Defective Bcl-2 expression in memory B cells from common variable immunodeficiency patients.

Common variable immunodeficiency (CVID) is a primary immunodeficiency characterized by hypogammaglobulinemia and different degrees of B cell compartment alteration. Memory B cell differentiation requires the orchestrated activation of several intracellular signaling pathways that lead to the activation of a number of factors, such as nuclear factor kappa B (NF-κB) which, in turn, promote transcriptional programs required for long-term survival. The aim of this study was to determine if disrupted B cell differentiation, survival and activation in B cells in CVID patients could be related to defects in intracellular signaling pathways. For this purpose, we selected intracellular readouts that reflected the strength of homeostatic signaling pathways in resting cells, as the protein expression levels of the Bcl-2 family which transcription is promoted by NF-κB. We found reduced Bcl-2 protein levels in memory B cells from CVID patients. We further explored the possible alteration of this crucial prosurvival signaling pathway in CVID patients by analysing the expression levels of mRNAs from anti-apoptotic proteins in naive B cells, mimicking T cell-dependent activation in vitro with CD40L and interleukin (IL)-21. BCL-XL mRNA levels were decreased, together with reduced levels of AICDA, after naive B-cell activation in CVID patients. The data suggested a molecular mechanism for this tendency towards apoptosis in B cells from CVID patients. Lower Bcl-2 protein levels in memory B cells could compromise their long-term survival, and a possible less activity of NF-κB in naive B cells, may condition an inabilityto increase BCL-XL mRNA levels, thus not promoting survival in the germinal centers.

Influence of social cognition as a mediator between cognitive reserve and psychosocial functioning in patients with first episode psychosis.

BACKGROUND: Social cognition has been associated with functional outcome in patients with first episode psychosis (FEP). Social cognition has also been associated with neurocognition and cognitive reserve. Although cognitive reserve, neurocognitive functioning, social cognition, and functional outcome are related, the direction of their associations is not clear. Therefore, the main aim of this study was to analyze the influence of social cognition as a mediator between cognitive reserve and cognitive domains on functioning in FEP both at baseline and at 2 years. METHODS: The sample of the study was composed of 282 FEP patients followed up for 2 years. To analyze whether social cognition mediates the influence of cognitive reserve and cognitive domains on functioning, a path analysis was performed. The statistical significance of any mediation effects was evaluated by bootstrap analysis. RESULTS: At baseline, as neither cognitive reserve nor the cognitive domains studied were related to functioning, the conditions for mediation were not satisfied. Nevertheless, at 2 years of follow-up, social cognition acted as a mediator between cognitive reserve and functioning. Likewise, social cognition was a mediator between verbal memory and functional outcome. The results of the bootstrap analysis confirmed these significant mediations (95% bootstrapped CI (-10.215 to -0.337) and (-4.731 to -0.605) respectively). CONCLUSIONS: Cognitive reserve and neurocognition are related to functioning, and social cognition mediates in this relationship.

A comparative MRI study for white matter hyperintensities detection: 2D-FLAIR, FSE PD 2D, 3D-FLAIR and FLAIR MIP.

OBJECTIVE: The main objective of this study was to not only determine the most appropriate sequence for the analysis of white matter hyperintensities (WMH) on MRI but also to confirm the advantage of three-dimensional (3D) acquisition, as it has been suggested in previous studies, and to test the convenience of using maximum intensity projection (MIP) algorithms on 3D-fluid-attenuated inversion-recovery (FLAIR) images for a quicker evaluation of brain MR studies. METHODS: The number of WMH was compared in 40 patients and a control group of 10 volunteers using 4 different imaging modalities: two dimensional (2D)-FLAIR, 2D fast spin echo proton density (FSE PD), 3D-FLAIR and FLAIR MIP. Four experienced radiologists took part in the imaging analysis. All studies were performed on a 1.5-T whole-body MR unit. RESULTS: A statistically significant difference between the number of lesions detected on 3D acquisitions (FLAIR CUBE® or FLAIR MIP sequences) compared with those on 2D-FLAIR or 2D FSE PD was demonstrated. There is no significant difference between 3D-FLAIR and FLAIR MIP, therefore both of them can be used with similar results. CONCLUSION: 3D-FLAIR sequences should replace conventional 2D-FLAIR and/or FSE PD sequences in the MR acquisition protocol when WMH are suspected. MIP reformat algorithms are less time consuming, therefore these can also be used to simplify the detection. ADVANCES IN KNOWLEDGE: 3D sequences are superior for WMH depiction. Moreover, MIP algorithms allow easier analyses with similar results.

