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Oxidative damage and inflammation are both implicated in the genesis of hypertension; however, the mechanisms by which these stimuli promote hypertension are not fully understood. Here, we have described a pathway in which hypertensive stimuli promote dendritic cell (DC) activation of T cells, ultimately leading to hypertension. Using multiple murine models of hypertension, we determined that proteins oxidatively modified by highly reactive γ-ketoaldehydes (isoketals) are formed in hypertension and accumulate in DCs. Isoketal accumulation was associated with DC production of IL-6, IL-1β, and IL-23 and an increase in costimulatory proteins CD80 and CD86. These activated DCs promoted T cell, particularly [CD8.sup.+] T cell, proliferation; production of IFN-γ and IL-17A; and hypertension. Moreover, isoketal scavengers prevented these hypertension-associated events. Plasma F2-isoprostanes, which are formed in concert with isoketals, were found to be elevated in humans with treated hypertension and were markedly elevated in patients with resistant hypertension. Isoketal-modified proteins were also markedly elevated in circulating monocytes and DCs from humans with hypertension. Our data reveal that hypertension activates DCs, in large part by promoting the formation of isoketals, and suggest that reducing isoketals has potential as a treatment strategy for this disease., Introduction It is well established that inflammation is involved in the genesis of hypertension (1). T cells and macrophages accumulate in the kidneys and vasculature of animals with experimental hypertension [...]

Triple-negative breast cancer (TNBC) is a highly diverse group of cancers, and subtyping is necessary to better identify molecular-based therapies. In this study, we analyzed gene expression (GE) profiles from [...]

Many breast cancers exhibit a degree of dependence on estrogen for tumor growth. Although several therapies have been developed to treat individuals with estrogen-dependent breast cancers, some tumors show de novo or acquired resistance, rendering them particularly elusive to current therapeutic strategies. Understanding the mechanisms by which these cancers develop resistance would enable the development of new and effective therapeutics. In order to determine mechanisms of escape from hormone dependence in estrogen receptor-positive (ER-positive) breast cancer, we established 4 human breast cancer cell lines after long-term estrogen deprivation (LTED). LTED cells showed variable changes in ER levels and sensitivity to 17 -estradiol. Proteomic profiling of LTED cells revealed increased phosphorylation of the mammalian target of rapamy-cin (mTOR) substrates p70S6 kinase and p85S6 kinase as well as the PI3K substrate AKT. Inhibition of PI3K and mTOR induced LTED cell apoptosis and prevented the emergence of hormone-independent cells. Using reverse-phase protein microarrays, we identified a breast tumor protein signature of PI3K pathway activation that predicted poor outcome after adjuvant endocrine therapy in patients. Our data suggest that upon adaptation to hormone deprivation, breast cancer cells rely heavily on PI3K signaling. Our findings also imply that acquired resistance to endocrine therapy in breast cancer may be abrogated by combination therapies targeting both ER and PI3K pathways., Introduction Two-thirds of breast cancers express estrogen receptor α (ER) and/or progesterone receptor, which typically indicate a degree of estrogen dependence for growth. Treatment options for such patients include endocrine [...]

The DNA damage response (DDR) has a critical role in maintaining genome integrity and serves as a barrier to tumorigenesis by promoting cell-cycle arrest, DNA repair, and apoptosis. The DDR is activated not only by genotoxic agents that induce DNA damage, but also during aberrant cell-division cycles caused by activated oncogenes and inactivated tumor suppressors. Here we use RNAi and cDNA overexpression screens in human cells to identify genes that, when deregulated, lead to activation of the DDR. The RNAi screen identified 73 genes that, when silenced in at least two cell types, cause DDR activation. Silencing several of these genes also caused an increased frequency of micronuclei, a marker of genetically unstable cells. The cDNA screen identified 97 genes that when overexpressed induce DDR activation in the absence of any exogenous genotoxic agent, with an overrepresentation of genes linked to cancer. Secondary RNAi screens identified CDK2-interacting protein (CINP) as a cell-cycle checkpoint protein. CINP interacts with ATR-interacting protein and regulates ATR-dependent signaling, resistance to replication stress, and G2 checkpoint integrity. ataxia telangiectasia-mutated and Rad3-related | ATR-interacting protein | checkpoint | DNA damage response www.pnas.org/cgi/doi/10.1073/pnas.0909345106

