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Javier Menárguez

Publications and source records attributed to Javier Menárguez.

13 recordsLinked to original sources
PubMed2006

Tumor microenvironment and mitotic checkpoint are key factors in the outcome of classic Hodgkin lymphoma.

Around 20% to 30% of patients with Hodgkin lymphoma (HL) do not benefit from standard therapies and finally succumb to their disease. The factors that influence the outcome of HL have not been elucidated, underscoring the demand for the identification of biologic risk factors and new therapeutic targets. We analyzed the gene expression profiles of samples from 29 patients with advanced classic HL treated with standard therapy and compared the expression profiles of patients with favorable and unfavorable clinical outcome. Using supervised methods, we identified 145 genes associated with outcome, which were grouped into 4 signatures representing genes expressed by either the tumoral cells (genes involved in the regulation of mitosis and cell growth/apoptosis) or the tumor microenvironment. The relationship between the expression of 8 representative genes and survival was successfully validated in an independent series of 235 patients by quantification of protein expression levels on tissue microarrays. Analysis of centrosomes and mitotic checkpoint confirmed the existence of an abnormal transition through mitosis in HL cells. Therefore, genes related to tumor microenvironment, cell growth/apoptosis, and regulation of mitosis are associated with treatment response and outcome of patients with HL.

Adolescent↗
PubMed2005

Progression of secondary hyperparathyroidism involves deregulation of genes related to DNA and RNA stability.

BACKGROUND: Renal secondary hyperparathyroidism in its late stages becomes autonomous, so excessive parathyroid hormone (PTH) secretion no longer responds to physiologic stimuli or to aggressive medical treatment. METHODS: To gain molecular understanding of progression of renal secondary hyperparathyroidism, normal and hyperplastic parathyroid tissue with diffuse and nodular growth were analyzed. The results were also compared to parathyroid adenomas. The analysis was performed by high-density oligonucleotide microarray and bidirectional subtraction library. RESULTS: Analysis of the DNA arrays found 16 overexpressed and 132 repressed genes in the nodules while the subtraction library produced 34 overexpressed and 40 repressed genes. The differentially expressed genes between diffuse and nodular samples included some related to DNA stability and repair (TALDO1, PRDX2, DDB1, XRCC1, and POLB), RNA stability and degradation (OASL and AUF1), protein synthesis and processing (PFDN5, HSPD1, and NACA), cell growth (CDC25C and GRPR), and tumorigenesis and cell cycle (VIL2 and TPD52). CONCLUSION: According to the function described for the deregulated genes, when secondary hyperparathyroidism becomes autonomous and refractory to treatment, RNA degradation may be increased while DNA integrity may be compromised. These two mechanisms, combined with deregulation of genes related to growth and differentiation show the complex pathway of parathyroid glands' evolution in renal hyperparathyroidism and may explain the large amount of molecular cytogenetic aberrations found in refractory hyperparathyroidism. Considering that some of the genes with altered expression in nodular hyperplasia lead to irreversible consequences in the genomic integrity of the cells, an adequate and early management of the secondary hyperparathyroidism of chronic kidney disease becomes mandatory.

Adult↗
PubMed2004

Variability in the degree of expression of phosphorylated IkappaBalpha in chronic lymphocytic leukemia cases with nodal involvement.

