Exome-wide analysis of rare coding variation identifies novel associations with COPD and airflow limitation in MOCS3, IFIT3 and SERPINA12.

Several regions of the genome have shown to be associated with COPD in genome-wide association studies of common variants.To determine rare and potentially functional single nucleotide polymorphisms (SNPs) associated with the risk of COPD and severity of airflow limitation.3226 current or former smokers of European ancestry with lung function measures indicative of Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2 COPD or worse were genotyped using an exome array. An analysis of risk of COPD was carried out using ever smoking controls (n=4784). Associations with %predicted FEV1 were tested in cases. We followed-up signals of interest (p<10(-5)) in independent samples from a subset of the UK Biobank population and also undertook a more powerful discovery study by meta-analysing the exome array data and UK Biobank data for variants represented on both arrays.Among the associated variants were two in regions previously unreported for COPD; a low frequency non-synonymous SNP in MOCS3 (rs7269297, pdiscovery=3.08×10(-6), preplication=0.019) and a rare SNP in IFIT3, which emerged in the meta-analysis (rs140549288, pmeta=8.56×10(-6)). In the meta-analysis of % predicted FEV1 in cases, the strongest association was shown for a splice variant in a previously unreported region, SERPINA12 (rs140198372, pmeta=5.72×10(-6)). We also confirmed previously reported associations with COPD risk at MMP12, HHIP, GPR126 and CHRNA5. No associations in novel regions reached a stringent exome-wide significance threshold (p<3.7×10(-7)).This study identified several associations with the risk of COPD and severity of airflow limitation, including novel regions MOCS3, IFIT3 and SERPINA12, which warrant further study

Assessing Status of and Resistance to Phytophthora Root Rot on True Fir (Abies spp.)

Many fir species (Abies) are susceptible to Phytophthora Root Rot (PRR). Poor drainage and standing water facilitate pathogen survival, proliferation, and spore dispersal. Disease is caused by numerous Phytophthora spp. that constitute regionally-adapted communities. Survey results of diseased Abies in U.S. Christmas tree farms demonstrated a nearly uniform community profile dominated by P. cambivora on noble fir in the Pacific Northwest, and a more diverse array of Phytophthora species collected from Fraser, Turkish, balsam, and Canaan firs in the Great Lakes and Eastern states. It was concluded that Phytophthora community compositions vary in response to host availability, environment, and anthropogenic distribution of infested host material.Aside from short-term chemical and cultural individual-tree protection, there are few feasible methods for altering the environment to provide perennial disease abatement. An alternative approach is to reform host conduciveness to disease by identifying resistant members of a population through the application of molecular tools. As a precursor to molecular marker development, a multifactorial study was performed to characterize host phenotypes in response to multiple species of Phytophthora under variable environmental conditions. It was demonstrated that P. cinnamomi and P. taxon kelmania cause greater root damage and more mortality than P. pini or P. cambivora and that disease is more severe at warmer temperatures. Furthermore, it was established that there is a spectrum of resistances among the various species of Abies, ranging from highly susceptible noble and Fraser firs to more resistant Turkish and Nordmann firs.Previous observations of PRR-resistant Turkish fir plantings have indicated that the ability to resist disease is not uniform among seed sources. To test variability among Turkish fir families, a collection of 36 seed sources was inoculated with 5 Phytophthora species under saturated field conditions. Chi square analysis indicated that 4 seed sources were significantly more susceptible; however, mortality of less than 10% in the most susceptible Turkish fir families in comparison to 100% mortality in Fraser and noble fir suggested that Turkish fir is a PRR-resistant Abies species. Significantly more disease caused by P. cryptogea in this field study confirmed previous observations of variability in Phytophthora species aggressiveness

Characterizing Douglas-fir tissue colonization by the "sudden oak death" pathogen, Phytophthora ramorum

