The research of multicomponent drugs, such as in Chinese Medicine, on both mechanism dissection and drug discovery is challenging, especially the approaches to systematically evaluating the efficacy at a molecular level. Here, we presented a network pharmacology-based approach to evaluating the efficacy of multicomponent drugs by genome-wide transcriptional expression data and applied it to Shenmai injection (SHENMAI), a widely used Chinese Medicine composed of red ginseng (RG) and Radix Ophiopogonis (RO) in clinically treating myocardial ischemia (MI) diseases. The disease network, MI network in this case, was constructed by combining the protein-protein interactions (PPI) involved in the MI enriched pathways. The therapeutic efficacy of SHENMAI, RG, and RO was therefore evaluated by a network parameter, namely, network recovery index (NRI), which quantitatively evaluates the overall recovery rate in MI network. The NRI of SHENMAI, RG, and RO were 0.876, 0.494, and 0.269 respectively, which indicated SHENMAI exerts protective effects and the synergistic effect of RG and RO on treating myocardial ischemia disease. The successful application of SHENMAI implied that the proposed network pharmacology-based approach could help researchers to better evaluate a multicomponent drug on a systematic and molecular level.
Transforming growth factor (TGF)-β/Smad signaling plays an important role in colon cancer development, progression and metastasis. In this study we demonstrated that the microRNA-130a/301a/454 family is up-regulated in colon cancer tissues compared to paired adjacent normal mucosa, which share the same 3′-untranslational region (3′-UTR) binding seed sequence and are predicated to target Smad4. In colorectal cancer HCT116 and SW480 cells, overexpression of miRNA-130a/301a/454 mimics enhances cell proliferation and migration, while inhibitors of these miRNAs affect cell survival. The biological function of miRNA-130a/301a/454 on colon cancer cells is likely mediated by suppression of Smad4, and the up-regulation of the miRNAs is correlated with Smad4 down-regulation in human colon cancers. Collectively, these results suggest that miRNA-130a/301a/454 are novel oncogenic miRNAs contributing to colon tumorigenesis by regulating TGF-β/Smad signaling, which may have potential application in cancer therapy.
While there is accumulating evidence that use of non-steroidal anti-inflammatory drugs (NSAIDs) decreases breast cancer risk, little is known about the impact of NSAIDs on survival after breast cancer diagnosis.
We assessed whether recent, pre-diagnostic NSAID use and lifetime cumulative aspirin use before diagnosis were associated with survival among 1,024 women with incident, primary, invasive breast cancer.
Recent, pre-diagnostic use of aspirin, ibuprofen, and acetaminophen, and lifetime use of aspirin up to diagnosis were not associated with either all-cause mortality or breast cancer specific mortality. Neither dose nor frequency of use was associated with risk. Associations were not different for pre- and post-menopausal women.
In our data, pre-diagnostic NSAID use and lifetime cumulative aspirin use were not associated with breast cancer survival.
Our findings do not support a role of NSAIDs prior to diagnosis in breast cancer survival.
Exposure to ionizing radiation may induce a heritable genomic instability phenotype that results in a persisting and enhanced genetic and functional change among the progeny of irradiated cells. Since radiation-induced bystander effects have been demonstrated with a variety of biological end points under both in vitro and in vivo conditions, this raises the question whether cytoplasmic irradiation or the radiation-induced bystander effect can also lead to delayed genomic instability. In the present study, we used the Radiological Research Accelerator Facility charged-particle microbeam for precise nuclear or cytoplasmic irradiation. The progeny of irradiated and the bystander human hamster hybrid (AL) cells were analyzed using multicolor banding (mBAND) to examine persistent chromosomal changes. Our results showed that the numbers of metaphase cells involving changes of human chromosome 11 (including rearrangement, deletion and duplication) were significantly higher than that of the control in the progeny of both nuclear and cytoplasmic targeted cells. These chromosomal changes could also be detected among the progeny of bystander cells. mBAND analyses of clonal isolates from nuclear and cytoplasm irradiations as well as the bystander cell group showed that chromosomal unstable clones were generated. Analyses of clonal stability after long-term culture indicated no significant change in the number of unstable clones for the duration of culture in each irradiated group. These results suggest that genomic instability that is manifested after ionizing radiation exposure is not dependent on direct damage to the cell nucleus.