Escleritis necrotizante c-ANCA positivo y esclerosis múltiple compatible con Wegener ocular: tratamiento con rituximab / C-ANCA positive necrotising scleritis and multiple sclerosis compatible with ocular Wegener: treatment with rituximab

CASO CLÍNICO: Paciente diagnosticada de escleritis necrotizante c-ANCA+, seudotumor orbitario y posible esclerosis múltiple; en 2003 realizó tratamiento con ciclofosfamida oral y esteroides con respuesta parcial. Entre 2005-2010 sufrió episodios oculares autolimitados. En 2010 se realizó un primer trasplante escleral, con mala evolución. Se inició tratamiento con rituximab y se realizó segundo injerto con buena evolución. A los 12 meses no se observaron cambios en resonancia magnética y el segundo injerto cicatrizó. DISCUSIÓN: La enfermedad de Wegener con afectación limitada a la órbita y/o el ojo es una entidad poco frecuente. La anatomía patológica, analítica de sangre, clínica y buena respuesta al tratamiento son clave para su diagnóstico

CASE REPORT: A patient diagnosed with necrotizing scleritis, c-ANCA + an orbital pseudotumour, and possible multiple sclerosis in 2003 was treated with oral cyclophosphamide and steroids with partial response. Between 2005-2010 she suffered self-limited episodes. In 2010 a first scleral transplant was performed with poor outcome. She was treated with rituximab, and a second graft was performed with good results. At 12 months there was no change in magnetic resonance and the second graft healed. DISCUSSION: Wegener's disease with limited involvement of the orbit and/or the eye is a rare condition. The histopathology, blood analysis, symptoms and good response to treatment are the key to its diagnosis

[C-ANCA positive necrotising scleritis and multiple sclerosis compatible with ocular Wegener: treatment with rituximab]. / Escleritis necrotizante c-ANCA positivo y esclerosis múltiple compatible con Wegener ocular: tratamiento con rituximab.

CASE REPORT: A patient diagnosed with necrotizing scleritis, c-ANCA+ an orbital pseudotumour, and possible multiple sclerosis in 2003 was treated with oral cyclophosphamide and steroids with partial response. Between 2005-2010 she suffered self-limited episodes. In 2010 a first scleral transplant was performed with poor outcome. She was treated with rituximab, and a second graft was performed with good results. At 12 months there was no change in magnetic resonance and the second graft healed. DISCUSSION: Wegener's disease with limited involvement of the orbit and/or the eye is a rare condition. The histopathology, blood analysis, symptoms and good response to treatment are the key to its diagnosis.

Análisis de la adecuación de las indicaciones clínicas en los estudios de neurorradiología / Analysis of the appropriateness of the clinical indications for neuroimaging studies

Objetivos. Conocer las indicaciones clínicas más frecuentes que dan lugar a las distintas pruebas diagnósticas en neurorradiología. Analizar para cada tipo de exploración la rentabilidad diagnóstica de la prueba solicitada según la indicación clínica. Cuantificar el número de exploraciones radiológicas adicionales generadas como consecuencia de la detección de patología en el estudio inicial o de la solicitud de una exploración inadecuada por parte del médico peticionario. Material y métodos. Se ha revisado la indicación clínica y el informe radiológico de las exploraciones de tomografía computarizada (TC) y resonancia magnética (RM) de cerebro, cabeza y cuello realizadas durante un período de 30 días en tres hospitales de nivel intermedio de similares características. Se contabilizan los estudios que presentan hallazgos patológicos y los normales. Se recogen aquellos casos que precisaron de algún estudio radiológico adicional. Resultados. La TC de cerebro y la RM cerebral son las exploraciones más solicitadas. En el área de neurología son la cefalea, el traumatismo craneoencefálico y el déficit neurológico agudo las indicaciones que justifican la mayoría de los estudios. En el área otorrinolaringológica, la pérdida de audición es la indicación de mayor demanda. El porcentaje de exploraciones patológicas oscila entre el 6 y el 71% según la indicación clínica. En un 3,5% de los casos se precisaron exploraciones radiológicas adicionales. Conclusiones. La mayoría de las exploraciones neurorradiológicas derivan de un grupo de indicaciones clínicas especialmente prevalentes; sin embargo, en muchos casos el grado de concordancia entre el diagnóstico clínico y el radiológico presenta un amplio margen de mejora (AU)

