Filling the gap between chemical carcinogenesis and the hallmarks of cancer: a temporal perspective

Background Cancer is believed to arise through the perturbation of pathways and the order of pathway perturbation events can enhance understanding and evaluation of carcinogenicity. This order has not been examined so far, and this study aimed to fill this gap by attempting to gather evidence on the potential temporal sequence of events in carcinogenesis. Design The methodology followed was to discuss first the temporal sequence of hallmarks of cancer from the point of view of pathological specimens of cancer (essentially branched mutations) and then to consider the hallmarks of cancer that one well‐known carcinogen, benzo(a)pyrene, can modify. Results Even though the sequential order of driving genetic alterations can vary between and within tumours, the main cancer pathways affected are almost ubiquitous and follow a generally common sequence: resisting cell death, insensitivity to antigrowth signals, sustained proliferation, deregulated energetics, replicative immortality and activation of invasion and metastasis. The first 3 hallmarks can be regarded as almost simultaneous while angiogenesis and avoiding immune destruction are perhaps the only hallmarks with a varying position in the above sequence. Conclusions Our review of hallmarks of cancer and their temporal sequence, based on mutational spectra in biopsies from different cancer sites, allowed us to propose a hypothetical temporal sequence of the hallmarks. This sequence can add molecular support to the evaluation of an agent as a carcinogen as it can be used as a conceptual framework for organising and evaluating the strength of existing evidence

Международная трудовая миграция и нелегальная миграция в России

Огляд монографії: Метелев С.Е. Международная трудовая миграция и нелегальная миграция в России. Монография. – М.: Юнити. – 2006. – 175 с

Prevalence and risk factors for chronic kidney disease of unknown cause in Malawi: a cross-sectional analysis in a rural and urban population

Background: An epidemic of chronic kidney disease of unknown cause (CKDu) is occurring in rural communities in tropical regions of low-and middle-income countries in South America and India. Little information is available from Southern African countries which have similar climatic and occupational characteristics to CKDu-endemic countries. We investigated whether CKDu is prevalent in Malawi and identified its potential risk factors in this setting. / Methods: We conducted a cross-sectional study from January–August 2018 collecting bio samples and anthropometric data in two Malawian populations. The sample comprised adults > 18 years (n = 821) without diabetes, hypertension, and proteinuria. Estimates of glomerular filtration rate (eGFR) were calculated using the CKD-EPI equation. Linear and logistic regression models were applied with potential risk factors, to estimate risk of reduced eGFR. / Results: The mean eGFR was 117.1 ± 16.0 ml/min per 1.73m2 and the mean participant age was 33.5 ± 12.7 years. The prevalence of eGFR< 60 was 0.2% (95% confidence interval (95% CI) 0.1, 0.9); the prevalence of eGFR< 90 was 5% (95% CI =3.2, 6.3). We observed a higher prevalence in the rural population (5% (3.6, 7.8)), versus urban (3% (1.4, 6.7)). Age and BMI were associated with reduced eGFR< 90 [Odds ratio (OR) (95%CI) =3.59 (2.58, 5.21) per ten-year increment]; [OR (95%CI) =2.01 (1.27, 3.43) per 5 kg/m2 increment] respectively. No increased risk of eGFR < 90 was observed for rural participants [OR (95%CI) =1.75 (0.50, 6.30)]. / Conclusions: Reduced kidney function consistent with the definition of CKDu is not common in the areas of Malawi sampled, compared to that observed in other tropical or sub-tropical countries in Central America and South Asia. Reduced eGFR< 90 was related to age, BMI, and was more common in rural areas. These findings are important as they contradict some current hypothesis that CKDu is endemic across tropical and sub-tropical countries. This study has enabled standardized comparisons of impaired kidney function between and within tropical/subtropical regions of the world and will help form the basis for further etiological research, surveillance strategies, and the implementation and evaluation of interventions