Background/Aims:Accumulation of advanced glycation end-products, the well-recognized pro-inflammatory molecules, has been detected in renal tissues including tubules. The aim of the present study was to investigate the role of advanced glycation end-products modified low density lipoprotein (AGE-LDL) in inflammatory cytokines production in human proximal tubular epithelial cells and the underlying mechanism. Methods: The Interleukin-6 (IL-6) and Interleukin-8 (IL-8) production was examined by real-time PCR and ELISA. The expression of Toll-like receptor 2 and 4 (TLR2/4) was detected by flow cytometry and western blot. The interaction of TLR2/4 with AGE-LDL was examined by co-immunoprecipitation assay. The involvement of MyD88 and the downstream molecules in inflammatory cytokines production was examined by siRNA and pharmacologic inhibitors, respectively. Results: AGE-LDL interacted with TLR2 and TLR4. TLR4 siRNA showed stronger inhibition on AGE-LDL-induced IL-6 and IL-8 production than that of TLR2 siRNA. Silencing MyD88, but not TRIF, inhibited AGE-LDL-induced IL-6 and IL-8 production. AGE-LDL stimulation led to phosphorylation of JNK, p38, Akt and the p65 subunit of nuclear factor-κB (NF-κB). Pharmacologic inhibitor of Akt suppressed AGE-LDL-induced activation of NF-κB, but the inhibitor of JNK, p38 or ERK1/2 had no effect. Blocking MyD88, p38, JNK, Akt or NF-κB attenuated AGE-LDL-triggered IL-6 production. Conclusion: AGE-LDL induced IL-6 and IL-8 production via TLR2/4-MyD88-dependent pathway in tubular epithelial cells. These data suggest that activation of TLRs signaling in tubular epithelial cells by AGE-LDL might be a novel mechanism for the tubulointerstitial inflammation.
AGE-LDL; Toll like receptor; MyD88; NF-κB; IL-6.
It is evident that epigenetic factors, especially DNA methylation, play essential roles in obesity development. Using pig as a model, here we investigated the systematic association between DNA methylation and obesity. We sampled eight variant adipose and two distinct skeletal muscle tissues from three pig breeds living within comparable environments but displaying distinct fat level. We generated 1,381 gigabases (Gb) of sequence data from 180 methylated DNA immunoprecipitation (MeDIP) libraries, and provided a genome-wide DNA methylation map as well as a gene expression map for adipose and muscle studies. The analysis showed global similarity and difference among breeds, sexes and anatomic locations, and identified the differentially methylated regions (DMRs). The DMRs in promoters are highly associated with obesity development via expression repression of both known obesity-related genes and novel genes. This comprehensive map provides a solid basis for exploring epigenetic mechanisms of adipose deposition and muscle growth.
Effects of high fat diet (HFD) on obesity and, subsequently, on diabetes are highly variable and modulated by genetics in both humans and rodents. In this report, we characterized the response of Goto-Kakizaki (GK) rats, a spontaneous polygenic model for lean diabetes and healthy Wistar-Kyoto (WKY) controls, to high fat feeding from weaning to 20 weeks of age. Animals fed either normal diet or HFD were sacrificed at 4, 8, 12, 16 and 20 weeks of age and a wide array of physiological measurements were made along with gene expression profiling using Affymetrix gene array chips. Mining of the microarray data identified differentially regulated genes (involved in inflammation, metabolism, transcription regulation, and signaling) in diabetic animals, as well as the response of both strains to HFD. Functional annotation suggested that HFD increased inflammatory differences between the two strains. Chronic inflammation driven by heightened innate immune response was identified to be present in GK animals regardless of diet. In addition, compensatory mechanisms by which WKY animals on HFD resisted the development of diabetes were identified, thus illustrating the complexity of diabetes disease progression.
