Cancer Plasticity: The Role of mRNA Translation.

Tumor progression is associated with dedifferentiated histopathologies concomitant with cancer cell survival within a changing, and often hostile, tumor microenvironment. These processes are enabled by cellular plasticity, whereby intracellular cues and extracellular signals are integrated to enable rapid shifts in cancer cell phenotypes. Cancer cell plasticity, at least in part, fuels tumor heterogeneity and facilitates metastasis and drug resistance. Protein synthesis is frequently dysregulated in cancer, and emerging data suggest that translational reprograming collaborates with epigenetic and metabolic programs to effectuate phenotypic plasticity of neoplasia. Herein, we discuss the potential role of mRNA translation in cancer cell plasticity, highlight emerging histopathological correlates, and deliberate on how this is related to efforts to improve understanding of the complex tumor ecology.

Chromatin Remodeling Factors Isw2 and Ino80 Regulate Chromatin, Replication, and Copy Number of the Saccharomyces cerevisiae Ribosomal DNA Locus.

In the budding yeast Saccharomyces cerevisiae, ribosomal RNA genes are encoded in a highly repetitive tandem array referred to as the ribosomal DNA (rDNA) locus. The yeast rDNA is the site of a diverse set of DNA-dependent processes, including transcription of ribosomal RNAs by RNA polymerases I and III, transcription of noncoding RNAs by RNA polymerase II, DNA replication initiation, replication fork blocking, and recombination-mediated regulation of rDNA repeat copy number. All of this takes place in the context of chromatin, but little is known about the roles played by ATP-dependent chromatin remodeling factors at the yeast rDNA. In this work, we report that the Isw2 and Ino80 chromatin remodeling factors are targeted to this highly repetitive locus. We characterize for the first time their function in modifying local chromatin structure, finding that loss of these factors decreases the fraction of actively transcribed 35S ribosomal RNA genes and the positioning of nucleosomes flanking the ribosomal origin of replication. In addition, we report that Isw2 and Ino80 promote efficient firing of the ribosomal origin of replication and facilitate the regulated increase of rDNA repeat copy number. This work significantly expands our understanding of the importance of ATP-dependent chromatin remodeling for rDNA biology.

The Yeast INO80 Complex Operates as a Tunable DNA Length-Sensitive Switch to Regulate Nucleosome Sliding.

The yeast INO80 chromatin remodeling complex plays essential roles in regulating DNA damage repair, replication, and promoter architecture. INO80's role in these processes is likely related to its ability to slide nucleosomes, but the underlying mechanism is poorly understood. Here we use ensemble and single-molecule enzymology to study INO80-catalyzed nucleosome sliding. We find that the rate of nucleosome sliding by INO80 increases ∼100-fold when the flanking DNA length is increased from 40 to 60 bp. Furthermore, once sliding is initiated, INO80 moves the nucleosome rapidly at least 20 bp without pausing to re-assess flanking DNA length, and it can change the direction of nucleosome sliding without dissociation. Finally, we show that the Nhp10 module of INO80 plays an auto-inhibitory role, tuning INO80's switch-like response to flanking DNA. Our results indicate that INO80 is a highly processive remodeling motor that is tightly regulated by both substrate cues and non-catalytic subunits.

Role of maternal occupational physical activity and psychosocial stressors on adverse birth outcomes.

OBJECTIVES: We examined the association of an array of estimated maternal occupational physical activities and psychosocial stressors during pregnancy with odds for preterm birth (PTB) and small-for-gestational age (SGA). METHODS: Data for infants born without major birth defects delivered from 1997 to 2009 whose mothers reported working at least 1 month during pregnancy were obtained from the National Birth Defects Prevention Study. We linked occupational codes to the US Department of Labor's Occupational Information Network, which provides estimates of exposure for multiple domains of physical activity and psychosocial stressors by occupational categories. We conducted factor analysis using principal components extraction with 17 occupational activities and calculated factor scores. ORs for PTB and SGA across quartiles of factor scores in each trimester were computed using logistic regression. RESULTS: Factor analysis grouped occupational domains into 4 groups based on factor loadings. These groups were 'occupational physical activity', 'interpersonal stressor', 'automated work' and 'job responsibility'. High levels of 'occupational physical activity' were significantly associated with SGA (adjusted OR (AOR) for highest quartile compared with lowest quartile of factor score: 1.36; 95% CIs 1.02 to 1.82; p for trend=0.001) and were also positively associated with PTB (AOR: 1.24; 95% CI 0.93 to 1.64; p for trend=0.01). No clear results were observed across domains of psychosocial stressors. CONCLUSIONS: Our findings expand understanding of associations between occupational physical activity and psychosocial stressors and PTB and SGA and suggest that additional research is needed to further examine these relationships.

