Bortezomib decreases Rb phosphorylation and induces caspase-dependent apoptosis in Imatinib-sensitive and -resistant Bcr-Abl1-expressing cells.

The use of c-abl-specific inhibitors such as Imatinib (IM) or Dasatinib has revolutionized the treatment of chronic myeloid leukemia (CML). However, a significant percentage of patients become resistant to IM. In this report, we have analyzed the possibility of using the proteasome as a molecular target in CML. Our results show that cells that express Bcr-Abl1 are more sensitive to the inhibition of the proteasome with Bortezomib (Btz) than control cells. This treatment reduces the proliferation of Bcr-Abl1-expressing cells, by inactivating NF-kappaB2 and decreasing the phosphorylation of Rb, eventually leading to an increase in caspase-dependent apoptosis. Furthermore, we show that Btz also induces cell-cycle arrest and apoptosis in cells expressing Bcr-Abl1 mutants that are resistant to IM. These results unravel a new molecular target of Btz, that is the Rb pathway, and open new possibilities in the treatment of CML especially for patients that become resistant to IM because of the presence of the T315I mutation.

Increased plasma xanthine oxidase activity is related to nuclear factor kappa beta activation and inflammatory markers in familial combined hyperlipidemia.

BACKGROUND AND AIMS: Xanthine oxidase (XO) has been described as one of the major enzymes producing free radicals in blood. Oxidative stress and inflammatory processes have been implicated in the pathogenesis of endothelial dysfunction and the progression of atherosclerosis but until now, there is little data about the influence of vascular prooxidant systems and inflammation in familial combined hyperlipidemia (FCH). Our goal was to evaluate whether XO activity was altered in FCH and if it was related to the inflammatory process represented by NFkB, IL-6 and hsCRP, and assessing the correlation between XO activity and insulin resistance (IR). METHOD AND RESULTS: 40 Non-related subjects with FCH and 30 control subjects were included, all of them non-diabetic, normotensive and non-smokers. We measured lipid profile, glucose, insulin, uric acid, XO activity, malondialdehyde (MDA), IL-6 and hsCRP in plasma and NFkB activity in circulating mononuclear cells. Patients with FCH showed significantly higher levels of uric acid, XO activity, MDA, NFkB activity, IL-6 and hsCRP than controls. XO activity was independently related to NFkB activity with an odds ratio of 4.082; to IL-6 with an odds ratio of 4.191; and to IR with an odds ratio of 3.830. Furthermore, mean NFkB activity, IL-6 levels, and IR were highest in the highest percentile of XO activity. CONCLUSIONS: Subjects with FCH showed increased XO and NFkB activities and low grade inflammatory markers related to atherosclerosis. XO activity was correlated with higher inflammatory activity and IR. These data could explain, in part, the high cardiovascular disease risk present in these patients.

[Aortoenteric fistulas: clinical presentation and helical computed tomography findings]. / Fístulas aortoentéricas: presentación clínica y hallazgos por tomografía computarizada helicoidal.

Aortoenteric fistula (AEF) is an uncommon complication of abdominal aorta aneurysms. They are divided into two types: primary AEF due to a spontaneous communication of the lumen of an aortic aneurysm and an intestinal loop, usually the duodenum, and secondary AEF, which are more common and occur in patients who have undergone surgical repair of aneurysms with prosthetic implants. The most frequent presenting sign of AEF is upper gastrointestinal bleeding. Clinical suspicion is essential in the diagnostic approach to AEF and the most commonly used techniques for its diagnosis are endoscopy and computed tomography (CT). However, it is not unusual for the results of these techniques to be negative and for the diagnosis to be made at surgery. We present three cases of AEF (one primary) with distinct patterns of upper gastrointestinal bleeding, in which preoperative diagnosis was allowed by clinical and helical CT findings. We discuss the role of this technique in the diagnosis of this entity and describe the findings that allow AEF to be suspected or confirmed.

