bluuebunny/crossref_metadata_2025 huggingface dataset:
Angiotensin II Subtype 2 Receptor: Potential Therapy
Authors: Siragy Helmy M.
Published: November 2009

The angiotensin II type 2 (AT2R) receptor is highly expressed during fetal development but rapidly declines with aging and is limited to certain organs. However, this receptor is reexpressed in response stress or injury. AT2R is believed to play a protective role by counteracting the effects of the angiotensin II type 1 receptor. AT2R enhances vasodilation, renal sodium excretion, and nitric oxide production. AT2R also has antiproliferation, antihypertrophy, and anti‐inflammation effects. The role of AT2R in human health and disease is not well established yet, mainly due to the lack of tools to manipulate this receptor. With the recent development of an AT2R nonpeptide agonist, the function of this receptor and its role in disease management is being investigated.
Measuring evolutionary responses to global warming: cautionary lessons fromDrosophila
Authors: RODRÍGUEZ‐TRELLES FRANCISCO , RODRÍGUEZ MIGUEL ÁNGEL
Published: November 2009

Abstract. 1. Understanding evolutionary responses to global climate warming can be dauntingly complex. But, primarily, it requires careful quantification of rates of temporal change of biomonitors.

2. Long‐term biomonitoring programs capitalize on traits for which there already exist retrospective measurements. Those programs are thus faced with the decision as to the appropriate time to update historical records, especially in species whose gene frequencies cycle over the successive seasons. In these cases, the time during the year at which descendant populations are sampled needs to take into account effects of the lengthening growing season that can impose direct selection on specific genotypes and, concomitantly, indirect selection on photoperiodic response.

3. Standardising new and past collections by calendar date can lead to an overestimation of the magnitude of long‐term responses to global warming; standardising by equivalent seasonal temperature conditions can lead to an underestimation of the magnitude of long‐term responses to global warming.

4. The results of a recent monitoring study withDrosophilaindicate that caution should be exercised in how the updating of historical records is used to quantify evolutionary responses to global warming.
Simple mechanical analogs of rapid adiabatic passage in atomic physics
Authors: Shore B. W. , Gromovyy M. V. , Yatsenko L. P. , Romanenko V. I.
Published: November 2009

We discuss two mechanical systems in which the approximate equations of motion are the same as the rapid adiabatic passage of a two-state quantum-mechanical system, such as that which occurs with quasistatic interactions and from the quasiperiodic action of a chirped-frequency laser pulse. We discuss a pair of masses on springs, weakly coupled by another spring, one of whose spring constants varies slowly, and a pair of coupled pendula, where the length of one pendulum slowly changes. In each example an approximation analogous to the rotating-wave approximation used in the corresponding quantum system brings the second-order macroscopic equations of motion into first-order form, and a slow variation in a system parameter characteristic leads to adiabatic change and rapid adiabatic passage.
Anabolic-androgenic steroid use among young male and female athletes: is the game to blame?: Table 1
Authors: Harmer P A
Published: November 2009

The use of anabolic-androgenic steroids (AAS) by young athletes has been a primary concern of sports governing bodies because of the implications for unfair advantage in performance and the potential for adverse side effects. Research over several decades indicated a lifetime prevalence of AAS use for adolescent males of 4–6% and for females of 1.5–3%, indicating a problem involving millions of athletes and a potential epidemic of AAS-related pathologies. However, recent studies have questioned the presumption that participation in organised sport is the primary risk factor for AAS use in adolescents as well as the extant estimates of the magnitude of the problem. Increasing evidence indicates that AAS use is associated with non-athletes and is linked to a broader syndrome of problem behaviours rather than efforts to achieve sporting success, and that sports participation may be protective against AAS use. Moreover, employing lifetime prevalence to gauge AAS use limits accurate evaluation of the personal and public health risk as the majority of respondents are not habitual users. Previous studies may have also inflated prevalence values through ambiguously worded survey questions and other design flaws, and few data are available on actual dosages. Prevention efforts need to be focused beyond organised sport and target the general adolescent population rather than athletes and should be founded on interventions with demonstrated efficacy for delinquent, antisocial and self-destructive behaviours rather than the ethical imperative of fair play.
Assess and interpret the visual fields at the bedside
Authors: Cooper S A , Metcalfe R A
Published: November 2009

Understanding and applying a bedside visual field assessment is an important skill for the neurologist. By appreciating some basic anatomical and physiological principles it is possible to target the examination appropriately, thus gaining important diagnostic information with the minimum of fuss. Specific patterns of visual loss are caused by damage at various sites within the visual pathway. This review focuses on techniques that can be used at the bedside to identify common visual field defects and cites examples by dividing the visual system into its component parts. We urge the use of an appropriately sized red pin and berate the well worn “waggling finger” technique.
Stable Carbon and Nitrogen Isotope Tracers of Trophic Dynamics in Natural Populations and Fisheries of the Lahontan Lake System, Nevada
Authors: Estep Marilyn L. F. , Vigg Steven
Published: November 2009

