Taxanes have resulted in improved survival for breast cancer patients, but often cause neurological toxicities. Identification of biomarkers related to toxicities could be important for dictating ...treatment regimen. We evaluated single nucleotide polymorphisms (SNPs) in the Fanconi Anemia (FA)/BRCA pathway in relation to grade 3/4 neurotoxicities in patients (
n
= 888) from SWOG0221, a phase III adjuvant trial for breast cancer of 4 dose/schedules of cyclophosphamide (C), doxorubicin (A), and paclitaxel (T). In a separate cohort, we measured the correlation of significant
FANCD2
SNPs with corresponding gene expression. For
FANCD2
, permutation testing revealed that 4 (out of 20) SNPs were significantly associated with an almost two-fold increased risk of toxicity. Two
FANCD2
haplotypes were also associated with neurological toxicity, with odds ratios (OR) in the overall population of 1.8 (95% confidence interval (CI) 1.3, 2.5) and 1.7 (95% CI, 1.2, 2.4). Although numbers were small, an African-American-specific haplotype was associated with an almost 3-fold increase in risk of neurologic toxicity (OR = 2.84, 95% CI = 1.2, 6.9). Expression analyses revealed that significant
FANCD2
SNPs were associated with
FANCD2
expression levels (
P
= 0.03). There were no associations between SNPs in
BRCA1
and neurotoxicities. In this trial of CA+T for breast cancer, SNPs in
FANCD2
, but not in
BRCA1
, were associated with a 70–80% increase in the odds of grade 3/4 neurological toxicities and increased expression of the gene. If replicated, women with these genotypes should be closely monitored for toxicities and could be targeted for preventive measures or alternative therapeutic approaches.
Summary
Introduction
Ready‐to‐eat meals sold by food outlets that are accessible to the general public are an important target for public health intervention. We conducted a systematic review to ...assess the impact of such interventions.
Methods
Studies of any design and duration that included any consumer‐level or food‐outlet‐level before‐and‐after data were included.
Results
Thirty studies describing 34 interventions were categorized by type and coded against the Nuffield intervention ladder: restrict choice = trans fat law (n = 1), changing pre‐packed children's meal content (n = 1) and food outlet award schemes (n = 2); guide choice = price increases for unhealthier choices (n = 1), incentive (contingent reward) (n = 1) and price decreases for healthier choices (n = 2); enable choice = signposting (highlighting healthier/unhealthier options) (n = 10) and telemarketing (offering support for the provision of healthier options to businesses via telephone) (n = 2); and provide information = calorie labelling law (n = 12), voluntary nutrient labelling (n = 1) and personalized receipts (n = 1). Most interventions were aimed at adults in US fast food chains and assessed customer‐level outcomes. More ‘intrusive’ interventions that restricted or guided choice generally showed a positive impact on food‐outlet‐level and customer‐level outcomes. However, interventions that simply provided information or enabled choice had a negligible impact.
Conclusion
Interventions to promote healthier ready‐to‐eat meals sold by food outlets should restrict choice or guide choice through incentives/disincentives. Public health policies and practice that simply involve providing information are unlikely to be effective.
Despite the rhizotoxicity of aluminum (Al) being identified over 100 years ago, there is still no consensus regarding the mechanisms whereby root elongation rate is initially reduced in the ...approximately 40% of arable soils worldwide that are acidic. We used high-resolution kinematic analyses, molecular biology, rheology, and advanced imaging techniques to examine soybean (Glycine max) roots exposed to Al. Using this multidisciplinary approach, we have conclusively shown that the primary lesion of Al is apoplastic. In particular, it was found that 75μM Al reduced root growth after only 5 min (or 30 min at 30μM Al), with Al being toxic by binding to the walls of outer cells, which directly inhibited their loosening in the elongation zone. An alteration in the biosynthesis and distribution of ethylene and auxin was a second, slower effect, causing both a transient decrease in the rate of cell elongation after 1.5 h but also a longer term gradual reduction in the length of the elongation zone. These findings show the importance of focusing on traits related to cell wall composition as well as mechanisms involved in wall loosening to overcome the deleterious effects of soluble Al.
Four-factor prothrombin complex concentrates (PCCs), which contain factor II, FVII, FIX, and FX, have shown the potential to reverse the anticoagulant effect of rivaroxaban in healthy volunteers. The ...purpose of this study was to determine whether a three-factor PCC, which contains little FVII, has a similar effect.