diabetes; high fat diet; gene expression; microarray
The mechanism for the observed association of alcohol consumption breast cancer risk is not known; understanding that mechanism could improve understanding of breast carcinogenesis and optimize prevention strategies. Alcohol may impact breast malignancies or tumor progression by altering DNA methylation. We examined promoter methylation of three genes, the E- cadherin, p16, and RAR-β2 genes in archived breast tumor tissues from participants in a population-based case-control study. Real time methylation-specific PCR was performed on 803 paraffin-embedded samples; and lifetime alcohol consumption was queried. Unordered polytomous and unconditional logistic regression were used to derive adjusted odds ratios (OR) and 95% confidence intervals (CI). RAR-β2 methylation was not associated with drinking. Among premenopausal women, alcohol consumption was also not associated with promoter methylation for E- cadherin and p16 genes. In case-case comparisons of postmenopausal breast cancer, compared to lifetime never drinkers, promoter methylation likelihood was increased for higher alcohol intake for E - cadherin (OR = 2.39, 95% CI, 1.15–4.96), in particular for those with ER-negative tumors (OR = 4.13, 95% CI, 1.16–14.72), and decreased for p16 (OR = 0.52, 95% CI, 0.29-0.92). There were indications that the association with p16 was stronger for drinking at younger ages. Methylation was also associated with drinking intensity independent of total consumption for both genes. We found alcohol consumption was associated with DNA methylation in postmenopausal breast tumors, suggesting that the association of alcohol and breast cancer may be related, at least in part, to altered methylation, and may differ by drinking pattern.
alcohol consumption; breast cancer; epidemiology; epigenetics; promoter methylation
To investigate the placental proteome differences between pregnant women complicated with gestational diabetes mellitus (GDM) and those with normal glucose tolerance (NGT).
We used two-dimensional electrophoresis (2DE) to separate and compare placental protein levels from GDM and NGT groups. Differentially expressed proteins between the two groups were identified by MALDI-TOF/TOF mass spectrometry and further confirmed by Western blotting. The mRNA levels of related proteins were measured by realtime RT-PCR. Immunohistochemistry (IHC) was performed to examine the cellular location of the proteins expressed in placenta villi.
Twenty-one protein spots were differentially expressed between GDM and NGT placenta villi in the tested samples, fifteen of which were successfully identified by mass spectrometry. The molecular functions of these differentially expressed proteins include blood coagulation, signal transduction, anti-apoptosis, ATP binding, phospholipid binding, calcium ion binding, platelet activation, and tryptophan-tRNA ligase activity. Both protein and mRNA levels of Annexin A2, Annexin A5 and 14-3-3 protein ζ/δ were up-regulated, while the expression of the Ras-related protein Rap1A was down-regulated in the GDM placenta group.
Placenta villi derived from GDM pregnant women exhibit significant proteome differences compared to those of NGT mothers. The identified differentially expressed proteins are mainly associated with the development of insulin resistance, transplacental transportation of glucose, hyperglucose-mediated coagulation and fibrinolysis disorders in the GDM placenta villi.
Recent genome-wide association studies have revealed several new candidate genes for breast cancer, including FGFR2. The associations were also replicated in several other independent studies. The next important step is to study whether these common variants interact with known breast cancer risk factors, exogenous exposures, and tumor characteristics. In a population-based case-control study of 1170 breast cancer cases and 2115 controls, we examined genetic associations of four intronic FGFR2 SNPs and breast tumor characteristics and assessed the potential interactions with smoking, alcohol consumption, adiposity, and known breast cancer risk factors. FGFR2 variants were significantly associated with breast cancer risk regardless of estrogen and progesterone receptor status, metastasis, lymph node involvement, histologic and nuclear grade. The FGFR2-breast cancer association was modified by smoking status, with increased risk for former and current smokers compared to never smokers; former/current smokers carrying two copies of the rs1219648 minor allele were at highest risk with a crude OR (95% CI) of 2.11 (1.52–2.92) compared to never smokers with no rs1219648 variant alleles. Our study found no evidence for modification of FGFR2 and breast cancer by alcohol intake nor adiposity, even when analyses were stratified by menopausal status. While these results require further replication, they may provide new insight into the possible new exposures that may interact with FGFR2 susceptibility alleles.