The influence of combined inorganic N on the growth of N2-fixing blue-green algae (Aphanizomenon flos-aquae) in Lahontan Reservoir was detected with N isotopic compositions (δ15N = + 1.2 to + 7.0) that were enriched in 15N. In Pyramid Lake, however, the δ15N of the entire food web was influenced by a contribution of isotopically light N released from N2-fixing blue-green algae (Nodularia spumigena). Carbon isotope ratios (δ13C) of these unpalatable, blue-green algae from both lakes were different enough from the zooplankton and higher animals to preclude a direct trophic link. An enrichment in 13C with trophic level in the food chain was measured in both lakes. Carbon isotope ratio measurements clearly illustrated the isotopic similarity between hatchery-raised Lahontan cutthroat trout (Salmo clarki henshawi) and cui-ui (Chasmistes cujus) and the artificial diet, but differed from the δ13C of their wild counterparts consuming natural foods. There is a consistent isotope fractionation between the δ13C of scales and the δ13C of muscle from fish that is species specific. This finding demonstrates that fish scales, as well as muscle, can be used to determine diet.
Prey Selection by Freshwater Predators with Different Foraging Strategies
Authors: Cooper Scott D. , Smith Daniel W. , Bence James R.
Published: November 2009

We observed several freshwater predators, including the odonate larvae Pachydiplax longipennis and Anax junius, the hemipterans Notonecta unifasciata and Buenoa scimitra, the dytiscid larva Acilius semisulcatus, and juvenile Gambusia affinis, feeding on a variety of microcrustacean prey and determined the frequency of the component parts of predator–prey interactions (encounter, attack, capture, ingestion). Encounter rates were the most important determinant of predator selectivity when predators were presented with a variety of microcrustacean prey. When only copepod species were used as prey, however, both encounter rates and capture success were important in determining predator diets. We used our data to test hypotheses concerning relationships between predator foraging mode and patterns of prey selection: mobile predators exhibited stronger selection for sedentary prey than did sit-and-wait predators; our own and literature data also indicated that macroinvertebrate sit-and-wait predators are better able to capture, and have higher selectivity for evasive prey than do mobile predators. A predator's attack acceleration, however, may be a better predictor of its selectivity for evasive versus nonevasive prey than its mean swimming speed.
Protein restriction during pregnancy affects maternal liver lipid metabolism and fetal brain lipid composition in the rat
Authors: Torres Nimbe , Bautista Claudia J. , Tovar Armando R. , Ordáz Guillermo , Rodríguez-Cruz Maricela , Ortiz Victor , Granados Omar , Nathanielsz Peter W. , Larrea Fernando , Zambrano Elena
Published: November 2009

Suboptimal developmental environments program offspring to lifelong metabolic problems. The aim of this study was to determine the impact of protein restriction in pregnancy on maternal liver lipid metabolism at 19 days of gestation (dG) and its effect on fetal brain development. Control (C) and restricted (R) mothers were fed with isocaloric diets containing 20 and 10% of casein. At 19 dG, maternal blood and livers and fetal livers and brains were collected. Serum insulin and leptin levels were determinate in mothers. Maternal and fetal liver lipid and fetal brain lipid quantification were performed. Maternal liver and fetal brain fatty acids were quantified by gas chromatography. In mothers, liver desaturase and elongase mRNAs were measured by RT-PCR. Maternal body and liver weights were similar in both groups. However, fat body composition, including liver lipids, was lower in R mothers. A higher fasting insulin at 19 dG in the R group was observed (C = 0.2 ± 0.04 vs. R = 0.9 ± 0.16 ng/ml, P < 0.01) and was inversely related to early growth retardation. Serum leptin in R mothers was significantly higher than that observed in C rats (C = 5 ± 0.1 vs. R = 7 ± 0.7 ng/ml, P < 0.05). In addition, protein restriction significantly reduced gene expression in maternal liver of desaturases and elongases and the concentration of arachidonic (AA) and docosahexanoic (DHA) acids. In fetus from R mothers, a low body weight (C = 3 ± 0.3 vs. R = 2 ± 0.1 g, P < 0.05), as well as liver and brain lipids, including the content of DHA in the brain, was reduced. This study showed that protein restriction during pregnancy may negatively impact normal fetal brain development by changes in maternal lipid metabolism.
Simple modeling allows prediction of steady-state glucose disposal rate from early data in hyperinsulinemic glucose clamps
Authors: Singal Pooja , Muniyappa Ranganath , Chisholm Robin , Hall Gail , Chen Hui , Quon Michael J. , Mather Kieren J.
Published: November 2009

After a constant insulin infusion is initiated, determination of steady-state conditions for glucose infusion rates (GIR) typically requires ≥3 h. The glucose infusion follows a simple time-dependent rise, reaching a plateau at steady state. We hypothesized that nonlinear fitting of abbreviated data sets consisting of only the early portion of the clamp study can provide accurate estimates of steady-state GIR. Data sets from two independent laboratories were used to develop and validate this approach. Accuracy of the predicted steady-state GDR was assessed using regression analysis and Altman-Bland plots, and precision was compared by applying a calibration model. In the development data set ( n = 88 glucose clamp studies), fitting the full data set with a simple monoexponential model predicted reference GDR values with good accuracy (difference between the 2 methods −0.37 mg·kg−1·min−1) and precision [root mean square error (RMSE) = 1.11], validating the modeling procedure. Fitting data from the first 180 or 120 min predicted final GDRs with comparable accuracy but with progressively reduced precision [fitGDR-180 RMSE = 1.27 ( P = NS vs. fitGDR-full); fitGDR-120 RMSE = 1.56 ( P < 0.001)]. Similar results were obtained with the validation data set ( n = 183 glucose clamp studies), confirming the generalizability of this approach. The modeling approach also derives kinetic parameters that are not available from standard approaches to clamp data analysis. We conclude that fitting a monoexponential curve to abbreviated clamp data produces steady-state GDR values that accurately predict the GDR values obtained from the full data sets, albeit with reduced precision. This approach may help reduce the resources required for undertaking clamp studies.
Seasonal proteomic changes reveal molecular adaptations to preserve and replenish liver proteins during ground squirrel hibernation
Authors: Epperson L. Elaine , Rose James C. , Carey Hannah V. , Martin Sandra L.
Published: November 2009

