Hepatic cytochrome P450 3A drug metabolism is reduced in cancer patients who have an acute-phase response

Inflammatory disease states (infection, arthritis) are associated with reduced drug oxidation by the cytochrome P450 3A system. Many chemotherapy agents are metabolised through this pathway, and disease may therefore influence inter-individual differences in drug pharmacokinetics. The purpose of this study was to assess cytochrome P450 3A function in patients with advanced cancer, and its relation to the acute-phase response. We evaluated hepatic cytochrome P450 3A function in 40 patients with advanced cancer using the erythromycin breath test. Both the traditional C20min measure and the recently proposed 1/TMAX values were estimated. The marker of acute-phase response, C-reactive protein and the pro-inflammatory cytokines IL-6, IL-1β, TNFα and IL-8 were measured in serum or plasma at baseline. Cancer patients with an acute phase response (C-reactive protein >10 mg l−1, n=26) had reduced metabolism as measured with the erythromycin breath test 1/TMAX (Kruskal–Wallis Anova, P=0.0062) as compared to controls (C-reactive protein ⩽10 mg l−1, n=14). Indeed, metabolism was significantly associated with C-reactive protein over the whole concentration range of this acute-phase marker (r=−0.64, Spearman Rank Correlation, P<0.00001). C-reactive protein serum levels were significantly correlated with those of IL-6 (Spearman coefficient=0.58, P<0.0003). The reduction in cytochrome P450 3A function with acute-phase reaction was independent of the tumour type and C-reactive protein elevation was associated with poor performance status. This indicates that the sub-group of cancer patients with significant acute-phase response have compromised drug metabolism, which may have implications for the safety of chemotherapy in this population

Systems genetics identifies Sestrin 3 as a regulator of a proconvulsant gene network in human epileptic hippocampus

Gene-regulatory network analysis is a powerful approach to elucidate the molecular processes and pathways underlying complex disease. Here we employ systems genetics approaches to characterize the genetic regulation of pathophysiological pathways in human temporal lobe epilepsy (TLE). Using surgically acquired hippocampi from 129 TLE patients, we identify a gene-regulatory network genetically associated with epilepsy that contains a specialized, highly expressed transcriptional module encoding proconvulsive cytokines and Toll-like receptor signalling genes. RNA sequencing analysis in a mouse model of TLE using 100 epileptic and 100 control hippocampi shows the proconvulsive module is preserved across-species, specific to the epileptic hippocampus and upregulated in chronic epilepsy. In the TLE patients, we map the trans-acting genetic control of this proconvulsive module to Sestrin 3 (SESN3), and demonstrate that SESN3 positively regulates the module in macrophages, microglia and neurons. Morpholino-mediated Sesn3 knockdown in zebrafish confirms the regulation of the transcriptional module, and attenuates chemically induced behavioural seizures in vivo

Pollination and dispersal trait spectra recover faster than the growth form spectrum during spontaneous succession in sandy old‐fields

Question: Spontaneous succession is the most natural and cost‐effective solution for grassland restoration. However, little is known about the time required for the recovery of grassland functionality, i.e., for the recovery of reproductive and vegetative processes typical of pristine grasslands. Since these processes operate at different scales, we addressed the question: do reproductive and vegetative processes require different recovery times during spontaneous succession? Location: Kiskunság sand region (Central Hungary). Methods: As combinations of plant traits can be used to highlight general patterns in ecological processes, we compared reproductive (pollination‐ and dispersal‐related) and vegetative (growth form) traits between recovered grasslands of different age (&lt;10 years old; 10–20 years old; 20–40 years old) and pristine grasslands. Results: During spontaneous succession, the reproductive trait spectra became similar to those of pristine grasslands earlier than the vegetative ones. In arable land abandoned for 10 years, pollination‐ and dispersal‐related trait spectra did not show significant difference to those of pristine grasslands; anemophily and anemochory were the prevailing strategies. Contrarily, significant differences in the growth form spectrum could be observed even after 40 years of abandonment; in recovered grasslands erect leafy species prevailed, while the fraction of dwarf shrubs and tussock‐forming species was significantly lower than in pristine grasslands. Conclusions: The recovery of the ecological processes of pristine grasslands might require different amounts of time, depending on the spatial scale at which they operate. The reproductive trait spectra recovered earlier than the vegetative one, since reproductive attributes first determine plant species sorting at the regional level towards their respective habitats. The recovery of the vegetative trait spectrum needs more time as vegetative‐based interactions operate on a smaller spatial scale. Thus, vegetative traits might be more effective in the long‐term assessment of restoration success than the reproductive ones

Clinical pharmacology of cancer therapies in older adults

This abbreviated review outlines the physiologic changes associated with aging, and examines how these changes may affect the pharmacokinetics and pharmacodynamics of anticancer therapies. We also provide an overview of studies that have been conducted evaluating the pharmacology of anticancer therapies in older adults, and issue a call for further research