Breast cancer; FGFR2; gene-environment interactions
Base excision repair (BER) and nucleotide excision repair (NER) pathways repair damaged DNA, and polymorphisms in these genes might affect breast cancer susceptibility. We evaluated associations between seven single-nucleotide polymorphisms in four DNA repair genes (ERCC4 rs1799801, XPC rs2227998, rs2228001, rs2228000, OGG1 rs1052133 and XRCC1 rs25487 and rs25486) and breast cancer risk, examining modification by smoking and alcohol consumption, using data from the Western New York Exposures and Breast Cancer Study. Women aged 35–79 years with incident breast cancer (n = 1170) and age- and race-matched controls (n = 2115) were enrolled. Genotyping was performed using matrix-assisted laser desorption ionization time-of-flight mass spectrometry. Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CIs). No significant associations were observed in premenopausal women. Among postmenopausal women, rs25487 and rs25486 (OR = 1.24; 95% CI 1.01–1.51 and OR = 1.23; 95% CI 1.01–1.49, respectively, for combined heterozygous and homozygous variant compared with reference) were associated with increased risk of breast cancer. Postmenopausal women carrying the variant allele of the synonymous XPC polymorphism (rs2227998) were also at borderline significantly increased risk (OR = 1.24; 95% CI 1.01–1.52, heterozygous variant compared with reference; OR = 1.22; 95% CI 1.01–1.48, for combined heterozygous and homozygous variant compared with reference). There was no evidence of genotype–smoking and genotype–alcohol consumption interactions for pre- and postmenopausal women. These results indicate that some of the variants in BER and NER genes may influence risk of postmenopausal breast cancer.
Low-flow push-pull perfusion is a sampling method that yields better spatial resolution than competitive methods like microdialysis. Because of the low flow rates used (50 nL/min) it is challenging to use this technique at high temporal resolution which requires methods of collecting, manipulating, and analyzing nanoliter samples. High temporal resolution also requires control of Taylor dispersion during sampling. To meet these challenges, push-pull perfusion was coupled with segmented flow to achieve in vivo sampling at 7 s temporal resolution at 50 nL/min flow rates. By further miniaturizing the probe inlet, sampling with 200 ms resolution at 30 nL/min (pull only) was demonstrated in vitro. Using this method, L-glutamate was monitored in the striatum of anesthetized rats. Up to 500 samples of 6 nL each were collected at 7 s intervals, segmented by an immiscible oil and stored in a capillary tube. The samples were assayed offline for L-glutamate at a rate of 15 samples/min by pumping them into a reagent addition tee fabricated from Teflon where reagents were added for a fluorescent enzyme assay. Fluorescence of the resulting plugs was monitored downstream. Microinjection of 70 mM potassium in physiological buffered saline evoked L-glutamate concentration transients that had an average maxima of 4.5 ± 1.1 μM (n = 6 animals, 3–4 injections each) and rise times of 22 ± 2 s. These results demonstrate that low-flow push-pull perfusion with segmented flow can be used for high temporal resolution chemical monitoring and in complex biological environments.
Use of non-steroidal anti-inflammatory drugs (NSAIDs) has been associated with reduced risk of breast cancer, though findings have been inconsistent. This inconsistency may result from differences in etiology for breast tumors of different subtypes. We examined the association between NSAID use and breast cancer characterized by molecular subtypes in a population-based case-control study in Western New York. Cases (n=1,170) were women with incident, primary, histologically confirmed breast cancer. Controls (n=2,115) were randomly selected from NY Department of Motor Vehicles records (<65yrs) or Medicare rolls (≥65yrs). Participants answered questions regarding their use of aspirin and ibuprofen in the year prior to interview and their use of aspirin throughout their adult life. Logistic regression models estimated odds ratios (OR) and 95% confidence intervals (95% CI). Recent and lifetime aspirin use was associated with reduced risk, with no differences by subtype. Recent use of ibuprofen was significantly associated with increased risk of ER+/PR+ (OR 1.33, 95% CI: 1.09–1.62), HER2− (OR 1.27, 95% CI: 1.05–1.53), and p53− breast cancers (OR 1.28, 95% CI: 1.04–1.57), as well as luminal A or B breast cancers. These findings support the hypothesis of heterogeneous etiologies of breast cancer subtypes and that aspirin and ibuprofen vary in their effects.
