A large genotyping project within the Breast Cancer Association Consortium (BCAC) recently identified 41 associations between single nucleotide polymorphisms (SNPs) and overall breast cancer (BC) ...risk. We investigated whether the effects of these 41 SNPs, as well as six SNPs associated with estrogen receptor (ER) negative BC risk are modified by 13 environmental risk factors for BC. Data from 22 studies participating in BCAC were pooled, comprising up to 26,633 cases and 30,119 controls. Interactions between SNPs and environmental factors were evaluated using an empirical Bayes‐type shrinkage estimator. Six SNPs showed interactions with associated p‐values (pint) <1.1 × 10−3. None of the observed interactions was significant after accounting for multiple testing. The Bayesian False Discovery Probability was used to rank the findings, which indicated three interactions as being noteworthy at 1% prior probability of interaction. SNP rs6828523 was associated with increased ER‐negative BC risk in women ≥170 cm (OR = 1.22, p = 0.017), but inversely associated with ER‐negative BC risk in women <160 cm (OR = 0.83, p = 0.039, pint = 1.9 × 10−4). The inverse association between rs4808801 and overall BC risk was stronger for women who had had four or more pregnancies (OR = 0.85, p = 2.0 × 10−4), and absent in women who had had just one (OR = 0.96, p = 0.19, pint = 6.1 × 10−4). SNP rs11242675 was inversely associated with overall BC risk in never/former smokers (OR = 0.93, p = 2.8 × 10−5), but no association was observed in current smokers (OR = 1.07, p = 0.14, pint = 3.4 × 10−4). In conclusion, recently identified BC susceptibility loci are not strongly modified by established risk factors and the observed potential interactions require confirmation in independent studies.
What's new?
The recent discovery of 47 susceptibility loci associated with all or estrogen receptor‐negative breast cancer provided new opportunities for genetic risk prediction but it remained unclear how exposure levels of environmental (non‐genetic) risk factors influenced the risk assessment. In this gene‐environment study, the international team examined interactions between the single nucleotide polymorphisms and 13 established environmental risk factors including parity, height and alcohol consumption. Notably, relative risks of breast cancer associated with the susceptibility loci were not strongly modified by environmental risk factors, a finding that, if confirmed, has important implications for the risk assessment in breast cancer.
Of the three domains of life (Eukarya, Bacteria, and Archaea), the least understood is Archaea and its associated viruses. Many Archaea are extremophiles, with species that are capable of growth at ...some of the highest temperatures and extremes of pH of all known organisms. Phylogenetic rRNA-encoding DNA analysis places many of the hyperthermophilic Archaea (species with an optimum growth ≥80°C) at the base of the universal tree of life, suggesting that thermophiles were among the first forms of life on earth. Very few viruses have been identified from Archaea as compared to Bacteria and Eukarya. We report here the structure of a hyperthermophilic virus isolated from an archaeal host found in hot springs in Yellowstone National Park. The sequence of the circular double-stranded DNA viral genome shows that it shares little similarity to other known genes in viruses or other organisms. By comparing the tertiary and quaternary structures of the coat protein of this virus with those of a bacterial and an animal virus, we find conformational relationships among all three, suggesting that some viruses may have a common ancestor that precedes the division into three domains of life >3 billion years ago.
We report the derivatization of hyperbranched poly(acrylic acid) (PAA) films with a wide range of amino- or alcohol-terminated molecules. These molecules can include moieties such as pyrene, ...ferrocene, poly(ethylene glycol), 15-crown-5, and a dye. To derivatize PAA films, we activate their carboxylic acid groups with isobutyl chloroformate and allow them to react with amine- or alcohol-containing molecules. Infrared spectroscopy demonstrates the formation of amide and ester bonds upon coupling as well as the presence of the derivative functional groups. Excimer fluorescence from pyrene-containing films implies a high density of pyrene groups. However, we can control the amount of pyrene in the film (and obtain monomer fluorescence) by varying the concentration of Py(CH2)3CONH(CH2)2NH2 in the derivatization solution. Cyclic voltammetry of ferrocene-containing films shows an electrochemically addressable ferrocenyl surface coverage of (6 ± 3) × 10-9 mol/cm2 in three-layer PAA films. PAA films and their derivatives are stable under sonication, Soxhlet extraction, and acidic and basic conditions. PAA films also respond to external stimuli. The ellipsometric thickness of PAA films increases by ≈45% upon deprotonation of the film's carboxylic acid groups and returns to its original thickness after acidification. Using surface acoustic wave mass sensors, we observed that pure PAA films adsorb or absorb volatile organic compounds (VOCs), although the amount is in the monolayer range. Fluorination of PAA films increases the amount of polar VOCs absorbed by an order of magnitude.
