Vascular targeted therapies in oncology

Neovascularization is intimately involved in tumor survival, progression, and spread, factors known to contribute significantly to treatment failures. Thus, strategies targeting the tumor blood vessel support network may offer not only unique therapeutic opportunities in their own right, but also novel means of enhancing the efficacies of conventional anticancer treatments. This article reviews one such therapeutic approach directed at the tumor blood vessel support network. Vascular disrupting therapies seek the destruction of the established neovasculature of actively growing tumors. The goal of these therapies is to cause a rapid and catastrophic shutdown in the vascular function of the tumor in order to arrest the blood flow and produce tumor cell death as a result of oxygen and nutrient deprivation and the build up of waste products. The authors’ work is supported by the National Cancer Institute (Public Health Service grants CA084408 and CA089655) and the Danish Cancer Society.     

Methyl-branched poly(hydroxyalkanoate) biosynthesis from 13-methyltetradecanoic acid and mixed isostearic acid isomer substrates

Nonylphenol, the most abundant environmental pollutant with endocrine disrupting activity, is also toxic to plants and microorganisms, but its actual impact in the field is unknown. In this study, diversity of culturable soil microfungal and plant communities was assessed in a disused industrial estate, at three sites featuring different nonylphenol pollution. Although soil microfungal assemblages varied widely among the sites, no significant correlation was found with point pollutant concentrations, thus suggesting indirect effects of soil contamination on microfungal assemblages. The potential of indigenous fungi and plants to remove nonylphenol was assessed in mesocosm experiments. Poplar plants and a fungal consortium consisting of the most abundant strains in the nonylphenol-polluted soil samples were tested alone or in combination for their ability to reduce, under greenhouse conditions, nonylphenol levels either in a sterile, artificially contaminated sand substrate, or in two non-sterile soils from the original industrial area. Introduction of indigenous fungi consistently reduced nonylphenol levels in all substrates, up to ca. 70% depletion, whereas introduction of the plant proved to be effective only with high initial pollutant levels. In native non-sterile soil, nonylphenol depletion following fungal inoculation correlated with biostimulation of indigenous fungi, suggesting positive interactions between introduced and resident fungi. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Elevated endogenous testosterone concentrations potentiate muscle androgen receptor responses to resistance exercise

The purpose of this study was to determine the influence of endogenous circulating testosterone (T) on muscle androgen receptor (AR) responses to acute resistance exercise (RE). Six healthy men (26 ± 4 years; 176 ± 5 cm; 75.8 ± 11.4 kg) performed a knee extension exercise protocol on two occasions separated by 1–3 weeks. Rest preceded one trial (i.e., control [CON] trial) and a high-volume upper-body RE protocol designed to increase circulating T preceded the other trial (i.e., high T [HT] trial). Serial blood samples were obtained throughout each trial to determine circulating T concentrations. Biopsies of the vastus lateralis were obtained pre-RE (REST), 10-min post-RE (+10), and 180-min post-RE (+180) to determine muscle AR content. Circulating T concentrations remained stable during CON. Alternately, HT significantly (p ≤ 0.05) increased T concentrations above resting values (+16%). Testosterone area-under-the-time curve during HT exceeded CON by 14%. AR content remained stable from REST to +10 in both trials. Compared to the corresponding +10 value, muscle AR content at +180 tended to decrease during CON (−33%; p = 0.10) but remained stable during HT (+40%; p = 0.17). Muscle AR content at +180 during the HT trial exceeded the corresponding CON value. In conclusion, acute elevations in circulating T potentiated muscle AR content following RE.     

Degradation of 17β-estradiol and its conjugates: Effects of initial concentration and MLSS concentration

There have been many strong retrospective observations regarding adverse effects in reproductive and fertile developments in human and the wildlife caused by the endocrine disrupting compounds (EDCs) present in the aquatic environment recently. Degradation by biomass is one of the main removal mechanisms for 17β-estradiol (E2), the most important EDC, and its conjugates from sewage in wastewater treatment plants. In this batch study, the degradation rates of E2 and its conjugates were found to be affected by initial concentration of concerned pollutants and mixed liquor suspended solids (MLSS) concentration of activated sludge tested. Quantitative analysis was performed by liquid chromatography tandem mass spectrometry (LC-MS-MS). Overall, Michaelis–Menten Model adequately described the degradation of E2 and its conjugates over the range of the initial concentrations and MLSS concentrations tested. The degradation rates increased with the increase of initial concentration and MLSS concentration.     