Objectives. To determine the most common clinical indications for different diagnostic neuroimaging tests. To analyze the diagnostic yield for each type of test in function of its clinical indication. To quantify the number of additional imaging tests generated as a consequence of pathological findings on the initial study or of the physician's requesting an inappropriate study. Material and methods. We reviewed the clinical indications and radiological report for computed tomography (CT) and magnetic resonance imaging (MRI) studies of the brain, head, and neck carried out during a 30-day period in three intermediate level hospitals with similar characteristics. We counted the studies with pathological findings and those with normal findings. We recorded cases that required additional imaging studies. Results. CT and MRI studies of the brain are the most frequently requested neuroimaging studies. The most common indications for examinations requested from the neurology department were headache, head trauma, and acute neurological deficit. The most common indication for examinations requested from the ear, nose, and throat department was hearing loss. The percentage of examinations with pathological findings ranged from 6% to 71% depending on the clinical indication. Additional imaging studies were necessary in 3.5% of the cases. Conclusions. Most neuroimaging studies are performed for especially prevalent clinical indications; however, in many cases the degree of concordance between the clinical and radiological diagnosis shows there is much room for improvement (AU)

IGFBP-3 methylation-derived deficiency mediates the resistance to cisplatin through the activation of the IGFIR/Akt pathway in non-small cell lung cancer.

Although many cancers initially respond to cisplatin (CDDP)-based chemotherapy, resistance frequently develops. Insulin-like growth factor-binding protein-3 (IGFBP-3) silencing by promoter methylation is involved in the CDDP-acquired resistance process in non-small cell lung cancer (NSCLC) patients. Our purpose is to design a translational-based profile to predict resistance in NSCLC by studying the role of IGFBP-3 in the phosphatidyl inositol 3-kinase (PI3K) signaling pathway. We have first examined the relationship between IGFBP-3 expression regulated by promoter methylation and activation of the epidermal growth factor receptor (EGFR), insulin-like growth factor-I receptor (IGFIR) and PI3K/AKT pathways in 10 human cancer cell lines and 25 NSCLC patients with known IGFBP-3 methylation status and response to CDDP. Then, to provide a helpful tool that enables clinicians to identify patients with a potential response to CDDP, we have calculated the association between our diagnostic test and the true outcome of analyzed samples in terms of cisplatin IC50; the inhibitory concentration that kills 50% of the cell population. Our results suggest that loss of IGFBP-3 expression by promoter methylation in tumor cells treated with CDDP may activate the PI3K/AKT pathway through the specific derepression of IGFIR signaling, inducing resistance to CDDP. This study also provides a predictive test for clinical practice with an accuracy and precision of 0.84 and 0.9, respectively, (P=0.0062). We present a biomarker test that could provide clinicians with a robust tool with which to decide on the use of CDDP, improving patient clinical outcomes.

Analysis of the appropriateness of the clinical indications for neuroimaging studies.

OBJECTIVES: To determine the most common clinical indications for different diagnostic neuroimaging tests. To analyze the diagnostic yield for each type of test in function of its clinical indication. To quantify the number of additional imaging tests generated as a consequence of pathological findings on the initial study or of the physician's requesting an inappropriate study. MATERIAL AND METHODS: We reviewed the clinical indications and radiological report for computed tomography (CT) and magnetic resonance imaging (MRI) studies of the brain, head, and neck carried out during a 30-day period in three intermediate level hospitals with similar characteristics. We counted the studies with pathological findings and those with normal findings. We recorded cases that required additional imaging studies. RESULTS: CT and MRI studies of the brain are the most frequently requested neuroimaging studies. The most common indications for examinations requested from the neurology department were headache, head trauma, and acute neurological deficit. The most common indication for examinations requested from the ear, nose, and throat department was hearing loss. The percentage of examinations with pathological findings ranged from 6% to 71% depending on the clinical indication. Additional imaging studies were necessary in 3.5% of the cases. CONCLUSIONS: Most neuroimaging studies are performed for especially prevalent clinical indications; however, in many cases the degree of concordance between the clinical and radiological diagnosis shows there is much room for improvement.