Data linkage between the National Birth Defects Prevention Study and the Occupational Information Network (O*NET) to assess workplace physical activity, sedentary behaviors, and emotional stressors during pregnancy.

BACKGROUND: Knowledge of the prevalence of work-related physical activities, sedentary behaviors, and emotional stressors among pregnant women is limited, and the extent to which these exposures vary by maternal characteristics remains unclear. METHODS: Data on mothers of 6,817 infants without major birth defects, with estimated delivery during 1997 through 2009 who worked during pregnancy were obtained from the National Birth Defects Prevention Study. Information on multiple domains of occupational exposures was gathered by linking mother's primary job to the Occupational Information Network Version 9.0. RESULTS: The most frequent estimated physical activity associated with jobs during pregnancy was standing. Of 6,337 mothers, 31.0% reported jobs associated with standing for ≥75% of their time. There was significant variability in estimated occupational exposures by maternal age, race/ethnicity, and educational level. CONCLUSIONS: Our findings augment existing literature on occupational physical activities, sedentary behaviors, emotional stressors, and occupational health disparities during pregnancy.

Losses, Expansions, and Novel Subunit Discovery of Adaptor Protein Complexes in Haptophyte Algae.

The phylum Haptophyta (Diaphoratickes) contains marine algae that perform biomineralization, extruding large, distinctive calcium carbonate scales (coccoliths) that completely cover the cell. Coccolith production is an important part of global carbon cycling; however, the membrane trafficking pathway by which they are secreted has not yet been elucidated. In most eukaryotes, post-Golgi membrane trafficking involves five heterotetrameric adaptor protein (AP) complexes, which impart cargo selection specificity. To better understand coccolith secretion, we performed comparative genomic, phylogenetic, and transcriptomic analyses of the AP complexes in Emiliania huxleyi strains 92A, Van556, EH2, and CCMP1516, and related haptophytes Gephyrocapsa oceanica and Isochrysis galbana; the latter has lost the ability to biomineralize. We show that haptophytes have a modified membrane trafficking system (MTS), as we found both AP subunit losses and duplications. Additionally, we identified a single conserved subunit of the AP-related TSET complex, whose expression suggests a functional role in membrane trafficking. Finally, we detected novel alpha adaptin ear and gamma adaptin ear proteins, the first of their kind to be described outside of opisthokonts. These novel ear proteins and the sculpting of the MTS may support the capacity for biomineralization in haptophytes, enhancing their ability to perform this highly specialized form of secretion.

Maternal Hypertension During Pregnancy and the Risk of Congenital Heart Defects in Offspring: A Systematic Review and Meta-analysis.

Maternal hypertension is common during pregnancy, and multiple studies have reported on an association between maternal hypertension and congenital heart defects (CHDs) in offspring; however, there is variability in the quality of these studies. A systematic review and meta-analysis was conducted on the associations between untreated and treated maternal hypertension and the risk of CHDs, evaluating CHDs overall as well as specific CHD subtypes. A systematic search of peer-reviewed articles published before August 2013 identified 16 studies evaluating the associations between untreated and treated maternal hypertension and CHDs. Summary relative risk (RR) estimates were calculated using fixed-effects models and random-effects models. Significant associations were observed between maternal hypertension and overall CHDs, for both treated [RR 2.0; 95 % confidence interval (CI) 1.5, 2.7] and untreated (RR 1.4; 95 % CI 1.2, 1.7) hypertension, as well as for overall hypertension regardless of treatment status (RR 1.8; 95 % CI 1.5, 2.2). The magnitude of effect was similar for the majority of CHD subtypes evaluated. The effects were also similar among women with hypertension who used one of multiple specific hypertension medications. There was no evidence of publication bias, and our results were robust to several factors considered in sensitivity analyses (e.g., source of exposure data, adjustment for potential confounders, and study design). Maternal hypertension was associated with CHDs. By understanding the specific mechanisms involved, appropriate strategies may be developed to reduce this risk, in order to prevent CHDs.

Maternal smoking during pregnancy and the risk of congenital heart defects in offspring: a systematic review and metaanalysis.