In human breast cancer, loss of carcinoma cell--specific response to TGF-[beta] signaling has been linked to poor patient prognosis. However, the mechanisms through which TGF-[beta] regulates these processes remain largely unknown. In an effort to address this issue, we have now identified gene expression signatures associated with the TGF-[beta] signaling pathway in human mammary carcinoma cells. The results strongly suggest that TGF-[beta] signaling mediates intrinsic, stromal-epithelial, and host-tumor interactions during breast cancer progression, at least in part, by regulating basal and oncostatin M--induced CXCL1, CXCL5, and CCL20 chemokine expression. To determine the clinical relevance of our results, we queried our TGF-[beta]--associated gene expression signatures in 4 human breast cancer data sets containing a total of 1,319 gene expression profiles and associated clinical outcome data. The signature representing complete abrogation of TGF-[beta] signaling correlated with reduced relapse-free survival in all patients; however, the strongest association was observed in patients with estrogen receptor--positive (ER-positive) tumors, specifically within the luminal A subtype. Together, the results suggest that assessment of TGF-[beta] signaling pathway status may further stratify the prognosis of ER-positive patients and provide novel therapeutic approaches in the management of breast cancer., Introduction TGF-[beta] ligands are key factors in the regulation of tumor initiation, progression, and metastasis. In human breast cancer, alterations in the carcinoma cell response to TGF-[beta] signaling have been [...]

The Blinder-Oaxaca (B-O) decomposition has been widely used in continuous outcome comparisons between two groups of people; however, controversies and limitations with this method remain. In this paper, operating under the same-model structure, we suggest employing a multiple regression using a dummy variable to represent discrimination, and we compare this strategy with results obtained from a B-O decomposition and a Neumark decomposition, both in theory and using a simulation study. In addition, we extend these methods to cover binary outcomes. Keywords: Blinder-Oaxaca decompostion, Neumark decomposition, multiple regression, discrimination DOI 10.3233/JEM-2009-0320

Many phytochemicals in fruits and vegetables have been shown to have cancer-inhibitory effects in animal studies. These effects on cancer, however, have not been clearly demonstrated in human studies. This study investigated the association between fruit and vegetable intakes and the risk of adenomateus polyps. Participants were part of the Tennessee Colorectal Polyp Study. Eligible participants aged 40-75 y were recruited from patients undergoing colonoscopy at 2 medical centers in Nashville, Tennessee from 2003 to 2005. Cases had at least one adenoma and controls were polyp free. Dietary intake was assessed using a self-administered FFQ. Associations between dietary intakes and adenoma risk were evaluated using unconditional logistic regression with restricted cubic function spline. In multivariate analyses of 764 cases and 1517 controls, increased intakes of total fruits, berries, fruit juice, and green leafy vegetables were associated with reduced adenoma risk. The odds ratio for upper tertile intake compared with lower was 0.66 (95% CI = 0.51-0.86) for total fruits, 0.64 (95% CI = 0.47-0.87) for berries, 0.72 (95% CI = 0.56-0.92) for fruit juice, and 0.74 (95% CI = 0.58-0.96) for green vegetables. This study provides additional evidence that high total fruit intake and certain fruit and vegetable intakes may be associated with a reduced risk of colorectal adenomas. J. Nutr. 139: 340-344, 2009.

ABSTRACT Background Promoter hypermethylation coupled with loss of heterozygosity at the same locus results in loss of gene function in many tumor cells. The "rules" governing which genes are methylated [...]

