Troxacitabine prodrugs for pancreatic cancer

Troxacitabine is a cytotoxic deoxycytidine analogue with an unnatural L-configuration, which is activated by deoxycytidine kinase (dCK). The configuration is responsible for differences in the uptake and metabolism of troxacitabine compared to other deoxynucleoside analogues. The main drawback in the use of most nucleoside anticancer agents originates from their hydrophilic nature, which property requires a high and frequent dosage for an intravenous administration. To overcome this problem several troxacitabine prodrugs modified in the aminogroup with a linear aliphatic chain with a higher lipophilicity were developed. To determine whether these prodrugs have an advantage over Troxacitabine pancreatic cancer cell lines were exposed to Troxacitabine and the lipophilic prodrugs. The addition of linear aliphatic chains to troxacitabine increased sensitivity of pancreatic cancer cell lines to the drug > 100-fold, possibly due to a better uptake and retention of the drug.     

Targeting of the mouse Slc39a2 (Zip2) gene reveals highly cell-specific patterns of expression, and unique functions in zinc, iron, and calcium homeostasis

Fourteen members of the Slc39a superfamily of metal ion uptake transporters have been identified in mice and humans, but the physiological functions of most remain obscure. Herein, we created mice with Zip2 (Slc39a2) genes in which the open reading frame was replaced with that of the enhanced green fluorescent protein (EGFP), to study temporal and spatial patterns of Zip2 gene expression and examine the physiological roles of this transporter. Expression of this gene was remarkably cell-type specific and developmentally regulated in pericentral hepatocytes, developing keratinocytes, and a subset of immature dendritic cells in the immune system. In addition, the Zip2 gene was transiently expressed in giant trophoblast cells in the placenta. Although the Zip2 gene was not essential under conditions of normal dietary zinc, it played an important role in adapting to dietary zinc deficiency during pregnancy, and in the homeostasis of iron in the liver as well as iron and calcium in developing embryos. These studies suggest that active expression of the Zip2 gene in these few specific cell types, aforementioned, plays a particularly important role during zinc deficiency. These studies further reveal novel interactions between zinc transporter function and the homeostasis of other essential metals.     

In vivo and in vitro activity and mechanism of action of the multidrug cytarabine-L-glycerylyl-fluorodeoxyuridine

Multidrugs have the potential to bypass resistance. We investigated the in vitro activity and resistance circumvention of the multidrug cytarabine-L-fluorodeoxyuridine (AraC-L-5FdU), linked via a glycerophospholipid linkage. Cytotoxicity was determined using sensitive (A2780, FM3A/0) and resistant (AG6000, AraC resistant, deoxycytidine kinase deficient; FM3A/TK-, 5FdU resistant, thymidine kinase deficient) cell lines. Circumvention of nucleoside transporter and activating enzymes was determined using specific inhibitors, HPLC analysis and standard radioactivity assays. AraC-L-5FdU was active (IC50: 0.03 microM in both A2780 and FM3A/0), had some activity in AG6000 (IC50: 0.28 microM), but no activity in FM3A/TK(-) (IC50: 18.3 microM). AraC-nucleotides were not detected in AG6000. 5FdU-nucleotides were detected in all cell lines. AraC-L-5FdU did not inhibit TS in FM3A/TK(-) (5%). Since phosphatase/nucleotidase-inhibition reduced cytotoxicity 7-70-fold, cleavage seems to be outside the cell, presumably to nucleotides, and then to nucleosides. The multidrug was orally active in the HT-29 colon carcinoma xenografts which are resistant toward the single drugs.     

Attitudes towards urban howler monkeys (Alouatta caraya) in Paraguay

Primates - Increasing urbanisation is encroaching into natural habitats and sometimes forcing wildlife into urban centres. Whether or not wildlife can thrive in an urban environment is dependent on...     

Fish scale shape follows predictable patterns of variation based on water column position,body size,and phylogeny

Evolutionary Ecology - The influence of environment and phylogeny on morphological characteristics of organisms is well documented. However, little is known about how these factors influence scale...     