We performed an open-label, single-center, parallel-group study comparing the effect of a three-factor PCC (Profilnine SD) with that of a four-factor PCC (Beriplex P/N) on the pharmacodynamics of rivaroxaban in 35 healthy volunteers. After receiving 4 days of rivaroxaban 20 mg twice daily to obtain supratherapeutic steady-state concentrations, volunteers were randomized to receive a single 50 IU kg(-1) bolus dose of four-factor PCC, three-factor PCC or saline 4 h after the morning dose of rivaroxaban on day 5, and the effects of these interventions on prothrombin time and thrombin generation were determined. Within 30 min, four-factor PCC reduced mean prothrombin time by 2.5-3.5 s, whereas three-factor PCC produced only a 0.6-1.0-s reduction. In contrast, three-factor PCC reversed rivaroxaban-induced changes in thrombin generation more than four-factor PCC.
This study demonstrates the potential of both three-factor and four-factor PCCs to at least partially reverse the anticoagulant effects of rivaroxaban in healthy adults. The discrepant effects of the PCC preparations may reflect differences in the procoagulant components present in each.
Premature menopause is a serious long-term side effect of chemotherapy. We evaluated long-term pregnancy and disease-related outcomes for patients in S0230/POEMS, a study in premenopausal women with ...stage I-IIIA estrogen receptor-negative, progesterone receptor-negative breast cancer to be treated with cyclophosphamide-containing chemotherapy. Women were randomly assigned to standard chemotherapy with or without goserelin, a gonadotropin-releasing hormone agonist, and were stratified by age and chemotherapy regimen. All statistical tests were two-sided. Of 257 patients, 218 were eligible and evaluable (105 in the chemotherapy + goserelin arm and 113 in the chemotherapy arm). More patients in the chemotherapy + goserelin arm reported at least one pregnancy vs the chemotherapy arm (5-year cumulative incidence = 23.1%, 95% confidence interval CI = 15.3% to 31.9%; and 12.2%, 95% CI = 6.8% to 19.2%, respectively; odds ratio = 2.34; 95% CI = 1.07 to 5.11; P = .03). Randomization to goserelin + chemotherapy was associated with a nonstatistically significant improvement in disease-free survival (hazard ratio HR = 0.55; 95% CI = 0.27 to 1.10; P = .09) and overall survival (HR = 0.45; 95% CI = 0.19 to 1.04; P = .06). In this long-term analysis of POEMS/S0230, we found continued evidence that patients randomly assigned to receive goserelin + chemotherapy were not only more likely to avoid premature menopause, but were also more likely to become pregnant without adverse effect on disease-related outcomes.
We determined female genome sizes using flow cytometry for 211 Drosophila melanogaster sequenced inbred strains from the Drosophila Genetic Reference Panel, and found significant conspecific and ...intrapopulation variation in genome size. We also compared several life history traits for 25 lines with large and 25 lines with small genomes in three thermal environments, and found that genome size as well as genome size by temperature interactions significantly correlated with survival to pupation and adulthood, time to pupation, female pupal mass, and female eclosion rates. Genome size accounted for up to 23% of the variation in developmental phenotypes, but the contribution of genome size to variation in life history traits was plastic and varied according to the thermal environment. Expression data implicate differences in metabolism that correspond to genome size variation. These results indicate that significant genome size variation exists within D. melanogaster and this variation may impact the evolutionary ecology of the species. Genome size variation accounts for a significant portion of life history variation in an environmentally dependent manner, suggesting that potential fitness effects associated with genome size variation also depend on environmental conditions.
We use a series of cosmological N-body simulations for a flat Λ cold dark matter (ΛCDM) cosmology to investigate the structural properties of dark matter haloes, at redshift zero, in the mass range 3 ...× 109 h−1 ≲Mvir ≲ 3 × 1013 h−1 M⊙. These properties include the concentration parameter, c, the spin parameter, λ, and the mean axis ratio, . For the concentration–mass relation we find c∝ in agreement with the model proposed by Bullock et al., but inconsistent with the alternative model of Eke et al. The normalization of the concentration–mass relation, however, is 15 per cent lower than suggested by Bullock et al. The results for λ and are in good agreement with previous studies, when extrapolated to the lower halo masses probed here, while c and λ are anticorrelated, in that high-spin haloes have, on average, lower concentrations. In an attempt to remove unrelaxed haloes from the sample, we compute for each halo the offset parameter, xoff, defined as the distance between the most bound particle and the centre of mass, in units of the virial radius. Removing haloes with large xoff increases the mean concentration by ∼10 per cent, lowers the mean spin parameter by ∼15 per cent, and removes the most prolate haloes. In addition, it largely removes the anticorrelation between c and λ, though not entirely. We also investigate the relation between halo properties and their large-scale environment density. For low-mass haloes we find that more concentrated haloes live in denser environments than their less concentrated counterparts of the same mass, consistent with recent correlation function analyses. Note, however, that the trend is weak compared to the scatter. For the halo spin parameters we find no environment dependence, while there is a weak indication that the most spherical haloes reside in slightly denser environments. Finally, using a simple model for disc galaxy formation we show that haloes that host low surface brightness galaxies are expected to be hosted by a biased subset of haloes. Not only do these haloes have spin parameters that are larger than average, they also have concentration parameters that are ∼15 per cent lower than the average at a given halo mass. We discuss the implications of all these findings for the claimed disagreement between halo concentrations inferred from low surface brightness rotation curves, and those expected for a ΛCDM cosmology.