Effect of Substrate Orientation on Phase Separation in Epitaxial GaInAsSb

The effect of substrate misorientation on phase separation in Ga{sub 1-x}In{sub x}As{sub y}Sb{sub 1-y} nominally lattice-matched to GaSb is reported. The layers were grown at 575 C by organometallic vapor phase epitaxy on vicinal (001) GaSb substrates, miscut 2{sup o} {yields} (-111)A, (1-11)B, or (101). Ga{sub 1-x}In{sub x}As{sub y}Sb{sub 1-y} (x {approx} 0.1, y {approx} 0.09) layers, which have 300-K photoluminescence (PL) peak emission at {approx}2.1 {micro}m, grow step-bunched and exhibit minimal phase separation. The full width at half maximum of 4-K PL spectra is slightly smaller at 7 meV for layers grown on substrates miscut toward (1-11)B compared to 9 meV for layers grown on substrates miscut toward (-1-11)A and (101). Ga{sub 1-x}In{sub x}As{sub y}Sb{sub 1-y} layers with higher alloy composition (0.16 {le} x {le} 0.19, 0.14 {ge} y {le} 0.17), which have 300-K PL peak emission at {approx}2.4 {micro}m, have significant phase separation. These layers are characterized by increased lattice constant variations and epitaxial tilt, broad PL spectra with significant band tailing, and strong contrast modulation in transmission electron microscopy. The degree of decomposition depends on substrate miscut direction: Ga{sub 1-x}In{sub x}As{sub y}Sb{sub 1-y} layers grown on (001) 2{sup o} {yields} (1-11)B substrates are more homogeneous than those grown on (001) 2{sup o} {yields} (-1-11)A and (001) 2{sup o} {yields} (101) substrates. The results are attributed to the smaller adatom diffusion length on substrates miscut toward (1-11)B

Self-Organized Superlattices in GaInAsSb Grown on Vicinal Substrates

Self-organized superlattices are observed in GaInAsSb epilayers grown lattice matched to vicinal GaSb substrates. The natural superlattice (NSL) is oriented at a slight angle of about 4{sup o} with respect to the vicinal (001) GaSb substrate. This vertical composition modulation is detected at the onset of growth. Layers in the NSL are continuous over the lateral extent of the substrate. Furthermore, the NSL persists throughout several microns of deposition. The NSLs have a period ranging from 10 to 30 nm, which is dependent on deposition temperature and GaInAsSb alloy composition. While the principle driving force for this type of phase separation is chemical, the mechanism for the self-organized microstructure is related to local strains associated with surface undulations. By using a substrate with surface undulations, the tilted NSL can be induced in layers with alloy compositions that normally do not exhibit this self-organized microstructure under typical growth conditions. These results underscore the complex interactions between compositional and morphological perturbations

Association Between Genetic Variants on Chromosome 15q25 Locus and Objective Measures of Tobacco Exposure

Background: Two single-nucleotide polymorphisms, rs1051730 and rs16969968, located within the nicotinic acetylcholine receptor gene cluster on chromosome 15q25 locus, are associated with heaviness of smoking, risk for lung cancer, and other smoking-related health outcomes. Previous studies have typically relied on self-reported smoking behavior, which may not fully capture interindividual variation in tobacco exposure. / Methods: We investigated the association of rs1051730 and rs16969968 genotype (referred to as rs1051730–rs16969968, because these are in perfect linkage disequilibrium and interchangeable) with both self-reported daily cigarette consumption and biochemically measured plasma or serum cotinine levels among cigarette smokers. Summary estimates and descriptive statistical data for 12 364 subjects were obtained from six independent studies, and 2932 smokers were included in the analyses. Linear regression was used to calculate the per-allele association of rs1051730–rs16969968 genotype with cigarette consumption and cotinine levels in current smokers for each study. Meta-analysis of per-allele associations was conducted using a random effects method. The likely resulting association between genotype and lung cancer risk was assessed using published data on the association between cotinine levels and lung cancer risk. All statistical tests were two-sided. / Results: Pooled per-allele associations showed that current smokers with one or two copies of the rs1051730–rs16969968 risk allele had increased self-reported cigarette consumption (mean increase in unadjusted number of cigarettes per day per allele = 1.0 cigarette, 95% confidence interval [CI] = 0.57 to 1.43 cigarettes, P = 5.22 × 10−6) and cotinine levels (mean increase in unadjusted cotinine levels per allele = 138.72 nmol/L, 95% CI = 97.91 to 179.53 nmol/L, P = 2.71 × 10−11). The increase in cotinine levels indicated an increased risk of lung cancer with each additional copy of the rs1051730–rs16969968 risk allele (per-allele odds ratio = 1.31, 95% CI = 1.21 to 1.42). / Conclusions: Our data show a stronger association of rs1051730–rs16969968 genotype with objective measures of tobacco exposure compared with self-reported cigarette consumption. The association of these variants with lung cancer risk is likely to be mediated largely, if not wholly, via tobacco exposure

Mechanisms of life-course socioeconomic inequalities in adult systemic inflammation: Findings from two cohort studies