Hibernators are unique among mammals in their ability to survive extended periods of time with core body temperatures near freezing and with dramatically reduced heart, respiratory, and metabolic rates in a state known as torpor. To gain insight into the molecular events underlying this remarkable physiological phenotype, we applied a proteomic screening approach to identify liver proteins that differ between the summer active (SA) and the entrance (Ent) phase of winter hibernation in 13-lined ground squirrels. The relative abundance of 1,600 protein spots separated on two-dimensional gels was quantitatively determined using fluorescence difference gel electrophoresis, and 74 unique proteins exhibiting significant differences between the two states were identified using liquid chromatography followed by tandem mass spectrometry (LC-MS/MS). Proteins elevated in Ent hibernators included liver fatty acid-binding protein, fatty acid transporter, and 3-hydroxy-3-methylglutaryl-CoA synthase, which support the known metabolic fuel switch to lipid and ketone body utilization in winter. Several proteins involved in protein stability and protein folding were also elevated in the Ent phase, consistent with previous findings. In contrast to transcript screening results, there was a surprising increase in the abundance of proteins involved in protein synthesis during Ent hibernation, including several initiation and elongation factors. This finding, coupled with decreased abundance of numerous proteins involved in amino acid and nitrogen metabolism, supports the intriguing hypothesis that the mechanism of protein preservation and resynthesis is used by hibernating ground squirrels to help avoid nitrogen toxicity and ensure preservation of essential amino acids throughout the long winter fast.
A General Total Variation Minimization Theorem for Compressed Sensing Based Interior Tomography
Authors: Han Weimin , Yu Hengyong , Wang Ge
Published: November 2009

Recently, in the compressed sensing framework we found that a two‐dimensional interior region‐of‐interest (ROI) can be exactly reconstructed via the total variation minimization if the ROI is piecewise constant (Yu and Wang, 2009). Here we present a general theorem charactering a minimization property for a piecewise constant function defined on a domain in any dimension. Our major mathematical tool to prove this result is functional analysis without involving the Dirac delta function, which was heuristically used by Yu and Wang (2009).
Fluorescence Intensity Normalisation: Correcting for Time Effects in Large-Scale Flow Cytometric Analysis
Authors: Dendrou Calliope A. , Fung Erik , Esposito Laura , Todd John A. , Wicker Linda S. , Plagnol Vincent
Published: November 2009

A next step to interpret the findings generated by genome-wide association studies is to associate molecular quantitative traits with disease-associated alleles. To this end, researchers are linking disease
risk alleles with gene expression quantitative trait loci (eQTL). However, gene expression at the
mRNA level is only an intermediate trait and flow cytometry analysis can provide more downstream
and biologically valuable protein level information in multiple cell subsets simultaneously using freshly
obtained samples. Because the throughput of flow cytometry is currently limited, experiments may
need to span over several weeks or months to obtain a sufficient sample size to demonstrate genetic
association. Therefore, normalisation methods are needed to control for technical variability and compare
flow cytometry data over an extended period of time. We show how the use of normalising
fluorospheres improves the repeatability of a cell surface CD25-APC mean fluorescence intensity phenotype
on CD4+ memory T cells. We investigate two types of normalising beads: broad spectrum and
spectrum matched. Lastly, we propose two alternative normalisation procedures that are usable in the
absence of normalising beads.
Mohs Micrographic Surgery for Dermatofibrosarcoma Protuberans of the Vulva
Authors: Doufekas K. , Duncan T. J. , Williamson K. M. , Varma S. , Nunns D.
Published: November 2009

Introduction. Dermatofibrosarcoma Protuberans (DFSP) is a rare cutaneous tumour of low/intermediate malignant potential, which occasionally arises on the vulva. Historically, the treatment has been wide local excision (WLE). Mohs micrographic surgery (MMS) is now recommended to ensure precise margin control. MMS to treat DFSP of the trunk and extremities is well documented. However, no report to date has described its use in vulval DFSP.Case History. A 39 year old woman presented with a longstanding nodule in the left labium majus. Histology after surgical removal showed an incompletely excised DFSP. MMS was undertaken with primary closure of the defect. Three years following treatment there is no evidence of recurrence.Discussion. The local recurrence rate of DFSP after WLE ranges from 0–75%. Finger-like projections from DFSP into surrounding tissue often results in incomplete excision. Representative vertical sections used in WLE assess less than 1% of the total tumour margin. MMS uses systematic horizontal sectioning. 100% of the tumour margin is microscopically examined. MMS is now advocated to ensure precise margin control.
Chaotic Patterns in Aeroelastic Signals
Authors: Marques F. D. , Vasconcellos R. M. G.
Published: November 2009

This work presents the analysis of nonlinear aeroelastic time series from wing vibrations due to airflow separation during wind tunnel experiments. Surrogate data method is used to justify the application of nonlinear time series analysis to the aeroelastic system, after rejecting the chance for nonstationarity. The singular value decomposition (SVD) approach is used to reconstruct the state space, reducing noise from the aeroelastic time series. Direct analysis of reconstructed trajectories in the state space and the determination of Poincaré sections have been employed to investigate complex dynamics and chaotic
patterns. With the reconstructed state spaces, qualitative analyses may be done, and the attractors evolutions with parametric variation are presented. Overall results reveal complex system dynamics associated with highly separated flow effects together with nonlinear coupling between aeroelastic modes. Bifurcations to the nonlinear aeroelastic system are observed for two investigations, that is, considering oscillations‐induced aeroelastic evolutions with varying freestream speed, and aeroelastic evolutions at constant freestream speed and varying oscillations. Finally, Lyapunov exponent calculation is proceeded in order to infer on chaotic behavior. Poincaré mappings also suggest bifurcations and chaos, reinforced by the attainment of maximum positive Lyapunov exponents.
A MultiScale Gibbs-Helmholtz Constrained Cubic Equation of State
Authors: Lucia Angelo
Published: November 2009

