Dermcidin expression is associated with disease progression and survival among breast cancer patients

Improved diagnostic screening has led to earlier detection of many tumors, but screening may still miss many aggressive tumor types. Proteomic and genomic profiling studies of breast cancer samples have identified tumor markers that may help improve screening for more aggressive, rapidly growing breast cancers. To identify potential blood-based biomarkers for the early detection of breast cancer, we assayed serum samples via matrix-assisted laser desorption ionization–time of flight mass spectrometry from a rat model of mammary carcinogenesis. We found elevated levels of a fragment of the protein dermcidin (DCD) to be associated with early progression of N-methylnitrosourea-induced breast cancer, demonstrating significance at weeks 4 (p = 0.045) and 5 (p = 0.004), a time period during which mammary pathologies rapidly progress from ductal hyperplasia to adenocarcinoma. The highest serum concentrations were observed in rats bearing palpable mammary carcinomas. Increased DCD was also detected with immunoblotting methods in 102 serum samples taken from women just prior to breast cancer diagnosis. To validate these findings in a larger population, we applied a 32-gene in vitro DCD response signature to a dataset of 295 breast tumors and assessed correlation with intrinsic breast cancer subtypes and overall survival. The DCD-derived gene signature was significantly associated with subtype (p < 0.001) and poorer overall survival [HR (95 % CI) = 1.60 (1.01–2.51), p = 0.044]. In conclusion, these results present novel evidence that DCD levels may increase in early carcinogenesis, particularly among more aggressive forms of breast cancer

Cruciferous vegetable supplementation in a controlled diet study alters the serum peptidome in a GSTM1-genotype dependent manner

<p>Abstract</p> <p>Background</p> <p>Cruciferous vegetable intake is inversely associated with the risk of several cancers. Isothiocyanates (ITC) are hypothesized to be the major bioactive constituents contributing to these cancer-preventive effects. The polymorphic glutathione-<it>S</it>-transferase (GST) gene family encodes several enzymes which catalyze ITC degradation <it>in vivo</it>.</p> <p>Methods</p> <p>We utilized high throughput proteomics methods to examine how human serum peptides (the "peptidome") change in response to cruciferous vegetable feeding in individuals of different <it>GSTM1 </it>genotypes. In two randomized, crossover, controlled feeding studies (EAT and 2EAT) participants consumed a fruit- and vegetable-free basal diet and the basal diet supplemented with cruciferous vegetables. Serum samples collected at the end of the feeding period were fractionated and matrix assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry spectra were obtained. Peak identification/alignment computer algorithms and mixed effects models were used to analyze the data.</p> <p>Results</p> <p>After analysis of spectra from EAT participants, 24 distinct peaks showed statistically significant differences associated with cruciferous vegetable intake. Twenty of these peaks were driven by their <it>GSTM1 </it>genotype (i.e., <it>GSTM1+ </it>or <it>GSTM1- </it>null). When data from EAT and 2EAT participants were compared by joint processing of spectra to align a common set, 6 peaks showed consistent changes in both studies in a genotype-dependent manner. The peaks at 6700 <it>m/z </it>and 9565 <it>m/z </it>were identified as an isoform of transthyretin (TTR) and a fragment of zinc α2-glycoprotein (ZAG), respectively.</p> <p>Conclusions</p> <p>Cruciferous vegetable intake in <it>GSTM1+ </it>individuals led to changes in circulating levels of several peptides/proteins, including TTR and a fragment of ZAG. TTR is a known marker of nutritional status and ZAG is an adipokine that plays a role in lipid mobilization. The results of this study present evidence that the <it>GSTM1</it>-genotype modulates the physiological response to cruciferous vegetable intake.</p

Oral treatment with a zinc complex of acetylsalicylic acid prevents diabetic cardiomyopathy in a rat model of type-2 diabetes: activation of the Akt pathway.

