Guideline-concordant endometrial cancer treatment and survival in the Women's Health Initiative Life and Longevity After Cancer study

In the Women's Health Initiative (WHI) Life and Longevity After Cancer (LILAC) cohort, we examined predictors of guideline-concordant treatment among endometrial cancer (EC) survivors and associations between receipt of guideline-concordant treatment and survival. Receipt of guideline-concordant EC treatment was defined according to year-specific National Comprehensive Cancer Network (NCCN) guidelines. Multivariable logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for predictors of guideline-concordant treatment receipt. We estimated multivariable-adjusted hazard ratios (HRs) and 95% CIs for relationships between guideline-concordant treatment and overall survival using Cox proportional hazards regression. We included 629 women with EC, of whom 83.6% (n = 526) received guideline-concordant treatment. Receipt of guideline-concordant treatment was less common among women with nonendometrioid histology (OR = 0.24, 95% CI = 0.13–0.45) but was more common among women living in the Midwest (OR = 2.09, 95% CI = 1.06–4.12) or West (OR = 3.02, 95% CI = 1.49–6.13) compared to the Northeast. In Cox regression models adjusted for age, histology and stage, receipt of guideline-concordant EC treatment was borderline associated with improved overall survival (HR = 0.80, 95% CI = 0.60–1.01) in the overall population. Guideline-concordant treatment was also linked with better overall survival among women with low-grade uterine-confined endometrioid EC or widely metastatic endometrioid EC. Guideline-concordant treatment varies by some patient characteristics and those women in receipt of guideline-concordant care had borderline improved survival. Studies evaluating regional differences in treatment along with randomized clinical trials to determine appropriate treatment regimens for women with aggressive tumor characteristics are warranted.     

Physiologic and behavioral responses to stress,temperament, and incidence of infection and atopic disorders in the first year of life: a pilot study

The purpose of this pilot study was to explore relationships among physiologic and behavioral responses to a standardized stressor (routine immunization), parent-reported temperament, and numbers of infections and atopic disorders in the first year of life. Infants were studied during 2- (n = 30) and 4-month (n = 24) routine clinic visits. Behavioral data were coded from videotapes filmed for 90 seconds after immunizations. Salivary cortisol measured physiologic arousal; specimens were obtained before and after immunizations. Two-month-old infants with higher levels of cortisol required more time to calm after immunization. Relationships were found between the temperament characteristics of persistence and adaptability and infections at 12 months.     

Effect of inactivation of gtf genes on adherence of Streptococcus downei

The activity of glucosyltransferases (GTF), a group of enzymes that synthesize water-soluble and -insoluble glucans from sucrose, significantly contributes to the cariogenicity of mutans streptococci. Streptococcus downei produces four glucosyltransferases, GTFI, which produces insoluble glucan, and GTFS, GTFT, and GTFU, which synthesize soluble glucans. We have previously reported that inactivation of gtfS results in altered adherence and have now examined its interaction with other enzymes by constructing mutants which were gtfS, gtfS/gtfT, gtfS/gtfI and gtfI. The mutants were tested for their ability to accumulate on wires and on plastic microtiter trays in the presence of sucrose. The gtfS mutant displayed a reduced ability to adhere compared to the wild type but there was no further reduction of adherence in a gtfS/gtfT mutant. In contrast, the gtfS/gtfI double mutant showed a drastic reduction in adherence and when gtfI alone was inactivated, bacteria were unable to adhere to a hard surface. The results confirmed that insoluble glucan is required for strong adherence to a smooth surface but that the amount and structure of this glucan is dependent upon the availability of soluble glucans to act as primer molecules.     

In‐home salivary melatonin collection: Methodology for children and adolescents

In‐home salivary collection quality and adherence to a prescribed collection methodology for evaluation of dim light melatonin onset (DLMO) is unknown in children. Primary aims of this study were to 1) describe a novel family centered methodology for in‐home salivary collection; 2) determine the acceptance and feasibility of this methodology; 3) measure adherence to collection instructions; and 4) identify patterns between participants’ age and quality of samples collected. After receiving instructional handouts from the study team, families utilized in‐home salivary melatonin collection. Participants (N = 64) included 39 children (21 female, mean age 9.5 ± 1.61 years) and 25 adolescents (11 female, mean age 15.9 ± 2.12 years) with craniopharyngioma. Participants were 90% adherent to collection schedule, and 89% of the samples collected were of sufficient quantity and quality, with no differences found between age (child vs. adolescent) and melatonin sample quantity and quality. In‐home saliva collection provides an acceptable and feasible method to collect salivary melatonin and biomarkers in children and adolescents.     