Fístulas aortoentéricas: presentación clínica y hallazgos por tomografía computarizada helicoidal / Aortoenteric fistulas: clinical presentation and helical computed tomography findings

Las fístulas aortoentéricas son una complicación infrecuente de los aneurismas de aorta abdominal. Se dividen en 2 tipos: primarias, debidas a la comunicación espontánea de la luz de un aneurisma aórtico y un asa intestinal, principalmente el duodeno, y secundarias, más frecuentes que las anteriores, que ocurren en pacientes intervenidos de reparación quirúrgica de aneurismas con implantación de prótesis. El signo clínico de presentación más frecuente de las fístulas aortoentéricas es una hemorragia digestiva alta. La sospecha clínica supone un pilar fundamental en la aproximación diagnóstica de las fístulas aortoentéricas, y la endoscopia y la tomografía computarizada son las técnicas más usadas para su diagnóstico, aunque no es infrecuente que estas técnicas sean negativas y se realice el diagnóstico en la cirugía. Presentamos 3 casos de fístulas aortoentéricas (una de ellas primaria) con diferentes patrones de hemorragia digestiva alta, en los que el contexto clínico y los hallazgos de tomografía computarizada helicoidal permitieron su diagnóstico preoperatorio; discutimos el papel de esta técnica para el diagnóstico, y describimos los diferentes hallazgos que permiten sospechar o confirmar una fístula aortoentérica

Aortoenteric fistula (AEF) is an uncommon complication of abdominal aorta aneurysms. They are divided into two types: primary AEF due to a spontaneous communication of the lumen of an aortic aneurysm and an intestinal loop, usually the duodenum, and secondary AEF, which are more common and occur in patients who have undergone surgical repair of aneurysms with prosthetic implants. The most frequent presenting sign of AEF is upper gastrointestinal bleeding. Clinical suspicion is essential in the diagnostic approach to AEF and the most commonly used techniques for its diagnosis are endoscopy and computed tomography (CT). However, it is not unusual for the results of these techniques to be negative and for the diagnosis to be made at surgery. We present three cases of AEF (one primary) with distinct patterns of upper gastrointestinal bleeding, in which preoperative diagnosis was allowed by clinical and helical CT findings. We discuss the role of this technique in the diagnosis of this entity and describe the findings that allow AEF to be suspected or confirmed

Inhibiting cyclin-dependent kinase/cyclin activity for the treatment of cancer and cardiovascular disease.

Excessive cell proliferation contributes to the pathobiology of human diseases with a high health and socio-economic impact, including cancer and vascular occlusive diseases (e. g., atherosclerosis, in-stent restenosis, transplant vasculopathy, and vessel bypass graft failure). Recent advances in the understanding of the molecular networks governing the hyperplastic growth of tumors and vascular obstructive neointimal lesions have provided new perspectives for preventive and therapeutic strategies against these disorders. Mammalian cell proliferation requires the activation of several cyclin-dependent protein kinases (CDKs). Postranslational activation of CDKs is a complex process that involves their association with regulatory subunits called cyclins. The activity of CDK/cyclin holoenzymes is negatively regulated through their interaction with members of the CDK family of inhibitory proteins (CKIs). Moreover, over fifty low molecular weight pharmacological CDK inhibitors that target the ATP-binding pocket of the catalytic site of CDKs have been identified. In this review, we will discuss the use of pharmacological and gene therapy strategies against CDK/cyclins in animal models and clinical trials of cancer and cardiovascular disease.

Control of vascular smooth muscle cell growth by cyclin-dependent kinase inhibitory proteins and its implication in cardiovascular disease.

While quiescence is a defining characteristic of differentiated vascular smooth muscle cells (VSMCs) residing within the medial layer of elastic arteries in the adult organism, mature VSMCs can undergo phenotypic modulation and reenter the cell cycle in response to several physiological and pathological stimuli. Abnormal VSMC proliferation is thought to contribute to the pathogenesis of vascular occlusive lesions, including atherosclerosis, vessel renarrowing after successful angioplasty (restenosis), and graft atherosclerosis after coronary transplantation. Therefore, elucidating the molecular mechanisms limiting VSMC growth is currently the subject of active research. This review will focus on the role of cyclin-dependent kinase inhibitory proteins in the regulation of VSMC proliferation and its implication in intimal lesion formation during the pathogenesis of vascular proliferative diseases.