Epistasis has been dismissed by some as having little role in the genetic architecture of complex human disease. The authors argue that this view is the result of a misconception and explain why ...exploring epistasis is likely to be crucial to understanding and predicting complex disease.
Purpose
The aim of this study was to evaluate changes in hip geometry parameters following treatment with teriparatide (TPD), denosumab (Dmab) and zoledronate (ZOL) in real-life setting.
Methods
We ...studied 249 patients with osteoporosis (OP) with mean SD age of 71.5 11.1 years divided into 3 treatment groups; Group A received TPD;
n
= 55, Group B (Dmab);
n
= 116 and Group C (ZOL);
n
= 78 attending a routine metabolic bone clinic. Bone mineral density (BMD) was measured by DXA at the lumbar spine (LS), total hip (TH) and femoral neck (FN) prior to treatment and after 2 years (Group A), after a mean treatment duration of 3.3 1.3 years (Group B) and after 1, 2 and 3 doses of ZOL (Group C) to assess treatment response. Hip structural analysis (HSA) was carried out retrospectively from DXA-acquired femur images at the narrow neck (NN), the intertrochanter (IT) and femoral shaft (FS).
Results
Changes in
p
arameters of hip geometry and mechanical strength were seen in the following treatment. Percentage change in cross-sectional area (CSA): 3.561.6 %
p
= 0.01 and cross-sectional moment of inertia (CSMI): 4.11.8 %
p
= 0.029 increased at the NN only in Group A. Improvement in HSA parameters at the IT were seen in group B: CSA: 3.30.67%
p
< 0.001, cortical thickness (Co Th): 2.80.78%
p
= 0.001, CSMI: 5.91.3%
p
< 0.001, section modulus (Z):6.21.1%
p
< 0.001 and buckling ratio (BR): − 3.00.86%
p
= 0.001 with small changes at the FS: CSA: 1.20.4%
p
= 0.005, Z:1.6 0.76%,
p
= 0.04
.
Changes at the IT were also seen in Group C (after 2 doses): CSA: 2.50.77%
p
= 0.017, Co Th: 2.40.84%
p
= 0.012, CSMI: 3.91.3%
p
=
0.017
, Z:5.21.16%
p
< 0.001 and BR: − 3.10.88%
p
= 0.001 and at the NN (following 3 doses): outer diameter (OD): 4.01.4%
p
= 0.0005, endocortical diameter(ED): 4.31.67%
p
= 0.009, CSA:5.21.8%
p
= 0.003, CSMI: 9.33.8%
p
= 0.019
.
Conclusions
Analysis of the effect of OP therapies on hip geometry is useful in understanding the mechanisms of their anti-fracture effect and may provide additional information on their efficacy.
To determine the optimal dose and schedule of anthracycline and taxane administration as adjuvant therapy for early-stage breast cancer.
A 2 × 2 factorial design was used to test two hypotheses: (1) ...that a novel continuous schedule of doxorubicin-cyclophosphamide was superior to six cycles of doxorubicin-cyclophosphamide once every 2 weeks and (2) that paclitaxel once per week was superior to six cycles of paclitaxel once every 2 weeks in patients with node-positive or high-risk node-negative early-stage breast cancer. With 3,250 patients, a disease-free survival (DFS) hazard ratio of 0.82 for each randomization could be detected with 90% power with two-sided α = .05. Overall survival (OS) was a secondary outcome.
Interim analyses crossed the futility boundaries for demonstrating superiority of both once-per-week regimens and once-every-2-weeks regimens. After a median follow-up of 6 years, a significant interaction developed between the two randomization factors (DFS P = .024; OS P = .010) in the 2,716 patients randomly assigned in the original design, which precluded interpretation of the two factors separately. Comparing all four arms showed a significant difference in OS (P = .040) but not in DFS (P = .11), with all treatments given once every 2 weeks associated with the highest OS. This difference in OS seemed confined to patients with hormone receptor-negative/human epidermal growth factor receptor 2 (HER2) -negative tumors (P = .067), with no differences seen with hormone receptor-positive/HER2-negative (P = .90) or HER2-positive tumors (P = .40).
Patients achieved a similar DFS with any of these regimens. Subset analysis suggests the hypothesis that once-every-2-weeks dosing may be best for patients with hormone receptor-negative/HER2-negative tumors.
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