MicroRNAs as novel epigenetic biomarkers for human cancer

MicroRNAs (miRNAs) are regulatory, non-coding RNAs that are approximately 22 nucleotides in length. Nearly 1000 unique miRNAs encoded in the human genome have been identified, shedding new light on the posttranscriptional regulation of more than one-third of human genes. These miRNAs are involved in numerous biological processes, including development, differentiation, apoptosis, homeostasis and stem cell biology. Aberrant miRNA expression patterns also play a substantial role in carcinogenesis. It is believed that genetic and epigenetic regulation is responsible for changes in miRNA expression in cancer development, however the exact mechanisms remain unclear. miRNAs are involved in almost all aspects of cancer biology such as apoptosis, invasion, metastasis and angiogenesis. Thanks to this wide range of biological functions, the analysis of changes in overall miRNA expression occurring within human tumours has helped identify miRNA signatures associated with diagnosis, staging, progression, prognosis and response to treatment. This positions miRNA- targeting therapeutics as a novel and promising tool for cancer treatment (AU)

Monoclonal antibodies for medical oncology: a few critical perspectives

Incorporation of antibodies as weapons for cancer therapy has meant a turning point in the survival, clinical and radiological response of many oncology patients. These drugs are effective, well designed missiles that either alone or in combination with chemotherapy are unavoidable weapons for breast, lung and colon cancer as well as for haematological tumours. In addition, incoming monoclonal antibodies (mAbs) and folder-like proteins will be incorporated into clinical practice in the near future. This review aims to discuss a few imminent indications of current mAbs that are used for solid tumours and to briefly introduce future mAbs to the reader (AU)

DUSP1/MKP1 promotes angiogenesis, invasion and metastasis in non-small-cell lung cancer.

DUSP1/MKP1 is a dual-specific phosphatase that regulates MAPKs activity, with an increasingly recognized role in tumor biology. To understand more about the involvement of DUSP1 in lung cancer, we performed gene expression analyses of parental and DUSP1-interfered H460 non-small-cell lung cancer (NSCLC) cells. Downregulation of DUSP1 induced changes in the expression levels of genes involved in specific biological pathways, including angiogenesis, MAP kinase phosphatase activity, cell-cell signaling, growth factor and tyrosine-kinase receptor activity. Changes in the expression of some of these genes were due to modulation of c-Jun-N-terminal kinase and/or p38 activity by DUSP1. Complementary functional assays were performed to focus on the implication of DUSP1 in angiogenesis and metastasis. In H460 cells, interference of DUSP1 resulted in a diminished capacity to invade through Matrigel, to grow tumors in nude mice and also to induce metastasis through tail-vein injection. Furthermore, the angiogenic potential of H460 cells was also impaired, correlating with a decrease in VEGFC production and indicating that DUSP1 could be required to induce angiogenesis. Finally, we studied whether a similar relationship occurred in patients. In human NSCLC specimens, DUSP1 was mainly expressed in those tumor cells close to CD31 vascular structures and a statistically significant correlation was found between VEGFC and DUSP1 expression. Overall, these results provide evidence for a role of DUSP1 in angiogenesis, invasion and metastasis in NSCLC.

CT and MRI Correlations in Patients with Suspected Cholesteatoma after Surgery.

The study of postoperative ear cavities in patients who underwent surgery for cholesteatoma is a difficult challenge for radiologists. In our study we make a correlation between CT and MRI findings, useful tools in patients with suspected residual or recurrent cholesteatoma. The use of different MRI sequences especially DWI can help radiologists to discriminate between cholesteatoma and other different processes.

IGFBP-3 hypermethylation-derived deficiency mediates cisplatin resistance in non-small-cell lung cancer.

Cisplatin-based chemotherapy is the paradigm of non-small-cell lung cancer (NSCLC) treatment; however, it also induces de novo DNA-hypermethylation, a process that may be involved in the development of drug-resistant phenotypes by inactivating genes required for drug-cytotoxicity. By using an expression microarray analysis, we aimed to identify those genes reactivated in a set of two cisplatin (CDDP) resistant and sensitive NSCLC cell lines after epigenetic treatment. Gene expression, promoter methylation and CDDP-chemoresponse were further analyzed in three matched sets of sensitive/resistant cell lines, 23 human cancer cell lines and 36 NSCLC specimens. Results revealed specific silencing by promoter hypermethylation of IGFBP-3 in CDDP resistant cells, whereas IGFBP-3 siRNA interference, induced resistance to CDDP in sensitive cells (P<0.001). In addition, we found a strong correlation between methylation status and CDDP response in tumor specimens (P<0.001). Thus, stage I patients, whose tumors harbor an unmethylated promoter, had a trend towards increased disease-free survival (DFS). We report that a loss of IGFBP-3 expression, mediated by promoter-hypermethylation, results in a reduction of tumor cell sensitivity to cisplatin in NSCLC. Basal methylation status of IGFBP-3 before treatment may be a clinical biomarker and a predictor of the chemotherapy outcome, helping to identify patients who are most likely to benefit from CDDP therapy alone or in combination with epigenetic treatment.

