in the lymphomagenesis, especially, in the context of HCV infection and autoimmune diseases.

Asunto(s)

Crioglobulinemia/virología , Hepatitis C/complicaciones , Linfoma de Células B/virología , Sialoglicoproteínas/sangre , Estudios de Casos y Controles , Crioglobulinemia/sangre , Crioglobulinemia/complicaciones , Femenino , Hepacivirus/genética , Hepacivirus/aislamiento & purificación , Hepatitis C/sangre , Hepatitis C/virología , Humanos , Linfoma de Células B/sangre , Linfoma de Células B/clasificación , Linfoma de Células B/complicaciones , Masculino , Persona de Mediana Edad , Osteopontina , ARN Viral/sangre

RESUMEN

Mutation of BRAF has been proposed to contribute to melanoma development. However, it remains unclear whether or not BRAF mutation is associated with any particular stage of melanoma progression. Tumor biopsy specimens from patients with melanoma were analyzed to determine whether the frequency of BRAF mutation in metastatic melanoma differed from primary melanoma. BRAF mutation was present in 15 of 23 (61%) patients with primary melanoma and in 7 of 12 (58%) patients with metastatic melanoma. These results suggest that BRAF mutation in melanoma is most likely to occur prior to the development of metastatic disease.

Asunto(s)

Melanoma/genética , Melanoma/patología , Mutación/genética , Proteínas Proto-Oncogénicas B-raf/genética , Adulto , Anciano , Anciano de 80 o más Años , Biopsia , Análisis Mutacional de ADN , Femenino , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia/genética , Metástasis de la Neoplasia/patología

RESUMEN

Osteopontin (OPN) is an inflammatory cytokine highly expressed in multiple sclerosis (MS) plaques. In a previous work, we showed that four OPN polymorphisms form three haplotypes (A, B, and C) and that homozygotes for haplotype-A display lower OPN levels than non-AA subjects. In this work, we evaluated the distribution of these OPN haplotypes in 425 MS patients and 688 controls. Haplotype-A homozygotes had about 1.5 lower risk of developing MS than non-AA subjects. Clinical analysis of 288 patients showed that AA patients displayed slower switching from a relapsing remitting to a secondary progressive form and milder disease with slower evolution of disability. MS patients displayed increased OPN serum levels, which were partly due to the increased frequency of non-AA subjects. Moreover in AA patients, OPN levels were higher than in AA controls and similar to those found in both non-AA patients and controls, which suggests a role of the activated immune response. These data suggest that OPN genotypes may influence MS development and progression due to their influence on OPN levels.

Asunto(s)

Haplotipos/genética , Esclerosis Múltiple/genética , Sialoglicoproteínas/genética , Adulto , Progresión de la Enfermedad , Ensayo de Inmunoadsorción Enzimática/estadística & datos numéricos , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/fisiopatología , Osteopontina , Estabilidad del ARN , ARN Mensajero/metabolismo , Índice de Severidad de la Enfermedad , Sialoglicoproteínas/sangre , Regulación hacia Arriba