Richter, J.A. (José Ángel)
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- Factors related to increased resting energy expenditure in men with liver cirrhosis(2016) Prieto-Frías, C. (Cesár); Conchillo, M. (M.); Payeras, M. (Marina); Iñarrairaegui, M. (Mercedes); D'Avola, D. (Delia); Frühbeck, G. (Gema); Salvador, J. (Javier); Rodriguez, M. (Macarena); Richter, J.A. (José Ángel); Mugueta, C. (Carmen); Gil-Maria, J. (Jesús); Herrero, I. (Ignacio); Prieto, J. (Jesús); Sangro, B. (Bruno); Quiroga, J. (Jorge)Objective Hypermetabolism in cirrhosis is associated with a high risk of complications and mortality. However, studies about underlying mechanisms are usually focussed on isolated potential determinants and specific etiologies, with contradictory results. We aimed at investigating differences in nutrition, metabolic hormones, and hepatic function between hypermetabolic and nonhypermetabolic men with cirrhosis of the liver. Patients and methods We prospectively enrolled 48 male cirrhotic inpatients. We evaluated their resting energy expenditure (REE) and substrate utilization by indirect calorimetry, body composition by dual-energy X-ray absorptiometry, liver function, and levels of major hormones involved in energy metabolism by serum sample tests. Patients with ascites, specific metabolic disturbances, and hepatocellular carcinoma were excluded. Results REE and REE adjusted per fat-free mass (FFM) were significantly increased in cirrhotic patients. Overall, 58.3% of cirrhotic patients were classified as hypermetabolic. Groups did not differ significantly in age, etiology of cirrhosis, liver function, presence of ascites, use of diuretics, β-blockers, or presence of transjugular intrahepatic portosystemic shunts. Hypermetabolic cirrhotic patients had lower weight, BMI (P< 0.05), nonprotein respiratory quotient (P< 0.01), leptin (P<0.05), and leptin adjusted per fat mass (FM) (P<0.05), but higher FFM% (P< 0.05) and insulin resistance [homeostatic model assessment-insulin resistance (HOMA-IR)] (P<0.05). Only HOMA-IR, leptin/FM, and FFM% were independently related to the presence of hypermetabolism. Conclusion Hypermetabolic cirrhotic men are characterized by lower weight, higher FFM%, insulin resistance, and lower leptin/FM when compared with nonhypermetabolic men. HOMA-IR, FFM%, and leptin/FM were independently associated with hypermetabolism, and may serve as easily detectable markers of this condition in daily clinical practice
- Renal hemodynamics and the renin-angiotensin system in cirrhosis(Consejo Superior de Investigaciones Científicas, 1989) Aliaga, L. (Luis); Richter, J.A. (José Ángel); Prieto, J. (Jesús); Quiroga, J. (Jorge); Zozaya, J.M. (José Manuel)The interrelationship between renal hemodynamics and the renin-angiotensin-aldosterone system in 28 nonazotemic cirrhotic patients has been studied. Patients were divided into three groups: A) Patients without ascites nor edema; B) Patients with ascites and a relatively high sodium excretion (41.9 ± 12.9 mmol/day); and C) Patients with ascites and very low sodium excretion (4.8 ± 0.6 mmol/day). Renin and aldosterone levels significantly increased in group C. A significant correlation was observed between plasma aldosterone concentration and urinary sodium excretion, and between plasma renin activity and aldosterone levels. There were no significant differences in urine flow, glomerular filtration rate, effective renal plasma flow, or renal blood flow between the three groups of patients, in spite of marked differences in renin and aldosterone levels. Renal perfusion was not related to plasma renin activity either in the overall sample of patients or in the individual groups. These results show that factors other than total renal perfusion are involved in renin secretion in cirrhosis.