Mortality in critically ill patients with acute renal failure (ARF) remains high. Hyperglycemia associated with insulin resistance has been associated with adverse outcomes in critically ill intensive care unit (ICU) patients but has not been examined specifically in patients with ARF. We used data from a subcohort (n = 90) of the Program to Improve Care in Acute Renal Disease (PICARD), an observational study of 618 adult ICU patients with ARF in whom nephrology service consultation was obtained. We obtained simultaneous measurements of serum glucose, insulin, insulin-like growth factor (IGF)-I, and IGF-1 binding proteins (IGFBP) in 90 patients. Daily glucose determinations were obtained from a larger fraction of the PICARD cohort (n = 509). Among the 90 patients with intensive metabolic monitoring, glucose concentrations in survivors were significantly lower than in nonsurvivors throughout the 5-wk period (P = 0.008, adjusted P = 0.013). In the larger PICARD cohort (n = 509), hyperglycemia was also significantly associated with in-hospital mortality. Mean insulin concentrations were significantly higher (431 [+ or -] 508 vs. 234 [+ or -] 189 pmol/l, P = 0.03), mean homeostasis model of insulin resistance levels were significantly higher (24.1 [+ or -] 30.0 vs. 11.7 [+ or -] 12.5, P = 0.04), and IGFBP-3 concentrations were significantly lower (1,190 [+ or -] 498 vs. 1,470 [+ or -] 581 [micro]g/l, P = 0.02) among nonsurvivors compared with survivors. Insulin resistance as defined by hyperglycemia in the setting of higher insulin concentrations may be associated with mortality in critically ill patients with ARF. The IGF-IGFBP axis may play an important role in this process. glucose; homeostasis model of insulin resistance; insulin-like growth factor-1; insulin-like growth factor binding protein-3; catabolism

Instability of repetitive sequences is a hallmark of human cancer, and its enhancement has been linked to oxidative stress. Malondialdehyde is an endogenous product of oxidative stress that reacts with guanine to form the exocyclic adduct, pyrimido[1,2-[alpha]]purin-10(3H)-one ([M.sub.1]G). We used site-specifically modified single- and double-stranded vectors to investigate the mutagenic potential of [M.sub.1]G in bacteria and mammalian cells. [M.sub.1]G induced frameshift mutations (-1 and -2) when positioned in a reiterated [(CpG).sub.4] sequence but not when positioned in a nonreiterated sequence in Escherichia coli and in COS-7 cells. The frequency of frameshift mutations was highest when [M.sub.1]G was placed at the third G in the sequence. [M.sub.1]G induced base pair substitutions at comparable frequencies in both sequence contexts in COS-7 cells. These studies indicate that [M.sub.1]G, an endogenously generated product of oxidative stress, induces sequence-dependent frameshift mutations and base pair substitutions in bacteria and in mammalian cells. This finding suggests a potential role for the [M.sub.1]G lesion in the induction of mutations commonly associated with human diseases.

Limited use of substrate ecospace by a meager infauna in streams and lakes is indicated by analysis of more than 10 000 observations of bioturbation in Permian through Jurassic freshwater deposits. In contrast, marine substrates have been inhabited and bioturbated since the Cambrian; colonization of freshwater substrates differed fundamentally from that of marine substrates. Bioturbation-enhanced flux of dissolved materials across the sediment-water interface was not operating until after the Paleozoic in freshwater ecosystems. Keywords: bioturbation, burrowing, Triassic, Permian.

Byline: Charles D. Blanke (1), Michael Stipanov (2), Jason Morrow (3), Mace Rothenberg (2), Rebecca Chinery (4), Yu Shyr (5), Robert Coffey (6), David H. Johnson (2), Steven D. Leach (7), R. Daniel Beauchamp (7) Keywords: antioxidant; chemotherapy Abstract: Six patients with incurable malignancies wereoriginally treated with vitamin E, 3200 IU/day for fourteendays, followed by the same dose of vitamin E daily plus LCV(20 mg/m.sup.2 iv bolus daily x 5) with 5FU (425mg/m.sup.2 iv bolus immediately following LCV). The sameschedule of LCV and 5FU was repeated 4 weeks later, then every5 weeks indefinitely. When 3 of the first 6 had grade 3/4toxicity, six more patients were treated on the identicaldrugs and schedule. Seven of twelve total patients had one ormore grade 3/4 toxicities. Neutropenia, abdominal pain, anddiarrhea were most common. No patient had a documentedresponse, though seven patients did have stable disease.Though the combination of vitamin E and chemotherapy wastoxic, this trial demonstrated maximal therapeutic doses ofvitamin E can be combined with standard 5FU and LCV, withoutsignificantly increasing the side effects of thechemotherapy itself. Author Affiliation: (1) Division of Hematology and Medical Oncology, Department of Medicine, Oregon Health Sciences University, Portland, OR, USA (2) Division of Medical Oncology Department of Medicine, Vanderbilt-Ingram Cancer Center, Nashville, TN, USA (3) Division of Clinical Pharmacology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Nashville, TN, USA (4) GI Research Unit, Mayo Foundation, Rochester, MN, USA (5) Division of Biostatistics, Department of Preventive Medicine, Vanderbilt-Ingram Cancer Center, Nashville, TN, USA (6) Division of Gastroenterology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Nashville, TN, USA (7) Division of Surgical Oncology, Department of General Surgery, Vanderbilt-Ingram Cancer Center, Nashville, TN, USA Article History: Registration Date: 11/10/2004