Inhibition of cellular proliferation by drug targeting of cyclin-dependent kinases.

Abnormal cellular proliferation is associated with the pathology of several diseases, including cancer, atherosclerosis and restenosis post-angioplasty. Therefore, antiproliferative therapies may be a suitable approach to treat these disorders. Candidate targets for such strategies include specific components of the cell cycle machinery. Progression through the cell cycle in mammalian cells requires the activation of several cyclin-dependent protein kinases (CDKs) through their association with regulatory subunits called cyclins. Active CDK/cyclin holoenzymes phosphorylate cellular proteins including the retinoblastoma susceptibility gene product (pRb) and the related pocket proteins p107 and p130. Several compounds have been described that directly or indirectly inhibit the activity of CDKs, which results in a suppression of cell growth. In this review, we will discuss the use of drugs targeting CDKs and their therapeutic application in animal models and clinical trials.

An inverse correlation between stress resistance and stuck fermentations in wine yeasts. A molecular study.

During alcoholic fermentations yeast cells are subjected to several stress conditions and, therefore, yeasts have developed molecular mechanisms in order to resist this adverse situation. The mechanisms involved in stress response have been studied in Saccharomyces cerevisiae laboratory strains. However a better understanding of these mechanisms in wine yeasts could open the possibility to improve the fermentation process. In this work an analysis of the stress response in three wine yeasts has been carried out by studying the expression of several representative genes under several stress conditions which occur during fermentation. We propose a simplified method to study how these stress conditions affect the viability of yeast cells. Using this approach an inverse correlation between stress-resistance and stuck fermentations has been found. We also have preliminary data about the use of the HSP12 gene as a molecular marker for stress-resistance in wine yeasts.

[Levels of lipoprotein(a), other lipids and lipoproteins in adolescents from the health area of Alcoy]. / Niveles de lipoproteína (a), otros lípidos y lipoproteínas en adolescentes del área sanitaria de Alcoy.

Several epidemiological and necroscopic evidences suggest that, despite that the ischemic cardiopathy (IC) can be generally detected only since the fourth decade of life, it starts during the first years of life and adolescence. We have studied 278 teen-agers, with 13-14 years of age, attending the 8th school year (primary education) in five schools of Alcoy. 117 were males and 161 females. Levels of lipoprotein (a) (Lp[a]), total cholesterol (TC), cholesterol linked to high density lipoproteins (C-HDL) and its subfractions (C-HDL2 and C-HDL3), triglycerides (TG), apoproteins A-I and B (Apo A and Apo B) were determined. Cholesterol linked to low density lipoproteins (C-LDL) was calculated using the Friedewald-Fredrickson's equation. Mean values and standard deviation were: Lp(a) = 29.99 +/- 33.61 mg/dl., TC = 160.4 +/- 25.4 mg/dl., C-HDL = 54.0 +/- 12.3 mg/dl., C-HDL2 = 8.7 +/- 6.5 mg/dl., C-HDL3 = 46.2 +/- 18.6 mg/dl., TG = 72.6 +/- 26.8 mg/dl., C-LDL = 91.6 +/- 22.0 mg/dl., Apo A = 136.4 +/- 24.2 mg/dl., Apo B = 60.7 +/- 21.7 mg/dl. 38% teen-agers had Lp(a) levels higher than 30 mg/dl., 7.5% had levels of TC higher than 200 mg/dl., 12.8% had levels of C-HDL equal or higher than 40 mg/dl. and 4.7% had levels of C-LDL equal or higher than 130 mg/dl. From our study, we can conclude that, despite that the levels of TC, C-LDL and C-HDL in these teen-agers are within relatively normal limits, there is a high percentage with levels of Lp(a) actually considered as a risk factor.