- A cyclin-D1 interaction with BAX underlies its oncogenic role and potential as a therapeutic target in mantle cell lymphoma(National Academy of Sciences, 2011-07-26) Fresquet, V. (Vicente); Beltran, E. (E.); Rieger, M. (Melissa); Lossos, I.S. (Izidore S.); Martinez-Climent, J.A. (José Ángel); Montes-Moreno, S. (Santiago); Gesk, S. (Stefan); Almada, L.L. (Luciana L.); Richter, J.A. (José Ángel); Raquel; Siebert, R. (Reiner); Sagardoy, A. (Ainara); Martinez-Useros, J. (Javier); Fernandez-Zapico, M.E. (Martín E.); Prosper-Cardoso, F. (Felipe); Calasanz-Abinzano, M.J. (Maria Jose); Piris, M.A. (Miguel A.); Sesma, I. (Izaskun)The chromosomal translocation t(11;14)(q13;q32) leading to cyclin-D1 overexpression plays an essential role in the development of mantle cell lymphoma (MCL), an aggressive tumor that remains incurable with current treatment strategies. Cyclin-D1 has been postulated as an effective therapeutic target, but the evaluation of this target has been hampered by our incomplete understanding of its oncogenic functions and by the lack of valid MCL murine models. To address these issues, we generated a cyclin-D1-driven mouse model in which cyclin-D1 expression can be regulated externally. These mice developed cyclin-D1-expressing lymphomas capable of recapitulating features of human MCL. We found that cyclin-D1 inactivation was not sufficient to induce lymphoma regression in vivo; however, using a combination of in vitro and in vivo assays, we identified a novel prosurvival cyclin-D1 function in MCL cells. Specifically, we found that cyclin-D1, besides increasing cell proliferation through deregulation of the cell cycle at the G(1)-S transition, sequestrates the proapoptotic protein BAX in the cytoplasm, thereby favoring BCL2's antiapoptotic function. Accordingly, cyclin-D1 inhibition sensitized the lymphoma cells to apoptosis through BAX release. Thus, genetic or pharmacologic targeting of cyclin-D1 combined with a proapoptotic BH3 mimetic synergistically killed the cyclin-D1-expressing murine lymphomas, human MCL cell lines, and primary lymphoma cells. Our study identifies a role of cyclin-D1 in deregulating apoptosis in MCL cells, and highlights the potential benefit of simultaneously targeting cyclin-D1 and survival pathways in patients with MCL. This effective combination therapy also might be exploited in other cyclin-D1-expressing tumors.
- Homozygous deletions localize novel tumor suppressor genes in B-cell lymphomas(American Society of Hematology, 2007) Marin, M. (Miguel); Fresquet, V. (Vicente); Beltran, E. (E.); Dyer, M.J.S. (Martin J. S.); Rosenwald, A. (Andreas); Pinkel, D. (Daniel); Karran, E.L. (E. L.); Martinez-Climent, J.A. (José Ángel); Richter, J.A. (José Ángel); Siebert, R. (Reiner); Mestre-Escorihuela, C. (Cinta); Marugan, I. (Isabel); Sanchez, L. (Lydia); Staudt, L.M. (Louis M.); Rubio-Moscardo, F. (Fanny); Climent, J. (Javier); Wheat, L.M. (Luise M.); Prosper-Cardoso, F. (Felipe); Aguirre-Ena, X. (Xabier); Sugimoto, K.J. (Kei-Ji); Garcia, J.F. (José Francisco)Integrative genomic and gene-expression analyses have identified amplified oncogenes in B-cell non-Hodgkin lymphoma (B-NHL), but the capability of such technologies to localize tumor suppressor genes within homozygous deletions remains unexplored. Array-based comparative genomic hybridization (CGH) and gene-expression microarray analysis of 48 cell lines derived from patients with different B-NHLs delineated 20 homozygous deletions at 7 chromosome areas, all of which contained tumor suppressor gene targets. Further investigation revealed that only a fraction of primary biopsies presented inactivation of these genes by point mutation or intragenic deletion, but instead some of them were frequently silenced by epigenetic mechanisms. Notably, the pattern of genetic and epigenetic inactivation differed among B-NHL subtypes. Thus, the P53-inducible PIG7/LITAF was silenced by homozygous deletion in primary mediastinal B-cell lymphoma and by promoter hypermethylation in germinal center lymphoma, the proapoptotic BIM gene presented homozygous deletion in mantle cell lymphoma and promoter hypermethylation in Burkitt lymphoma, the proapoptotic BH3-only NOXA was mutated and preferentially silenced in diffuse large B-cell lymphoma, and INK4c/P18 was silenced by biallelic mutation in mantle-cell lymphoma. Our microarray strategy has identified novel candidate tumor suppressor genes inactivated by genetic and epigenetic mechanisms that substantially vary among the B-NHL subtypes.