Although a previous metaanalysis indicated that maternal smoking during pregnancy increased the risk of congenital heart defects (CHD) in offspring, the effect of smoking on individual CHD subtypes was not determined. Because CHDs are anatomically, clinically, epidemiologically, and developmentally heterogeneous, the authors conducted a systematic review and metaanalysis of the association between maternal smoking during pregnancy and the risk of CHDs, including CHD subtypes among offspring. Two types of summary relative risk (RR) estimates (any smoking vs no smoking and increasing categories of smoking, i.e., light, medium, and heavy) were calculated for CHDs as a group and for a number of CHD subtypes using both fixed- and random-effects models. Random effects estimates were reported if there was evidence of heterogeneity among the studies. Consistent with the previous metaanalysis, the authors observed a positive association between maternal smoking during pregnancy and the risk of CHDs as a group (RR, 1.11; 95 % confidence interval [CI], 1.02-1.21; number of cases [n] = 18,282). Additionally, women who smoked during pregnancy were more likely to have a child with 12 (71 %) of 17 CHD subtypes analyzed compared with women who did not smoke. The highest risk was for septal defects as a group (RR, 1.44; 95 % CI, 1.16-1.79; n = 2977). The evidence of dose response was observed for septal defects as a group, atrial septal defects, and atrioventricular septal defects. This systematic review and metaanalysis suggests that maternal smoking is modestly associated with an increased risk of CHDs and some CHD subtypes.

Association between thyroxine levels at birth and choanal atresia or stenosis among infants in Texas, 2004-2007.

BACKGROUND: The causes of choanal atresia or stenosis (CA) are largely unknown. Infant thyroxine (T(4) ) levels collected during newborn screening may be proxy measures for a risk factor present during the critical period of development. Therefore, we conducted a case-control study to examine the association between newborn T(4) levels and CA. METHODS: Data for cases with CA and controls were obtained from the Texas Birth Defects Registry for the period of 2004 to 2007. Information on infant T(4) levels at birth was obtained from the Texas Newborn Screening Program. Controls (n = 3570) were drawn from unaffected births in Texas for the same period and frequency matched to cases (n = 69) on year of birth, then linked to the newborn screening database. Logistic regression was used to evaluate the association between continuous and categorical infant T(4) levels and nonsyndromic CA. RESULTS: After adjustment for gestational age and year of birth, infant T(4) levels were inversely associated with CA (adjusted odds ratio [AOR], 0.85; 95% confidence interval [CI], 0.80-0.90). We observed a linear trend (p < 0.001) across quartiles of T(4) ; compared to infants with low levels, AORs for CA were 0.50 (95% CI, 0.28-0.91), 0.39 (95% CI, 0.20-0.75), and 0.15 (95% CI, 0.06-0.40) for infants with medium-to-low, medium, and high levels, respectively. CONCLUSIONS: Our findings suggest a role of low thyroid hormone levels in the development of CA, or that low newborn T(4) levels are potential proxy measures of a risk factor present during the critical period. Birth Defects Research (Part A), 2012.

Maternal occupational exposure to polycyclic aromatic hydrocarbons and congenital heart defects among offspring in the national birth defects prevention study.

BACKGROUND: There is evidence in experimental model systems that exposure to polycyclic aromatic hydrocarbons (PAHs) results in congenital heart defects (CHDs); however, to our knowledge, this relationship has not been examined in humans. Therefore, we conducted a case-control study assessing the association between estimated maternal occupational exposure to PAHs and CHDs in offspring. METHODS: Data on CHD cases and control infants were obtained from the National Birth Defects Prevention Study for the period of 1997 to 2002. Exposure to PAHs was assigned by industrial hygienist consensus, based on self-reported maternal occupational histories from 1 month before conception through the third month of pregnancy. Logistic regression was used to evaluate the association between maternal occupational PAH exposure and specific CHD phenotypic subtypes among offspring. RESULTS: The prevalence of occupational PAH exposure was 4.0% in CHD case mothers (76/1907) and 3.6% in control mothers (104/2853). After adjusting for maternal age, race or ethnicity, education, smoking, folic acid supplementation, and study center, exposure was not associated with conotruncal defects (adjusted odds ratio [AOR], 0.98; 95% confidence interval [CI], 0.58-1.67), septal defects (AOR, 1.28; 95% CI, 0.86-1.90), or with any isolated CHD subtype. CONCLUSIONS: Our findings do not support an association between potential maternal occupational exposure to PAHs and various CHDs in a large, population-based study. For CHD phenotypic subtypes in which modest nonsignificant associations were observed, future investigations could be improved by studying populations with a higher prevalence of PAH exposure and by incorporating information on maternal and fetal genotypes related to PAH metabolism. Birth Defects Research (Part A), 2012.

