Pretreatment mitochondrial priming correlates with clinical response to cytotoxic chemotherapy

Cytotoxic chemotherapy targets elements common to all nucleated human cells, such as DNA and microtubules, yet it selectively kills tumor cells. Here we show that clinical response to these drugs correlates with, and may be partially governed by, the pretreatment proximity of tumor cell mitochondria to the apoptotic threshold, a property called mitochondrial priming. We used BH3 profiling to measure priming in tumor cells from patients with multiple myeloma, acute myelogenous and lymphoblastic leukemia, and ovarian cancer. This assay measures mitochondrial response to peptides derived from proapoptotic BH3 domains of proteins critical for death signaling to mitochondria. Patients with highly primed cancers exhibited superior clinical response to chemotherapy. In contrast, chemoresistant cancers and normal tissues were poorly primed. Manipulation of mitochondrial priming might enhance the efficacy of cytotoxic agents.     

Errors in greenhouse forcing and soil carbon sequestration estimates in freshwater wetlands: a comment on Mitsch et al. (2013)

Radiative forcing feedbacks from wetlands have been an important component of past climate change and will likely be so in the future, so accurately assessing the carbon (C) and radiative balances of wetlands remains an important research priority. This commentary shows that the paper by Mitsch et al. (Landscape Ecol 28:583–597, 2013) seriously underestimated the radiative forcing effect of methane (CH₄) emissions and overestimated soil C sequestration in freshwater wetlands. The model that they used is flawed in double counting the atmospheric decay of CH₄ and incorporating a single 100 year CH₄ global warming potential. They also used a small number of sites and short-term soil dating that resulted in unrealistically high soil C sequestration rates, ignoring decay of the entire soil C pool and allochthonous inputs of C. They calculated the radiative balance instead of the radiative forcing of natural wetlands, making their calculations irrelevant to anthropogenic climate change. Irrespective of the radiative forcing of wetlands, they provide essential ecosystem services that are important to protect.     

Ex vivo γ-retroviral gene therapy of dogs with X-linked severe combined immunodeficiency and the development of a thymic T cell lymphoma

We have previously shown that in vivo γ-retroviral gene therapy of dogs with X-linked severe combined immunodeficiency (XSCID) results in sustained T cell reconstitution and sustained marking in myeloid and B cells for up to 4 years with no evidence of any serious adverse effects. The purpose of this study was to determine whether ex vivo γ-retroviral gene therapy of XSCID dogs results in a similar outcome. Eight of 12 XSCID dogs treated with an average of dose of 5.8 × 10(6) transduced CD34(+) cells/kg successfully engrafted producing normal numbers of gene-corrected CD45RA(+) (na?ve) T cells. However, this was followed by a steady decrease in CD45RA(+) T cells, T cell diversity, and thymic output as measured by T cell receptor excision circles (TRECs) resulting in a T cell lymphopenia. None of the dogs survived past 11 months post treatment. At necropsy, few gene-corrected thymocytes were observed correlating with the TREC levels and one of the dogs was diagnosed with a thymic T cell lymphoma that was attributed to the gene therapy. This study highlights the outcome differences between the ex vivo and in vivo approach to γ-retroviral gene therapy and is the first to document a serious adverse event following gene therapy in a canine model of a human genetic disease.     

Accuracy of genomic breeding values for residual feed intake in crossbred beef cattle

The benefit of using genomic breeding values (GEBV) in predicting ADG, DMI, and residual feed intake for an admixed population was investigated. Phenotypic data consisting of individual daily feed intake measurements for 721 beef cattle steers tested over 5 yr was available for analysis. The animals used were an admixed population of spring-born steers, progeny of a cross between 3 sire breeds and a composite dam line. Training and validation data sets were defined by randomly splitting the data into training and testing data sets based on sire family so that there was no overlap of sires in the 2 sets. The random split was replicated to obtain 5 separate data sets. Two methods (BayesB and random regression BLUP) were used to estimate marker effects and to define marker panels and ultimately the GEBV. The accuracy of prediction (the correlation between the phenotypes and GEBV) was compared between SNP panels. Accuracy for all traits was low, ranging from 0.223 to 0.479 for marker panels with 200 SNP, and 0.114 to 0.246 for marker panels with 37,959 SNP, depending on the genomic selection method used. This was less than accuracies observed for polygenic EBV accuracies, which ranged from 0.504 to 0.602. The results obtained from this study demonstrate that the utility of genetic markers for genomic prediction of residual feed intake in beef cattle may be suboptimal. Differences in accuracy were observed between sire breeds when the random regression BLUP method was used, which may imply that the correlations obtained by this method were confounded by the ability of the selected SNP to trace breed differences. This may also suggest that prediction equations derived from such an admixed population may be useful only in populations of similar composition. Given the sample size used in this study, there is a need for increased feed intake testing if substantially greater accuracies are to be achieved.     