In 2001, Koch's Postulates confirmed Douglas-fir as a host for P. ramorum. Naturallyinfected saplings have been observed in California forests, and studies on artificially inoculated Douglas-fir stems and shoots have established susceptibility parameters. In 2009, P. ramorum stem cankers were recently observed on 8-year old plantation grown Douglas-fir in Great Britain. These findings substantiate the importance of research to characterize the behavior of P. ramorum in Douglas-fir and assess the potential risk that this pathogen poses to Douglas-fir ecosystems. Goals of this research included determining which tissues are colonized by P. ramorum, whether woody tissues can support sporulation, the likelihood of stem infections occurring through intact bark, and pathogen viability in foliage. Methods included isolation, ELISA, and histology of infected stem tissues; RT-PCR and isolation to determine colonization of foliage, and baiting studies to determine the ability of bark to reduce colonization of Rhododendron leaves by the pathogen. ELISA showed that pathogen proteins were detectable in the phloem, cambium, and superficial xylem, with infrequent detection in asymptomatic tissues. The pathogen was not able to be isolated from non-discolored tissues. ELISA and isolation results were highly positively correlated (r2 =0.62, p=0.78), and histological observations supported results from these techniques. Bark reduced infection on leaf baits by up to 83%. Pathogen DNA was detectable in foliage using qPCR methods, but the pathogen could not be isolated. Evidence of sporulation in stem tissues was not observed. The pathogen may infect into the shallow xylem tissues of wounded Douglas-fir stems, but spore formation is not apparent. The lack of isolation from non-discolored tissues suggests that proteins detected by ELISA may be elicitins secreted in advance of hyphae. The inability to isolate from needles may indicate chemical inhibitors that render the pathogen non-viable subsequent to initial infection. The ability of Douglas-fir bark to suppress infection of leaf baits suggests that bark is inhibitory to P. ramorum and that stem infection through intact bark may be limited. Characterizing P. ramorum colonization of Douglas-fir is important for understanding host susceptibility and pathogen behavior to enhance our ability to assess risk and thwart the spread of this exotic pathogen

Choice of Starting Dose for Biopharmaceuticals in First-in-Human Phase I Cancer Clinical Trials.

BACKGROUND. First-in-human (FIH) trials of low-molecular-weight anticancer agents conventionally derive a safe start dose (SD) from one-tenth the severely toxic dose in 10% of rodents or one-sixth the highest nonseverely toxic dose (HNSTD) in nonrodent species. No consensus has been reached on whether this paradigm can be safely applied to biotechnology-derived products (BDPs). MATERIALS AND METHODS. A comprehensive search was conducted to identify all BDPs (excluding immune checkpoint inhibitors and antibody drug conjugates) with sufficient nonclinical and clinical data to assess the safety of hypothetical use of one-sixth HNSTD in an advanced cancer FIH trial. RESULTS. The search identified 23 BDPs, of which 21 were monoclonal antibodies. The median ratio of the maximum tolerated or maximum administered dose (MTD or MAD) to the actual FIH SD was 36 (range, 8–500). Only 2 BDPs reached the MTD. Hypothetical use of one-sixth HNSTD (allometrically scaled to humans) would not have exceeded the MTD or MAD for all 23 BDPs and would have reduced the median ratio of the MTD or MAD to a SD to 6.1 (range, 3.5–55.3). Pharmacodynamic (PD) markers were included in some animal toxicology studies and were useful to confirm the hypothetical SD of one-sixth HNSTD. CONCLUSION. One-sixth HNSTD would not have resulted in unacceptable toxicities in the data available. Supporting its use could reduce the number of dose escalations needed to reach the recommended dose. A low incidence of toxicities in animals and humans underscores the need to identify the pharmacokinetic and PD parameters to guide SD selection of BDPs for FIH cancer trials. IMPLICATIONS FOR PRACTICE: Start dose (SD) for biotechnology-derived products (BDPs) can be safely derived from one-sixth the highest nonseverely toxic dose in nonrodent species and may reduce the number of dose escalations needed to reach the recommended dose in first-in-human studies while limiting unnecessary exposure to high drug levels in humans. The use of this type of SD could improve the design of phase I studies of BDPs by making them more efficient. The role of preclinical pharmacodynamic markers was useful in confirming the hypothetical SD, and attempts should be explored in future animal studies to identify such parameters

Data from: Exposure to mitochondrial genotoxins and dopaminergic neurodegeneration in Caenorhabditis elegans

No description availabl