PURPOSE: Based on previous preliminary observations, we hypothesize that the molecular and clinical variability of chronic lymphocytic leukemia (CLL) reflects differences in the degree of nuclear factor (NF)-kappaB activation, as determined by the expression of phosphorylated IkappaBalpha (p-IkappaBalpha). EXPERIMENTAL DESIGN: The expression profile (mRNA and protein expression) was analyzed with the Centro Nacional de Investigaciones Oncologicas Oncochip, a cDNA microarray containing 6386 cancer-related genes, and a tissue microarray (TMA). The results were correlated with the IgV(H) mutational status, ZAP-70 expression, cytogenetic alterations, and clinical outcome. RESULTS: We found correlations between the presence of p-IkappaBalpha, a surrogate marker of NF-kappaB activation, and changes in the expression profile (mRNA and protein expression) and clinical outcome in a series of CLL cases with lymph node involvement. Activation of NF-kappaB, as determined by the expression of p-IkappaBalpha, was associated with the expression of a set of genes comprising key genes involved in the control of B-cell receptor signaling, signal transduction, and apoptosis, including SYK, LYN, BCL2, CCR7, BTK, PIK3CD, and others. Cases with increased expression of p-IkappaBalpha showed longer overall survival than cases with lower expression. A Cox regression model was derived to estimate some parameters of prognostic interest: IgV(H) mutational status, ZAP-70, and p-IkappaBalpha expression. The multivariate analysis disclosed p-IkappaBalpha and ZAP-70 expression as independent prognostic factors of survival. CONCLUSIONS: A variable degree of activation of NF-kappaB, as determined by the expression of p-IkappaBalpha, is an identifiable event in CLL, and is correlated with changes in the expression profile and overall survival.

Adult↗
PubMed2003

The molecular signature of mantle cell lymphoma reveals multiple signals favoring cell survival.

Mantle cell lymphoma (MCL) is a prototypical neoplastic disease in which a common cytogenetic alteration, t11;14, leading to cyclin D1 overexpression, is associated with other changes that need to be considered in an explanation of the clinical, morphological, and molecular variability of this disease. Using a cDNA microarray (Oncochip-CNIO) containing clones for 6386 cancer-related genes, we have analyzed the expression profiles of a series of 38 cases. After normalization with the expression profiling of sorted mantle zone lymphocytes, we have related the findings to conventional clinical and molecular variables, including immunoglobulin variable heavy chain somatic mutation, blastoid cytology, increased proliferation, and long-term survival. MCL signature (446 genes) includes genes involved in apoptosis, cell cycle, signal transduction, and cell structure. Especially striking was the presence of multiple concurrent alterations in the tumor necrosis factor and nuclear factor kappaB pathway, and the overexpression of IL10R and SPARC genes. We also identified a molecular signature for the presence of immunoglobulin variable heavy chain somatic mutation, which includes a number of genes potentially relevant in cancer (CDC14A, ras, and others). Signatures for proliferation and blastoid cytology were also found. An integrated analysis of these data yields a gene-expression based survival predictor (26 genes grouped into two clusters), which distinguishes half of the patients with a survival probability of 52% at 5 years. The predictive model has been confirmed by cross-validation. In conclusion, MCL seems to combine a disease-specific signature and different sets of genes of which the expression is associated with key clinical, molecular, and immunophenotypical events.

Adult↗
PubMed2003

Polymorphisms G691S/S904S of RET as genetic modifiers of MEN 2A.

Multiple endocrine neoplasia type 2A (MEN 2A) is associated with specific germ-line missense mutations in the RET proto-oncogene. Only a minor fraction of human disorders are simple monogenic diseases, and the identification of polymorphisms that increase susceptibility, including variations in pathological phenotypes, to human diseases is one of the key problems in medical genetics. To explore this idea, we analyzed the polymorphisms G691S (exon 11) and S904S (TCC-TCG, exon 15) of RET in 198 individuals corresponding to 35 unrelated Spanish MEN 2A families (104 patients with oncogenic MEN 2A mutation and 94 healthy relatives). We found strong cosegregation between both polymorphisms (100% Fisher's exact test, P < 0.001) using a control population containing 653 healthy individuals (362 females and 291 males). Interestingly, we found that the homozygous for these polymorphisms were, on average, 10 years younger at diagnosis compared with heterozygous and wild-type homozygous (P = 0.037). Taken together, all these findings could indicate that the G691S and S904S variants of RET have a modifier effect on the age at onset of MEN 2A. Moreover, compared with the control population, the homozygote status was significantly more prevalent in a series of 110 sporadic thyroid carcinoma (odds ratio = 2.36), suggesting that these polymorphisms may play a role as a low penetrance risk factor.