Aspirin; Breast Cancer; HER-2; Hormone Receptor; Ibuprofen; P53; Non-Steroidal Anti-Inflammatory Drugs
Many studies have suggested that hepatitis B virus (HBV) genotypes show not only geographical distribution and race specificity, but also are associated with disease progression and response to interferon treatment. The objective of this study was to develop a nested polymerase chain reaction (nPCR) assay for genotypes A-D and subgenotypes B1, B2, C1 and C2 of hepatitis B virus (HBV) and to investigate the distribution characteristics of HBV genotypes/subgenotype in China.
After redesigning the primers and optimizing the reaction conditions using common Taq polymerase, the sensitivity, specificity and reproducibility of the method were evaluated using plasmids and serum samples. In total, 642 serum samples from patients with chronic HBV infection were applied to investigate the distribution of HBV genotype and subgenotype in China.
The genotype and subgenotype could be identified when the HBV DNA load of a sample was ≥102.3 IU/mL. For the 639 successfully genotyped samples, the sequencing results of 130 randomly selected samples (20.3%, 130/639) were consistent with those of the nPCR method. The present study showed that HBV genotype B (11.2%, 72/642), C (68.2%, 438/642) and D (7.2%, 46/642) were circulating in China, while genotype C was the dominant strain except for western region where genotype D was the prevalent strain. The main subgenotypes of genotypes B and C were B2 (87.5%, 63/72) and C2 (92.9%, 407/438), respectively.
The low-cost nPCR method would be a useful tool for clinical and epidemiological investigation in the regions where genotypes A-D are predominant.
Genotype; Hepatitis B virus; Nested PCR; Subgenotype; Type-specific nested PCR
The Goto-Kakizaki (GK) rat, a polygenic non-obese model of type 2 diabetes, is a useful surrogate for study of diabetes-related changes independent of obesity. GK rats and appropriate controls were killed at 4, 8, 12, 16 and 20 weeks post-weaning and differential muscle gene expression along with body and muscle weights, plasma hormones and lipids, and blood cell measurements were carried out. Gene expression analysis identified 204 genes showing 2-fold or greater differences between GK and controls in at least 3 ages. Array results suggested increased oxidative capacity in GK muscles, as well as differential gene expression related to insulin resistance, which was also indicated by HOMA-IR measurements. In addition, potential new biomarkers in muscle gene expression were identified that could be either a cause or consequence of T2DM. Furthermore, we demonstrate here the presence of chronic inflammation evident both systemically and in the musculature, despite the absence of obesity.
type 2 diabetes; skeletal muscle; inflammation; microarrays; gene expression
Chronic inflammation has been consistently associated with cancers of several sites, including the breast, and inhibition of inflammation through the use of non-steroidal anti-inflammatory drugs (NSAIDs) has been inversely associated with risk. As NSAIDs bind with cyclooxygenase-2 (COX-2), genetic variation in COX-2 may influence breast cancer risk by affecting inflammatory response and response to NSAID use. We identified eight single nucleotide polymorphisms (SNPs) for COX-2 and examined their association with risk of breast cancer in a population-based case–control study in Western New York. Cases had incident, first primary, histologically confirmed breast cancer (n = 1077). Controls (n = 1910) were randomly selected from NY Department of Motor Vehicles records (<65) or Medicare rolls (≥65). Participants were queried on adult lifetime use of aspirin and recent use of ibuprofen. Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI). One SNP, rs2745559, was associated with an increased risk of breast cancer (OR 1.23, 95% CI 1.03–1.46). Associations with other variants were not evident. Significant interaction (P interaction = 0.04) between recent aspirin use and rs4648261 was also observed. Variation in COX-2 was modestly associated with breast cancer risk, indicating that COX-2 may play a role in breast carcinogenesis. Better understanding of the role of COX-2 genetic variation and interaction with NSAID use in breast carcinogenesis has potential to inform prevention strategies.
