Publications

Cancer is a disease driven by both somatic mutations that increase survival and proliferation of cell lineages and the evolution of genes associated with cancer risk in populations. Several genes associated with cancer in humans, hereafter cancer genes, show evidence of germline positive selection among species. Taking advantage of a large collection of mammalian genomes, we systematically looked for signatures of germline positive selection in 430 cancer genes available in COSMIC. We identified 40 cancer genes with a robust signal of positive selection in mammals. We found evidence for fewer selective constraints—higher number of non-synonymous substitutions per non-synonymous site to the number of synonymous substitutions per synonymous site (dN/dS)—and higher incidence of positive selection—more positively selected sites—in cancer genes bearing germline and recessive mutations that predispose to cancer. This finding suggests a potential association between relaxed selection, positive selection, and risk of hereditary cancer. On the other hand, we did not find significant differences in terms of tissue or gene type. Human cancer genes under germline positive selection in mammals are significantly enriched in the processes of DNA repair, with high presence of Fanconi anaemia/Breast Cancer A (FA/BRCA) pathway components and T cell proliferation genes. We also show that the inferred positively selected sites in the two genes with the strongest signal of positive selection, i.e., BRCA2 and PTPRC, are in regions of functional relevance, which could be relevant to cancer susceptibility.

Douglas Theobald recently developed an interesting test putatively capable of quantifying the evidence for a Universal Common Ancestry uniting the three domains of life (Eukarya, Archaea and Bacteria) against hypotheses of Independent Origins for some of these domains. We review here his model, in particular in relation to the treatment of Horizontal Gene Transfer (HGT) and to the quality of sequence alignment.

Resumen en: Cluster analysis was applied to the results of the determination of the aliphatic hydrocarbons (pristane, C18, C19, C20, C22, C24, C28, C32 and C36) in ...

Objectives: Clinical studies have documented morning-evening, administration-time differences in antihypertensive efficacy, duration of action, safety profile and/or effects on the circadian blood pressure (BP) pattern of several different classes of BP-lowering medications. Despite these findings, most hypertensive subjects ingest all their BP-lowering agents in a single morning dose. The MAPEC study investigated if chronotherapy of hypertension has any influence in cardiovascular morbidity and mortality. Methods: This prospective study investigated 3344 subjects (1718 men), 52.6 ± 14.5 years of age. At baseline, BP was measured every 20-min intervals 07:00 to 23:00 h and every 30-min at night for 48 h. Physical activity was simultaneously monitored every minute by wrist actigraphy. The same evaluation procedure was scheduled yearly or more frequently (quarterly) if treatment adjustment was required to improve BP control. The Cox proportional-hazard model was used to estimate relative risks of cardiovascular events associated with use of antihypertensive treatment and circadian time of treatment. Results: At the last evaluation, 625 subjects were normotensive and 606 untreated hypertensives according to ambulatory BP criteria. Among the remaining subjects, 1068 were receiving all antihypertensive medication on awakening, and 1045 were ingesting some antihypertensive agent at bedtime. Compared with normotensive subjects, the relative risk of cardiovascular events was highest for patients ingesting all drugs on awakening (3.84 [2.48–5.95]) and lowest for those receiving all medication at bedtime (0.95 [0.44–2.07]; P = 0.907 compared to normotensive subjects; P < 0.001 compared to all other groups). Compared with untreated subjects, cardiovascular risk was significantly higher with increasing number of drugs on awakening, but consistently lower, independently of the number of drugs, when medication was ingested at bedtime. Non-dipping was significantly lower (28 vs. 61%) among subjects treated at bedtime. Conclusions: In subjects with essential hypertension, pharmacologic therapy should take into account when to treat with respect to the rest-activity pattern of each patient. Treatment at bedtime not only improves BP control and decreases the prevalence of non-dipping, but also significantly reduces cardiovascular risk to the level of normotension.

Poly(dimethylsiloxane) (PDMS) elastomer films synthesized through a cross-linking reaction between hydroxyl-terminated or vinyl-terminated PDMS have been homogeneously doped with silica-coated Au nanoparticles. The nanocomposite synthesis involves mixing a preformed colloid of surface-modified metal nanoparticles with the elastomer film precursors. The homogeneous distribution of nanoparticles is demonstrated through the presence of well defined plasmon absorbance bands in the visible, which clearly show that the composites retain the characteristic optical properties of single Au nanoparticles. The metal particle concentration could be easily tailored either through the amount or the concentration of the nanoparticle colloid added. Since the Au nanoparticles are not cross-linked to the polymer and the concentration of particles is relatively low, we postulate that the presence of the nanoparticles does not affect the mechanical properties of the films, though this remains to be confirmed.

Ambulatory blood pressure (BP) measurements (ABPM) correlate more closely with target organ damage and cardiovascular events than clinical cuff measurements. ABPM reveals the significant circadian variation in BP, which in most individuals presents a morning increase, small post-prandial decline, and more extensive lowering during nocturnal rest. However, under certain pathophysiological conditions, the nocturnal BP decline may be reduced (non-dipper pattern) or even reversed (riser pattern). This is clinically relevant because the non-dipper and riser circadian BP patterns constitute a risk factor for left ventricular hypertrophy, microalbuminuria, cerebrovascular disease, congestive heart failure, vascular dementia, and myocardial infarction. Hence, there is growing interest in how to best tailor and individualize the treatment of hypertension according to the specific circadian BP pattern of each patient. All previous trials that have demonstrated an increased cardiovascular risk in non-dipper as compared to dipper patients have relied on the prognostic significance of a single ABPM baseline profile from each participant without accounting for possible changes in the BP pattern during follow-up. Moreover, the potential benefit (i.e., reduction in cardiovascular risk) associated with the normalization of the circadian BP variability (conversion from non-dipper to dipper pattern) from an appropriately envisioned treatment strategy is still a matter of debate. Accordingly, the MAPEC (Monitorización Ambulatoria de la Presión Arterial y Eventos Cardiovasculares, i.e., Ambulatory Blood Pressure Monitoring and Cardiovascular Events) study was designed to investigate whether the normalization of the circadian BP profile toward more of a dipper pattern by chronotherapeutic strategies (i.e., specific timing during the 24 h of BP-lowering medications according to the 24 h BP pattern) reduces cardiovascular risk. The prospective MAPEC study investigates 3,000 diurnally active men and women >/=18 yrs of age. At inclusion, BP and wrist activity are measured for 48 h. The initial evaluation also includes a detailed medical history, an electrocardiogram, and screening laboratory blood and urine tests. The same evaluation procedure is scheduled yearly or more frequently (quarterly) if treatment adjustment is required for BP control. Cardiovascular morbidity and mortality are thus evaluated on the basis of changes in BP during follow-up. The MAPEC study, now on its fourth year of follow-up, investigates the potential decrease in cardiovascular, cerebrovascular, and renal risk from the proper modeling of the circadian BP profile by the timed administration (chronotherapy) of antihypertensive medication, beyond the reduction of clinic-determined daytime or ABPM-determined 24 h mean BP levels.