bluuebunny/crossref_metadata_2025 huggingface dataset:
Engineered Knottin Peptides: A New Class of Agents for Imaging Integrin Expression in Living Subjects
Authors: Kimura Richard H. , Cheng Zhen , Gambhir Sanjiv Sam , Cochran Jennifer R.
Published: March 2009

There is a critical need for molecular imaging agents to detect cell surface integrin receptors that are present in human cancers. Previously, we used directed evolution to engineer knottin peptides that bind with high affinity (∼10 to 30 nmol/L) to integrin receptors that are overexpressed on the surface of tumor cells and the tumor neovasculature. To evaluate these peptides as molecular imaging agents, we site-specifically conjugated Cy5.5 or 64Cu-1,4,7,10-tetra-azacyclododecane-N,N′,N″,N‴-tetraacetic acid (DOTA) to their N termini, and used optical and positron emission tomography (PET) imaging to measure their uptake and biodistribution in U87MG glioblastoma murine xenograft models. NIR fluorescence and microPET imaging both showed that integrin binding affinity plays a strong role in the tumor uptake of knottin peptides. Tumor uptake at 1 hour postinjection for two high-affinity (IC50, ∼20 nmol/L) 64Cu-DOTA–conjugated knottin peptides was 4.47% ± 1.21% and 4.56% ± 0.64% injected dose/gram (%ID/g), compared with a low-affinity knottin peptide (IC50, ∼0.4 μmol/L; 1.48 ± 0.53%ID/g) and c(RGDyK) (IC50, ∼1 μmol/L; 2.32 ± 0.55%ID/g), a low-affinity cyclic pentapeptide under clinical development. Furthermore, 64Cu-DOTA–conjugated knottin peptides generated lower levels of nonspecific liver uptake (∼2%ID/g) compared with c(RGDyK) (∼4%ID/g) 1 hour postinjection. MicroPET imaging results were confirmed by in vivo biodistribution studies. 64Cu-DOTA–conjugated knottin peptides were stable in mouse serum, and in vivo metabolite analysis showed minimal degradation in the blood or tumor upon injection. Thus, engineered integrin-binding knottin peptides show great potential as clinical diagnostics for a variety of cancers. [Cancer Res 2009;69(6):2435–42]
TWIST-1 Is Overexpressed in Neoplastic Choroid Plexus Epithelial Cells and Promotes Proliferation and Invasion
Authors: Hasselblatt Martin , Mertsch Sonja , Koos Björn , Riesmeier Barbara , Stegemann Heike , Jeibmann Astrid , Tomm Manuel , Schmitz Nicole , Wrede Brigitte , Wolff Johannes E. , Zheng Wei , Paulus Werner
Published: March 2009

The pathogenesis of choroid plexus papillomas, intraventricular papillary neoplasms most often occurring sporadically in children and young adults, remains poorly understood. To identify pathways operative in the development of choroid plexus papillomas, gene expression profiles obtained from laser-microdissected human choroid plexus papilloma cells (n = 7) were compared with that of normal choroid plexus epithelial cells laser microdissected from autopsy tissue (n = 8). On DNA microarray data analysis, 53 probe sets were differentially expressed in choroid plexus papilloma tumor cells (>7-fold). Up-regulation of TWIST1, WIF1, TRPM3, BCLAF1, and AJAP1, as well as down-regulation of IL6ST was confirmed using quantitative reverse transcription-PCR. Knockdown of Twist1 gene expression in the rat choroid plexus epithelial cell line Z310 significantly reduced proliferation as assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and cell invasion in a Matrigel assay, whereas cell migration was not affected. Screening for expressional changes of cancer-related genes upon Twist1 knockdown revealed up-regulation of Cdkn1a, Cflar, and Serpinb2 and down-regulation of Figf. To conclude, using gene expression profiling, several genes differentially expressed in human choroid plexus papillomas could be identified. Among those, TWIST1 is highly expressed in choroid plexus papillomas and promotes proliferation and invasion. [Cancer Res 2009;69(6):2219–23]
Diaphanous-Related Formins Are Required for Invadopodia Formation and Invasion of Breast Tumor Cells
Authors: Lizárraga Floria , Poincloux Renaud , Romao Maryse , Montagnac Guillaume , Le Dez Gaëlle , Bonne Isabelle , Rigaill Guillem , Raposo Graça , Chavrier Philippe
Published: March 2009