Byline: Jonathan E. Dowell (1), David H. Johnson (1), John S. Rogers (2), Yu Shyr (1), Nancy McCullough (1), Peggy Krozely (1), Russell F. DeVore (1) Keywords: MGI-114; non-small cell lung cancer; 6-hydroxymethylacylfulvene; chemotherapy; irofulven Abstract: Purpose: To test the efficacy and safety ofthe novel antitumor agent MGI-114 (NSC 683863) in patientswith advanced non-small cell lung cancer (NSCLC) previouslytreated with chemotherapy. Methods: A two-stageaccrual design was used to ensure detection of a true responserate of at least 20% with a type I error of .04.Eligible patients received 11 mg/m.sup.2 daily for fiveconsecutive days. Cycles were repeated every 28 days.Results: Fifteen patients received a total of 34cycles of MGI-114. All patients had a performance status of 0or 1. Eleven patients had previously received carboplatin andpaclitaxel +/- radiation. Two patients had receivedcisplatin and CPT-11, one patient had received weeklypaclitaxel, and one patient had received carboplatin anddocetaxel. None of the first 15 patients enrolled experiencedobjective tumor response, and the study was closed. Fortypercent of patients developed aY= grade 2 thrombocytopenia.Grade 3 nausea and aY= grade 2 vomiting were observed in40% and 47% of patients respectively.Thirty-three percent of patients experienced aY= grade 2fatigue. Conclusions: MGI-114, at this dose andschedule, does not have significant activity as second linetherapy for patients with advanced NSCLC. Author Affiliation: (1) The Vanderbilt Clinic, Vanderbilt-Ingram Cancer Center, Nashville, TN, USA (2) Department of Medicine, School of Medicine, West Virginia University, Morgantown, WV, USA Article History: Registration Date: 11/10/2004

Children with bronchopulmonary dysplasia (BPD) may weigh less and have smaller head circumference measurements than children without histories of BPD. BPD is chronic lung insufficiency caused by long-term use of an artificial ventilator during the newborn period. Researchers analyzed the growth measurements of 406 eight- to 10-year-old children who had very low birth weights. Ninety-five children had experienced BPD. These children were more likely to have lower birth weights, to be premature, and to experience complications as newborns. They were prone to develop cerebral palsy. Although children with BPD had lower weight and head circumference measurements than children without BPD, these differences were not significant after accounting for confounding factors such as male sex and black race., ABSTRACT. Objective. To determine the effect of bronchopulmonary dysplasia (BPD) on growth at school age. Design. A prospective cohort study. Methods. The sample included 406 children selected from a reconstructed cohort of infants of very low birth weight previously enrolled in a multisite, randomized, controlled clinical trial. The children were contacted at 8 to 10 years of age. Height, weight, and head circumference (HC) were measured. Possible confounders including sociodemographic data, and neonatal factors were also recorded. Results. The children in the BPD group were significantly smaller in weight (z score, -0.50 [+ or -] 1.19 SD vs -0.06 [+ or -] 1.30 SD) and HC (z score, -1.41 [+ or -] 1.32 SD vs -0.63 [+ or -] 1.62 SD) than those without BPD. However, after controlling for cofounders (using analysis of covariance), no significant differences were demonstrated between the two groups. Power analyses showed that a difference of at least 0.43 z score units could have been detected. The previously documented associations between BPD and suspected confounders were reconfirmed. Conclusions. Significant differences were noted between children with and without BPD for weight and HC but not height. When possible confounders were taken into account, the differences were no longer appreciated. Thus, the previously reported poor growth in children with BPD may have been related to other factors and not necessarily to BPD. Pediatrics 1995;95:855-859; bronchopulmonary dysplasia, growth, outcome, very low birth weight, prematurity., Bronchopulmonary dysplasia (BPD) continues to be an important sequela of prematurity and respiratory distress syndrome despite the routine use of surfactant replacement therapy. The incidence of BPD varies from 5% [...]