BACKGROUND: Type-2 diabetics have an increased risk of cardiomyopathy, and heart failure is a major cause of death among these patients. Growing evidence indicates that proinflammatory cytokines may induce the development of insulin resistance, and that anti-inflammatory medications may reverse this process. We investigated the effects of the oral administration of zinc and acetylsalicylic acid, in the form of bis(aspirinato)zinc(II)-complex Zn(ASA)2, on different aspects of cardiac damage in Zucker diabetic fatty (ZDF) rats, an experimental model of type-2 diabetic cardiomyopathy. METHODS: Nondiabetic control (ZL) and ZDF rats were treated orally with vehicle or Zn(ASA)2 for 24 days. At the age of 29-30 weeks, the electrical activities, left-ventricular functional parameters and left-ventricular wall thicknesses were assessed. Nitrotyrosine immunohistochemistry, TUNEL-assay, and hematoxylin-eosin staining were performed. The protein expression of the insulin-receptor and PI3K/AKT pathway were quantified by Western blot. RESULTS: Zn(ASA)2-treatment significantly decreased plasma glucose concentration in ZDF rats (39.0 +/- 3.6 vs 49.4 +/- 2.8 mM, P < 0.05) while serum insulin-levels were similar among the groups. Data from cardiac catheterization showed that Zn(ASA)2 normalized the increased left-ventricular diastolic stiffness (end-diastolic pressure-volume relationship: 0.064 +/- 0.008 vs 0.084 +/- 0.014 mmHg/microl; end-diastolic pressure: 6.5 +/- 0.6 vs 7.9 +/- 0.7 mmHg, P < 0.05). Furthermore, ECG-recordings revealed a restoration of prolonged QT-intervals (63 +/- 3 vs 83 +/- 4 ms, P < 0.05) with Zn(ASA)2. Left-ventricular wall thickness, assessed by echocardiography, did not differ among the groups. However histological examination revealed an increase in the cardiomyocytes' transverse cross-section area in ZDF compared to the ZL rats, which was significantly decreased after Zn(ASA)2-treatment. Additionally, a significant fibrotic remodeling was observed in the diabetic rats compared to ZL rats, and Zn(ASA)2-administered ZDF rats showed a similar collagen content as ZL animals. In diabetic hearts Zn(ASA)2 significantly decreased DNA-fragmentation, and nitro-oxidative stress, and up-regulated myocardial phosphorylated-AKT/AKT protein expression. Zn(ASA)2 reduced cardiomyocyte death in a cellular model of oxidative stress. Zn(ASA)2 had no effects on altered myocardial CD36, GLUT-4, and PI3K protein expression. CONCLUSIONS: We demonstrated that treatment of type-2 diabetic rats with Zn(ASA)2 reduced plasma glucose-levels and prevented diabetic cardiomyopathy. The increased myocardial AKT activation could, in part, help to explain the cardioprotective effects of Zn(ASA)2. The oral administration of Zn(ASA)2 may have therapeutic potential, aiming to prevent/treat cardiac complications in type-2 diabetic patients

Newly Developed Mg2+–Selective Fluorescent Probe Enables Visualization of Mg2+ Dynamics in Mitochondria

Mg2+ plays important roles in numerous cellular functions. Mitochondria take part in intracellular Mg2+ regulation and the Mg2+ concentration in mitochondria affects the synthesis of ATP. However, there are few methods to observe Mg2+ in mitochondria in intact cells. Here, we have developed a novel Mg2+–selective fluorescent probe, KMG-301, that is functional in mitochondria. This probe changes its fluorescence properties solely depending on the Mg2+ concentration in mitochondria under physiologically normal conditions. Simultaneous measurements using this probe together with a probe for cytosolic Mg2+, KMG-104, enabled us to compare the dynamics of Mg2+ in the cytosol and in mitochondria. With this method, carbonyl cyanide p-(trifluoromethoxy) phenylhydrazone (FCCP)–induced Mg2+ mobilization from mitochondria to the cytosol was visualized. Although a FCCP–induced decrease in the Mg2+ concentration in mitochondria and an increase in the cytosol were observed both in differentiated PC12 cells and in hippocampal neurons, the time-courses of concentration changes varied with cell type. Moreover, the relationship between mitochondrial Mg2+ and Parkinson's disease was analyzed in a cellular model of Parkinson's disease by using the 1-methyl-4-phenylpyridinium ion (MPP+). A gradual decrease in the Mg2+ concentration in mitochondria was observed in response to MPP+ in differentiated PC12 cells. These results indicate that KMG-301 is useful for investigating Mg2+ dynamics in mitochondria. All animal procedures to obtain neurons from Wistar rats were approved by the ethical committee of Keio University (permit number is 09106-(1))

Risk of selected subsequent carcinomas in survivors of childhood cancer: a report from the Childhood Cancer Survivor Study

To determine the risk of subsequent carcinomas other than breast, thyroid, and skin, and to identify factors that influence the risk among survivors of childhood cancer. Subsequent malignant neoplasm history was determined in 13,136 participants (surviving > or = 5 years postmalignancy, diagnosed from 1970 to 1986 at age <21 years) of the Childhood Cancer Survivor Study to calculate standardized incidence ratios (SIRs), using Surveillance, Epidemiology, and End Results data. In 71 individuals, 71 carcinomas were diagnosed at a median age of 27 years and a median elapsed time of 15 years in the genitourinary system (35%), head and neck area (32%), gastrointestinal tract (23%), and other sites (10%). Fifty-nine patients (83%) had received radiotherapy, and 42 (59%) developed a second malignant neoplasm in a previous radiotherapy field. Risk was significantly elevated following all childhood diagnoses except CNS neoplasms, and was highest following neuroblastoma (SIR = 24.2) and soft tissue sarcoma (SIR = 6.2). Survivors of neuroblastoma had a 329-fold increased risk of renal cell carcinomas; survivors of Hodgkin's lymphoma had a 4.5-fold increased risk of gastrointestinal carcinomas. Significantly elevated risk of head and neck carcinoma occurred in survivors of soft tissue sarcoma (SIR = 22.6), neuroblastoma (SIR = 20.9), and leukemia (SIR = 20.9). Young survivors of childhood cancers are at increased risk of developing subsequent carcinomas typical of later adulthood, underscoring the importance of long-term follow-up and risk-based screening. Follow-up of the cohort is ongoing to determine lifetime risk and delineate individual characteristics that contribute to ris