Breast cancer; Cyclooxygenase-2; Non-steroidal anti-inflammatory drugs; Prostaglandinendoperoxide synthase 2; Single nucleotide polymorphism
Pyruvate dehydrogenase kinase 4 (PDK4) is a lipid status responsive gene involved in muscle fuel selection. Evidence is mounting in support of the therapeutic potential of PDK4 inhibitors to treat diabetes. Factors that regulate PDK4 mRNA expression include plasma corticosterone, insulin and free fatty acids. Our objective was to determine the impact of those plasma factors on PDK4 mRNA and to develop and validate a population mathematical model to differentiate aging, diet and disease effects on muscle PDK4 expression. The Goto-Kakizaki (GK) rat, a polygenic non-obese model of type 2 diabetes, was used as the diabetic animal model. We examined muscle PDK4 mRNA expression by real-time QRTPCR. Groups of GK rats along with controls fed with either a normal or high fat diet were sacrificed at 4, 8, 12, 16, and 20 weeks of age. Plasma corticosterone, insulin and free fatty acid were measured. The proposed mechanism-based model successfully described the age, disease and diet effects and the relative contribution of these plasma regulators on PDK4 mRNA expression. Muscle growth reduced the PDK4 mRNA production rate by 14% per gram increase. High fat diet increased the initial production rate constant in GK rats by 2.19-fold. The model indicated that corticosterone had a moderate effect and PDK4 was more sensitive to free fatty acid than insulin fluxes, which was in good agreement with the literature data.
population model; type 2 diabetes; disease progression; PDK4; Goto-Kakizaki rats
Infection around membranes is often found in guided bone regeneration (GBR). The excellent antibacterial properties of Ag-nHA-nTiO2/polyamide-66 (PA66) nanocomposite membranes have been demonstrated previously. The aim of this study was to observe the microstructure of an Ag-nHA-nTiO2/PA66 membrane and its effects on osteoblast-like cells in vitro. An Ag-nHA-nTiO2/PA66 membrane was used in the experimental group, and both nHA/PA66 and expanded poly tetrafluroethylene (e-PTFE) membranes were set as control. MG63 osteoblast-like cells were cultured on the three kinds of membrane and tissue culture polystyrene (TCP). The microstructure of the above membranes and the cells adhered on them were detected by scanning electronic microscope (SEM). Cell proliferation was determined by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, cell viability with a cell viability analyzer, and alkaline phosphatase (ALP) activity and Ca2+ concentration of osteoblast-like cell matrix by enzyme-linked immunosorbent assay. SEM showed that both Ag-nHA-nTiO2/PA66 membranes and nHA/PA66 membranes were composed of porous obverse face and smooth opposite face. The e-PTFE membranes showed elliptic surface structure with many tiny lined cracks. The MG63 cells adhered and proliferated well on all three kinds of membranes. Though cell viability on Ag-nHA-nTiO2/PA66 membranes was significantly lower than that of the control groups (P < 0.05), MTT values, ALP activity, and Ca2+ concentration did not differ significantly among the three kinds of membranes (P > 0.05). From these findings, it can be concluded that Ag-nHA-nTiO2/PA66 membranes are as biocompatible as nHA/ PA66 membranes and TCP, thus may be applied safely in GBR.
guided bone regeneration; hydroxyapatite; polyamide-66; silver; TiO2; MG63; osteoblast-like cells
Chronic inflammation is suspected to have a role in breast carcinogenesis. Results of studies of non-steroidal anti-inflammatory drugs (NSAIDs) and breast cancer have been inconsistent. Timing of exposure and analysis of individual NSAIDs should be considered.
We conducted a population-based case-control study in western New York State between 1996 and 2001. Cases, 35-79yrs, had incident, primary, histologically confirmed breast cancer (n=1170). Controls (n=2115) were randomly selected from NY Department of Motor Vehicles records (<65yrs) or Medicare rolls (≥65yrs). Participants were queried on use of aspirin, ibuprofen, and acetaminophen in the year prior and on aspirin during adulthood. Unconditional logistic regression was used to estimate adjusted odds ratios (OR) and 95% confidence intervals (95% CI).