- Assessment of indeterminate pulmonary nodules detected in lung cancer screening: Diagnostic accuracy of FDG PET/CT(Elsevier BV, 2016) Torre, W. (Wenceslao); Campo, A. (Arantza); Lozano, M.D. (María Dolores); Bastarrika, G. (Gorka); Sancho, L. (Lidia); Richter, J.A. (José Ángel); Sanchez-Salcedo, P. (Pablo); Torres, J.P. (Juan P.) de; Garcia-Velloso, M. J. (María José); Alcaide, A.B. (Ana Belén); Nuñez-Cordoba, J.M. (Jorge M.); Zulueta, J. (Javier)Background: A major drawback of lung cancer screening programs is the high frequency of false-positive findings on computed tomography (CT). We investigated the accuracy of selective 2-[fluorine-18]- fluoro-2-deoxy-d-glucose (FDG) Positron Emission Tomography/Computed Tomography (PET/CT) scan in assessing radiologically indeterminate lung nodules detected in lung cancer screening. Methods: FDG PET/CT was performed to characterize 64 baseline lung nodules >10 mm and 36 incidence nodules detected on low-dose CT screening in asymptomatic current or former smokers (83 men, age range 40–83 years) at high risk for lung cancer. CT images were acquired without intravenous contrast. Nodules were analyzed by size, density, and metabolic activity and visual scored on a 5-point scale for FDG uptake. Nodules were classified as negative for malignancy when no FDG uptake was observed, or positive when focal uptake was observed in the visual analysis, and the maximum standardized uptake value (SUVmax) was measured. Final diagnosis was based on histopathological evaluation or at least 24 months of follow-up. Results: A total of 100 nodules were included. The prevalence of lung cancer was 1%. The sensitivity, specificity, NPV and PPV of visual analysis to detect malignancy were 84%, 95%, 91%, and 91%, respectively, with an accuracy of 91% (AUC 0.893). FDG PET/CT accurately detected 31 malignant tumors (diameters 9–42 mm, SUVmax range 0.6–14.2) and was falsely negative in 6 patients. With SUVmax thresholds for malignancy of 1.5, 2, and 2.5, specificity was 97% but sensitivity decreased to 65%, 49%, and 46% respectively, and accuracy decreased to 85%, 79%, and 78% respectively (AUC 0.872). Conclusions: The visual analysis of FDG PET/CT scan is highly accurate in characterizing indeterminate pulmonary nodules detected in lung cancer screening with low-dose CT. Semi-quantitative analysis does not improve the accuracy of FDG PET/CT over that obtained with a qualitative method for lung nodule characterization.
- Significant dose reduction is feasible in FDG PET/CT protocols without compromising diagnostic quality(Elsevier, 2018) Marti-Climent, J.M. (Josep María); Peñuelas-Sanchez, I. (Ivan); Sancho, L. (Lidia); Morales-de-Alava, I. (Isabel); Guillen, F. (Fernando); Prieto-Azcárate, E. (Elena); Richter, J.A. (José Ángel); Garcia-Velloso, M. J. (María José); Moran, V. (Verónica); García-García, B. (Berta); Rodriguez-Fraile, M. (Macarena)Purpose: To reduce the radiation dose to patients by optimizing oncological FDG PET/CT protocols. Methods: The baseline PET/CT protocol in our institution for oncological PET/CT examinations consisted of the administration of 5.18 MBq/kg of FDG and a CT acquisition with a reference current-time product of 120 mAs. In 2016, FDG activity was reduced to 4.44 and 3.70 MBq/kg and reference CT current-time-product was reduced to 100 and 80 mAs. 322 patients scanned with different protocols were retrospectively evaluated. For each patient, effective dose was calculated. The overall image quality was subjectively rated by the referring physician on a 4-point scale (IQ score: 1 excellent, 2 good, 3 poor but interpretable, 4 poor not interpretable). Image quality was quantitatively evaluated measuring noise in the liver. Results: CT Results: Effective dose was progressively reduced from 9.5 ± 2.8 to 8.0 ± 2.3 and 6.2 ± 1.5 mSv (p < 0.001). A mean dose reduction of 34.9% was achieved. There was a significant degradation of IQ score (p < 0.05) and noise (p < 0.001). Nevertheless, the number of poor quality studies (IQ score >2) did not increase. PET Results: Effective dose was gradually reduced from 6.5 ± 1.4 to 5.7 ± 1.3 and 5.0 ± 1.0 mSv (p < 0.001). Average dose reduction was 23.4%. IQ score (p < 0.05) and noise (p < 0.001) significantly degraded for lower activity protocols. However, all images with reduced activity were scored as interpretable (IQ score ≤ 3). Conclusions: A significant radiation dose reduction of 28.7% was reached. Despite a slight reduction in image quality, the new regime was successfully implemented with readers reporting unchanged clinical confidence.