This paper presents a radically new approach to cubic equations of state (EOS) in which the Gibbs-Helmholtz equation is used to constrain the attraction or energy parameter, a. The resulting expressions for for pure components and for mixtures contain internal energy departure functions and completely avoid the need to use empirical expressions like the Soave alpha function. Our approach also provides a novel and thermodynamically rigorous mixing rule for . When the internal energy departure function is computed using Monte Carlo or molecular dynamics simulations as a function of current bulk phase conditions, the resulting EOS is a multiscale equation of state. The proposed new Gibbs-Helmholtz constrained (GHC) cubic equation of state is used to predict liquid densities at high pressure and validated using experimental data from literature. Numerical results clearly show that the GHC EOS provides fast and accurate computation of liquid densities at high pressure, which are needed in the determination of gas hydrate equilibria.
Hypoxia Regulates Insulin Receptor Substrate-2 Expression to Promote Breast Carcinoma Cell Survival and Invasion
Authors: Mardilovich Katerina , Shaw Leslie M.
Published: November 2009

Insulin receptor substrate-2 (IRS-2) belongs to the IRS family of adaptor proteins that function as signaling intermediates for growth factor, cytokine, and integrin receptors, many of which have been implicated in cancer. Although the IRS proteins share significant homology, distinct functions have been attributed to each family member in both normal and tumor cells. In cancer, IRS-2 is positively associated with aggressive tumor behavior. In the current study, we show that IRS-2 expression, but not IRS-1 expression, is positively regulated by hypoxia, which selects for tumor cells with increased metastatic potential. We identify IRS-2 as a novel hypoxia-responsive gene and establish that IRS-2 gene transcription increases in a hypoxia-inducible factor–dependent manner in hypoxic environments. IRS-2 is active to mediate insulin-like growth factor I–dependent signals in hypoxia, and enhanced activation of Akt in hypoxia is dependent on IRS-2 expression. Functionally, the elevated expression of IRS-2 facilitates breast carcinoma cell survival and invasion in hypoxia. Collectively, our results reveal a novel mechanism by which IRS-2 contributes to the aggressive behavior of hypoxic tumor cells. [Cancer Res 2009;69(23):8894–901]
Inhibition of the p38 Kinase Suppresses the Proliferation of Human ER-Negative Breast Cancer Cells
Authors: Chen Lu , Mayer Julie Ann , Krisko Tibor I. , Speers Corey W. , Wang Tao , Hilsenbeck Susan G. , Brown Powel H.
Published: November 2009

p38 kinases are members of the mitogen-activated protein kinase family that transduce signals from various environmental stresses, growth factors, and steroid hormones. p38 is highly expressed in aggressive and invasive breast cancers. Increased levels of activated p38 are markers of poor prognosis. In this study, we tested the hypothesis that blockade of p38 signaling would inhibit breast cancer cell proliferation. We studied breast cancer cell proliferation and cell cycle regulation upon p38 blockade by using three independent approaches: dominant-negative (DN) constructs, small interfering RNA (siRNA), and small molecule inhibitors. p38α and p38δ are the most abundant isoforms expressed by all examined human breast tumors and breast cancer cell lines. Expression of a DN p38 inhibited both anchorage-dependent and -independent proliferation of MDA-MB-468 cells. Silencing of p38α, but not p38δ, using siRNA suppressed MDA-MB-468 cell proliferation. Pharmacologic inhibitors of p38 significantly inhibited the proliferation of p53 mutant and ER-negative breast cancer cells. Whereas p38 has previously been considered as a mediator of stress-induced apoptosis, we propose that p38 may have dual activities regulating survival and proliferation depending on the expression of p53. Our data suggest that p38 mediates the proliferation signal in breast cancer cells expressing mutant but not wild-type p53. Because most ER-negative breast tumors express mutant p53, our results provide the foundation for future development of p38 inhibitors to target p38 for the treatment of p53 mutant and ER-negative breast cancers. [Cancer Res 2009;69(23):8853–61]
Fingerprint of Cell Metabolism in the Experimentally Observed Interstitial pH and pO2 in Solid Tumors
Authors: Molavian Hamid R. , Kohandel Mohammad , Milosevic Michael , Sivaloganathan Sivabal
Published: November 2009

Understanding cancer cell metabolism and targeting associated pathways is a field of increasing interest. Helmlinger and colleagues measured average pH and pO2 as functions of distance from a single blood vessel on the micrometer scale. We show that these results provide unique insight into cancer cell metabolism in vivo when combined with an appropriate mathematical model. We calculate pH as a function of distance from a single blood vessel and for a given metabolism while incorporating a single CO2 buffer with effective diffusion constants. By assuming that cancer cell metabolism is dominated by respiration with a smaller component of glycolysis in the normoxic state, by more balanced respiration and glycolysis in the hypoxic state, and by glycolysis alone in the anoxic state, we are able to semiquantitatively derive the experimental results of Helmlinger and colleagues. We also apply our model to glycolysis-impaired metabolism and show that the low pH and high pO2 observed in these tumors may be related to the substantial shift from a respiration-dominated metabolism to one in which glutaminolysis dominates. Based on this, we propose an in vivo experimental measurement of pH in a glycolysis-impaired tumor to validate the modeling results. [Cancer Res 2009;69(23):9141–7]
Human rRNA Gene Clusters Are Recombinational Hotspots in Cancer
Authors: Stults Dawn M. , Killen Michael W. , Williamson Erica P. , Hourigan Jon S. , Vargas H. David , Arnold Susanne M. , Moscow Jeffrey A. , Pierce Andrew J.
Published: November 2009