Cigarette smoking appears to oxidize fats, which could ultimately lead to atherosclerosis. Researchers took blood and urine samples from 10 smokers before and after they smoked three cigarettes in a 30-minute period. They also took blood and urine samples from 10 nonsmokers. All samples were tested for a group of chemicals called F2-isoprostanes, which are formed in the body when fats are oxidized. Seven of the smokers had higher blood levels of F2-isoprostanes than nonsmokers, even before they smoked the three cigarettes. They also had higher levels of F2-isoprostane metabolites in their urine, and lower levels of vitamin C in their blood. When eight of the smokers stopped smoking for two weeks, their blood levels of F2-isoprostane dropped significantly. Some of the smokers had blood levels of F2-isoprostanes that were not significantly higher than in nonsmokers, indicating that some people may be naturally resistant to the effects of smoking.

Primary care practitioners (PCPs) do not appear to be actively involved in providing cardiac care for children with serious heart disease. Researchers surveyed parents of 92 children with serious heart disease, PCPs of 79 children, and pediatric cardiologists (PCs) of 88 children to determine the perceived and actual role of PCPs in treating children with serious heart disease. Results revealed that 91% of parents relied on PCPs for their child's preventative medical care. Only 4% of parents reported PCP involvement in their child's cardiac care. Few parents expressed confidence in a PCP's ability to handle many specific needs of children with heart disease. Few parents discussed psychosocial, economic and genetic aspects of the child's illness with the PCP. Both PCPs and PCs saw a greater role for PCPs in providing care for heart disease and general chronic illness than did parents., Objective. To determine the roles of primary care physicians and specialists in the medical care of children with serious heart disease. Setting. Pediatric Cardiology Division; Tertiary Care Children's Hospital. Subjects. Convenience sample of parents, primary care physicians, and pediatric cardiologists of 92 children with serious heart disease. Design. Questionnaire study; questionnaires based on 16 medical care needs, encompassing basic primary care services, care specific to the child's heart disease and general issues related to chronic illness. Results. All children had a primary care physician (PCP), and both they and the parents (P) reported high utilization of PCP for basic primary care services. However, there was little involvement of PCP in providing care for virtually any aspect of the child's heart disease. Parents expressed a low level of confidence in the ability of PCP in general or their child's own PCP to meet many of their child's medical care needs. Both PCP and pediatric cardiologists (PC) were significantly more likely than parents to see a role for PCP in providing for care specific to the heart disease as well as more general issues related to chronic illness. PC and PCP generally agreed about the role PCP should play, although PC saw a bigger role for PCP in providing advice about the child's activity than PCP themselves did. PC were less likely to see the PCP as able to follow the child for long term complications than PCP did. PC were more likely than PCP to believe that PCP were too busy or were inadequately reimbursed to care for children with serious heart disease. Only about one-third of parents reported discussing psychosocial, family, economic, or genetic issues with any provider, and PCP were rarely involved in these aspects of chronic illness. Conclusions. Primary care physicians do not take an active role in managing either the condition-specific or the more general aspects of this serious chronic childhood illness. With appropriate information and support from their specialist colleagues primary care physicians could provide much of the care for this group of children. Generalists and specialists are both responsible for educating and influencing parents about the role primary care physicians can play in caring for children with serious chronic illness. Pediatrics 1994;94:284-290; primary care, chronic illness, congenital heart disease.

