Dietary cucurbitacin E reduces high-strength altitude training induced oxidative stress, inflammation and immunosuppression.

Professional athletes conduct high-intensitive hypoxic training often accompanied by the increase of many inflammatory-related cytokines and immunosuppression. Cucurbitacin E (CucE), as a triterpenoid isolated from Cucurbitaceae plants, exert potential anti-cancer and anti-inflammatory. However, it is unknown whether that the CucE could be used as dietary supplement for athletes to improve inflammatory response and immunosuppression. In this study, we established the simulative hypoxic training rat and monkey models and evaluated the effects of CucE on immune- and inflammation-related factors. Obvious improvement on pro-inflammatory factors and pro-lymphocyte proliferation activities were showed in CucE treated rats compared with the control. Further supplement of CucE in professional meals for cynomolgus monkeys with 4-weeks high-intensitive hypoxic training also exert effects on altitude-induced oxidative stress, inflammation and immunologic function. Furtherly, we explored the underlying mechanism of CucE in human Jurkat T cells and results showed that CucE may exhibit immunosuppressive effect by attenuating critical cytokine expression through down-regulating the NF-κB signaling pathway. In conclusion, CucE is expected to be a potential dietary supplement for athletes to ameliorate the inflammation and immunosuppression caused by high-intensitive exercise.

Spikes in acute:chronic workload ratio (ACWR) associated with a 5-7 times greater injury rate in English Premier League football players: a comprehensive 3-year study.

OBJECTIVES: We examined the relation between global positioning system (GPS)-derived workloads and injury in English Premier League football players (n=33) over three seasons. METHODS: Workload and injury data were collected over three consecutive seasons. Cumulative (1-weekly, 2-weekly, 3-weekly and 4-weekly) loads in addition to acute:chronic workload ratios (ACWR) (acute workload (1-week workload)) divided by chronic workload (previous 4-week average acute workload) were classified into discrete ranges by z-scores. Relative risk (RR) for each range was then calculated between injured and non-injured players using specific GPS variables: total distance, low-intensity distance, high-speed running distance, sprint distance, accelerations and decelerations. RESULTS: The greatest non-contact injury risk was when the chronic exposure to decelerations was low (<1731) and the ACWR was >2.0 (RR=6.7). Non-contact injury risk was also 5-6 times higher for accelerations and low-intensity distance when the chronic workloads were categorised as low and the ACWR was >2.0 (RR=5.4-6.6), compared with ACWRs below this. When all chronic workloads were included, an ACWR >2.0 was associated with a significant but lesser injury risk for the same metrics, plus total distance (RR=3.7-3.9). CONCLUSIONS: We recommend that practitioners involved in planning training for performance and injury prevention monitor the ACWR, increase chronic exposure to load and avoid spikes that approach or exceed 2.0.

Genome-Wide Association Study to Identify Susceptibility Loci That Modify Radiation-Related Risk for Breast Cancer After Childhood Cancer.

Background: Childhood cancer survivors treated with chest-directed radiotherapy have substantially elevated risk for developing breast cancer. Although genetic susceptibility to breast cancer in the general population is well studied, large-scale evaluation of breast cancer susceptibility after chest-directed radiotherapy for childhood cancer is lacking. Methods: We conducted a genome-wide association study of breast cancer in female survivors of childhood cancer, pooling two cohorts with detailed treatment data and systematic, long-term follow-up: the Childhood Cancer Survivor Study and St. Jude Lifetime Cohort. The study population comprised 207 survivors who developed breast cancer and 2774 who had not developed any subsequent neoplasm as of last follow-up. Genotyping and subsequent imputation yielded 16 958 466 high-quality variants for analysis. We tested associations in the overall population and in subgroups stratified by receipt of lower than 10 and 10 or higher gray breast radiation exposure. We report P values and pooled per-allele risk estimates from Cox proportional hazards regression models. All statistical tests were two-sided. Results: Among survivors who received 10 or higher gray breast radiation exposure, a locus on 1q41 was associated with subsequent breast cancer risk (rs4342822, nearest gene PROX1 , risk allele frequency in control subjects [RAF controls ] = 0.46, hazard ratio = 1.92, 95% confidence interval = 1.49 to 2.44, P = 7.09 × 10 -9 ). Two rare variants also showed potentially promising associations (breast radiation ≥10 gray: rs74949440, 11q23, TAGLN , RAF controls = 0.02, P = 5.84 × 10 -8 ; <10 gray: rs17020562, 1q32.3, RPS6KC1 , RAF controls = 0.0005, P = 6.68 × 10 -8 ). Associations were restricted to these dose subgroups, with consistent findings in the two survivor cohorts. Conclusions: Our study provides strong evidence that germline genetics outside high-risk syndromes could modify the effect of radiation exposure on breast cancer risk after childhood cancer.