The gene that produces the precursor RNA transcript to the three largest structural rRNA molecules (rDNA) is present in multiple copies and organized into gene clusters. The 10 human rDNA clusters represent <0.5% of the diploid human genome but are critically important for cellular viability. Individual genes within rDNA clusters possess very high levels of sequence identity with respect to each other and are present in high local concentration, making them ideal substrates for genomic rearrangement driven by dysregulated homologous recombination. We recently developed a sensitive physical assay capable of detecting recombination-mediated genomic restructuring in the rDNA by monitoring changes in lengths of the individual clusters. To prove that this dysregulated recombination is a potential driving force of genomic instability in human cancer, we assayed the rDNA for structural rearrangements in prospectively recruited adult patients with either lung or colorectal cancer, and pediatric patients with leukemia. We find that over half of the adult solid tumors show detectable rDNA rearrangements relative to either surrounding nontumor tissue or normal peripheral blood. In contrast, we find a greatly reduced frequency of rDNA alterations in pediatric leukemia. This finding makes rDNA restructuring one of the most common chromosomal alterations in adult solid tumors, illustrates the dynamic plasticity of the human genome, and may prove to have either prognostic or predictive value in disease progression. [Cancer Res 2009;69(23):9096–104]
Involvement of Mitochondrial DNA Sequence Variations and Respiratory Activity in Late Complications following Radiotherapy
Authors: Alsbeih Ghazi A. , Al-Harbi Najla M. , El-Sebaie Medhat M. , Al-Rajhi Nasser M. , Al-Hadyan Khaled S. , Abu-Amero Khaled K.
Published: November 2009

Purpose: Mitochondria and ionizing radiation overlap in a number of features; for instance, both generate harmful reactive oxygen species, and that radiation can induce cell death through the intermediary of mitochondria. Because a number of genetic variations in nuclear genes are frequently associated with response to cancer treatment, the aim of this case-control study was to test the hypothesis that mitochondrial DNA (mtDNA) genetic variations can contribute to patient-to-patient variability in normal tissue response to radiotherapy.

Experimental Design: Thirty-two nasopharyngeal carcinomas patients treated with definitive radiotherapy were included. The grade (G) of s.c. and deep tissue fibrosis was scored according to the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer grading system. Coding and RNA mtDNA (between 611 and 15,978 bp) were sequenced, and genetic variations were scored. Mitochondrial respiratory activity was measured by resazurin reduction assay.

Results: Data showed a significantly (P = 0.003) higher number of nonsynonymous genetic variations in the radiosensitive (G2-G3; 16 patients) as compared with the control (G0-G1; 16 patients) groups. The nonsynonymous A10398G variation in the ND3 gene was significantly associated with fibrotic reaction (P = 0.01). The radiosensitive patients had a 7-fold (95% confidence interval, 1.16-51.65) higher risk of developing moderate to severe fibrosis (G2-G3) following radiotherapy. This was significantly correlated with lower mitochondrial respiratory activity (P = 0.001).

Conclusion: Mitochondria contribute to radiation sensitivity, and genetic variations can be associated with late reactions to radiotherapy. Predictive markers of radiosensitivity should take into account mtDNA genetic variations in addition to variations in nuclear genes. (Clin Cancer Res 2009;15(23):7352–60)
Loss of HER2 Amplification Following Trastuzumab-Based Neoadjuvant Systemic Therapy and Survival Outcomes
Authors: Mittendorf Elizabeth A. , Wu Yun , Scaltriti Maurizio , Meric-Bernstam Funda , Hunt Kelly K. , Dawood Shaheenah , Esteva Francisco J. , Buzdar Aman U. , Chen Huiqin , Eksambi Sameena , Hortobagyi Gabriel N. , Baselga Jose , Gonzalez-Angulo Ana M.
Published: November 2009

Purpose: To evaluate HER2 status in residual tumor identified at the time of surgery in patients not achieving a pathologic complete response (pCR) and to determine the effect of alterations in HER2 status on recurrence-free survival (RFS).

Experimental Design: Clinicopathologic data for patients with HER2-overexpressing breast cancer receiving neoadjuvant therapy with a taxane, anthracycline, and concomitant trastuzumab between 2004 and 2007 were reviewed. Surgical specimens for patients achieving less than a pCR were assessed to determine if there was enough residual tissue to evaluate posttreatment HER2 status. RFS was determined using the Kaplan-Meier method and compared by the log-rank statistic.

Results: A pCR was achieved in 72 of the 142 (50.7%) patients. Residual tumor was sufficient to assess posttreatment HER2 status in 25 patients. Fluorescence in situ hybridization done on pretreatment specimens confirmed HER2 amplification before beginning therapy. Eight (32.0%) posttreatment tumors were found to be HER2-negative by fluorescence in situ hybridization. At a median follow-up of 37 months (range, 8-56 months), the RFS was significantly better for patients with tumors that retained HER2 amplification (87.5% versus 50%, P = 0.04).

