Statins and protein prenylation in cancer cell biology and therapy

El pdf del artículo es la versión post-print.The use of statins has scaled up to become one of the most prescribed medicines in the world and have been very useful in the manegement of cardiovascular diseases and related mortality. The disclosure of their chemical structure similar to that of hydroxy methyl glutaryl-CoA (HMG-CoA) revealed their ability to compete with and inhibit the rate-limiting enzyme HMG-CoA reductase that catalyzes the synthesis of mevalonate, which then serves as the precursor for isoprenoids and cholesterol in the mevalonate pathway. While most of the effects of statins are associated with the lowering of cellular cholesterol levels, it is clear that they also blunt the non-sterol branch of the mevalonate pathway, decreasing formation of isoprenoids and altering protein-prenylation, a critical event in the posttranslational modulation of proteins involved in the regulation of cell cycle progression, proliferation and signaling pathways. Randomized controlled trials for the prevention of cardiovascular diseases indicated that statins elicited provocative and unexpected benefits for reducing a number of different types of cancers, including colorectal carcinoma, melanoma, prostate and hepatocellular carcinoma, although in other cancer types the preclinical expectations of statins were dissapointing. In this review, we will describe the evidence and mechanisms underlying the potential beneficial use of statins and the role of protein prenylation in cancer prevention. Of relevance, the combination of statins with other anti cancer drugs may be a significant asset in malignancies resistant to current therapy. © 2012 Bentham Science Publishers.The work was supported by CIBEREHD, Fundación Mutua Madrileña, Fundació la Marató de TV3, PI11/03025 (META) and grants PI09/0056 (Instituto de Salud Carlos III), SAF2009-11417, SAF2008-02199, SAF2011-23031 (Plan Nacional de I+D), Spain; and P50-AA-11999 (Research Center for Liver and Pancreatic Diseases, NIAAA/NIH).Peer Reviewe

Lysosomal Cholesterol Accumulation Sensitizes to Acetaminophen Hepatotoxicity by Impairing Mitophagy

The role of lysosomes in acetaminophen (APAP) hepatotoxicity is poorly understood. Here, we investigated the impact of genetic and drug-induced lysosomal cholesterol (LC) accumulation in APAP hepatotoxicity. Acid sphingomyelinase (ASMase) mice exhibit LC accumulation and higher mortality after APAP overdose compared to ASMase littermates. ASMase hepatocytes display lower threshold for APAP-induced cell death and defective fusion of mitochondria-containing autophagosomes with lysosomes, which decreased mitochondrial quality control. LC accumulation in ASMase hepatocytes caused by U18666A reproduces the susceptibility of ASMase hepatocytes to APAP and the impairment in the formation of mitochondria-containing autolysosomes. LC extraction by 25-hydroxycholesterol increased APAP-mediated mitophagy and protected ASMase mice and hepatocytes against APAP hepatotoxicity, effects that were reversed by chloroquine to disrupt autophagy. The regulation of LC by U18666A or 25-hydroxycholesterol did not affect total cellular sphingomyelin content or its lysosomal distribution. Of relevance, amitriptyline-induced ASMase inhibition in human hepatocytes caused LC accumulation, impaired mitophagy and increased susceptibility to APAP. Similar results were observed upon glucocerebrosidase inhibition by conduritol β-epoxide, a cellular model of Gaucher disease. These findings indicate that LC accumulation determines susceptibility to APAP hepatotoxicity by modulating mitophagy, and imply that genetic or drug-mediated ASMase disruption sensitizes to APAP-induced liver injury.The work was supported by grants SAF-2011-23031, SAF-2012-34831 from Plan Nacional de I+ D, Spain, Fundació Marató de TV3, La Mutua Madrileña, PI11/0325 (META) grant from the Instituto Salud Carlos III, and by the support of CIBEREHD; the center grant P50-AA-11999 Research Center for Liver and Pancretic Diseases funded by NIAAA/NIH; R01 DK067215 and Liver Center P30DK48522 Cell Culture, Analytical/Metabolic Intstrumentation and Cell and Tissue Imaging Cores.Peer Reviewe

Mesophilic anaerobic co-digestion of two-phase olive-mill waste and cattle manure: Optimization of semi-continuous process

