Age-related difference in susceptibility of ApcMin/+ mice towards the chemopreventive efficacy of dietary aspirin and curcumin

The nonsteroidal anti-inflammatory drug aspirin and the spice curcumin retard adenoma formation when administered long-term to ApcMin/+ mice, a model of human familial adenomatous polyposis coli. Both agents interfere with cyclooxygenase activity. When aspirin is administered to ApcMin/+ mice only postweaning, but not before, it is inefficacious, while curcumin given postweaning is active. Here the hypothesis was tested that dietary aspirin (0.05%) or curcumin (0.2%) prevent or delay adenoma formation in offsprings when administered to ApcMin/+ mothers and up to the end of weaning, but not afterwards. Whereas curcumin was without effect when administered in this way, aspirin reduced numbers of intestinal adenomas by 21%. When aspirin given up to the end of weaning was combined with curcumin administered from the end of weaning for the rest of the animals' lifetime, intestinal adenoma numbers were reduced by 38%. The combination was not superior to intervention postweaning with curcumin alone. These results show that aspirin exerts chemopreventive activity in the ApcMin/+ mouse during tumour initiation/early promotion, while curcumin is efficacious when given at a later stage of carcinogenic progression. Thus, the results suggest that in this mouse model aspirin and curcumin act during different ‘windows’ of neoplastic development

Magnesium intake and colorectal cancer risk in the Netherlands Cohort Study

Energy-adjusted magnesium intake was nonsignificantly inversely related to risk of colorectal cancer (n=2328) in the Netherlands Cohort Study on Diet and Cancer that started in 1986 (n=58 279 men and 62 573 women). Statistically significant inverse trends in risk were observed in overweight subjects for colon and proximal colon cancer across increasing quintiles of magnesium uptake (P-trend, 0.05 and 0.02, respectively). Although an overall protective effect was not afforded, our results suggest an effect of magnesium in overweight subjects, possibly through decreasing insulin resistance

The effects of traditional, superset, and tri-set resistance training structures on perceived intensity and physiological responses.

PURPOSE: Investigate the acute and short-term (i.e., 24 h) effects of traditional (TRAD), superset (SS), and tri-set (TRI) resistance training protocols on perceptions of intensity and physiological responses. METHODS: Fourteen male participants completed a familiarisation session and three resistance training protocols (i.e., TRAD, SS, and TRI) in a randomised-crossover design. Rating of perceived exertion, lactate concentration ([Lac]), creatine kinase concentration ([CK]), countermovement jump (CMJ), testosterone, and cortisol concentrations was measured pre, immediately, and 24-h post the resistance training sessions with magnitude-based inferences assessing changes/differences within/between protocols. RESULTS: TRI reported possible to almost certainly greater efficiency and rate of perceived exertion, although session perceived load was very likely lower. SS and TRI had very likely to almost certainly greater lactate responses during the protocols, with changes in [CK] being very likely and likely increased at 24 h, respectively. At 24-h post-training, CMJ variables in the TRAD protocol had returned to baseline; however, SS and TRI were still possibly to likely reduced. Possible increases in testosterone immediately post SS and TRI protocols were reported, with SS showing possible increases at 24-h post-training. TRAD and SS showed almost certain and likely decreases in cortisol immediately post, respectively, with TRAD reporting likely decreases at 24-h post-training. CONCLUSIONS: SS and TRI can enhance training efficiency and reduce training time. However, acute and short-term physiological responses differ between protocols. Athletes can utilise SS and TRI resistance training, but may require additional recovery post-training to minimise effects of fatigue

Homo-PROTACs:bivalent small-molecule dimerizers of the VHL E3 ubiquitin ligase to induce self-degradation

E3 ubiquitin ligases are key enzymes within the ubiquitin proteasome system which catalyze the ubiquitination of proteins, targeting them for proteasomal degradation. E3 ligases are gaining importance as targets to small molecules, both for direct inhibition and to be hijacked to induce the degradation of non-native neo-substrates using bivalent compounds known as PROTACs (for 'proteolysis-targeting chimeras'). We describe Homo-PROTACs as an approach to dimerize an E3 ligase to trigger its suicide-type chemical knockdown inside cells. We provide proof-of-concept of Homo-PROTACs using diverse molecules composed of two instances of a ligand for the von Hippel-Lindau (VHL) E3 ligase. The most active compound, CM11, dimerizes VHL with high avidity in vitro and induces potent, rapid and proteasome-dependent self-degradation of VHL in different cell lines, in a highly isoform-selective fashion and without triggering a hypoxic response. This approach offers a novel chemical probe for selective VHL knockdown, and demonstrates the potential for a new modality of chemical intervention on E3 ligases.Targeting the ubiquitin proteasome system to modulate protein homeostasis using small molecules has promising therapeutic potential. Here the authors describe Homo-PROTACS: small molecules that can induce the homo-dimerization of E3 ubiquitin ligases and cause their proteasome-dependent degradation

Linear viscoelasticity - bone volume fraction relationships of bovine trabecular bone