Accumulated workloads and the acute:chronic workload ratio relate to injury risk in elite youth football players.

AIM: The purpose of this study was to investigate the relationship between physical workload and injury risk in elite youth football players. METHODS: The workload data and injury incidence of 32 players were monitored throughout 2 seasons. Multiple regression was used to compare cumulative (1, 2, 3 and 4-weekly) loads and acute:chronic (A:C) workload ratios (acute workload divided by chronic workload) between injured and non-injured players for specific GPS and accelerometer-derived variables:total distance (TD), high-speed distance (HSD), accelerations (ACC) and total load. Workloads were classified into discrete ranges by z-scores and the relative risk was determined. RESULTS: A very high number of ACC (≥9254) over 3 weeks was associated with the highest significant overall (relative risk (RR)=3.84) and non-contact injury risk (RR=5.11). Non-contact injury risk was significantly increased when a high acute HSD was combined with low chronic HSD (RR=2.55), but not with high chronic HSD (RR=0.47). Contact injury risk was greatest when A:C TD and ACC ratios were very high (1.76 and 1.77, respectively) (RR=4.98). CONCLUSIONS: In general, higher accumulated and acute workloads were associated with a greater injury risk. However, progressive increases in chronic workload may develop the players' physical tolerance to higher acute loads and resilience to injury risk.

Barefoot vs common footwear: A systematic review of the kinematic, kinetic and muscle activity differences during walking.

Habitual footwear use has been reported to influence foot structure with an acute exposure being shown to alter foot position and mechanics. The foot is highly specialised thus these changes in structure/position could influence functionality. This review aims to investigate the effect of footwear on gait, specifically focussing on studies that have assessed kinematics, kinetics and muscle activity between walking barefoot and in common footwear. In line with PRISMA and published guidelines, a literature search was completed across six databases comprising Medline, EMBASE, Scopus, AMED, Cochrane Library and Web of Science. Fifteen of 466 articles met the predetermined inclusion criteria and were included in the review. All articles were assessed for methodological quality using a modified assessment tool based on the STROBE statement for reporting observational studies and the CASP appraisal tool. Walking barefoot enables increased forefoot spreading under load and habitual barefoot walkers have anatomically wider feet. Spatial-temporal differences including, reduced step/stride length and increased cadence, are observed when barefoot. Flatter foot placement, increased knee flexion and a reduced peak vertical ground reaction force at initial contact are also reported. Habitual barefoot walkers exhibit lower peak plantar pressures and pressure impulses, whereas peak plantar pressures are increased in the habitually shod wearer walking barefoot. Footwear particularly affects the kinematics and kinetics of gait acutely and chronically. Little research has been completed in older age populations (50+ years) and thus further research is required to better understand the effect of footwear on walking across the lifespan.

Characterisation of the N'1 isoform of the cyclic AMP-dependent protein kinase (PK-A) catalytic subunit in the nematode, Caenorhabditis elegans.

Multiple isoforms of the cyclic AMP-dependent protein kinase (PK-A) catalytic (C) subunit, arise as a consequence of the use of alternative splicing strategies during transcription of the kin-1 gene in the nematode, Caenorhabditis elegans. N-myristoylation is a common co-translational modification of mammalian PK-A C-subunits; however, the major isoform (N'3), originally characterised in C. elegans, is not N-myristoylated. Here, we show that N'1 isoforms are targets for N-myristoylation in C. elegans. We have demonstrated the in vivo incorporation of radioactivity into N'1 C-subunit isoforms, following incubation of nematodes with [(3)H]-myristic acid. HPLC and MALDI-TOF MS analysis of proteolytic digests of immunoprecipitates confirmed the presence of myristoyl-glycine in the C-subunit. In order to better understand the impact of the N'1 N-terminal sequence, and its myristoylation, on C-subunit activity, a chimerical C-subunit, consisting of the N'1 N-terminus from C. elegans and a murine core and C-terminal sequence was expressed. Myristoylation had no appreciable effect on the catalytic properties of the chimeric protein. However, the myristoylated chimeric protein did exhibit enhanced apolar targeting compared to the myristoylated wild-type murine polypeptide. This behaviour may reflect the inability of the N'1-encoded N-terminus sequence to correctly dock with a hydrophobic domain on the surface of the C-subunit.