Docetaxel induces moderate ovarian toxicity in mice, primarily affecting granulosa cells of early growing follicles

Advances in cancer therapy have focused attention on the quality of life of cancer survivors. Since infertility is a major concern following chemotherapy, it is important to characterize the drug-specific damage to the reproductive system to help find appropriate protective strategies. This study investigates the damage on neonatal mouse ovary maintained in vitro for 6 days, and exposed for 24 h (on Day 2) to clinically relevant doses of Docetaxel (DOC; low: 0.1 µM, mid: 1 µM, high: 10 µM). Furthermore, the study explores the putative protective action exerted by Tri-iodothyronine (T3; 10(−7) M). At the end of culture, morphological analyses and follicle counts showed that DOC negatively impacts on early growing follicles, decreasing primary follicle number and severely affecting health at the transitional and primary stages. Poor follicle health was mainly due to effects on granulosa cells, indicating that the effects of DOC on oocytes were likely to be secondary to granulosa cell damage. DOC damages growing follicles specifically, with no direct effect on the primordial follicle reserve. Immunostaining and western blotting showed that DOC induces activation of intrinsic, type II apoptosis in ovarian somatic cells; increasing the levels of cleaved caspase 3, cleaved caspase 8, Bax and cleaved poly(ADP-ribose) polymerase, while also inducing movement of cytochrome C from mitochondria into the cytosol. T3 did not prevent the damage induced by the low dose of DOC. These results demonstrated that DOC induces a gonadotoxic effect on the mouse ovary through induction of somatic cell apoptosis, with no evidence of direct effects on the oocyte, and that the damaging effect is not mitigated by T3

Análise espacial de fragmentos florestais na Bacia do Rio Itapemirim, ES

Os objetivos deste trabalho foi mapear e analisar a estrutura da paisagem florestal em uma área representativa da Bacia do Rio Itapemirim, ES, por meio de índices de ecologia da paisagem. O mapeamento dos fragmentos florestais foi obtido utilizando técnicas de fotointerpretação na escala de 1:1500 do ortofotomosaico do ano 2007. Para o cálculo dos índices de ecologia, foi utilizada a extensão Patch Analyst dentro do aplicativo computacional ArcGIS 9.3. Foram encontrados 3.285 fragmentos florestais em toda a área, representando 17% de cobertura florestal. Os fragmentos mapeados foram divididos em classes de tamanho, sendo fragmentos pequenos aqueles menores que 5 ha; de tamanho médio aqueles entre 5 e 50 ha; e grandes os maiores que 50 ha. Os fragmentos pequenos encontravam-se em maior número (2.236), seguidos pelos fragmentos de tamanho médio (749) e, por último, pelos fragmentos grandes, que compreenderam apenas 100 manchas. O número de fragmentos de cada classe de tamanho possui relação inversa com a contribuição em área dessa classe dentro da fragmentação florestal. As análises quantitativas por meio de métricas da paisagem foram feitas com os grupos de índices de área; densidade e tamanho, forma; proximidade e área central, sendo este último obtido em diferentes simulações de efeito de borda (20,40, 60, 80, 100, 140 e 200 m). Para todos os índices houve diferenciações com relação às classes de tamanho dos fragmentos florestais. A maior parte dos fragmentos florestais da bacia, são pequenos, menores que 5 ha, sendo que a distância de borda de 100 metros elimina completamente a área central desses fragmentos. Apesar dos fragmentos grandes apresentarem os formatos mais irregulares, estes possuem maior índice de área central, mesmo sob o efeito da maior distância de efeito de borda

Are food-deceptive orchid species really functionally specialized for pollinators?

Food-deceptive orchid species have traditionally been considered pollination specialized to bees or butterflies. However, it is unclear to which concept of specialization this assumption is related; if to that of phenotypic specialization or of functional specialization. The main aim of this work was to verify if pollinators of five widespread food-deceptive orchid species (Anacamptis morio (L.) R.M. Bateman, Pridgeon & M.W. Chase, Anacamptis pyramidalis (L.) Rich., Himantoglossum adriaticum H. Baumann, Orchis purpurea Huds. and Orchis simia Lam.) predicted from the phenotypic point of view matched with the observed ones. We addressed the question by defining target orchids phenotypic specialization on the basis of their floral traits, and we compared the expected guilds of pollinators with the observed ones. Target orchid pollinators were collected by conducting a meta-analysis of the available literature and adding unpublished field observations, carried out in temperate dry grasslands in NE Italy. Pollinator species were subsequently grouped into guilds and differences in the guild spectra among orchid species grouped according to their phenotype were tested. In contradiction to expectations derived from the phenotypic point of view, food-deceptive orchid species were found to be highly functionally generalized for pollinators, and no differences in the pollinator guild spectra could be revealed among orchid groups. Our results may lead to reconsider food-deceptive orchid pollination ecology by revaluating the traditional equation orchid-pollination specialization