Healthy lifestyles, systemic inflammation and breast cancer risk: a mediation analysis.

BACKGROUND: Despite the known association between healthy lifestyles and reduced risk of breast cancer, it remains unclear whether systemic inflammation, as a consequence of unhealthy lifestyles, may mediate the association. METHODS: A cohort study of 259,435 female participants in the UK Biobank was conducted to estimate hazard ratio (HR) for breast cancer according to 9 inflammation markers using Cox regression models. We further estimated the percentage of total association between healthy lifestyle index (HLI) and breast cancer that is mediated by these inflammation markers. RESULTS: During 2,738,705 person-years of follow-up, 8,889 cases of breast cancer were diagnosed among 259,435 women in the UK Biobank cohort. Higher level of C-reactive protein (CRP), systemic immune-inflammation index (SII), CRP-to-albumin Ratio (CAR), CRP-to-lymphocyte Ratio (CLR), monocyte-to-HDL-c ratio (MHR), and neutrophil-to-HDL-c ratio (NHR) were associated with increased breast cancer risk, while a higher lymphocyte-to-monocyte ratio (LMR) was associated with a lower risk. The inverse association between HLI and breast cancer was weakly mediated by CRP (8.5%), SII (1.71%), CAR (8.66%), CLR (6.91%), MHR (6.27%), and NHR (7.33%). When considering individual lifestyle factors, CRP and CAR each mediated 16.58% and 17.20%, respectively, of the associations between diet score and breast cancer risk, while the proportion mediated for physical activity and breast cancer were 12.13% and 11.48%, respectively. Furthermore, MHR was found to mediate 13.84% and 12.01% of the associations between BMI, waist circumference, and breast cancer. CONCLUSION: The association of HLI and breast cancer is weakly mediated by the level of inflammation, particularly by CRP and CAR. Systemic inflammatory status may be an intermediate in the biological pathway of breast cancer development.

The interaction between systemic inflammatory markers and polygenic risk score in breast cancer risk: A cohort study in the UK Biobank.

BACKGROUND: Systemic inflammatory markers have been widely used in cancer prognosis prediction recently. However, there is limited knowledge regarding their impact on breast cancer risk and their interaction with polygenic risk scores. METHODS: A cohort study of 202,403 female participants from the UK Biobank were analyzed to estimate the hazard ratio (HR) for the incidence and mortality of breast cancer based on inflammatory markers using Cox regression models. Additionally, we stratified the analysis by polygenic risk scores (PRS) for breast cancer, and examined the interaction between these markers and PRS through likelihood ratio tests and relative excess risk due to interaction (RERI). RESULTS: Women in the highest tertile of neutrophil-to-lymphocyte ratio (NLR), systemic immune-inflammation index (SII), and C-reactive protein (CRP) showed an increased risk of breast cancer [HR (95 %CI) = 1.10 (1.02-1.18), 1.09 (1.01-1.17) and 1.15 (1.05-1.25), respectively], as compared to those in the lowest tertile. Regarding breast cancer mortality, only NLR and CRP exhibited consistent results in the univariate model [HR (95 %CI) = 1.25 (0.99-1.58) and 1.39 (1.10-1.77), respectively]. When stratified by PRS, stronger associations between inflammatory markers and breast cancer risk were observed in the high PRS group. Furthermore, there was a significant additive interaction between CRP and PRS [RERI (95 % CI) = 0.30 (0.06-0.53)]. CONCLUSION: NLR and CRP are associated with breast cancer risk and mortality, and the effect of CRP is influenced by PRS. Systematic inflammatory markers, together with PRS, might be applied in combined screening for breast cancer.

Spatial patterns and the associated factors for breast cancer hospitalization in the rural population of Fujian Province, China.

BACKGROUND: Despite the known increasing incidence of breast cancer in China, evidence on the spatial pattern of hospitalization for breast cancer is scarce. This study aimed to describe the disparity of breast cancer hospitalization in the rural population of Southeast China and to explore the impacts of socioeconomic factors and heavy metal pollution in soil. METHODS: This study was conducted using the New Rural Cooperative Medical Scheme (NRCMS) claims data covering 20.9 million rural residents from 73 counties in Southeast China during 2015-2016. The associations between breast cancer hospitalization and socioeconomic factors and soil heavy metal pollutants were evaluated with quasi-Poisson regression models and geographically weighted Poisson regressions (GWPR). RESULTS: The annual hospitalization rate for breast cancer was 101.40/100,000 in the studied area and the rate varied across different counties. Overall, hospitalization for breast cancer was associated with road density (ß = 0.43, P = 0.02), urbanization (ß = 0.02, P = 0.002) and soil cadmium (Cd) pollution (ß = 0.01, P = 0.02). In the GWPR model, a stronger spatial association of Cd, road density and breast cancer hospitalization was found in the northeast regions of the study area while breast cancer hospitalization was mainly related to urbanization in the western regions. CONCLUSIONS: Soil Cd pollution, road density, and urbanization were associated with breast cancer hospitalization in different regions. Findings in this study might provide valuable information for healthcare policies and intervention strategies for breast cancer.