Anaerobic co-digestion of organic wastes is an effective technology for the management of two or more substrates with different characteristics. In this context, the main objective of this work was the optimization of biogas production for the treatment of a mixture of two-phase olive-mill waste (2POMW) and cattle manure (CM) (60:40 w/w) at mesophilic temperature range (35 degrees C). The effect of hydraulic retention time (HRT) on the performance and stability of the digestion process was studied. A decreasing series of HRTs in the range of 40-12 days was analyzed. The corresponding organic loading rates (OLR) were in the range 2.01-6.07 gVS/L(R)middotd. Pseudo steady-state operation of the reactor was established for HRTs between 40 and 15 days. For 15-days HRT, the maximum values of methane productivity (0.94 LCH4/L(R)middotd) and specific methane yield (0.52 LCH4/gVS(removed)) were obtained while total acidity (measured as acetic acid) in the effluent were < 150 mg/L, verifying process stability. In addition, the removal efficiencies of volatile solids (VS) and dissolved organic carbon (DOC) were 38 and 67 %, respectively. At 12-days HRT, decreases in methane production and organic matter removal efficiencies were observed, with values of 27 and 47 % for VS and DOC removal, respectively. Therefore, 12-days HRT was considered as inadequate for the anaerobic co-digestion of 2POMW and CM because a clear increase in volatile fatty acids was observed at the end of this period, leading to process destabilization and a decrease in biogas production

Relationship between sociometric types and academic goals in a sample of Spanish students of Secondary Education

El objetivo de este estudio fue analizar la relación entre tipos sociométricos, categorías conductuales y metas académicas en una muestra de 1349 estudiantes (51.7% chicos) de educación secundaria obligatoria. La identificación sociométrica de los estudiantes se realizó mediante el Programa Socio y las metas académicas fueron evaluadas mediante el AGTQ (Achievement Goals Tendencies Questionnaire). El AGTQ es una medida de autoinforme diseñada para medir tres orientaciones de metas: aprendizaje, logro y refuerzo social. Los resultados muestran que los estudiantes nominados positivamente por sus compañeros presentaron mayores puntuaciones en metas de aprendizaje y de logro que los estudiantes nominados negativamente. Además, los tipos sociométricos fueron predictores significativos de las metas académicas, ya que los estudiantes nominados positivamente por sus compañeros presentaron mayor probabilidad de alcanzar altas metas de aprendizaje y de logro que los estudiantes nominados negativamente.The aim of this study was to analyze the relationship between sociometric types, behavioral categories and academic goals in a sample of 1349 students (51.7% boys) of compulsory secondary education. The students’ sociometric identification was performed by the Programa Socio and academic goals was measured by the AGTQ (Achievement Goals Tendencies Questionnaire). The AGTQ is a self-report measure designed to measure three tendencies of goals: Learning goals, Achievement goals and Reinforcement Social goals. Results show that students nominated by their peers positively had higher scores on Learning and Achievement goals than students negatively nominated. Furthermore, sociometric types were significant predictors of academic goals, as students nominated by their peers positively were more likely to achieve high Learning goals and Achievement goals that students negatively nominated.Este trabajo ha sido realizado a través del Proyecto SEJ 2004-07311/EDUC perteneciente al Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica del MEC concedido al primer autor

Perfiles de ansiedad escolar: Diferencias en clima social y violencia entre iguales