Neanderthal exploitation of marine mammals in Gibraltar.

Two coastal sites in Gibraltar, Vanguard and Gorham's Caves, located at Governor's Beach on the eastern side of the Rock, are especially relevant to the study of Neanderthals. Vanguard Cave provides evidence of marine food supply (mollusks, seal, dolphin, and fish). Further evidence of marine mammal remains was also found in the occupation levels at Gorham's Cave associated with Upper Paleolithic and Mousterian technologies [Finlayson C, et al. (2006) Nature 443:850-853]. The stratigraphic sequence of Gibraltar sites allows us to compare behaviors and subsistence strategies of Neanderthals during the Middle Paleolithic observed at Vanguard and Gorham's Cave sites. This evidence suggests that such use of marine resources was not a rare behavior and represents focused visits to the coast and estuaries.

Molecular biology of pancreatic cancer

Pancreatic cancer is a leading cause of cancer death. This devastating disease has the horrible honour of close to equal incidence and mortality rates. Late diagnosis and a constitutive resistance to every chemotherapy approach are responsible for this scenario. However, molecular biology tools in cooperation with translational efforts have dissected several secrets that underlie pancreatic cancer. Progressive acquisition of malignant, invasive phenotypes from pre-malignant lesions, recent revelations on core signalling pathways and new targeted designed trials offer a better future for pancreatic cancer patients. This review will summarise recent advances in the molecular biology of pancreatic cancer (AU)

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Methylated DNA sequences for early cancer detection, molecular classification and chemotherapy response prediction.

Molecular studies of many types of cancer have revealed that clinically evident tumours carry multiple genetic and epigenetic abnormalities, including DNA sequence alterations, chromosome copy number changes and aberrant promoter hypermethylation. Together, these aberrant changes result in the activation of oncogenes and inactivation of tumour-suppressor genes (TSG). In many cases these abnormalities can be found in premalignant lesions and even in histological normal adjacent cells. Many tumour types are difficult to detect early and are frequently resistant to available chemotherapy and radiotherapy. Therefore, the early detection, chemoprevention and the design of new therapeutic strategies based on the increased understanding of cancer molecular changes are one of the great challenges nowadays. Insertions of a methyl group at the fifth carbon of cytosines within the dinucleotide 5'- CpG-3' is the best studied epigenetic mechanism. DNA methylation acts together with others mechanisms like histone modification, chromatin remodelling and microRNAs to mould the DNA structure according to the functional state required. The aberrant methylation of the CpG islands located at the promoter region of specific genes is a common and early event involved in cancer development. Thus, hypermethylated DNA sequences from tumours are one of the most promising markers for early detection screenings as well as tumour classification and chemotherapy response in many types of cancer.

Methylated DNA sequences for early cancer detection, molecular classification and chemotherapy response prediction

Molecular studies of many types of cancer have revealed that clinically evident tumours carry multiple genetic and epigenetic abnormalities, including DNA sequence alterations, chromosome copy number changes and aberrant promoter hypermethylation. Together, these aberrant changes result in the activation of oncogenes and inactivation of tumour-suppressor genes (TSG). In many cases these abnormalities can be found in premalignant lesions and even in histological normal adjacent cells. Many tumour types are difficult to detect early and are frequently resistant to available chemotherapy and radiotherapy. Therefore, the early detection, chemoprevention and the design of new therapeutic strategies based on the increased understanding of cancer molecular changes are one of the great challenges nowadays. Insertions of a methyl group at the fifth carbon of cytosines within the dinucleotide 5'- CpG-3' is the best studied epigenetic mechanism. DNA methylation acts together with others mechanisms like histone modification, chromatin remodelling and microRNAs to mould the DNA structure according to the functional state required. The aberrant methylation of the CpG islands located at the promoter region of specific genes is a common and early event involved in cancer development. Thus, hypermethylated DNA sequences from tumours are one of the most promising markers for early detection screenings as well as tumour classification and chemotherapy response in many types of cancer (AU)