The temporal trend of women's cancer in Changle, China and a migrant epidemiological study.

Background: Although the etiology of women's cancer has been extensively studied in the last few decades, there is still little evidence comparing the temporal pattern of these cancers among different populations. Methods: Cancer incidence and mortality data from 1988 to 2015 were extracted from the Changle Cancer Register in China, and cancer incidence data for Los Angeles were extracted from Cancer Incidence in Five Continents plus database. A Joinpoint regression model was used to analyze the temporal trends of incidence and mortality for breast, cervical, corpus uteri and ovarian cancers. The standardized incidence ratios were applied to compare the cancer risk across populations. Results: An increasing trend of incidence rate for breast, cervical, corpus uteri and ovarian cancer was observed in Changle, although the rate leveled off for breast and cervical cancer after 2010, although not statistically significant. The mortality rate of breast and ovarian cancer was slightly increased during this period, while we found a decreased mortality of cervical cancer from 2010. The mortality of corpus uteri cancer showed a decreasing and then increasing trend. The incidence of breast, corpus uteri and ovarian cancer in Chinese American immigrants in Los Angeles was significantly higher than indigenous Changle Chinese and lower than Los Angeles whites. However, the incidence of cervical cancer in Chinese American immigrants shifted from significantly exceeding to lower than Changle Chinese. Conclusion: The incidence and mortality of women's cancers in Changle were generally on the rise, and this study concluded that environmental changes were important factors affecting the occurrence of these cancers. Appropriate preventive measures should be taken to control the occurrence of women's cancers by addressing different influencing factors.

The association between plasma chemokines and breast cancer risk and prognosis: A mendelian randomization study.

Background: Despite the potential role of several chemokines in the migration of cytotoxic immune cells to prohibit breast cancer cell proliferation, a comprehensive view of chemokines and the risk and prognosis of breast cancer is scarce, and little is known about their causal associations. Methods: With a two-sample Mendelian randomization (MR) approach, genetic instruments associated with 30 plasma chemokines were created. Their genetic associations with breast cancer and its survival by molecular subtypes were extracted from the recent genome-wide association study of 133,384 breast cancer cases and 113,789 controls, with available survival information for 96,661 patients. We further tested the associations between the polygenic risk score (PRS) for chemokines and breast cancer in the UK Biobank cohort using logistic regression models, while the association with breast cancer survival was tested using Cox regression models. In addition, the association between chemokine expression in tumors and breast cancer survival was also analyzed in the TCGA cohort using Cox regression models. Results: Plasma CCL5 was causally associated with breast cancer in the MR analysis, which was significant in the luminal and HER-2 enriched subtypes and further confirmed using PRS analysis (OR = 0.94, 95% CI = 0.89-1.00). A potential causal association with breast cancer survival was only found for plasma CCL19, especially for ER-positive patients. Although not replicated in the UK Biobank, we still found an inverse association between CCL19 expression in tumors and breast cancer overall and relapse-free survival in the TCGA cohort (HR = 0.58, 95% CI = 0.35-0.95). Conclusion: We observed an inverse association between genetic predisposition to CCL5 and breast cancer, while CCL19 was associated with breast cancer survival. These associations suggested the potential of these chemokines as tools for breast cancer prevention and treatment.

Surface Modified Iron Oxide Nanoparticles as Fe Source Precursor to Induce the Formation of Prussian Blue Nanocubes.

Nano-sized Prussian blue (PB) cubes were synthesized at room temperature by simply stirring the mixture of surface modified iron oxide nanoparticles (IONPs) and potassium ferrocyanide in an aqueous acid solution. The nanocubes were characterized by transmission electron microscopy (TEM), scanning electron microscopy (SEM) and X-ray diffraction (XRD). The influence of different molecules modified on the surface of IONPs on the cube formation was discussed. The surface modification with dimercaptosuccinic acid (DMSA), 3-aminopropyltriethoxysilane (APTS) and citric acid (CA) all displayed a key role in the formation precess of PB nanocubes, but which could not be formed as bare IONPs or Fe3+ were used as precursor. Combined with the reaction process tracing with UV-vis absorption spectroscopy and TEM, a possible kinetically controlled growth mechanism was proposed where slower formation rate of amorphous PB due to very low release rate of Fe ions from the surface modified IONPs and subsequent recrystallization are responsible for the obtained PB nanocubes. The peroxidase-like catalytic activity of the synthesized nanocubes was investigated and catalysis was found to follow Michaelis-Menten kinetics. The potential of using such PB nanocubes as an effective MRI contrast agent was also demonstrated.

