Transgenic goats producing an improved version of cetuximab in milk [preprint]

Therapeutic monoclonal antibodies (mAbs) represent one of the most important classes of pharmaceutical proteins to treat human diseases. Most are produced in cultured mammalian cells which is expensive, limiting their availability. Goats, striking a good balance between a relatively short generation time and copious milk yield, present an alternative platform for the cost-effective, flexible, large-scale production of therapeutic mAbs. Here, we focused on cetuximab, a mAb against epidermal growth factor receptor, that is commercially produced under the brand name Erbitux and approved for anti-cancer treatments. We generated several transgenic goat lines that produce cetuximab in their milk. Two lines were selected for detailed characterization. Both showed stable genotypes and cetuximab production levels of up to 10g/L. The mAb could be readily purified and showed improved characteristics compared to Erbitux. The goat-produced cetuximab (gCetuximab) lacked a highly immunogenic epitope that is part of Erbitux. Moreover, it showed enhanced binding to CD16 and increased antibody-dependent cell-dependent cytotoxicity compared to Erbitux. This indicates that these goats produce an improved cetuximab version with the potential for enhanced effectiveness and better safety profile compared to treatments with Erbitux. In addition, our study validates transgenic goats as an excellent platform for large-scale production of therapeutic mAbs

Protecting biodiversity in British Columbia: Recommendations for developing species at risk legislation

British Columbia has the greatest biological diversity of any province or territory in Canada. Yet increasing numbers of species in British Columbia are threatened with extinction. The current patchwork of provincial laws and regulations has not effectively prevented species declines. Recently, the Provincial Government has committed to enacting an endangered species law. Drawing upon our scientific and legal expertise, we offer recommendations for key features of endangered species legislation that build upon strengths and avoid weaknesses observed elsewhere. We recommend striking an independent Oversight Committee to provide recommendations about listing species, organize Recovery Teams, and monitor the efficacy of actions taken. Recovery Teams would evaluate and prioritize potential actions for individual species or groups of species that face common threats or live in a common area, based on best available evidence (including natural and social science and Indigenous Knowledge). Our recommendations focus on implementing an adaptive approach, with ongoing and transparent monitoring and reporting, to reduce delays between determining when a species is at risk and taking effective actions to save it. We urge lawmakers to include this strong evidentiary basis for species recovery as they tackle the scientific and socioeconomic challenges of building an effective species at risk Act

Protecting biodiversity in British Columbia: Recommendations for developing species at risk legislation

British Columbia has the greatest biological diversity of any province or territory in Canada. Yet increasing numbers of species in British Columbia are threatened with extinction. The current patchwork of provincial laws and regulations has not effectively prevented species declines. Recently, the Provincial Government has committed to enacting an endangered species law. Drawing upon our scientific and legal expertise, we offer recommendations for key features of endangered species legislation that build upon strengths and avoid weaknesses observed elsewhere. We recommend striking an independent Oversight Committee to provide recommendations about listing species, organize Recovery Teams, and monitor the efficacy of actions taken. Recovery Teams would evaluate and prioritize potential actions for individual species or groups of species that face common threats or live in a common area, based on best available evidence (including natural and social science and Indigenous Knowledge). Our recommendations focus on implementing an adaptive approach, with ongoing and transparent monitoring and reporting, to reduce delays between determining when a species is at risk and taking effective actions to save it. We urge lawmakers to include this strong evidentiary basis for species recovery as they tackle the scientific and socioeconomic challenges of building an effective species at risk Act

Ultra-Stable Environment Control for the NEID Spectrometer: Design and Performance Demonstration