Conclusion: High pCR rates are achieved in patients with HER2-positive breast cancer treated with neoadjuvant trastuzumab in combination with anthracyclines and taxanes. One third of patients with significant residual disease loses HER2 amplification, and this change is associated with poor RFS. Residual tumor identified at the time of surgery should be reassessed for HER2 status, and novel adjuvant therapy strategies need to be studied in this population. (Clin Cancer Res 2009;15(23):7381–8)
Use of OralN-Acetylcysteine for Protection of Melanocytic Nevi against UV-Induced Oxidative Stress: Towards a Novel Paradigm for Melanoma Chemoprevention
Authors: Goodson Agnessa Gadeliya , Cotter Murray A. , Cassidy Pamela , Wade Mark , Florell Scott R. , Liu Tong , Boucher Kenneth M. , Grossman Douglas
Published: November 2009

Purpose: Induction of oxidative stress has been implicated in UV-induced melanoma. We sought to determine whether the antioxidant N-acetylcysteine (NAC) could be safely administered to protect melanocytic nevi from the oxidative stress resulting from acute UV exposure.

Experimental Design: Patients at increased risk for melanoma were recruited from a screening clinic. Induction and detection of oxidative stress (reactive oxygen species and glutathione depletion) was optimized in nevi following ex vivo UV irradiation. Nevi were removed from patients before, and following, oral ingestion of a single (1,200 mg) dose of NAC, and then these nevi were UV irradiated (4,000 J/m2).

Results: Oxidative stress was induced in nevi 24 to 48 hours following ex vivo UV irradiation. A single oral dose of NAC was well tolerated in all patients (n = 72). Basal levels of reduced glutathione and the NAC metabolite cysteine were well correlated between similar-appearing nevi from the same patient and were significantly increased in nevi removed 3 hours after NAC ingestion compared with nevi removed before drug ingestion. In approximately half (9 of 19) of patients tested, UV-induced glutathione depletion was attenuated in the postdrug (compared with predrug) nevus.

Conclusions: NAC can be safely administered to patients for the purpose of modulating UV-induced oxidative stress in nevi. This study suggests the feasibility of patients taking NAC prophylactically before acute UV exposure, to prevent pro-oncogenic oxidative stress in nevi and ultimately reduce long-term melanoma risk. (Clin Cancer Res 2009;15(23):7434–40)
Relationship between the Degree of Endolymphatic Hydrops and Electrocochleography
Authors: Yamamoto Masako , Teranishi Masaaki , Naganawa Shinji , Otake Hironao , Sugiura Makoto , Iwata Tomoyuki , Yoshida Tadao , Katayama Naomi , Nakata Seiichi , Sone Michihiko , Nakashima Tsutomu
Published: November 2009

The purpose of this study was to evaluate the relationship between the endolymphatic space image obtained using magnetic resonance imaging (MRI) and the results of electrocochleography. Electrocochleography recordings were obtained from 25 ears of 24 patients, who underwent MRI 1 day after the intratympanic injection of gadolinium diethylenetriamine pentaacetic acid bismethylamide. The average summating potential to action potential (SP/AP) ratio in patients with significant endolymphatic hydrops in the cochlea was 54 ± 17%. However, in some patients who had significant endolymphatic hydrops in the cochlea, the SP/AP ratio was not enlarged. This may imply that elevation of the SP/AP ratio is related to not only the degree of endolymphatic hydrops but also to the persistence of hydrops.
Structural and Ontogenetic Study of the Urachus in Human Fetuses
Authors: Pazos Helena M.F. , Costa Waldemar S. , Sampaio Francisco J.B. , Favorito Luciano A.
Published: November 2009

The objective of this work was to conduct an ontogenetic and structural study of the urachus. We studied 40 human fetuses (13–20 weeks post conception, WPC). The urachus was stained in Masson’s trichrome, to quantify connective tissue and smooth muscle and to determine the urachal lumen area. Weigert’s resorcin-fuchsin was used to observe elastic fibers, and picrosirius red and immunohistochemistry analysis were used to observe collagen. The images were captured with Olympus BX51 microscopy and an Olympus DP70 camera. The stereological analysis was done using the software Image Pro and Image J, to determine volumetric densities. For biochemical analysis, the collagen concentrations were expressed per milligram of dry tissue. Means were compared using the unpaired t test (p < 0.05). Quantitative analysis documented a statistically insignificant increase (p = 0.1475) in volumetric densities of smooth muscle in the urachus of males (23.02%), when compared with females (18.43%), and a statistically significant increase (p = 0.0439) in volumetric densities of connective tissue in the urachus of females, (67.64%) when compared with males (58.38%). Total collagen concentrations in the male (31,919–56.792 µg/mg, mean 45,656) and female fetuses (33,485–48,527 µg/mg, mean 42,308) did not differ significantly (p = 0.5912). At higher gestational ages, the urachal lumen area was smaller. In 13th WPC fetuses, the urachal lumen area was 16,301 µm2 and in 17th WPC fetuses, the urachal lumen area was 1,676 µm2. We determined that the urachal lumen was closed from the 17th WPC in all fetuses.
Focused in vivo Delivery of Plasmid DNA to the Porcine Vascular Wall via Intravascular Ultrasound Destruction of Microbubbles
Authors: Phillips Linsey C. , Klibanov Alexander L. , Bowles Douglas K. , Ragosta Michael , Hossack John A. , Wamhoff Brian R.
Published: November 2009