While laparoscopes are used for numerous minimally invasive (MI) procedures, MI liver resection and ablative surgery is infrequently performed. The paucity of cases is due to the restriction of the field of view by the laparoscope and the difficulty in determining tumor location and margins under video guidance. By merging MI surgery with interactive, image-guided surgery (IIGS), we hope to overcome localization difficulties present in laparoscopic liver procedures. One key component of any IIGS system is the development of accurate registration techniques to map image space to physical or patient space. This manuscript focuses on the accuracy and analysis of the direct linear transformation (DLT) method to register physical space with laparoscopic image space on both distorted and distortion-corrected video images. Experiments were conducted on a liver-sized plastic phantom affixed with 20 markers at various depths. After localizing the points in both physical and laparoscopic image space, registration accuracy was assessed for different combinations and numbers of control points (n) to determine the quantity necessary to develop a robust registration matrix. For n = 11, average target registration error (TRE) was 0.70 [+ or -] 0.20 mm. We also studied the effects of distortion correction on registration accuracy. For the particular distortion correction method and laparoscope used in our experiments, there was no statistical significance between physical to image registration error for distorted and corrected images. In cases where a minimum number of control points (n = 6) are acquired, the DLT is often not stable and the mathematical process can lead to high TRE values. Mathematical filters developed through the analysis of the DLT were used to prospectively eliminate outlier cases where the TRE was high. For n = 6, prefilter average TRE was 17.4 [+ or -] 153 mm for all trials; when the filters were applied, average TRE decreased to 1.64 [+ or -] 1.10 mm for the remaining trials. Index Terms--Image distortion correction, image-guided surgery, image registration, minimally invasive surgery.

In a previous study we demonstrated that automatic retrospective registration algorithms can frequently register magnetic resonance (MR) and computed tomography (CT) images of the brain with an accuracy of better than 2 mm, but in that same study we found that such algorithms sometimes fail, leading to errors of 6 mm or more. Before these algorithms can be used routinely in the clinic, methods must he provided for distinguishing between registration solutions that are clinically satisfactory and those that are not. One approach is to rely on a human observer to inspect the registration results and reject images that have been registered with insufficient accuracy. In this paper, we present a methodology for evaluating the efficacy of the visual assessment of registration accuracy. Since the clinical requirements for level of registration accuracy are likely to be application dependent, we have evaluated the accuracy of the observer's estimate relative to six thresholds: 1-6 mm. The performance of the observers was evaluated relative to the registration solution obtained using external fiducial markers that are screwed into the patient's skull and that are visible in both MR and CT images. This fiducial marker system provides the gold standard for our study. Its accuracy is shown to be approximately 0.5 mm. Two experienced, blinded observers viewed five pairs of clinical MR and CT brain images, each of which had each been misregistered with respect to the gold standard solution. Fourteen misregistrations were assessed for each image pair with misregistration errors distributed between 0 and 10 mm with approximate uniformity. For each misregistered image pair each observer estimated the registration error (in millimeters) at each of five locations distributed around the head using each of three assessment methods. These estimated errors were compared with the errors as measured by the gold standard to determine agreement relative to each of the six thresholds, where agreement means that the two errors lie on the same side of the threshold. The effect of error in the gold standard itself is taken into account in the analysis of the assessment methods. The results were analyzed by means of the Kappa statistic, the agreement rate, and the area of receiver-operating-characteristic (ROC) curves. No assessment performed well at 1 mm, but all methods performed well at 2 mm and higher. For these five thresholds, two methods agreed with the standard at least 80% of the time and exhibited mean ROC areas greater than 0.84. One of these same methods exhibited Kappa statistics that indicated good agreement relative to chance (Kappa > 0.6) between the pooled observers and the standard for these same live thresholds. Further analysis demonstrates that the results depend strongly on the choice of the distribution of misregistration errors presented to the observers. Index Terms - Accuracy, computed tomography (CT), image registration, magnetic resonance (MR), retrospective registration, visual assessment.