Introducción. La ansiedad escolar es definida como un conjunto de síntomas agrupados en respuestas cognitivas, psicofisiológicas y motoras emitidas por un individuo ante situaciones escolares que son percibidas como amenazantes y/o peligrosas. Entre variables escolares relevantes, la ansiedad escolar puede estar influida por la percepción del clima social y la violencia cotidiana observada en el centro por parte del alumnado. El objetivo de este estudio fue identificar si existen combinaciones entre las distintas situaciones que provocan ansiedad escolar dando lugar a diferentes perfiles ansiosos. Además, se persigue comprobar si existen diferencias entre estos perfiles en las variables percepción de clima social y violencia entre iguales. Método. La muestra estuvo compuesta por 365 alumnos de educación secundaria. La ansiedad escolar fue medida con el Inventario de Ansiedad Escolar, el clima social se midió con el Cuestionario de Clima Social del Centro Escolar y la violencia entre iguales mediante el Cuestionario de Violencia Escolar Cotidiana. Resultados. Los análisis de conglomerados identificaron tres perfiles de ansiedad escolar. Los resultados indicaron diferencias estadísticamente significativas entre los tres perfiles en las variables clima referente al profesorado entre los grupos con baja y alta ansiedad escolar y en experiencia personal de sufrir violencia entre el grupo con baja y media ansiedad escolar y entre el grupo con baja y alta ansiedad escolar. La magnitud de las diferencias halladas fue de baja a moderada. Discusión y Conclusiones. Los hallazgos de este estudio resultan relevantes ya que aportan un análisis más exhaustivo de la ansiedad escolar y de las diferencias observadas en otras variables relevantes en el ámbito educativo, como son el clima social del centro escolar y la violencia entre iguales.Introduction. School anxiety is often defined as a set of symptoms grouped into cognitive, psychophysiological and motor responses emitted by an individual in school situations that can be perceived as threatening and/or dangerous. School anxiety may be influenced - among other relevant school variables - by the perception of social climate and the daily violence witnessed by students at school. The aim of this study is to identify whether there are different combinations of school anxiety-provoking situations which give rise to different anxious profiles. Furthermore, it claims to verify whether there are differences between these profiles in terms of the variables: perception of social climate and peer violence. Method. The sample consists of 365 high school students. School anxiety was measured using the School Anxiety Inventory; the social climate was measured with the School Social Climate Questionnaire and peer violence with the Daily School Violence Questionnaire. Results. Cluster analyses have identified three profiles of school anxiety. The results showed statistically significant differences among the three anxiety profiles in the following variables: (1) teacher climate (low and high anxiety) and (2) personal experience of suffering violence (low and medium anxiety; low and high anxiety). The differences were of low-to-moderate intensity. Discussion and Conclusion. The findings of this study are relevant because they provide a more comprehensive analysis of school anxiety and differences in other relevant variables in an educational context, such as the school social climate and peer violence

Prevalence and genetic diversity of Trichomonas vaginalis in the general population of Granada and co-infections with Gardnerella vaginalis and Candida species

Purpose: Purulent or exudative genitourinary infections are a frequent cause of consultation in primary and specialized healthcare. The objectives of this study were: to determine the prevalence of Trichomonas vaginalis and co-infections with Candida spp. and Gardnerella vaginalis in vaginal secretion; and to use multilocus sequence typing (MLST) to analyse the genetic diversity of T. vaginalis strains. Methodology: The samples were submitted for analysis (n=5230) to a third-level hospital in Granada (Southern Spain) between 2011 and 2014; eight T. vaginalis strains isolated during 2015 were randomly selected for MLST analysis. Culture and nucleic acid hybridization techniques were used to detect microorganisms in the samples. Results: The prevalence of T. vaginalis was 2.4 % between 2011 and 2014, being higher during the first few months of both 2011 and 2012. Among samples positive for T. vaginalis, co-infection with G. vaginalis was detected in 29 samples and co-infection with Candida spp. in 6, while co-infection with all three pathogens was observed in 3 samples. The only statistically significant between-year difference in co-infection rates was observed for T. vaginalis with G. vaginalis due to an elevated rate in 2011. MLST analysis results demonstrated a high genetic variability among strains circulating in our setting. Conclusion: These findings emphasize the need for the routine application of diagnostic procedures to avoid the spread of this sexually transmitted infection

Gigantism: microsurgical treatment by transsphenoidal approach and prognostic factors