Elimination of damaged mitochondria through mitophagy reduces mitochondrial oxidative stress and increases tolerance to trichothecenes

Trichothecene mycotoxins are natural contaminants of small grain cereals and are encountered in the environment, posing a worldwide threat to human and animal health. Their mechanism of toxicity is poorly understood, and little is known about cellular protection mechanisms against trichothecenes. We previously identified inhibition of mitochondrial protein synthesis as a novel mechanism for trichothecene-induced cell death. To identify cellular functions involved in trichothecene resistance, we screened the Saccharomyces cerevisiae deletion library for increased sensitivity to nonlethal concentrations of trichothecin (Tcin) and identified 121 strains exhibiting higher sensitivity than the parental strain. The largest group of sensitive strains had significantly higher reactive oxygen species (ROS) levels relative to the parental strain. A dose-dependent increase in ROS levels was observed in the parental strain treated with different trichothecenes, but not in a petite version of the parental strain or in the presence of a mitochondrial membrane uncoupler, indicating that mitochondria are the main site of ROS production due to toxin exposure. Cytotoxicity of trichothecenes was alleviated after treatment of the parental strain and highly sensitive mutants with antioxidants, suggesting that oxidative stress contributes to trichothecene sensitivity. Cotreatment with rapamycin and trichothecenes reduced ROS levels and cytotoxicity in the parental strain relative to the trichothecene treatment alone, but not in mitophagy deficient mutants, suggesting that elimination of trichothecene-damaged mitochondria by mitophagy improves cell survival. These results reveal that increased mitophagy is a cellular protection mechanism against trichothecene-induced mitochondrial oxidative stress and a potential target for trichothecene resistance.Trichothecene mycotoxins are highly toxic secondary metabolites produced by Trichothecium, Myrothecium, Trichoderma, and Fusarium. Fusarium graminearum and Fusarium culmorum cause Fusarium head blight (FHB), which is one of the most damaging diseases of small grain cereals. FHB adversely affects the food supply because trichothecene mycotoxins, such as deoxynivalenol (DON), accumulate in the infected grain, presenting a food safety risk and health hazard to humans and animals (1). Controlling their accumulation in small grains remains a huge challenge. Trichothecenes cause growth retardation, hemorrhagic lesions, immune dysfunction, and emesis (2, 3) and are neurotoxic (4–6). Trichothecene poisoning causes acute gastroenteritis and has been linked to alimentary toxic aleukia (ATA) and Kashin–Beck disease, an endemic and chronic degenerative osteoarthritis (3).Trichothecenes inhibit protein synthesis by targeting ribosomal protein L3 in yeast (7–9). However, their toxicity is not entirely due to inhibition of cytosolic protein synthesis. In mammalian cells, DON induces activation of double-stranded RNA-associated protein kinase (PKR), promotes degradation of 28S rRNA, and up-regulates a number of microRNAs (3, 10). DON exposure stabilizes mRNAs encoding proinflammatory mRNAs (3, 10). In plants, T-2 toxin (T-2) and DON cause oxidative stress damage by increasing reactive oxygen species (ROS) levels (11).Despite the importance of trichothecenes in food safety and chronic environmental exposure, the molecular mechanism of their toxicity is not well-understood and there is a critical gap in our knowledge about the mechanisms that can protect cells against trichothecenes. To understand the trichothecene mechanism of action, we previously carried out a genome-wide screen of Saccharomyces cerevisiae for resistance to trichothecin (Tcin) and showed that the largest group of resistant strains were affected in mitochondrial functions (12). We showed that trichothecenes inhibit mitochondrial translation, before depolarization and fragmentation of the mitochondrial membrane and independent of the cytosolic translation inhibition (12, 13). Previous studies showed a link between ROS generation and mitochondrial translation (14, 15). Yeast mutants with impaired mitochondrial translation exhibited faulty oxidative phosphorylation resulting in toxic levels of ROS, overwhelming the cell’s antioxidant capacity, and causing oxidative stress (14). These results suggested that mitochondrial dysfunction and the resulting oxidative stress might contribute to trichothecene sensitivity. To obtain a comprehensive view of the cellular functions needed for tolerance to trichothecenes, we screened the complete set of viable S. cerevisiae deletion strains for increased sensitivity to Tcin, a representative type B trichothecene that has a similar IC₅₀ for Vero cells (0.5 µM) and yeast grown on nonfermentable media (0.75 µM) (12, 13). Analysis of the identified strains revealed a vital role for mitochondrial oxidative stress in trichothecene sensitivity and provided the first evidence to our knowledge for a prosurvival role for the autophagic degradation of damaged mitochondria or mitophagy in the reduction of trichothecene-mediated mitochondrial oxidative stress.