Phenotypic and genetic relationships among feeding behavior traits, feed intake, and residual feed intake in steers fed grower and finisher diets

Data from a 3-yr feeding trial of crossbred steers (n = 331) were used to examine the relationship between feeding behavior traits and feed efficiency in steers fed grower and finisher diets, successively. There were 2 feeding periods each year whereby the steers were fed a grower diet in the first feeding period (P1) and a finisher diet in the second feeding period (P2). Each feeding period lasted for a minimum of 10 wk, ad libitum. In addition to feed intake, records on 3 measures of feeding behavior [feeding duration (FD), head-down time (HDT), and feeding frequency (FF)] were collected using the GrowSafe feeding system. Residual feed intake (RFI) was calculated by regression, after which the steers were classified as low (<0.5 SD), medium (±0.5 SD), or high (>0.5 SD) from the mean. The steers had greater (P < 0.001) FD, HDT, and FF when the grower diet was fed but greater feeding rate (FR) when the finisher diet was fed. Including the measures of feeding behavior as covariates to the feed intake prediction model containing ADG, metabolic midweight, and ultrasound backfat accounted for more variation in DMI than models that did not contain these additional parameters. The FD and HDT were significantly different (P < 0.05) among the RFI classes regardless of the feeding period, whereas no differences (P > 0.90) were found for FR among the RFI classes. For the growing period and finishing period, respectively, FD had phenotypic correlations with HDT (0.79, 0.83), FF (0.14, 0.55), DMI (0.38, 0.34), and FR (-0.34, -0.21). Heritability estimates in P1 and P2 for FD, HDT, and FF were 0.25 ± 0.16, 0.14 ± 0.11; 0.14 ± 0.15, 0.09 ± 0.10; and 0.56 ± 0.19, 0.59 ± 0.18, respectively. Genetic correlations between P1 and P2 were 0.91 ± 0.26, 0.93 ± 0.37, and 0.94 ± 0.11 for FD, HDT, and FF, respectively. The results suggest that it may be appropriate to include feeding behavior traits as covariates to indicate measure(s) of animal activity in the calculation of RFI. Feeding behavior phenotypes were greater during the grower-fed period than the finisher-fed period. During these feeding periods, efficient steers exhibited fewer FF, shorter FD, and shorter HDT than inefficient steers.     

Cerebral vascular hamartoma in a geriatric cat

An 11-year-old castrated male domestic medium hair cat was presented with neurological signs consistent with a right thalamocortical lesion. Computed tomography (CT) images revealed a heterogeneously, hyperattenuating, poorly contrast enhancing intra-axial mass within the right lateral ventricle. The histological diagnosis at post-mortem examination was vascular hamartoma with hemorrhage and necrosis. This is the first report of a vascular hamartoma affecting the thalamocortex in a geriatric cat. Also, this is the first time that CT images of a feline cerebral vascular hamartoma have been reported.     

Discovery of Right Whales in the Gulf of Mexico

Two whales were observed closely for an hour off Sarasota, Florida, by residents who provided observations of structural details which identify only the right whale, Eubalaena glacialis, a temperate and subpolar species previously known to range to the Florida east coast, but not to enter the Gulf of Mexico.     

Tetrodotoxin derivatives: chemical structure and blockage of nerve membrane conductance

The nerve-impuilse-blocking actions of derivatives of tetrodotoxin have been tested on lobster and squid axons. The block produced by deoxytetrodotoxin was similar to that produced by tetrodotoxin and was probably caused by tetrodotoxin contamination. Tetrodaminotoxin and anhydrotetrodotoxin also produced a similar block but at such high concentrations that tetrodotoxin contamination cannot be ruled out. The hydroxyl group of C(4) and the hemilactal oxygen links play an important role for the nerve-blocking action.