Two key areas of emphasis in contemporary experimental exoplanet science are the detailed characterization of transiting terrestrial planets, and the search for Earth analog planets to be targeted by future imaging missions. Both of these pursuits are dependent on an order-of-magnitude improvement in the measurement of stellar radial velocities (RV), setting a requirement on single-measurement instrumental uncertainty of order 10 cm/s. Achieving such extraordinary precision on a high-resolution spectrometer requires thermo-mechanically stabilizing the instrument to unprecedented levels. Here, we describe the Environment Control System (ECS) of the NEID Spectrometer, which will be commissioned on the 3.5 m WIYN Telescope at Kitt Peak National Observatory in 2019, and has a performance specification of on-sky RV precision < 50 cm/s. Because NEID's optical table and mounts are made from aluminum, which has a high coefficient of thermal expansion, sub-milliKelvin temperature control is especially critical. NEID inherits its ECS from that of the Habitable-zone Planet Finder (HPF), but with modifications for improved performance and operation near room temperature. Our full-system stability test shows the NEID system exceeds the already impressive performance of HPF, maintaining vacuum pressures below $10^{-6}$ Torr and an RMS temperature stability better than 0.4 mK over 30 days. Our ECS design is fully open-source; the design of our temperature-controlled vacuum chamber has already been made public, and here we release the electrical schematics for our custom Temperature Monitoring and Control (TMC) system.Comment: Accepted for publication in JATI

Prospective Associations of Coronary Heart Disease Loci in African Americans Using the MetaboChip: The PAGE Study

Background: Coronary heart disease (CHD) is a leading cause of morbidity and mortality in African Americans. However, there is a paucity of studies assessing genetic determinants of CHD in African Americans. We examined the association of published variants in CHD loci with incident CHD, attempted to fine map these loci, and characterize novel variants influencing CHD risk in African Americans. Methods and Results: Up to 8,201 African Americans (including 546 first CHD events) were genotyped using the MetaboChip array in the Atherosclerosis Risk in Communities (ARIC) study and Women's Health Initiative (WHI). We tested associations using Cox proportional hazard models in sex- and study-stratified analyses and combined results using meta-analysis. Among 44 validated CHD loci available in the array, we replicated and fine-mapped the SORT1 locus, and showed same direction of effects as reported in studies of individuals of European ancestry for SNPs in 22 additional published loci. We also identified a SNP achieving array wide significance (MYC: rs2070583, allele frequency 0.02, P = 8.1×10−8), but the association did not replicate in an additional 8,059 African Americans (577 events) from the WHI, HealthABC and GeneSTAR studies, and in a meta-analysis of 5 cohort studies of European ancestry (24,024 individuals including 1,570 cases of MI and 2,406 cases of CHD) from the CHARGE Consortium. Conclusions: Our findings suggest that some CHD loci previously identified in individuals of European ancestry may be relevant to incident CHD in African Americans

Prospective associations of coronary heart disease loci in African Americans using the MetaboChip

Background: Coronary heart disease (CHD) is a leading cause of morbidity and mortality in African Americans. However, there is a paucity of studies assessing genetic determinants of CHD in African Americans. We examined the association of publishe

Identification of molecular mechanisms for cellular drug resistance by combining drug activity and gene expression profiles

Acquired drug resistance is a major problem in cancer treatment. To explore the genes involved in chemosensitivity and resistance, 10 human tumour cell lines, including parental cells and resistant subtypes selected for resistance against doxorubicin, melphalan, teniposide and vincristine, were profiled for mRNA expression of 7400 genes using cDNA microarray technology. The drug activity of 66 cancer agents was evaluated on the cell lines, and correlations between drug activity and gene expression were calculated and ranked. Hierarchical clustering of drugs based on their drug–gene correlations yielded clusters of drugs with similar mechanism of action. Genes correlated with drug sensitivity and resistance were imported into the PathwayAssist software to identify putative molecular pathways involved. A substantial number of both proapoptotic and antiapoptotic genes such as signal transducer and activator of transcription 1, mitogen-activated protein kinase 1 and focal adhesion kinase were found to be associated to drug resistance, whereas genes linked to cell cycle control and proliferation, such as cell division cycle 25A and signal transducer of activator of transcription 5A, were associated to general drug sensitivity. The results indicate that combined information from drug activity and gene expression in a resistance-based cell line panel may provide new knowledge of the genes involved in anticancer drug resistance and become a useful tool in drug development