Background: Safety concerns associated with drug-eluting stents have spurred interest in alternative vessel therapeutics following angioplasty. Microbubble contrast agents have been shown to increase gene transfection in vivo in the presence of ultrasound. Objectives/Methods: The purpose of this study was to determine whether an intravascular ultrasound (IVUS) catheter could mediate plasmid DNA transfection from microbubble carriers to the porcine coronary artery wall following balloon angioplasty. Results:In the presence of plasmid-coupled microbubbles in vitro only cells exposed to ultrasound from the modified IVUS catheter significantly expressed the transgene. A porcine left anterior descending coronary artery underwent balloon angioplasty followed by injection and insonation of microbubbles from the IVUS catheter at the site of angioplasty. After 3 days, an approximately 6.5-fold increase in transgene expression was observed in arteries that received microbubbles and IVUS compared to those that received microbubbles with no IVUS. Conclusions:The results of this study demonstrate for the first time that IVUS is required to enhance gene transfection from microbubble carriers to the vessel wall in vivo. This technology may be applied to both drug and gene therapy to reduce vessel restenosis.
Molecular Signaling Networks That Choreograph Epimorphic Fin Regeneration in Zebrafish – A Mini-Review
Authors: Tal Tamara L. , Franzosa Jill A. , Tanguay Robert L.
Published: November 2009

This short review provides a current synopsis of caudal fin regeneration in zebrafish with an emphasis on the molecular signaling networks that dictate epimorphic regeneration. At the outset, the fundamentals of caudal fin architecture and the stages of epimorphic regeneration are described. This is followed by a detailed look at the main networks implicated in fin regeneration, namely the Wnt, fibroblast growth factor, activin-βA, retinoic acid and hedgehog signaling pathways. Throughout this mini-review, these molecular networks are examined through the lens of wound healing, blastema formation or regenerative outgrowth, three of the main stages of epimorphic regeneration. Next, the emerging role of noncoding RNAs as regulators of regeneration and mechanisms of regenerative termination are discussed. Finally, the implications for future research and the broader field of regenerative medicine are examined.
Cetuximab-Based Treatment of Metastatic Anal Cancer: Correlation of Response with KRAS Mutational Status
Authors: Lukan Nadine , Ströbel Philipp , Willer Andreas , Kripp Melanie , Dinter Dietmar , Mai Sabine , Hochhaus Andreas , Hofheinz Ralf-Dieter
Published: November 2009

Background: No standard chemotherapy regimen can be defined for patients with metastatic squamous cell carcinoma of the anus due to the low incidence of this disease and the high cure rate of localized tumors. Anal cancers universally express the epidermal growth factor receptor (EGFR) and KRAS mutations have not been reported in anal cancer thus far. Methods: We report on 7 patients with metastatic anal cancer treated with cetuximab – a chimeric antibody against EGFR – on a compassionate use basis along with the results of KRAS mutational analysis. Results: Marked tumor shrinkage was noted in several patients using cetuximab monotherapy or cetuximab/irinotecan combination as first or subsequent treatment line (usually after failure of cisplatin-based regimens). Two out of seven patients harbored KRAS mutations. Both patients had progressive disease receiving cetuximab, while the remaining 5 patients had either a partial remission (n = 3), a minor remission (n = 1) or no change lasting ≥6 months after previous rapid tumor progression. Conclusion: Cetuximab-based treatment appears to be a valuable treatment option for patients with metastatic KRAS wild-type anal cancer after failure of or as an alternative to cisplatin/5-fluorouracil-based therapy.
A Pilot Study for Combination Chemotherapy Using Gemcitabine and S-1 for Advanced Pancreatic Cancer
Authors: Nakai Yousuke , Isayama Hiroyuki , Sasaki Takashi , Sasahira Naoki , Ito Yukiko , Kogure Hirofumi , Togawa Osamu , Matsubara Saburo , Arizumi Toshihiko , Yagioka Hiroshi , Yashima Yoko , Kawakubo Kazumichi , Mizuno Suguru , Yamamoto Keisuke , Hirano Kenji , Tsujino Takeshi , Ijichi Hideaki , Toda Nobuo , Tada Minoru , Kawabe Takao , Omata Masao
Published: November 2009

Objectives: We performed a pilot study of a modified combination chemotherapy regimen with S-1 plus gemcitabine for patients with advanced pancreatic cancer. Methods: Gemcitabine was administered at a dose of 1,000 mg/m2 in a 30-min intravenous injection on days 1 and 15. S-1 was administered orally at a dose of 40 mg/m2 twice daily for 14 consecutive days followed by a 14-day rest. Each cycle was repeated every 28 days. Results: Sixteen patients were enrolled. No complete response was observed and partial response was observed in 5 patients (31.3%), stable disease in 10 patients (62.5%) and progressive disease in 1 patient (6.3%). The median time to progression was 10.0 months (95% CI 4.4–N.A.) and the median survival time was 20.4 months (95% CI 8.6–24.1 months). The major toxicities were grade 3 neutropenia (25.0%) and grade 3 anemia (6.3%). There were no grade 4 toxicities. Conclusions: Combination therapy with gemcitabine and S-1 using the modified 4-week schedule was well tolerated and efficacious for advanced pancreatic cancer.
Changes of Renal AT1/AT2 Receptors and Structures in Ovine Fetuses following Exposure to Long-Term Hypoxia
Authors: Mao Caiping , Hou Jianquan , Ge Jianyi , Hu Yali , Ding Yang , Zhou Yun , Zhang Huiying , Xu Zhice , Zhang Lubo
Published: November 2009