Adolescent↗
PubMed2003

Parathyroidectomy: whom and when?

Hyperparathyroidism (HPT) is common in patients on dialysis, and parathyroidectomy (PTx) is often required. We present a retrospective, descriptive analysis of data corresponding to 148 patients on dialysis undergoing PTx due to severe refractory HPT (PTH 1401 +/- 497 pg/mL, Ca 10.6 +/- 0.8 mg/dL, P 6.9 +/- 1.7 mg/dL). Demographic data were compared with those recorded in 309 patients on dialysis not subjected to PTx who were managed at the same hospital. In the PTx group, the factors age (49.3 +/- 14 years), male gender (48.6%), and diabetes (0.7%) were significantly lower than in the non-PTx group (61.5 +/- 14.9 years, male gender 59%, diabetes 19.4%), while time on dialysis was longer (8.6 +/- 5.8 vs. 5.5 +/- 5.4 years). In 129 of the study patients (87.4%), four or more glands were identified, and total PTx plus autotransplantation (AT) in the forearm was performed. In the remaining 19 patients, two to three glands were identified, and AT was not undertaken. Four of the 19 patients were successfully operated on again for persistent HPT, seven showed PTH levels <250 pg/mL, and eight maintained severe HPT. Perioperative complications included one death due to cardiac insufficiency, two repeat operations due to bleeding, and one patient with chronic hoarseness. Hospital stay was prolonged in 20% of patients due to a hungry bone syndrome. Among those patients with PTx and AT, HPT recurred in 21 patients (16.2%) at 3.1 +/- 2.3 years. In 13 of these patients, autograft was removed at 7.5 +/- 2.9 years. Serum calcium and phosphate levels improved after PTx, and these results were maintained for 5 years (9.6 +/- 0.8 and 4.2 +/- 1.2 mg/dL, respectively). In conclusion, PTx with AT is a safe option for the treatment of severe HPT that is accompanied by low morbidity and mortality and a good outcome. Medical treatment should not be prolonged at the expense of long repeated bouts of hypercalcemia and/or hyperphosphatemia with their irreversible consequences.

Aged↗
PubMed2003

Response of parathyroid glands to calcitriol in culture: Is this response mediated by the genetic polymorphisms in vitamin D receptor?

BACKGROUND: Recently, we have developed a model of parathyroid tissue culture that allows the study of the response of the parathyroid glands to long-term effectors, such as calcitriol, and that is also useful to study the likely effect of the genetic polymorphisms in the functionality of the glands. The aim of this study was to evaluate the response to calcitriol of cultured parathyroid tissue from patients with secondary hyperparathyroidism (HPT) and the possible effect of vitamin D receptor (VDR) gene polymorphisms on this response. METHODS: Parathyroid glands (N = 37) from 34 parathyroidectomized patients (17 men, 17 women) were used. Several gland fragments were cultured for 60 hours in the presence of calcitriol 10(-9) mol/L or 10(-8) mol/L. DNA from each fragment was extracted to normalize the hormone secretion levels and to genotype the restriction sites ApaI, BsmI, TaqI, and FokI in the VDR gene. RESULTS: The percentages of secretion observed in the response to calcitriol were: 69%+/- 28% (range, 3-100) and 46%+/- 19% (range, 8-78) for calcitriol 10(-9) mol/L and 10(-8) mol/L, respectively (P = 0.004). None of the polymorphisms showed statistical differences in response to calcitriol with any of the concentrations used. CONCLUSION: Parathyroid glands cultured in vitro from patients with secondary HPT are able to respond to calcitriol decreasing PTH synthesis. These results, however, do not support the current hypothesis that VDR polymorphisms are involved in the modulation of the parathyroid gland response.