Readily transformable Nicotiana tabacum cv. SR1 (Petite Havana) was evaluated as a host for the bioassay of Xylella fastidiosa strains. Plant growing conditions and inoculation methods were optimized ...to enhance symptom expression 4 to 6 weeks post inoculation. Tobacco plants were inoculated with X. fastidiosa strains associated with almond leaf scorch disease (ALSD) and Pierce's disease (PD) of grapevine in California. All PD strains and the ALSD strain Dixon caused characteristic leaf scorch symptoms, whereas two other ALSD-associated strains (M12 and M23) caused severe leaf chlorosis followed by necrosis, leaf death, and drooping of older leaves. Symptoms began to develop 10 to 14 days post inoculation and proceeded to resemble those of X. fastidiosa-infected grape and almond. The presence of X. fastidiosa in affected plants was confirmed by reisolation of the pathogen, enzyme-linked immunosorbent assay, quantitative polymerase chain reaction (QPCR), and observation of X. fastidiosa cells by transmission and scanning electron microscopy, as well as by confocal laser scanning microscopy, in the xylem cells of inoculated plants. The pathogenicity of selected reisolated strains was confirmed by inoculation of grape plants in the greenhouse. The average levels of X. fastidiosa cells/g of tissue, estimated by QPCR, were higher for PD strains than for ALSD strains and reflected the relative titers of these strains in economic hosts. No symptoms were observed and bacteria were not detected in untreated tobacco or in tobacco inoculated with Xanthomonas campestris pv. campestris or water. Symptoms induced by Xylella fastidiosa in this bioassay were fully expressed within 2 months following inoculation. The described bioassay, under optimized environmental conditions, provides a useful system for studying X. fastidiosa strains (e.g., confirmation of pathogenicity and differentiation of PD and ALSD pathotypes) and for investigating X. fastidiosa-host interactions. N. tabacum cv. SR1 tobacco was a better bioassay host for X. fastidiosa than N. tabacum cvs. Havana, RP1, and TNN described previously.
Summary
Background Photodynamic therapy (PDT) is increasingly used for treatment of actinic keratoses (AKs) but is a cumbersome procedure. A thin self‐adhesive patch (PD P 506 A) containing ...5‐aminolaevulinic acid (5‐ALA) was developed to facilitate PDT.
Objectives To investigate efficacy and safety of the patch in comparison with placebo–PDT (superiority design, observer‐blinded; study AK 03) and standard therapy, cryosurgery (noninferiority design, open; study AK 04).
Methods Two separate confirmatory randomized parallel‐group phase III studies were set up. In total, 449 patients with up to eight mild to moderate AK study lesions located on the head were treated in 29 German study centres (study AK 03: 103 patients; study AK 04: 346 patients).
Results Twelve weeks after treatment, 5‐ALA patch–PDT proved to be superior to placebo–PDT (P < 0·001) and cryosurgery (P = 0·007). Efficacy rates on a lesion basis were 82% (AK 03) and 89% (AK 04) for PDT, 77% for cryosurgery and 19% (AK 03) and 29% (AK 04) for placebo–PDT. Local reactions at the treatment site occurred in almost all patients treated with 5‐ALA patch–PDT or cryosurgery. Headache was the only side‐effect not related to the treatment site which occurred in more than one patient.
Conclusions PD P 506 A is an innovative, easy‐to‐handle 5‐ALA patch for PDT of mild to moderate AK lesions. Compared with current PDT procedures, pretreatment (e.g. curettage) is not needed and handling is considerably facilitated. A single PDT treatment results in efficacy rates being statistically significantly superior to placebo and cryosurgery.
A new class of quasi-linear carbon molecules C
60
n
C
m
n−1
consisting of n fullerenes C
60
linked by n-1 carbyne-type C
m
fragments with a system of conjugated bonds is described. The possible ...geometric configurations of such molecules and crystals on their base are discussed. The structure optimization by the empirical (MM+), semiempirical (PM3), ab initio (HF/6-21) and DFT methods showed that these molecules are energetically stable. The performed electron band structure calculations of the crystals have shown them to be the semiconductors with band gap of 1.1-1.4 eV.
