Xenobiotic metabolizing enzyme gene polymorphisms predict response to lung volume reduction surgery

Background

In the National Emphysema Treatment Trial (NETT), marked variability in response to lung volume reduction surgery (LVRS) was observed. We sought to identify genetic differences which may explain some of this variability.

Methods

In 203 subjects from the NETT Genetics Ancillary Study, four outcome measures were used to define response to LVRS at six months: modified BODE index, post-bronchodilator FEV₁, maximum work achieved on a cardiopulmonary exercise test, and University of California, San Diego shortness of breath questionnaire. Sixty-four single nucleotide polymorphisms (SNPs) were genotyped in five genes previously shown to be associated with chronic obstructive pulmonary disease susceptibility, exercise capacity, or emphysema distribution.

Results

A SNP upstream from glutathione S-transferase pi (GSTP1; p = 0.003) and a coding SNP in microsomal epoxide hydrolase (EPHX1; p = 0.02) were each associated with change in BODE score. These effects appeared to be strongest in patients in the non-upper lobe predominant, low exercise subgroup. A promoter SNP in EPHX1 was associated with change in BODE score (p = 0.008), with the strongest effects in patients with upper lobe predominant emphysema and low exercise capacity. One additional SNP in GSTP1 and three additional SNPs in EPHX1 were associated (p < 0.05) with additional LVRS outcomes. None of these SNP effects were seen in 166 patients randomized to medical therapy.

Conclusion

Genetic variants in GSTP1 and EPHX1, two genes encoding xenobiotic metabolizing enzymes, were predictive of response to LVRS. These polymorphisms may identify patients most likely to benefit from LVRS.     

The N terminus of the serpin, tengpin, functions to trap the metastable native state

Serpins fold to a metastable native state and are susceptible to undergoing spontaneous conformational change to more stable conformers, such as the latent form. We investigated conformational change in tengpin, an unusual prokaryotic serpin from the extremophile Thermoanaerobacter tengcongensis. In addition to the serpin domain, tengpin contains a functionally uncharacterized 56-amino-acid amino-terminal region. Deletion of this domain creates a variant--tengpinDelta51--which folds past the native state and readily adopts the latent conformation. Analysis of crystal structures together with mutagenesis studies show that the N terminus of tengpin protects a hydrophobic patch in the serpin domain and functions to trap tengpin in its native metastable state. A 13-amino-acid peptide derived from the N terminus is able to mimick the role of the N terminus in stabilizing the native state of tengpinDelta51. Therefore, the function of the N terminus in tengpin resembles protein cofactors that prevent mammalian serpins from spontaneously adopting the latent conformation.     

A novel swine model for evaluation of potential intravascular hemostatic agents

Because uncontrolled hemorrhage is a leading cause of battlefield mortality, finding an intravenous treatment that could assist endogenous clotting mechanisms is a major mission for military researchers. Evaluation of potential intravenous hemostatic agents requires both in vitro and in vivo tests. For in vivo evaluation, we have developed a novel swine model in which 1) bleeding times (BT) and coagulation function could be ascertained after multiple doses of hemostatic drug administration and 2) a subsequent exsanguinating injury could be performed in the same animal, yielding screening information regarding the effects of drug pretreatment on blood loss and survival. Transection of small mesenteric arteries and veins allowed for multiple and reproducible BT measures that correlated with coagulation function. Subsequent excision of defined areas of the liver produced bleeding predominantly from small vessels (diameter, less than 2 mm) and parenchyma while resulting in 62% mortality without the use of either heparinization or aggressive fluid infusion. This swine model allows for multiple, repeatable BT measures in the same animal in experiments already involving laparotomy. Such a model is well suited for terminal studies to test effects of multiple doses of the same drug or multiple drugs on BT and allows for multiple, easily visualized measures that permit enhanced repeatability. The liver injury provides for numerous small vessel lesions that could be amenable to closure by coagulation. Therefore, drugs or mechanisms that enhance coagulation and concomitantly decrease blood loss and increase survival time may be accurately evaluated in this new model.     