Adult↗
PubMed2003

Comparative study of the expression of proteins involved in the cell cycle in renal secondary hyperparathyroidism.

BACKGROUND: In renal hyperparathyroidism, parathyroid cell proliferation seems to play a key role in the progression of the disease. Therefore, G1/S transition, a main cell cycle regulatory step, could be deregulated in these patients. METHODS: One hundred and one parathyroid glands, taken from parathyroidectomies performed on 41 patients on hemodialysis (HD), and 15 glands, taken from 7 patients with post-transplantation persistent hyperparathyroidism (HPT), were studied. Twelve normal parathyroid (PT) glands were used as the control. Biochemical data, immunohistochemical (IHC) profiles of G1/S transition regulators belonging to the two main pathways (cyclin D1/p16INK4A/pRb and p14ARF/p53/MDM2), and proliferation rate (Ki67) were correlated. RESULTS: All of the other proteins differed from normal IHC profiles in both groups that showed significant higher proliferating rates, decreases in p27KIP1, pRb, and cyclin D1, as well as increases in p16INK4A, p53, MDM2, and p21WAF1 levels, in comparison with normal PT glands, with the exception of cyclin D3. Contrary to patients with HPT who were on hemodialysis, in post-transplantation HPT, consistent correlations between biochemical data and IHC profiles were obtained. CONCLUSION: In both groups IHC profiles of proteins involved in G1/S transition regulation significantly differed from normal PT glands. The results support partial reversion to normal IHC profile in post-transplantation HPT.

Adult↗
PubMed2003

Chromosomal aberrations, the consequence of refractory hyperparathyroidism: its relationship with biochemical parameters.

BACKGROUND: It has been shown that refractory hyperparathyroidism (HPT) correlates biologically with a monoclonal true neoplasm, but the chromosomal changes and their relationship with biochemical variables such as high levels of phosphate, low levels of calcium (Ca), and calcitriol deficiency are still in need of a deeper analysis. METHODS: Comparative genomic hybridization was used to scan for DNA copy number changes in two groups of samples: 57 glands from refractory secondary HPT and 28 glands from refractory HPT after kidney transplantation. Biochemical HPT-related parameters from these patients were collected and analyzed. RESULTS: Sixty-one percent of the glands from dialysis patients and 53.6% of the glands from transplanted patients suffering severe secondary hyperparathyroidism had clonal chromosomal imbalances. Losses were far more common than gains. The most recurrent changes were losses of 1p (71%), monosomies of chromosomes 19 and 22 (45%), and losses of 20q (44%) and 16p (42%). The most frequent gains were 5q, 6q, and 13q. Biochemical parameters suggested that Ca excess is related to the development of these chromosomal aberrations, although it is not known if it is by playing a role in producing the alterations or merely as a reflection of HPT severity. Phosphate levels, despite their known effect in increasing the proliferation of the parathyroid glands, were not related to the chromosomal aberrations found in severe secondary HPT. CONCLUSION: Clonal recurrent chromosomal changes are present in more than half of the glands from patients with refractory HPT, which undergo extreme biochemical levels in hyperparathyroidism effectors. These changes support the idea of the monoclonal neoplastic nature of this disorder.

Biomarkers↗
PubMed2003

Large B-cell lymphoma presenting in the spleen: identification of different clinicopathologic conditions.