Effective stimulation of immune cells is crucial for the success of cancer immunotherapies. Current approaches to evaluate the efficiency of stimuli are mainly defined by known flow cytometry-based ...cell activation or cell maturation markers. This method however does not give a complete overview of the achieved activation state and may leave important side effects unnoticed. Here, we used an unbiased RNA sequencing (RNA-seq)-based approach to compare the capacity of four clinical-grade dendritic cell (DC) activation stimuli used to prepare DC-vaccines composed of various types of DC subsets; the already clinically applied GM-CSF and Frühsommer meningoencephalitis (FSME) prophylactic vaccine and the novel clinical grade adjuvants protamine-RNA complexes (pRNA) and CpG-P. We found that GM-CSF and pRNA had similar effects on their target cells, whereas pRNA and CpG-P induced stronger type I interferon (IFN) expression than FSME. In general, the pathways most affected by all stimuli were related to immune activity and cell migration. GM-CSF stimulation, however, also induced a significant increase of genes related to nonsense-mediated decay, indicating a possible deleterious effect of this stimulus. Taken together, the two novel stimuli appear to be promising alternatives. Our study demonstrates how RNA-seq based investigation of changes in a large number of genes and gene groups can be exploited for fast and unbiased, global evaluation of clinical-grade stimuli, as opposed to the general limited evaluation of a pre-specified set of genes, by which one might miss important biological effects that are detrimental for vaccine efficacy.
Previous data on glycogen synthase kinase 3 (GSK-3) inhibition in cancer models support a cytotoxic effect with selectivity for tumor cells compared to normal tissue but the effect of these ...inhibitors in glioma has not been widely studied. Here, we investigate their potential as cytotoxics in glioma.
We assessed the effect of pharmacologic GSK-3 inhibition on established (U87, U251) and patient-derived (GBM1, GBM4) glioblastoma (GBM) cell lines using cytotoxicity assays as well as undertaking a detailed investigation of the effect on cell cycle, mitosis, and centrosome biology. We also assessed drug uptake and efficacy of GSK-3 inhibition alone and in combination with radiation in xenograft models.
Using the selective GSK-3 inhibitor AZD2858, we demonstrated single agent cytotoxicity in two patient-derived glioma cell lines (GBM1, GBM4) and two established cell lines (U251 and U87) with IC
in the low micromolar range promoting centrosome disruption, failed mitosis, and S-phase arrest. Glioma xenografts exposed to AZD2858 also showed growth delay compared to untreated controls. Combined treatment with radiation increased the cytotoxic effect of clinical radiation doses in vitro and in orthotopic glioma xenografts.
These data suggest that GSK-3 inhibition promotes cell death in glioma through disrupting centrosome function and promoting mitotic failure and that AZD2858 is an effective adjuvant to radiation at clinical doses.
germline protein truncating variants (PTVs) are moderate-risk factors for ER-negative breast cancer. We previously described the spectrum of
PTVs in 114 European breast cancer cases. In the present, ...larger cohort, we report the spectrum and frequency of four common and 62 rare
PTVs found in 274 carriers detected among 44,803 breast cancer cases. We confirmed that p.Gln1701* was the most common PTV in Northern Europe with lower frequencies in Southern Europe. In contrast, p.Gly1906Alafs*12 was the most common PTV in Southern Europe with decreasing frequencies in Central and Northern Europe. We verified that p.Arg658* was prevalent in Central Europe and had highest frequencies in Eastern Europe. We also confirmed that the fourth most common PTV, p.Gln498Thrfs*7, might be a founder variant from Lithuania. Based on the frequency distribution of the carriers of rare PTVs, we showed that the
PTVs spectra in Southwestern and Central Europe were much more heterogeneous than those from Northeastern Europe. These findings will inform the development of more efficient
genetic testing strategies for breast cancer cases from specific European populations.
We investigated general job demands as a risk factor for lung cancer as well as their role in the association between occupational prestige and lung cancer.
In 13 case-control studies on lung cancer, ...as part of the international SYNERGY project, we applied indices for physical (PHI) and psychosocial (PSI) job demands - each with four categories (high to low). We estimated odds ratios (OR) and 95% confidence intervals (CI) for lung cancer by unconditional logistic regression, separately for men and women and adjusted for study centre, age, smoking behavior, and former employment in occupations with potential exposure to carcinogens. Further, we investigated, whether higher risks among men with low occupational prestige (Treiman's Standard International Occupational Prestige Scale) were affected by adjustment for the job indices.
In 30 355 men and 7371 women, we found increased risks (OR) for lung cancer with high relative to low job demands in both men PHI 1.74 (95% CI 1.56-1.93), PSI 1.33 (95% CI 1.17-1.51) and women PHI 1.62 (95% CI 1.24-2.11), PSI 1.31 (95% CI 1.09-1.56). OR for lung cancer among men with low occupational prestige were slightly reduced when adjusting for PHI low versus high prestige OR from 1.44 (95% CI 1.32-1.58) to 1.30 (95% CI 1.17-1.45), but not PSI.
Higher physical job demands were associated with increased risks of lung cancer, while associations for higher psychosocial demands were less strong. In contrast to physical demands, psychosocial demands did not contribute to clarify the association of occupational prestige and lung cancer.
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