Polymorphisms in estrogen biosynthesis and metabolism-related genes, ionizing radiation exposure, and risk of breast cancer among US radiologic technologists.

Ionizing radiation-associated breast cancer risk appears to be modified by timing of reproductive events such as age at radiation exposure, parity, age at first live birth, and age at menopause. However, potential breast cancer risk modification of low to moderate radiation dose by polymorphic estrogen metabolism-related gene variants has not been routinely investigated. We assessed breast cancer risk of 12 candidate variants in 12 genes involved in steroid metabolism, catabolism, binding, or receptor functions in a study of 859 cases and 1,083 controls within the US radiologic technologists (USRT) cohort. Using cumulative breast dose estimates from a detailed assessment of occupational and personal diagnostic ionizing radiation exposure, we investigated the joint effects of genotype on the risk of breast cancer. In multivariate analyses, we observed a significantly decreased risk of breast cancer associated with the CYP3A4 M445T minor allele (rs4986910, OR = 0.3; 95% CI 0.1-0.9). We found a borderline increased breast cancer risk with having both minor alleles of CYP1B1 V432L (rs1056836, CC vs. GG, OR = 1.2; 95% CI 0.9-1.6). Assuming a recessive model, the minor allele of CYP1B1 V432L significantly increased the dose-response relationship between personal diagnostic X-ray exposure and breast cancer risk, adjusted for cumulative occupational radiation dose (p (interaction) = 0.03) and had a similar joint effect for cumulative occupational radiation dose adjusted for personal diagnostic X-ray exposure (p (interaction) = 0.06). We found suggestive evidence that common variants in selected estrogen metabolizing genes may modify the association between ionizing radiation exposure and breast cancer risk.

No evidence for differences in DNA damage assessed before and after a cancer diagnosis.

The overwhelming majority of studies that have found increased cancer risk associated with functional deficits in DNA repair used a case-control design, in which measurements were made after cancer diagnosis. However, there are concerns about whether the cancer itself or cancer treatment affected the conclusions (reverse causation bias). We assessed the effect of cancer diagnosis among 26 breast cancer controls who had blood collected during 2001 to 2003 and again in 2005 to 2006 after being diagnosed with cancer. Using the alkaline comet assay, we quantified DNA damage in untreated lymphoblastoid cell lines. Comet distributed moment, olive tail moment, percentage of DNA in tail, and comet tail length were summarized as the geometric mean of 100 cells. For comet distributed moment, olive tail moment, tail DNA, and tail length, the proportions of women with before diagnosis values higher than after diagnosis were 65%, 50%, 50%, and 46%, respectively. We found no significant differences in the before or after diagnosis mean comet values. Median cut-points were determined from the before diagnosis distribution, and we used conditional logistic regression to calculate odds ratios (OR) and upper 95% bounds of the confidence intervals. ORs ranged from 0.6 to 0.9 with upper confidence interval bounds of 1.9 and 2.6, meaning biased ORs above 2.6 are unlikely. We found no evidence that reverse causation bias is an important concern in case-control studies using the comet assay applied to cell lines collected after cancer diagnosis. More work is needed to characterize the effect of cancer diagnosis on other phenotypic assays.

Polymorphisms in DNA repair genes, ionizing radiation exposure and risk of breast cancer in U.S. Radiologic technologists.

High-dose ionizing radiation exposure to the breast and rare autosomal dominant genes have been linked with increased breast cancer risk, but the role of low-to-moderate doses from protracted radiation exposure in breast cancer risk and its potential modification by polymorphisms in DNA repair genes has not been previously investigated among large numbers of radiation-exposed women with detailed exposure data. Using carefully reconstructed estimates of cumulative breast doses from occupational and personal diagnostic ionizing radiation, we investigated the potential modification of radiation-related breast cancer risk by 55 candidate single nucleotide polymorphisms in 17 genes involved in base excision or DNA double-strand break repair among 859 cases and 1083 controls from the United States Radiologic Technologists (USRT) cohort. In multivariable analyses, WRN V114I (rs2230009) significantly modified the association between cumulative occupational breast dose and risk of breast cancer (adjusted for personal diagnostic exposure) (p = 0.04) and BRCA1 D652N (rs4986850), PRKDC IVS15 + 6C > T (rs1231202), PRKDC IVS34 + 39T > C (rs8178097) and PRKDC IVS31 - 634C > A (rs10109984) significantly altered the personal diagnostic radiation exposure-response relationship (adjusted for occupational dose) (p < or = 0.05). None of the remaining 50 SNPs significantly modified breast cancer radiation dose-response relationships. The USRT genetic study provided a unique opportunity to examine the joint effects of common genetic variation and ionizing radiation exposure on breast cancer risk using detailed occupational and personal diagnostic exposure data. The suggestive evidence found for modification of radiation-related breast cancer risk for 5 of the 55 SNPs evaluated requires confirmation in larger studies of women with quantified radiation breast doses in the low-to-moderate range.