Purpose: We present the results of transsphenoidal microsurgical treatment in 14 patients with gigantism. The influence on the prognosis of factors such as the tumor size and preoperative levels of GH and IGF-1 is also quantified. Materials and methods: The patients, operated between 1982 and 2004, were reviewed retrospectively in June 2022. All patients had complete endocrinological studies in the preoperative period and a postoperative control between 6 days and 3 weeks. Follow-up has been supported with annual check-ups between 3 and 31 years. We have compared the preoperative levels of GH and IGF-1 of these patients with the levels of a series of acromegalic patients operated on in the same Center. Results: In this series there were 4 women and 10 men. The age ranged between 14 and 21 years. In 6 patients, postoperative hormone levels achieved the disease control criteria (42.8%). The CT/MRI studies revealed the existence of invasive tumors in 10 of the patients (71.4%). Postoperative CT/MRI showed no tumor tissue in 3 patients but in 7 patients there were tumor remains. The remaining 4 patients had abnormal images although not considered as tumor. A statistical comparison of preoperative serum GH and IGF-1 levels in patients with gigantism and patients with acromegaly showed a significant elevation in the former. Conclusion: Pituitary adenomas that cause gigantism are generally large and invasive, which makes them difficult to cure. High preoperative levels of GH and IGF-1 are also factors that decrease remission

The structural and electronic properties of nanostructured Ce1–x–yZrxTbyO2 ternary oxides: Unusual concentration of Tb3+ and metal_oxygen_metal interactions

10 pages, 12 figures, 1 table.Ceria-based ternary oxides are widely used in many areas of chemistry, physics, and materials science. Synchrotron-based time-resolved x-ray diffraction, x-ray absorption near-edge spectroscopy (XANES), Raman spectroscopy, and density-functional calculations were used to study the structural and electronic properties of Ce–Zr–Tb oxide nanoparticles. The nanoparticles were synthesized following a novel microemulsion method and had sizes in the range of 4–7 nm. The Ce1–x–yZrxTbyO2 ternary systems exhibit a complex behavior that cannot be predicted as a simple extrapolation of the properties of Ce1–xZrxO2, Ce1–xTbxO2, or the individual oxides (CeO2, ZrO2, and TbO2). The doping of ceria with Zr and Tb induces a decrease in the unit cell, but there are large positive deviations with respect to the cell parameters predicted by Vegard's rule for ideal solid solutions. The presence of Zr and Tb generates strain in the ceria lattice through the creation of crystal imperfections and O vacancies. The O K-edge and Tb LIII-edge XANES spectra for the Ce1–x–yZrxTbyO2 nanoparticles point to the existence of distinctive electronic properties. In Ce1–x–yZrxTbyO2 there is an unexpected high concentration of Tb3+, which is not seen in TbO2 or Ce1–xTbxO2 and enhances the chemical reactivity of the ternary oxide. Tb_O_Zr interactions produce a stabilization of the Tb(4f,5d) states that is responsible for the high concentration of Tb3+ cations. The behavior of Ce1–x–yZrxTbyO2 illustrates how important can be metal_oxygen_metal interactions for determining the structural, electronic, and chemical properties of a ternary oxide.The research carried out at the Chemistry Department of Brookhaven National Laboratory was financed through Contract No. DE-AC02-98CH10886 with the US Department of Energy (Division of Chemical Sciences). The NSLS is supported by the Divisions of Materials and Chemical Sciences of DOE. Work at the “Instituto de Catálisis y Petroleoquímica (CSIC)” was done with financial support from CICYT (Project No. MAT2000-1467).Peer reviewe

Tratamiento quirúrgico de la pseudoartrosis de la apófisis odontoides: Presentación de dos casos

Se presenta nuestra experiencia de dos casos de pseudoartrosis de apófisis odontoides tratadas quirúrgicamente mediante atornillado directo a compresión por vía anterior paraesternomocleidomastoidea. El resultado final fue satisfactorio en el primer caso, teniendo que realizarse una artrodesis posterior C1-C2 en el segundo. Se discute la posibilidad de un exceso de angulación posterioSe presenta nuestra experiencia de dos casos de pseudoartrosis de apófisis odontoides tratadas quirúrgicamente mediante atornillado directo a compresión por vía anterior paraesternomocleidomastoidea. El resultado final fue satisfactorio en el primer caso, teniendo que realizarse una artrodesis posterior C1-C2 en el segundo. Se discute la posibilidad de un exceso de angulación posterior en la colocación del tornillo como causa del fracaso de la técnica.en la colocación del tornillo como causa del fracaso de la técnica.Two cases of odontoid process non-union treated by direct screw compression through an anterior approach are presented. The outcome was satisfactory in one case. The other required posterior C1-C2 union because of anterior screwing failure. An excessive posterior angulation of the screw thought to be the cause of anterior fusion failure