Photosynthetic Energy Conversion Efficiency: Setting a Baseline for Gauging Future Improvements in Important Food and Biofuel Crops

The conversion efficiency (ε_c) of absorbed radiation into biomass (MJ of dry matter per MJ of absorbed photosynthetically active radiation) is a component of yield potential that has been estimated at less than half the theoretical maximum. Various strategies have been proposed to improve ε_c, but a statistical analysis to establish baseline ε_c levels across different crop functional types is lacking. Data from 164 published ε_c studies conducted in relatively unstressed growth conditions were used to determine the means, greatest contributors to variation, and genetic trends in ε_c across important food and biofuel crop species. ε_c was greatest in biofuel crops (0.049–0.066), followed by C₄ food crops (0.046–0.049), C₃ nonlegumes (0.036–0.041), and finally C₃ legumes (0.028–0.035). Despite confining our analysis to relatively unstressed growth conditions, total incident solar radiation and average growing season temperature most often accounted for the largest portion of ε_c variability. Genetic improvements in ε_c, when present, were less than 0.7% per year, revealing the unrealized potential of improving ε_c as a promising contributing strategy to meet projected future agricultural demand.Substantial increases in yield are needed to feed and fuel the world’s growing human population. With an estimated population of nine billion people by the middle of this century (Lutz and Samir, 2010) and rising affluence resulting in greater consumption of grain-fed animal products (Cirera and Masset, 2010), different studies predict that, by midcentury, global crop production will need to increase 60% to 120% over 2005 levels without the expansion of agricultural land area (Tilman et al., 2011; Alexandratos and Bruinsma, 2012).Doubling yields in major food and fuel crops requires considerable effort, especially as yields are beginning to plateau in many major food crops. Yield increases necessary for doubling productivity by midcentury are estimated at 1.16% to 1.31% each year in all cereals (Hall and Richards, 2013), 1.7% per year in wheat (Triticum aestivum; Rosegrant and Agcaoili, 2010), and 2.4% (noncompounding average per year) across all major grain crops (Ray et al., 2013). However, global mean increases from the past 20 to 30 years suggest that yield gains in rice (Oryza sativa) and wheat are approximately 1% (Lopes et al., 2012; Manès et al, 2012; Ray et al., 2013) and declining in some areas of the world (Cassman et al., 2010; Fischer and Edmeades, 2010; Long and Ort, 2010; Ray et al., 2013). Global yearly increases are estimated at 1.3% in soybean (Glycine max) and 1.6% in maize (Zea mays), with similar concerns that yield trends may also be decreasing in some major growing regions (Lobell and Gourdji, 2012; Ray et al., 2013).Efforts to increase yields in the next few decades must also account for environmental and sustainability goals (Sayer et al., 2013) as well as heightened environmental stresses predicted to occur due to climate change, which are already responsible for some of the stagnation in yield increases. Anthropogenic sources of greenhouse gases have caused an approximately 1°C increase in land surface temperatures since 1900, and global mean surface temperatures are likely to increase by up to 2.4°C to 4.8°C by the end of the century (IPCC, 2013). Drought is also expected to become more frequent and intense in many regions of the world (Dai, 2011; IPCC, 2013). Of the variability present in major food crop yield gains, 30% can be explained by climate change alone (Lobell and Field, 2007), with drastic decreases in barley (Hordeum vulgare), maize, rice, sorghum (Sorghum bicolor), soybean, and wheat yields as average growing season temperatures surpass the temperature optimum for each crop (Lobell and Gourdji, 2012). Current levels of atmospheric CO₂ concentration [CO₂] are the highest they have been in at least 800,000 years (IPCC, 2013). Elevated [CO₂] increases water use efficiency (Ainsworth and Long, 2005, Bernacchi et al., 2007, Leakey et al., 2009), but probably not to an extent that would mitigate the resulting reductions in yield caused by higher temperature and higher vapor pressure deficit (Ort and Long, 2014). Additionally, any fertilization effects on C₃ yields due to elevated [CO₂] would be at least in part negated by drought and temperature stress, leaving yield increases far from optimal (Long et al., 2006a; Lobell and Gourdji, 2012).