Disadvantaged socioeconomic conditions in childhood heighten systemic inflammatory levels in adulthood; however, life-course mechanisms underlying this association are largely unknown. In the present observational study, we investigated the roles of adulthood socioeconomic and lifestyle factors in mediating this association. Participants were from two prospective Swiss population-based cohorts (N = 5,152, mean age 60 years). We estimated the total effect of paternal occupational position on adult heightened systemic inflammatory levels (C-reactive protein>3 mg/L), and the indirect effects via adulthood socioeconomic positions (SEPs: education and occupational position), financial hardship, and lifestyle factors (body mass index, smoking status, physical inactivity, and alcohol consumption). We estimated odds ratio (OR) and proportion mediated using counterfactual-based mediation models. Individuals whose father had a low occupational position had an OR of 1.51 [95% confidence interval (CI): 1.25, 1.84] for heightened inflammation compared to their more advantaged counterparts. This was jointly mediated (33 [95% CI: 14, 69]%) by adulthood SEPs, whereby the pathway through education followed by occupational position mediated 30 [95% CI: 11, 64]%, while the pathway via occupational position only mediated 3 [95% CI: 4, 13]%. Individuals with the lowest life-course SEPs had an OR of 2.27 [95% CI: 1.71, 2.98] for heightened inflammation compared to having the highest life-course SEPs. This was jointly mediated (63 [95% CI: 44, 97]%) by financial hardship and lifestyle factors. Our study supports a cumulative effect of life-course SEPs on adult heightened systemic inflammation along the pathway paternal occupational position -> education -> adult occupational position. Financial hardship and lifestyle factors in adulthood mediate half of that effect

Epigenome-wide association study reveals decreased average methylation levels years before breast cancer diagnosis

Interest in the potential of DNA methylation in peripheral blood as a biomarker of cancer risk is increasing. We aimed to assess whether epigenome-wide DNA methylation measured in peripheral blood samples obtained before onset of the disease is associated with increased risk of breast cancer. We report on three independent prospective nested case-control studies from the European Prospective Investigation into Cancer and Nutrition (EPIC-Italy; n = 162 matched case-control pairs), the Norwegian Women and Cancer study (NOWAC; n = 168 matched pairs), and the Breakthrough Generations Study (BGS; n = 548 matched pairs). We used the Illumina 450k array to measure methylation in the EPIC and NOWAC cohorts. Whole-genome bisulphite sequencing (WGBS) was performed on the BGS cohort using pooled DNA samples, combined to reach 50× coverage across ~16 million CpG sites in the genome including 450k array CpG sites. Mean β values over all probes were calculated as a measurement for epigenome-wide methylation

Identification of the safe(r) by design alternatives for nanosilver-enabled wound dressings

The use of silver nanoparticles (NPs) in medical devices is constantly increasing due to their excellent antimicrobial properties. In wound dressings, Ag NPs are commonly added in large excess to exert a long-term and constant antimicrobial effect, provoking an instantaneous release of Ag ions during their use or the persistence of unused NPs in the wound dressing that can cause a release of Ag during the end-of-life of the product. For this reason, a Safe-by-Design procedure has been developed to reduce potential environmental risks while optimizing functionality and costs of wound dressings containing Ag NPs. The SbD procedure is based on ad-hoc criteria (e.g., mechanical strength, antibacterial effect, leaching of Ag from the product immersed in environmental media) and permits to identify the best one among five pre-market alternatives. A ranking of the SbD alternatives was obtained and the safer solution was selected based on the selected SbD criteria. The SbD framework was also applied to commercial wound dressings to compare the SbD alternatives with products already on the market. The iterative procedure permitted to exclude one of the alternatives (based on its low mechanical strength) and proved to be an effective approach that can be replicated to support the ranking, prioritisation, and selection of the most promising options early in the innovation process of nano-enabled medical devices as well as to encourage the production of medical devices safer for the environment

Phase-controlled, heterodyne laser-induced transient grating measurements of thermal transport properties in opaque material

The methodology for a heterodyned laser-induced transient thermal grating technique for non-contact, non-destructive measurements of thermal transport in opaque material is presented. Phase-controlled heterodyne detection allows us to isolate pure phase or amplitude transient grating signal contributions by varying the relative phase between reference and probe beams. The phase grating signal includes components associated with both transient reflectivity and surface displacement whereas the amplitude grating contribution is governed by transient reflectivity alone. By analyzing the latter with the two-dimensional thermal diffusion model, we extract the in-plane thermal diffusivity of the sample. Measurements on a 5 {\mu}m thick single crystal PbTe film yielded excellent agreement with the model over a range of grating periods from 1.6 to 2.8 {\mu}m. The measured thermal diffusivity of 1.3 \times 10-6 m2/s was found to be slightly lower than the bulk value.Comment: 19 pages, 6 figure