Abstract
Many tumors compensate with a resistance mechanism once a signaling pathway is inhibited, as evidenced in patients treated with small molecule inhibitors of EGFR which frequently show ...increased expression of c-Met or HGF. Since both EGFR and c-Met signal through the same survival and anti-apoptotic pathways, inhibition of the pair of receptors could improve overall efficacy. This was demonstrated clinically, where the combination of onartuzumab and erlotinib showed promising Phase II trials in lung cancer patients.
Centyrins are small proteins (~10 kDa) of an emerging class of proteins termed alternative scaffolds. They are engineered to bind to target molecules with high specificity and affinity, but are structurally simpler molecules than antibodies in that that they are single chain, unglycosylated proteins that lack disulfide bonds. In addition, monomeric Centyrins can be linked together such that one molecule can bind to and inhibit multiple targets.
Anti-EGFR and anti-c-Met Centyrins were selected for their ability to inhibit ligand-induced phosphorylation. Molecules with a wide range of affinities were identified and bispecific molecules were generated. Phosphorylation of EGFR, c-Met, and ERK were monitored in cells treated with individual monomeric Centyrins, a mixture of monomeric Centyrins, or linked bispecific Centyrins. One bispecific EGFR/c-Met Centyrin provided a 134-fold increase in potency in inhibition of phosphorylation of c-Met compared to the mixture of the two Centyrins. The increase in potency observed in cell signaling translated to enhanced anti-proliferative activity with a potency >100-fold compared to that of the mixture of monospecific Centyrins. The bispecific EGFR/c-Met Centyrins were produced as fusion proteins linked to an albumin binding domain in order to reduce kidney filtration and evaluated in SCID-beige mice implanted with tumor cells engineered to express human HGF. Interestingly, all of the Centyrins tested significantly reduced the size of the tumors compared to the control and the degree of tumor growth inhibition correlated with the affinity to both EGFR and c-Met. In a second tumor model, complete tumor regressions were observed in all mice treated with the bispecific EGFR/c-Met Centyrin.
The Centyrin platform could offer benefits over currently available treatment options. Our data demonstrate that in addition to inhibiting two targets simultaneously, a single bispecific molecule allows for significant avidity at the cellular level. This could translate into a lower dosing regimen that allows for improved efficacy through avidity and decreased toxicity. We anticipate that avidity will allow for improved specificity for tumor compared to normal tissue. In addition, the small size of Centyrins may provide an advantage for tumor targeting and accumulation.
Citation Format: Donna Klein, Steve Jacobs, Moores Sheri, Mark Anderson, Ricardo Attar, Alexander Barnakov, Kerry Brosnan, Barbara Bushey, Kristen Chevalier, Diana Chin, Carla Cornejo, Mike Diem, Linus Hyun, Elise Kuhar, Francis McCabe, Kristen Picha, Tracy Spinka-Doms, Edward Swift, Karyn O'Neil. Bispecific Centyrin simultaneously targeting EGFR and c-Met demonstrates improved activity compared to the mixture of single agents. abstract. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-312. doi:10.1158/1538-7445.AM2013-LB-312
Genetically engineered crops in the United States Fernandez-Cornejo, Jorge; Wechsler, Seth; Livingston, Mike ...
African journal of food, agriculture, nutrition, and development : AJFAND,
03/2014, Letnik:
14, Številka:
1
Journal Article
Recenzirano
More than 15 years after their first successful commercial introduction in the United States, genetically engineered (GE) seeds have been widely adopted by U.S. corn, soybean, and cotton farmers. ...Still, some questions persist regarding the potential benefits and risks of GE crops. The report finds that, although the pace of research and development (measured by the number of USDA-approved field tests) peaked in 2002, other measures show that biotech firms continue to develop new GE seed varieties at a rapid pace. Also, U.S. farmers continue to adopt GE seeds at a robust rate, and seed varieties with multiple (stacked) traits have increased at a very rapid rate. Insecticide use has decreased with the adoption of insect-resistant crops, and herbicide-tolerant crops have enabled the substitution of glyphosate for more toxic and persistent herbicides. However, overreliance on glyphosate and a reduction in the diversity of weed management practices have contributed to the evolution of glyphosate resistance in some weed species.