Polymorphisms in apoptosis- and proliferation-related genes, ionizing radiation exposure, and risk of breast cancer among U.S. Radiologic Technologists.

BACKGROUND: Although genes involved in apoptosis pathways and DNA repair pathways are both essential for maintaining genomic integrity, genetic variants in DNA repair have been thought to increase susceptibility to radiation carcinogenesis, but similar hypotheses have not generally been raised about apoptosis genes. For this reason, potential modification of the relationship between ionizing radiation exposure and breast cancer risk by polymorphic apoptosis gene variants have not been investigated among radiation-exposed women. METHODS: In a case-control study of 859 cases and 1,083 controls within the U.S. Radiologic Technologists cohort, we assessed breast cancer risk with respect to 16 candidate variants in eight genes involved in apoptosis, inflammation, and proliferation. Using carefully reconstructed cumulative breast dose estimates from occupational and personal diagnostic ionizing radiation, we also investigated the joint effects of these polymorphisms on the risk of breast cancer. RESULTS: In multivariate analyses, we observed a significantly decreased risk of breast cancer associated with the homozygous minor allele of CASP8 D302H [rs1045485, odds ratio (OR), 0.3; 95% confidence interval (95% CI), 0.1-0.8]. We found a significantly increased breast cancer risk with increasing minor alleles for IL1A A114S (rs17561); heterozygote OR 1.2 (95% CI, 1.0-1.4) and homozygote OR 1.5 (95% CI, 1.1-2.0), P(trend) = 0.008. Assuming a dominant genetic model, IL1A A114S significantly modified the dose-response relationship between cumulative personal diagnostic radiation and breast cancer risk, adjusted for occupational dose (P(interaction) = 0.004). CONCLUSION: The U.S. Radiologic Technologists breast cancer study provided a unique opportunity to examine the joint effects of common genetic variation and ionizing radiation exposure to the breast using detailed occupational and personal diagnostic dose data. We found evidence of effect modification of the radiation and breast cancer dose-response relationship that should be confirmed in studies with more cases and controls and quantified radiation breast doses in the low-to-moderate range.

Expression of multiple isoforms of the cAMP-dependent protein kinase (PK-A) catalytic subunit in the nematode, Caenorhabditis elegans.

The cAMP-dependent protein kinase (protein kinase A, PK-A) plays a central role in the regulation of many aspects of eukaryotic cellular activity. In the free-living nematode, Caenorhabditis elegans, two genes encode PK-A-like catalytic subunits. The kin-1 gene has the potential to generate, through alternative splicing events, a multiplicity of catalytic subunit isoforms; in contrast, the F47F2.1b gene appears to encode just a single authentic catalytic subunit-like protein. Here, we report on the occurrence of, and developmental changes in the expression of, polypeptide products of these genes in both C. elegans and the closely related nematode, C. briggsae. Polypeptides derived from the F47F2.1 gene and its orthologue were detected in mixed stage populations of C. elegans and C. briggsae, respectively. Likewise, a number of polypeptides arising as a result of alternative splicing of transcripts from kin-1, or its orthologue in C. briggsae, were identified in mixed stage populations of nematodes. These isoforms included polypeptides with N-termini encoded by exons N'1 or N'4 and C-termini encoded by exons 7 or N. The expression of isoforms with an N-terminus encoded by the N'1 exon is of significance because the amino acid sequence encoded by this exon encompasses an N-myristoylation motif. Isoform abundance appears to be related to developmental stage. Substantial differences in polypeptide expression profiles can be seen in embryonic and adult nematodes. The functional significance of this PK-A catalytic subunit isoform diversity is discussed.