A key role for Chd1 in histone H3 dynamics at the 3' ends of long genes in yeast.

Chd proteins are ATP-dependent chromatin remodeling enzymes implicated in biological functions from transcriptional elongation to control of pluripotency. Previous studies of the Chd1 subclass of these proteins have implicated them in diverse roles in gene expression including functions during initiation, elongation, and termination. Furthermore, some evidence has suggested a role for Chd1 in replication-independent histone exchange or assembly. Here, we examine roles of Chd1 in replication-independent dynamics of histone H3 in both Drosophila and yeast. We find evidence of a role for Chd1 in H3 dynamics in both organisms. Using genome-wide ChIP-on-chip analysis, we find that Chd1 influences histone turnover at the 5' and 3' ends of genes, accelerating H3 replacement at the 5' ends of genes while protecting the 3' ends of genes from excessive H3 turnover. Although consistent with a direct role for Chd1 in exchange, these results may indicate that Chd1 stabilizes nucleosomes perturbed by transcription. Curiously, we observe a strong effect of gene length on Chd1's effects on H3 turnover. Finally, we show that Chd1 also affects histone modification patterns over genes, likely as a consequence of its effects on histone replacement. Taken together, our results emphasize a role for Chd1 in histone replacement in both budding yeast and Drosophila melanogaster, and surprisingly they show that the major effects of Chd1 on turnover occur at the 3' ends of genes.

An exploratory case-only analysis of gene-hazardous air pollutant interactions and the risk of childhood medulloblastoma.

BACKGROUND: There is evidence that exposure to chlorinated solvents may be associated with childhood medulloblastoma and primitive neuroectodermal tumor (M/PNET) risk. Animal models suggest genes related to detoxification and DNA repair are important in the carcinogenicity of these pollutants; however, there have been no human studies assessing the modifying effects of these genotypes on the association between chlorinated solvents and childhood M/PNET risk. PROCEDURE: We conducted a case-only study to evaluate census tract-level exposure to chlorinated solvents and the risk of childhood M/PNET in the context of detoxification and DNA repair genotypes. Cases (n = 98) were obtained from Texas Children's Hospital and MD Anderson Cancer Center. Key genotypes (n = 22) were selected from the Illumina Human 1M Quad SNP Chip. Exposure to chlorinated solvents (methylene chloride, perchloroethylene, trichloroethylene, and vinyl chloride) was estimated from the US EPA's 1999 Assessment System for Population Exposure Nationwide (ASPEN). Logistic regression was used to estimate the case-only odds ratios and 95% confidence intervals (CIs). RESULTS: There were 11 significant gene-environment interactions associated with childhood M/PNET risk. However, after correcting for multiple comparisons, only the interaction between high trichloroethylene levels and OGG1 rs293795 significantly increased the risk of childhood M/PNET risk (OR = 9.24, 95% CI: 2.24, 38.24, Q = 0.04). CONCLUSIONS: This study provides an initial assessment of the interaction between ambient levels of chlorinated solvents and potentially relevant genotypes on childhood M/PNET risk. Our results are exploratory and must be validated in animal models, as well as additional human studies.

Chemical disinfection of high-consequence transboundary animal disease viruses on nonporous surfaces.

Disinfection is a critical part of the response to transboundary animal disease virus (TADV) outbreaks by inactivating viruses on fomites to help control infection. To model the inactivation of TADV on fomites, we tested selected chemicals to inactivate Foot and Mouth Disease virus (FMDV), African Swine Fever virus (ASFV), and Classical Swine Fever virus (CSFV) dried on steel and plastic surfaces. For each of these viruses, we observed a 2 to 3 log reduction of infectivity due to drying alone. We applied a modified surface disinfection method to determine the efficacy of selected disinfectants to inactivate surface-dried high-titer stocks of these three structurally different TADV. ASFV and FMDV were susceptible to sodium hypochlorite (500 and 1000 ppm, respectively) and citric acid (1%) resulting in complete disinfection. Sodium carbonate (4%), while able to reduce FMDV infectivity by greater than 4-log units, only reduced ASFV by 3 logs. Citric acid (2%) did not totally inactivate dried CSFV, suggesting it may not be completely effective for disinfection in the field. Based on these data we recommend disinfectants be formulated with a minimum of 1000 ppm sodium hypochlorite for ASFV and CSFV disinfection, and a minimum of 1% citric acid for FMDV disinfection.