Obsessive-compulsive disorder (OCD) and Tourette Syndrome (TS) are highly heritable neurodevelopmental disorders that are thought to share genetic risk factors. However, the identification of ...definitive susceptibility genes for these etiologically complex disorders remains elusive. Here, we report a combined genome-wide association study (GWAS) of TS and OCD in 2723 cases (1310 with OCD, 834 with TS, 579 with OCD plus TS/chronic tics (CT)), 5667 ancestry-matched controls, and 290 OCD parent-child trios. Although no individual single nucleotide polymorphisms (SNPs) achieved genome-wide significance, the GWAS signals were enriched for SNPs strongly associated with variations in brain gene expression levels, i.e. expression quantitative loci (eQTLs), suggesting the presence of true functional variants that contribute to risk of these disorders. Polygenic score analyses identified a significant polygenic component for OCD (p=2×10
−4
), predicting 3.2% of the phenotypic variance in an independent data set. In contrast, TS had a smaller, non-significant polygenic component, predicting only 0.6% of the phenotypic variance (p=0.06). No significant polygenic signal was detected across the two disorders, although the sample is likely underpowered to detect a modest shared signal. Furthermore, the OCD polygenic signal was significantly attenuated when cases with both OCD and TS/CT were included in the analysis (p=0.01). Previous work has shown that TS and OCD have some degree of shared genetic variation. However, the data from this study suggest that there are also distinct components to the genetic architectures of TS and OCD. Furthermore, OCD with co-occurring TS/CT may have different underlying genetic susceptibility compared to OCD alone.
The origin of Plasmodium falciparum, the etiological agent of the most dangerous forms of human malaria, remains controversial. Although investigations of homologous parasites in African Apes are ...crucial to resolve this issue, studies have been restricted to a chimpanzee parasite related to P. falciparum, P. reichenowi, for which a single isolate was available until very recently. Using PCR amplification, we detected Plasmodium parasites in blood samples from 18 of 91 individuals of the genus Pan, including six chimpanzees (three Pan troglodytes troglodytes, three Pan t. schweinfurthii) and twelve bonobos (Pan paniscus). We obtained sequences of the parasites' mitochondrial genomes and/or from two nuclear genes from 14 samples. In addition to P. reichenowi, three other hitherto unknown lineages were found in the chimpanzees. One is related to P. vivax and two to P. falciparum that are likely to belong to distinct species. In the bonobos we found P. falciparum parasites whose mitochondrial genomes indicated that they were distinct from those present in humans, and another parasite lineage related to P. malariae. Phylogenetic analyses based on this diverse set of Plasmodium parasites in African Apes shed new light on the evolutionary history of P. falciparum. The data suggested that P. falciparum did not originate from P. reichenowi of chimpanzees (Pan troglodytes), but rather evolved in bonobos (Pan paniscus), from which it subsequently colonized humans by a host-switch. Finally, our data and that of others indicated that chimpanzees and bonobos maintain malaria parasites, to which humans are susceptible, a factor of some relevance to the renewed efforts to eradicate malaria.
The recent global expansion of biofuel production, led by the US, Brazil and the European Union (EU), has introduced a significant new demand on agriculture affecting the production, prices, and ...trade of agricultural commodities related to biofuels. US ethanol production is already using a substantial and increasing share of the US corn crop: about 14% of the total corn crop in 2005/2006. The increased demand for corn has also contributed to higher corn prices and to an expansion in the total amount of cropland used to grow corn at the expense of other crops. Brazil began producing ethanol from sugar cane to use as fuel in the 1970s. Since then, the area of land used to grow sugar cane and other crops (particularly soybeans) has grown rapidly. As cropland and pasture have replaced forest and cerrado in the Brazilian Amazonia, around 7 million hectares were converted to agriculture from 1980 to 1995. However, Brazilian agricultural officials assert that future increases in cropland devoted to sugar cane will come from pastureland rather than from forestland. Given the complexity of agricultural markets, evaluating the repercussions of a growing global market for biofuels is not simple. Economists found very quickly that most existing agricultural models lacked the necessary components and data to account for biofuel production, especially at the global level. This exposed a need to improve the current analytical modelling frameworks and data systems. To help cover this gap, the Economic Research Service (ERS) of the US Department of Agriculture (USDA) developed FARM II, a revised and updated version of the Future Agricultural Resources Model (FARM) that allows the study of the impacts of global biofuel production and examines the economic and environmental tradeoffs, as well as the distribution of benefits and costs across countries, regions, producers, and consumers. This paper summarizes a study made using the FARM II model augmented to account for biofuels related sectors. We focus on ethanol production in the medium term; that is, around 2015. We assume that while improvements in current technology and the impact of biotechnology will improve yields and technical plant efficiency, the medium term impact of ethanol from cellulose and other technological breakthroughs will be small. Under those assumptions, we also explore the implications of biofuels on pesticide use.
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