Trabecular bone has been previously recognized as time-dependent (viscoelastic) material, but the relationships of its viscoelastic behaviour with bone volume fraction (BV/TV) have not been investigated so far. Therefore, the aim of the present study was to quantify the time-dependent viscoelastic behaviour of trabecular bone and relate it to BV/TV. Uniaxial compressive creep experiments were performed on cylindrical bovine trabecular bone samples ([Formula: see text] ) at loads corresponding to physiological strain level of 2000 [Formula: see text] . We assumed that the bone behaves in a linear viscoelastic manner at this low strain level and the corresponding linear viscoelastic parameters were estimated by fitting a generalized Kelvin–Voigt rheological model to the experimental creep strain response. Strong and significant power law relationships ([Formula: see text] ) were found between time-dependent creep compliance function and BV/TV of the bone. These BV/TV-based material properties can be used in finite element models involving trabecular bone to predict time-dependent response. For users’ convenience, the creep compliance functions were also converted to relaxation functions by using numerical interconversion methods and similar power law relationships were reported between time-dependent relaxation modulus function and BV/TV

Multimarker RT–PCR assay for the detection of minimal residual disease in sentinel lymph nodes of breast cancer patients

The presence of metastases in lymph nodes is the most powerful prognostic factor in breast cancer patients. Routine histological examination of lymph nodes has limited sensitivity for the detection of breast cancer metastases. The aim of the present study was to develop a multimarker reverse transcriptase–polymerase chain reaction (RT—PCR) assay for the detection of minimal residual disease in sentinel nodes of breast cancer patients. RNA was extracted from 30 sentinel lymph nodes (SLN) obtained from 28 patients, three primary breast cancers (positive controls), three lymph nodes from patients with benign diseases, and peripheral blood lymphocytes of 10 healthy volunteers (negative controls). RT–PCR was performed using the following markers; cytokeratin (CK)-19, NY-BR-1 and mammaglobin B. RT–PCR results were compared to enhanced histopathologic examination and immunohistochemistry (IHC). All three positive controls showed strong PCR amplification for all three markers. None of the 13 negative controls was amplified by any of the three markers. Among the 30 SLN analysed, breast cancer metastases were detected in six SLNs by routine histology, in eight by IHC and in 15 by RT–PCR. We conclude that a multimarker RT–PCR assay probing for NY-BR-1, mammaglobin-B, and CK-19 is more sensitive compared to enhanced pathologic examination. This method may prove to be of value in breast cancer staging and prognosis evaluation

The First Cellular Models Based on Frataxin Missense Mutations That Reproduce Spontaneously the Defects Associated with Friedreich Ataxia

BACKGROUND:Friedreich ataxia (FRDA), the most common form of recessive ataxia, is due to reduced levels of frataxin, a highly conserved mitochondrial iron-chaperone involved in iron-sulfur cluster (ISC) biogenesis. Most patients are homozygous for a (GAA)(n) expansion within the first intron of the frataxin gene. A few patients, either with typical or atypical clinical presentation, are compound heterozygous for the GAA expansion and a micromutation. METHODOLOGY:We have developed a new strategy to generate murine cellular models for FRDA: cell lines carrying a frataxin conditional allele were used in combination with an EGFP-Cre recombinase to create murine cellular models depleted for endogenous frataxin and expressing missense-mutated human frataxin. We showed that complete absence of murine frataxin in fibroblasts inhibits cell division and leads to cell death. This lethal phenotype was rescued through transgenic expression of human wild type as well as mutant (hFXN(G130V) and hFXN(I154F)) frataxin. Interestingly, cells expressing the mutated frataxin presented a FRDA-like biochemical phenotype. Though both mutations affected mitochondrial ISC enzymes activities and mitochondria ultrastructure, the hFXN(I154F) mutant presented a more severe phenotype with affected cytosolic and nuclear ISC enzyme activities, mitochondrial iron accumulation and an increased sensitivity to oxidative stress. The differential phenotype correlates with disease severity observed in FRDA patients. CONCLUSIONS:These new cellular models, which are the first to spontaneously reproduce all the biochemical phenotypes associated with FRDA, are important tools to gain new insights into the in vivo consequences of pathological missense mutations as well as for large-scale pharmacological screening aimed at compensating frataxin deficiency

Local Cattle and Badger Populations Affect the Risk of Confirmed Tuberculosis in British Cattle Herds

Background: The control of bovine tuberculosis (bTB) remains a priority on the public health agenda in Great Britain, after launching in 1998 the Randomised Badger Culling Trial (RBCT) to evaluate the effectiveness of badger (Meles meles) culling as a control strategy. Our study complements previous analyses of the RBCT data (focusing on treatment effects) by presenting analyses of herd-level risks factors associated with the probability of a confirmed bTB breakdown in herds within each treatment: repeated widespread proactive culling, localized reactive culling and no culling (survey-only). Methodology/Principal Findings: New cases of bTB breakdowns were monitored inside the RBCT areas from the end of the first proactive badger cull to one year after the last proactive cull. The risk of a herd bTB breakdown was modeled using logistic regression and proportional hazard models adjusting for local farm-level risk factors. Inside survey-only and reactive areas, increased numbers of active badger setts and cattle herds within 1500 m of a farm were associated with an increased bTB risk. Inside proactive areas, the number of M. bovis positive badgers initially culled within 1500 m of a farm was the strongest predictor of the risk of a confirmed bTB breakdown. Conclusions/Significance: The use of herd-based models provide insights into how local cattle and badger populations affect the bTB breakdown risks of individual cattle herds in the absence of and in the presence of badger culling. These measures of local bTB risks could be integrated into a risk-based herd testing programme to improve the targeting o