- Diagnostic value of quantitative SPECT/CT in assessing active sacroiliitis in patients with axial spondylarthritis and/or inflammatory low back pain(Gobierno de Navarra, 2022) Cuadrado, M.J. (M.J); Prieto, E. (Elena); Bondia, J.M. (J. M.); Ribelles, M.J. (María Jesús); Aquerreta, D. (Dámaso); Richter, J.A. (José Ángel); Ornilla-Laraudogoitia, E.T. (Enrique Tomás); Sancho, L. (Luis); Beorlegui, C. (Carmen)Background. The diagnostic accuracy of bone scintigraphy (BS) increases with SPECT/CT imaging. It would therefore be appropriate to reassess the diagnostic utility of scintigraphy in sacroiliitis with axial spondyloarthritis (SpA). The aim of this study was to compare the diagnostic performance of MRI, SPECT/CT and a combination of both techniques in sacroiliitis, and to evaluate the correlation between quantitative SPECT/CT indices and quantitative MRI inflammatory lesion scores. Methods. Thirty-one patients with active SpA and 22 patients with inflammatory low back pain underwent MRI and SPECT/CT of the sacroiliac joints. The diagnostic accuracy of both techniques was calculated using clinical diagnosis as the gold standard. The correlation between MRI and SPECT/CT was calculated by comparing the SPECT/CT activity indices and the Berlin/SPARCC scoring systems for MRI. Results. The sensitivity and specificity values in quantitative SPECT/CT, taking the sacroiliac/promontory ratio of >1.36 as the cut-off value, were close to those from MRI published in the literature. The combination of both techniques increased sensitivity while maintaining high specificity. There was a moderate correlation between SPECT/CT and MRI total scores. This correlation was improved by using solely the MRI inflammation scores. Conclusion. Quantitative SPECT/CT showed better diagnostic accuracy than planar scintigraphy and showed a moderate correlation with MRI scores in active sacroiliitis. The combination of both tests increased the diagnostic accuracy. Quantitative SPECT/CT could play a relevant role in the diagnosis of active sacroiliitis in patients with high a suspicion of SpA and a negative/inconclusive MRI test or in patients with whom MRI studies cannot be carried out.
- Correlaciones entre la SPECT cerebral y la evaluación neuropsicológica en los estadios leve y moderado de la enfermedad de Alzheimer(Universidad de Navarra, 1999) Gamez, C. (C.); Martinez-Lage, J.M. (José M.); Richter, J.A. (José Ángel); Larumbe, R. (R.); Marti, J.M. (J.M.); Arbizu, J. (Javier)Se evaluaron 34 pacientes con enfermedad de Alzheimer (EA) probable (EA leve = 16; EA moderada = 18) y 12 controles mediante un estudio semicuantitativo de SPECT con 99mTc-HMPAO y la batería de tests neuropsicológicos CERAD. Resultados: La hipoperfusión temporal (p < 0,01) y los tests de memoria (p < 0,001) permitieron diferenciar los controles de los pacientes con EA leve. En estos pacientes se observaron también correlaciones significativas (p < 0,05) entre: test de recuerdo diferido-hipoperfusión temporal, test de aprendizaje-hipoperfusión temporoparietal y frontal y praxis visuoconstructiva-hipoperfusión temporal posterior. Los pacientes con EA moderada mostraron, respecto a la EA leve, una mayor hipoperfusión temporal (p < 0,01), parietal y frontal (p < 0,05), junto a un empeoramiento de la praxis (p < 0,001) y los test de memoria (p < 0,05). Conclusiones: La SPECT y la evaluación neuropsicológica permiten distinguir entre controles y pacientes con estadios leve y moderado de la EA, existiendo una estrecha correlación entre ambos métodos desde las etapas iniciales de la enfermedad.