Metabolic engineering based on systems biology for chemicals production

Microorganisms have been the main sources for the production of chemicals. Production of chemicals requires the development of low-cost and higher-yield processes. Towards this goal, microbial strains with higher levels of production should be first considered. Metabolic engineering has been used extensively over the past two to three decades to increase production of these chemicals. Advances in omics technology and computational simulation are allowing us to perform metabolic engineering at the systems level. By combining the results of omics analyses and computational simulation, systems biology allows us to understand cellular physiology and characteristics, which can subsequently be used for designing strategies. Here, we review the current status of metabolic engineering based on systems biology for chemical production and discuss future prospects.     

Distribution of endocrine cells in the digestive tract of Alligator sinensis during the active and hibernating period

The digestive tract is the largest endocrine organ in the body; the distribution pattern of endocrine cells varies with different pathological and physiological states. The aim of the present study was to investigate the distributed density of 5-hydroxytryptamine (5-HT), gastrin (GAS), somatostatin (SS) and vasoactive intestinal peptide (VIP) immunoreactive (IR) cells in the digestive tract of Alligator sinensis during the active and hibernating period by immunohistochemical (IHC) method. The results indicated that 5-HT-IR cells were distributed throughout the entire digestive tract, which were most predominant in duodenum and jejunum. The density increased significantly in stomach and duodenum during hibernation. GAS-IR cells were limited in small stomach and small intestine. The density decreased significantly in small stomach during hibernation, while increased in duodenum. What's more, most of the endocrine cells in duodenum were generally spindle shaped with long cytoplasmic processes ending in the lumen during hibernation. SS-IR cells were limited in stomach and small stomach. The density increased in stomach while decreased in small stomach during hibernation, meanwhile, fewer IR cells occurred in small intestine. VIP-IR cells occurred in stomach and small stomach. The density decreased in small stomach, while increased in stomach during hibernation. These results indicated that the endocrine cells in different parts of digestive tract varied differently during hibernation, their changes were adaptive response to the hibernation.     

Pre- and postnatal bisphenol A treatment results in persistent deficits in the sexual behavior of male rats, but not female rats, in adulthood

Perinatal administration of the endocrine disruptor bisphenol A (BPA) reportedly inhibits the sexual behavior of sexually naïve adult male rats. In order to evaluate the effects of BPA administration during early development on later reproductive behavior, we administered one of five doses of bisphenol A daily to pregnant female rats throughout gestation and lactation, and quantified the appetitive and consummatory sexual behaviors of the resultant male and female offspring over multiple sexual encounters in adulthood. Males receiving low dose perinatal BPA (50 μg/kg bw/day) showed persistent deficits in sexual behavior in adulthood. Males receiving the highest dose (5 mg/kg bw/day), however, were indistinguishable from controls with respect to consummatory sexual behaviors but showed decreased latencies to engage in those behaviors when sexually naïve, with significant non-linear, or U-shaped, dose-response relationships observed on the first and last day of testing. Adult female sexual behavior was not affected by early BPA administration at any dose tested. These results are consistent with previous reports that BPA exerts behavioral effects especially at low doses, and further indicates that BPA can cause lasting impairment of sexual behavior in males, but does not alter the normal development of female appetitive or consummatory sexual behaviors. To our knowledge, this is the first report indicating that adult sexual performance is impaired in sexually experienced animals following perinatal exposure to bisphenol A.     

Isolation, identification and quantitation of hydroxycinnamic acid conjugates, potential platform chemicals, in the leaves and stems of Miscanthus × giganteus using LC-ESI-MSn

Miscanthus × giganteus is a source of platform chemicals and bioethanol through fermentation. Cinnamates in leaves and stems were analysed by LC–ESI-MSⁿ. Free phenols were extracted and separated chromatographically. More than 20 hydroxycinnamates were identified by UV and LC–ESI-MSⁿ. Comparative LC–MS studies on the leaf extract showed isomers of O-caffeoylquinic acid (3-CQA, 4-CQA and 5-CQA), O-feruloylquinic acid (3-FQA, 4-FQA and 5-FQA) and para-coumaroylquinic acid (3-pCoQA and 5-pCoQA). Excepting 3-pCoQA, all were also detected in stem. 5-CQA dominated in leaf; a mandelonitrile–caffeoylquinic acid dominated in stem. Three minor leaf components were distinguished by fragmentation patterns in a targetted MS² experiment as dicaffeoylquinic acid isomers. Others (M_r 516) were tentatively identified as hexosylcaffeoyl-quinates. Three positional isomers of O-caffeoylshikimic acid were minor components. p-Hydroxybenzaldehyde was also a major component in stem. This is the first report of the hydroxycinnamic acid profile of leaves and stems of M. × giganteus.