Recent aspirin use was inversely associated with breast cancer risk (adjusted OR 0.80, 95% CI: 0.68-0.94); the strongest reduction in risk was observed among those who took ≥2 pills/day on days that aspirin was taken (OR 0.74, 95% CI: 0.61-0. 90). Adult lifetime use was also associated with breast cancer risk (>10 days/month, adjusted OR 0.68, 95% CI: 0.46-1.00). Use of ibuprofen or acetaminophen was not associated with breast cancer.
This is the first study to investigate the association of adult lifetime aspirin intake with breast cancer risk. Our findings provide evidence that aspirin use throughout a woman's life may confer some benefit.
Aspirin; Breast Cancer; Ibuprofen; Inflammation; Non-steroidal Anti-inflammatory Drugs
The title compound, [Fe(C9H10BN6)2], is a polymorph of a compound reported previously [Oliver et al. (1980 ▶). Inorg. Chem.
19, 165–168]. In the previous report, the compound crystallized in the monoclinic space group P21/c (Z = 4), whereas the crystal symmetry of the compound reported here is tetragonal (P42/ncm, Z = 4). The molecular structure is comprised of two hydrotris(1-pyrazolyl)borate ligands (Tp−) and a central FeII ion, which is coordinated by six pyrazole N atoms from two two Tp− ligands, yielding a distorted bipyramidal FeN6 geometry. The complete molecule exhibits symmetry 2/m.
Dietary lignan intakes have been associated with reduced breast cancer risks; however, no previous studies have investigated whether lignan intake might be associated with breast cancer survival. We examined the association of dietary lignan intakes with survival in 1122 women with primary, incident, histologically confirmed breast cancer identified between 1996 and 2001, and with vital status determined through December 31, 2006. Diet in the 12–24 months before diagnosis was assessed with an extensive food frequency questionnaire, and potential confounders assessed from an extensive epidemiologic interview and abstracted clinical data. Lignan intake was calculated using published food composition data. Hazard ratios (HR), and 95% confidence intervals (CIs) for dietary lignan intakes with all cause, and breast cancer mortality were estimated using Cox proportional hazards adjusting for age, education, race, total energy intake, tumor stage, and body mass index. Of the 1122 women with complete dietary data, 160 had died by the end of follow-up. Among postmenopausal women only, those in the highest versus lowest quartile of lignan intakes had a statistically significant reduction in the risk of all cause mortality (HR 0.49, 95% CI 0.26–0.91) and a significantly reduced risk of breast cancer mortality (HR 0.29, 95% CI 0.11–0.76). Higher intakes of dried beans (HR 0.61, 95% CI 0.36–1.03), but not fruits, vegetables, or grains, were also weakly associated with overall mortality. In summary, our results suggest that higher lignan intakes may be associated with improved survival among postmenopausal women with breast cancer.
Breast cancer; Diet; Lignans; Phytoestrogens; Survival
Inter-individual variation in DNA repair capacity is thought to modulate breast cancer risk. The phenotypic mutagen sensitivity assay (MSA) measures DNA strand breaks in lymphocytes; women with familial and sporadic breast cancers have a higher mean number of breaks per cell (MBPC) then women without breast cancer. Here, we explore the relationships between the MSA and the Rad51 gene, which encodes a DNA repair enzyme that interacts with BRCA1 and BRCA2, in BRCA1 mutation carriers and women with sporadic breast cancer.
Peripheral blood lymphoblasts from women with known BRCA1 mutations underwent the MSA (n = 138 among 20 families). BRCA1 and Rad51 genotyping and sequencing were performed to identify SNPs and haplotypes associated with the MSA. Positive associations from the study in high-risk families were subsequently examined in a population-based case-control study of breast cancer (n = 1170 cases and 2115 controls).
Breast cancer diagnosis was significantly associated with the MSA among women from BRCA1 families (OR = 3.2 95%CI: 1.5-6.7; p = 0.004). The Rad51 5'UTR 135 C>G genotype (OR = 3.64; 95% CI: 1.38, 9.54; p = 0.02), one BRCA1 haplotype (p = 0.03) and in a polygenic model, the E1038G and Q356R BRCA1 SNPs were significantly associated with MBPC (p = 0.009 and 0.002, respectively). The Rad51 5'UTR 135C genotype was not associated with breast cancer risk in the population-based study.