Effective PEGylation of Fe3O4 Nanomicelles for In Vivo MR Imaging.

A practical and effective strategy for synthesizing PEGylated Fe3O4 nanomicelles is established. In this strategy, a magnetic fluid of the Fe3O4 nanomicelles was synthesized with amphiphilic PEGylated phospholipid as surfactant and soybean oil as stabilizer under simple mechanical stirring and subsequent ultrasonication. Transmission electron microscope (TEM) measurement indicated that the sample is monodisperse spherical Fe3O4 nanoparticles with internal core size of 9 nm and external nanomicelle shell thickness of 1.5 nm. The final hydrodynamic size of the sample is 19.5 nm and its zeta potential is - 38.5 mV, suggesting good stability of the magnetic nanomicelles in water. To assess the ability of magnetic nanomicelles to escape reticuloendothelial system (RES) uptake, in vitro cell phagocytosis experiments were conducted using murine macrophages (RAW264.7). The results indicated that the PEGylation can effectively prevent the uptake of the nanomicelles by the macrophages. Using a mouse model of 4T1 breast cancer, the nanomicelles provided a good magnetic resonance imaging (MRI) capability to sensitively detect tumor by enhanced permeability and retention (EPR) effect. The PEGylated monodisperse magnetic nanomicelles would become a potential contrast agent for passive targeting diagnosis of tumor by MR imaging.

Dual enzyme-like activities of iron oxide nanoparticles and their implication for diminishing cytotoxicity.

Iron oxide nanoparticles (IONPs) are frequently used in biomedical applications, yet their toxic potential is still a major concern. While most studies of biosafety focus on cellular responses after exposure to nanomaterials, little is reported to analyze reactions on the surface of nanoparticles as a source of cytotoxicity. Here we report that different intracellular microenvironment in which IONPs are located leads to contradictive outcomes in their abilities to produce free radicals. We first verified pH-dependent peroxidase-like and catalase-like activities of IONPs and investigated how they interact with hydrogen peroxide (H(2)O(2)) within cells. Results showed that IONPs had a concentration-dependent cytotoxicity on human glioma U251 cells, and they could enhance H(2)O(2)-induced cell damage dramatically. By conducting electron spin resonance spectroscopy experiments, we showed that both Fe(3)O(4) and γ-Fe(2)O(3) nanoparticles could catalyze H(2)O(2) to produce hydroxyl radicals in acidic lysosome mimic conditions, with relative potency Fe(3)O(4) > γ-Fe(2)O(3), which was consistent with their peroxidase-like activities. However, no hydroxyl radicals were observed in neutral cytosol mimic conditions with both nanoparticles. Instead, they decomposed H(2)O(2) into H(2)O and O(2) directly in this condition through catalase-like activities. Transmission electron micrographs revealed that IONPs located in lysosomes in cells, the acidic environment of which may contribute to hydroxyl radical production. This is the first study regarding cytotoxicity based on their enzyme-like activities. Since H(2)O(2) is continuously produced in cells, our data indicate that lysosome-escaped strategy for IONP delivery would be an efficient way to diminish long-term toxic potential.

Ultra-small particles of iron oxide as peroxidase for immunohistochemical detection.

Dimercaptosuccinic acid (DMSA) modified ultra-small particles of iron oxide (USPIO) were synthesized through a two-step process. The first step: oleic acid (OA) capped Fe(3)O(4) (OA-USPIO) were synthesized by a novel oxidation coprecipitation method in H(2)O/DMSO mixing system, where DMSO acts as an oxidant simultaneously. The second step: OA was replaced by DMSA to obtain water-soluble nanoparticles. The as-synthesized nanoparticles were characterized by TEM, FTIR, TGA, VSM, DLS, EDS and UV-vis. Hydrodynamic sizes and Peroxidase-like catalytic activity of the nanoparticles were investigated. The hydrodynamic sizes of the nanoparticles (around 24.4 nm) were well suited to developing stable nanoprobes for bio-detection. The kinetic studies were performed to quantitatively evaluate the catalytic ability of the peroxidase-like nanoparticles. The calculated kinetic parameters indicated that the DMSA-USPIO possesses high catalytic activity. Based on the high activity, immunohistochemical experiments were established: using low-cost nanoparticles as the enzyme instead of expensive HRP, Nimotuzumab was conjugated onto the surface of the nanoparticles to construct a kind of ultra-small nanoprobe which was employed to detect epidermal growth factor receptor (EGFR) over-expressed on the membrane of esophageal cancer cell. The proper sizes of the probes and the result of membranous immunohistochemical staining suggest that the probes can be served as a useful diagnostic reagent for bio-detection.