- 18F-FDG metabolism in a rat model of chronic infarction: a 17-sector semiquantitative analysis(SCHATTAUER, 2007) Marti-Climent, J.M. (Josep María); Collantes, M. (María); Peñuelas-Sanchez, I. (Ivan); Gavira, J.J. (Juan José); Richter, J.A. (José Ángel); Barba, J. (Joaquín); Garcia-Velloso, M. J. (María José); Ecay, M. (Margarita); Mazo, M. (Manuel); Garcia-Rodriguez, A. (Alba); Garcia-de-Jalon, J.A. (José A.); Prosper-Cardoso, F. (Felipe); Abizanda-Sarasa, G. (Gloria)Strategies to establish the functional benefit of cell therapy in cardiac regeneration and the potential mechanism are needed. Aims: Development of a semi-quantitative method for non invasive assessment of cardiac viability and function in a rat model of myocardial infarction (MI) based on the use of microPET. Animals, methods: Ten rats were subjected to myocardial imaging 2, 7, 14, 30, 60 and 90 days after left coronary artery ligation. Intravenous 18F-fluoro-2-deoxy-2-D-glucose (18F-FDG) was administered and regional 18F activity concentrations per unit area were measured in 17 regions of interest (ROIs) drawn on cardiac polar maps. By comparing the differences in 18F uptake between baseline and each of the follow up time points, parametric polar maps of statistical significance (PPMSS) were calculated. Left ventricular ejection fraction (LVEF) was blindly assessed echocardiographically. All animals were sacrificed for histopathological analysis after 90 days. Results: The diagnostic quality of 18F-FDG microPET images was excellent. PPMSS demonstrated a statistically significant decrease in 18F concentrations as early as 48 hours after MI in 4 of the 17 ROIs (segments 7, 13, 16 and 17; p <0.05) that persisted throughout the study. Semi-quantitative analysis of 18F-FDG uptake correlated with echocardiographic decrease in LVEF (p <0.001). Conclusion: The use of PPMSS based on 18F-FDG-microPET provides valuable semi-quantitative information of heart glucose metabolism allowing for non-invasive follow up thus representing a useful strategy for assessment of novel therapies in cardiac regeneration.
- Reversion of epigenetically mediated BIM silencing overcomes chemoresistance in Burkitt lymphoma(American Society of Hematology, 2010) Fresquet, V. (Vicente); Rullan, A.J. (Antonio J.); Beltran, E. (E.); Roman-Gomez, J. (José); Hernandez, J.M. (J. M.); Martinez-Climent, J.A. (José Ángel); Panizo, C. (Carlos); Richter, J.A. (José Ángel); Prosper-Cardoso, F. (Felipe); Robles, E.F. (Eloy Francisco); Calasanz-Abinzano, M.J. (Maria Jose); Aguirre-Ena, X. (Xabier)In Burkitt lymphoma/leukemia (BL), achievement of complete remission with first-line chemotherapy remains a challenging issue, as most patients who respond remain disease-free, whereas those refractory have few options of being rescued with salvage therapies. The mechanisms underlying BL chemoresistance and how it can be circumvented remain undetermined. We previously reported the frequent inactivation of the proapoptotic BIM gene in B-cell lymphomas. Here we show that BIM epigenetic silencing by concurrent promoter hypermethylation and deacetylation occurs frequently in primary BL samples and BL-derived cell lines. Remarkably, patients with BL with hypermethylated BIM presented lower complete remission rate (24% vs 79%; P = .002) and shorter overall survival (P = .007) than those with BIM-expressing lymphomas, indicating that BIM transcriptional repression may mediate tumor chemoresistance. Accordingly, by combining in vitro and in vivo studies of human BL-xenografts grown in immunodeficient RAG2(-/-)γc(-/-) mice and of murine B220(+)IgM(+) B-cell lymphomas generated in Eμ-MYC and Eμ-MYC-BIM(+/-) transgenes, we demonstrate that lymphoma chemoresistance is dictated by BIM gene dosage and is reversible on BIM reactivation by genetic manipulation or after treatment with histone-deacetylase inhibitors. We suggest that the combination of histone-deacetylase inhibitors and high-dose chemotherapy may overcome chemoresistance, achieve durable remission, and improve survival of patients with BL.