Only a few series of splenic large B-cell lymphoma have been previously reported, including limited immunophenotypic studies and clinical data. Here we review the clinical data, morphology, and immunophenotype of series of 33 cases of large B-cell lymphoma presenting in the spleen. Three main groups of tumors are identified. Group A was characterized by macronodular tumors (20 cases), with predominantly stage I disease and a favorable clinical outcome. All cases were bcl6 positive. Group B was characterized by a micronodular pattern (nine cases), including a subset with T-cell-rich B-cell lymphoma features. Most of the patients in this group were diagnosed at advanced clinical stages and died of the disease. All cases were bcl6 positive. Group C was characterized by diffuse red pulp infiltration (four cases) and advanced clinical stages and showed an aggressive behavior. All but one case were bcl6 positive. The results of this series define a characteristic type of large B-cell lymphoma presenting in the spleen as a tumoral mass, associated with a relatively favorable clinical course. Additionally, they provide evidence that clinical presentation as a tumor confined to the spleen and the hilar lymph nodes is associated with lower aggressivity.

Adult↗
PubMed2002

Hodgkin and Reed-Sternberg cells harbor alterations in the major tumor suppressor pathways and cell-cycle checkpoints: analyses using tissue microarrays.

Tumoral cells in Hodgkin lymphoma (HL) display an increased growth fraction and diminished apoptosis, implying a profound disturbance of the cell cycle and apoptosis regulation. However, limitations of molecular techniques have prevented the analysis of the tumor suppressor pathways and cell-cycle checkpoints. Tissue microarray (TMA) is a powerful tool for analyzing a large number of molecular variables in a large series of tumors, although the feasibility of this technique has not yet been demonstrated in heterogeneous tumors. The expression of 29 genes regulating the cell cycle and apoptosis were analyzed by immunohistochemistry and in situ hybridization in 288 HL biopsies using TMA. The sensitivity of the technique was validated by comparing the results with those obtained in standard tissue sections. The results revealed multiple alterations in different pathways and checkpoints, including G1/S and G2/M transition and apoptosis. Striking findings were the overexpression of cyclin E, CDK2, CDK6, STAT3, Hdm2, Bcl2, Bcl-X(L), survivin, and NF-kappaB proteins. A multiparametric analysis identified proteins associated with increased growth fraction (Hdm2, p53, p21, Rb, cyclins A, B1, D3, and E, CDK2, CDK6, SKP2, Bcl-X(L), survivin, STAT1, and STAT3), and proteins associated with apoptosis (NF-kappaB, STAT1, and RB). The analysis also demonstrated that Epstein-Barr virus (EBV)-positive cases displayed a characteristic profile, confirming the pathogenic role of EBV in HL. Survival probability depends on multiple biologic factors, including overexpression of Bcl2, p53, Bax, Bcl-X(L), MIB1, and apoptotic index. In conclusion, Hodgkin and Reed-Sternberg cells harbor concurrent and overlapping alterations in the major tumor suppressor pathways and cell-cycle checkpoints. This appears to determine the viability of the tumoral cells and the clinical outcome.

Apoptosis↗
PubMed2002

Genetic analysis of RET, GFR alpha 1 and GDNF genes in Spanish families with multiple endocrine neoplasia type 2A.

Multiple endocrine neoplasia type 2A (MEN 2A) is associated with specific germline missense mutations in the RET proto-oncogene. This locus encodes a receptor tyrosine kinase whose activation requires the formation of a multimeric receptor complex including GDNF as a ligand and GFR alpha 1 as a coreceptor. In order to explore the role of RET, GFR alpha 1 and GDNF genes in the variation of phenotypes observed in MEN2A families, we analysed germline mutations of these genes in 4 unrelated Spanish MEN2A families (23 cases studied). We found 2 novel variants corresponding to a single change in position + 47 (intron 12) of RET and position +22 (intron 7) of GFR alpha 1. Furthermore, we observed strong co-segregation between 2 polymorphisms of RET [G691S (exon 11) and S904S (TCC-TCG, exon 15) (100%, Fisher's exact test, p< 0.001)]. More interestingly, we found that these polymorphisms occurred at a significantly high frequency in patients with age at onset < 20 years old (Kruskal-Wallis's and Fisher's exact test, p = 0.007). These findings suggest that the G691S and S904S variants of RET may somehow play a role on the age of onset of MEN 2A.

Alleles↗