Mutagen sensitivity might be a useful biomarker of penetrance among women with BRCA1 mutations because the MSA phenotype is partially explained by genetic variants in BRCA1 and Rad51.
In the title compound, [Zn(C7H4ClO3)2(C12H8N2)(H2O)], the ZnII cation is coordinated by two 4-chloro-2-salicylate anions, one 1,10-phenanthroline ligand and one water molecule in a square-pyramidal coordination geometry; the Zn cation lies 0.4591 (11) Å from the basal plane. The benzene rings of the anions are involved in π–π stacking. The centroid–centroid distance between parallel benzene rings of adjacent molecules is 3.9017 (17) Å, and the centroid–centroid distance between benzene and pyridine rings of adjacent molecules is 3.584 (2) Å. Intramolecular O—H⋯O hydrogen bonding is present.
High abundance protein depletion is a major challenge in the study of serum/plasma proteomics. Prior to this study, most commercially available kits for depletion of highly abundant proteins had only been tested and evaluated in adult serum/plasma, while the depletion efficiency on umbilical cord serum/plasma had not been clarified. Structural differences between some adult and fetal proteins (such as albumin) make it likely that depletion approaches for adult and umbilical cord serum/plasma will be variable. Therefore, the primary purposes of the present study are to investigate the efficiencies of several commonly-used commercial kits during high abundance protein depletion from umbilical cord serum and to determine which kit yields the most effective and reproducible results for further proteomics research on umbilical cord serum.
The immunoaffinity based kits (PROTIA-Sigma and 5185-Agilent) displayed higher depletion efficiency than the immobilized dye based kit (PROTBA-Sigma) in umbilical cord serum samples. Both the PROTIA-Sigma and 5185-Agilent kit maintained high depletion efficiency when used three consecutive times. Depletion by the PROTIA-Sigma Kit improved 2DE gel quality by reducing smeared bands produced by the presence of high abundance proteins and increasing the intensity of other protein spots. During image analysis using the identical detection parameters, 411 ± 18 spots were detected in crude serum gels, while 757 ± 43 spots were detected in depleted serum gels. Eight spots unique to depleted serum gels were identified by MALDI- TOF/TOF MS, seven of which were low abundance proteins.
The immunoaffinity based kits exceeded the immobilized dye based kit in high abundance protein depletion of umbilical cord serum samples and dramatically improved 2DE gel quality for detection of trace biomarkers.
Type 2 diabetes (T2DM) is a heterogeneous group of diseases that is progressive and involves multiple tissues. Goto-Kakizaki (GK) rats are a polygenic model with elevated blood glucose, peripheral insulin resistance, a non-obese phenotype, and exhibit many degenerative changes observed in human T2DM. As part of a systems analysis of disease progression in this animal model, this study characterized the contribution of adipose tissue to pathophysiology of the disease. We sacrificed subgroups of GK rats and appropriate controls at 4, 8, 12, 16 and 20 weeks of age and carried out a gene array analysis of white adipose tissue. We expanded our physiological analysis of the animals that accompanied our initial gene array study on the livers from these animals. The expanded analysis included adipose tissue weights, HbA1c, additional hormonal profiles, lipid profiles, differential blood cell counts, and food consumption. HbA1c progressively increased in the GK animals. Altered corticosterone, leptin, and adiponectin profiles were also documented in GK animals. Gene array analysis identified 412 genes that were differentially expressed in adipose tissue of GKs relative to controls. The GK animals exhibited an age-specific failure to accumulate body fat despite their relatively higher calorie consumption which was well supported by the altered expression of genes involved in adipogenesis and lipogenesis in the white adipose tissue of these animals, including Fasn, Acly, Kklf9, and Stat3. Systemic inflammation was reflected by chronically elevated white blood cell counts. Furthermore, chronic inflammation in adipose tissue was evident from the differential expression of genes involved in inflammatory responses and activation of natural immunity, including two interferon regulated genes, Ifit and Iipg, as well as MHC class II genes. This study demonstrates an age specific failure to accumulate adipose tissue in the GK rat and the presence of chronic inflammation in adipose tissue from these animals.