Background/Aims: The present study tested the hypothesis that chronic hypoxia adversely affects renal development in the ovine fetus. Methods: Kidneys were collected from near-term fetuses of pregnant ewes maintained at sea level or high altitude (3,801 m, PaO2: approx. 60 mm Hg) for 110 days (n = 6 for each group). Results: Long-term high altitude hypoxia reduced the fetal kidney/body weight ratio. Histological analysis showed a significant enlargement in the Bowman’s space and swelling of tubule epithelial cells in the kidney of the hypoxic fetus. The histological alterations were limited to the cortical, but not medullary, zone. These alterations were associated with an increase in serum creatinine and a decrease in the BUN-to-creatinine ratio in hypoxic fetuses. Angiotensin II receptors (AT1R and AT2R) were detected in the glomerular and tubular regions of the kidney. Chronic hypoxia caused a significant increase in AT1R and a decrease in AT2R protein and mRNA abundance, resulting in a large increase in the AT1R/AT2R ratio in the fetal kidney. Conclusion: The results demonstrate an adverse effect of chronic hypoxia on renal AT1R and AT2R expression and functions in the fetus, suggesting a possible role of fetal hypoxia in the programming of renal diseases in fetal origins.
“Vascular Age” Is Advanced in Children With Atherosclerosis-Promoting Risk Factors
Authors: Le Joseph , Zhang Danna , Menees Spencer , Chen Jie , Raghuveer Geetha
Published: November 2009

Background—

Obesity and familial dyslipidemia in children are associated with accelerated atherosclerosis by pathological examination. We sought to determine whether these children had increased carotid artery intima-media thickness (CIMT), a measure of subclinical atherosclerosis similar to 45-year-old adults. Adult CIMT percentile tables were used for comparison because normative CIMT data for children are limited.

Methods and Results—

Seventy children, ages 6 to 19 years, with obesity- and atherosclerosis-promoting risk factors such as dyslipidemia, hypertension, insulin resistance, and tobacco smoke exposure, or with familial dyslipidemia, underwent carotid artery ultrasound. Advanced “vascular age” (VA) was defined as having maximum CIMT that was ≥25th percentile for race- and sex-matched 45-year-old adults. Mean age was 13.0�3.3 years. Forty (57%) of 70 children had body mass index ≥95th percentile for age and sex. Maximum CIMT for obese children was 0.53�0.05 mm and for familial dyslipidemic children was 0.52�0.04 mm. Advanced VA was seen in 30 (75%) of obese children and 22 (73%) of familial dyslipidemic children. Thirty (75%) of obese children had >3 mutable atherosclerosis-promoting risk factors; these children had a nonsignificantly higher maximum CIMT compared with obese children with ≤3 risk factors (0.54�0.06 mm versus 0.52�0.03 mm,
P
=0.07). Obese children with high fasting triglyceride levels were more likely to have advanced VA.

Conclusions—

VA is advanced and comparable in obese children with atherosclerosis-promoting risk factors and in children with familial dyslipidemia. Advanced VA is prevalent in obese children with high fasting triglyceride levels.
Economic Outcomes of Treatment Strategies for Type 2 Diabetes Mellitus and Coronary Artery Disease in the Bypass Angioplasty Revascularization Investigation 2 Diabetes Trial
Authors: Hlatky Mark A. , Boothroyd Derek B. , Melsop Kathryn A. , Kennedy Laurence , Rihal Charanjit , Rogers William J. , Venkitachalam Lakshmi , Brooks Maria M.
Published: November 2009

Background—

The economic outcomes of clinical management strategies are important in assessing their value to patients.

Methods and Results—

Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) randomized patients with type 2 diabetes mellitus and angiographically documented, stable coronary disease to strategies of (1) prompt revascularization versus medical therapy with delayed revascularization as needed to relieve symptoms and (2) insulin sensitization versus insulin provision. Before randomization, the physician declared whether coronary artery bypass grafting or percutaneous coronary intervention would be used if the patient were assigned to revascularization. We followed 2005 patients for medical utilization and costs and assessed the cost-effectiveness of these management strategies. Medical costs were higher for revascularization than medical therapy, with a significant interaction with the intended method of revascularization (
P
<0.0001). In the coronary artery bypass grafting stratum, 4-year costs were $80 900 for revascularization versus $60 600 for medical therapy (
P
<0.0001). In the percutaneous coronary intervention stratum, costs were $73 400 for revascularization versus $67 800 for medical therapy (
P
<0.02). Costs also were higher for insulin sensitization ($71 300) versus insulin provision ($70 200). Other factors that significantly (
P
<0.05) and independently increased cost included insulin use and dose at baseline, female sex, white race, body mass index ≥30, and albuminuria. Cost-effectiveness based on 4-year data favored the strategy of medical therapy over prompt revascularization and the strategy of insulin provision over insulin sensitization. Lifetime projections of cost-effectiveness showed that medical therapy was cost-effective compared with revascularization in the percutaneous coronary intervention stratum ($600 per life-year added) with high confidence. Lifetime projections suggest that revascularization may be cost-effective in the coronary artery bypass grafting stratum ($47 000 per life-year added) but with lower confidence.

Conclusions—

Prompt coronary revascularization significantly increases costs among patients with type 2 diabetes mellitus and stable coronary disease. The strategy of medical therapy (with delayed revascularization as needed) appears to be cost-effective compared with the strategy of prompt coronary revascularization among patients identified a priori as suitable for percutaneous coronary intervention.

Clinical Trial Registration—

URL: http://www.clinicaltrials.gov. Unique Identifier: NCT00006305.