Extrahepatic cells contribute to the progenitor/stem cell response following reduced-size liver transplantation in mice

The extent to which extrahepatic cells participate in liver regeneration following transplantation is not known. Either full-size or reduced-size livers from wild-type mice were implanted into green fluorescent protein-positive (GFP(+)) transgenic recipient mice to determine whether regenerated liver contained host-derived GFP(+) hepatic cells. After reduced-size liver transplantation, GFP(+) cells were localized to the portal zone of the liver lobule. Interestingly, GFP(+) cells stained for CD117, a marker for progenitor cells, beginning 2 days after transplantation. A significant number of GFP(+) CD117(+) cells were identified in donor livers after 28 days. GFP(+) cells comprised nearly 9% of the donor liver 28 days after reduced-size liver transplant. Moreover, GFP(+) cells also expressed the hepatic progenitor cell marker A6 and novel marker hepatic-specific antigen (HSA), as well as stem cell antigen-1 (Sca-1). Interestingly, some GFP(-) cells also were stained for CD117 and A6, suggesting that both extrahepatic and intrahepatic stem cells were present and may have contributed to the regenerative response under these conditions. Reduced-size liver transplantation using GFP(+) transgenic mice supports the hypothesis that recipient-derived progenitor cells are present and may contribute to liver regeneration following transplantation.     

Age and species dependence of pial arteriolar responses to topical carbon monoxide in vivo

In newborn pigs, carbon monoxide (CO) contributes to regulation of cerebrovascular circulation. Results from isolated adult cerebral arteries suggest CO may have less dilatory potential in mature animals. However, few data are available on the direct effects of CO on cerebrovascular circulation in vivo except for those from newborn pigs. Therefore, we tested the hypothesis that i) rat cerebral arterioles dilate to CO in vivo and ii) CO-induced cerebrovascular dilatory responses are age dependent in pigs. Also, we examined whether the permissive role of nitric oxide in CO-induced dilation observed in piglets is present in older pigs and rats. Experiments used anesthetized newborn, 7-week-old, and juvenile (3- to 4-month-old) pigs and 3- to 4-month-old rats with closed cranial windows and topical applications of CO and sodium nitroprusside (SNP). Dilations to SNP were not different at different ages in pigs or between pigs and rats. CO produced pial arteriolar dilations in all groups. Dilation to 10(-5) M CO was reduced in juvenile pigs as compared to newborn and 7-week-old pigs, and tended to less at 10(-6) M CO. Dilations of rat pial arterioles to all concentrations were less than those of newborn and 7-week-old pigs, but not different from those of juvenile pig pial arterioles. In newborn and 7-week-old pigs, l-nitro-arginine (LNA) inhibited the dilation to CO, an effect reversed by a constant background of SNP. In contrast, LNA did not reduce dilation to CO in juvenile pigs or rats. In conclusion, rat pial arterioles like those in piglets dilate to CO in vivo, but there are age and species differences with regard to reactivity and interaction with NO.     

Size matters: variations in seagrass seed size at local scales affects seed performance

Hydrobiologia - Seed size can have an impact on angiosperm reproductive fitness. Ecological theory predicts plants that will produce larger seeds in stressful environments to increase the chances...     

Inhibition of harmful algal blooms caused by Aureococcus anophagefferens (Pelagophyceae) using native (Gracilaria tikvahiae) and invasive (Dasysiphonia japonica) red seaweeds from North America

Journal of Applied Phycology - Harmful algal blooms (HABs) caused by the pelagophyte Aureococcus anophagefferens have spread globally and are a threat to coastal ecosystems. Although some HAB...     

Ranking the direct threats to biodiversity in sub-Saharan Africa

Biodiversity and Conservation - Sub-Saharan Africa receives large investments in biodiversity conservation, and if these investments can be concentrated on the highest threats to biodiversity, the...     

Freshwater occurrence of the extinct dolphin Parapontoporia (Cetacea: Lipotidae) from the upper Pliocene nonmarine Tulare Formation of California

The diminutive, extinct longirostrine dolphin Parapontoporia is one of the most abundantly represented late Neogene odontocetes from the eastern North Pacific and is widely known from numerous marine strata of late Miocene and Pliocene age in California, Baja California and possibly Japan. Parapontoporia has been identified as the sister taxon of the recently extinct Chinese river dolphin (Lipotes vexillifer); unlike Lipotes, which exclusively inhabited freshwater, the depositional context of Parapontoporia suggests it was marine. A newly identified petrosal of Parapontoporia sp. was preserved alongside terrestrial vertebrates in the nonmarine Tulare Formation (upper Pliocene to Pleistocene, 2.2–0.6 Ma), California, which was deposited under lacustrine and fluviodeltaic conditions. Abundantly preserved freshwater molluscs and rare marine taxa suggest predominantly freshwater settings with intermittent periods of estuarine conditions. This occurrence of Parapontoporia indicates its presence in the San Joaquin basin after the retreat of the inland sea and suggests that this extinct odontocete may have been freshwater tolerant and an inhabitant of marine and freshwater settings, heralding the exclusively freshwater existence of its Recent sister taxon Lipotes vexillifer.