Proteolytic degradation of the extracellular matrix by metastatic tumor cells is initiated by the formation of invadopodia, i.e., actin-driven filopodia-like membrane protrusions endowed with matrix-degradative activity. A signaling cascade involving neural Wiskott-Aldrich syndrome protein and the Arp2/3 actin nucleating complex is involved in actin assembly at invadopodia. Yet, the mechanism of invadopodia formation is poorly understood. Based on their role as actin nucleators in cytoskeletal rearrangements, including filopodia formation, we examined the function of Diaphanous-related formins (DRF) in invadopodia formation and invasion by breast tumor cells. Using small interfering RNA silencing of protein expression in highly invasive MDA-MB-231 breast adenocarcinoma cells, we show that three members of the DRF family (DRF1–DRF3) are required for invadopodia formation and two-dimensional matrix proteolysis. We also report that invasion of a three-dimensional Matrigel matrix involves filopodia-like protrusions enriched for invadopodial proteins, including membrane type 1 matrix metalloproteinase, which depend on DRFs for their formation. These data identify DRFs as critical components of the invasive apparatus of tumor cells in two-dimensional and three-dimensional matrices and suggest that different types of actin nucleators cooperate during the formation of invadopodia. [Cancer Res 2009;69(7):2792–800]
A Role for CXCR2 in Senescence, but What about in Cancer?
Authors: Acosta Juan C. , Gil Jesús
Published: March 2009

Senescence is an irreversible arrest triggered by stresses such as telomere shortening, DNA damage, or oncogenic signaling. Oncogene-induced senescence occurs in preneoplastic lesions, but it is absent from full-blown malignancies suggesting a tumor suppressor function. We recently found that depletion of the receptor CXCR2 [which binds to chemokines such as interleukin (IL)-8 or GROα] delays both replicative senescence and impairs the senescence response to oncogenic signals. Our findings suggest that signaling by IL-8 and GROα might limit tumor growth by reinforcing senescence early in tumorigenesis. The challenge remains in how to integrate this with the well-known tumor promoting effects of IL-8 and GROα. [Cancer Res 2009;69(6):2167–70]
Critical Role of Smad2 in Tumor Suppression and Transforming Growth Factor-β–Induced Apoptosis of Prostate Epithelial Cells
Authors: Yang Jiayi , Wahdan-Alaswad Reema , Danielpour David
Published: March 2009

Transforming growth factor-β (TGF-β) functions as a tumor suppressor of the prostate through mechanisms that remain unresolved. Although TGF-β receptors directly activate both Smads 2 and 3, to date, Smad3 has been shown to be the essential mediator of most Smad-dependent TGF-β responses, including control of gene expression, cell growth, apoptosis, and tumor suppression. Using a robust lentiviral short hairpin RNA system to silence Smads 2 and/or 3 in the NRP-152 nontumorigenic rat prostate basal epithelial cell line, we provide the first evidence for Smad2 as a critical mediator of TGF-β–induced apoptosis and gene expression. Parallel analyses revealed that Smad3 is the major mediator of TGF-β–induced transcriptional and apoptotic responses in the NRP-154 rat prostate carcinoma cell line. Remarkably, silencing Smad2 alone caused malignant transformation of NRP-152 cells, as assayed by s.c. tumor growth in athymic mice, whereas silencing Smad3 alone did not induce tumors. Nevertheless, tumors induced by silencing both Smads 2 and 3 were larger than those from silencing Smad2 alone. Given previous reports that NRP-152 cells have a stem cell phenotype, we speculate a critical role for Smad2 as a tumor suppressor in the basal epithelial or stem cell compartment of the prostate. [Cancer Res 2009;69(6):2185–90]
Impaired Turnover of Prolactin Receptor Contributes to Transformation of Human Breast Cells
Authors: Plotnikov Alexandr , Varghese Bentley , Tran Thai H. , Liu Chengbao , Rui Hallgeir , Fuchs Serge Y.
Published: March 2009

Signaling by polypeptide hormone prolactin (PRL) is mediated by its cognate receptor (PRLr). PRLr is commonly stabilized in human breast cancer due to decreased phosphorylation of residue Ser349, which when phosphorylated recruits the βTrcp E3 ubiquitin ligase and facilitates PRLr degradation. Here, we show that an impaired PRLr turnover results in an augmented PRL signaling and PRL-induced transcription. Human mammary epithelial cells harboring degradation-resistant PRLr display accelerated proliferation and increased invasive growth. Conversely, a decrease in PRLr levels achieved by either pharmacologic or genetic means in human breast cancer cells dramatically reduced transformation and tumorigenic properties of these cells. Consequences of alteration of PRLr turnover for homeostasis of mammary cells and development of breast cancers, as well as the utility of therapies that target PRLr function in these malignancies, are discussed. [Cancer Res 2009;69(7):3165–72]
Molecular Dosimetry of 1,2,3,4-Diepoxybutane–Induced DNA-DNA Cross-Links in B6C3F1 Mice and F344 Rats Exposed to 1,3-Butadiene by Inhalation
Authors: Goggin Melissa , Swenberg James A. , Walker Vernon E. , Tretyakova Natalia
Published: March 2009

1,3-Butadiene (BD) is an important industrial and environmental chemical classified as a human carcinogen based on epidemiologic studies in occupationally exposed workers and animal studies in laboratory rats and mice. BD is metabolically activated to three epoxides that can react with nucleophilic sites in biomolecules. Among these, 1,2,3,4-diepoxybutane (DEB) is considered the ultimate carcinogen due to its high genotoxicity and mutagenicity attributed to its ability to form DNA-DNA cross-links. Our laboratory has developed quantitative high-performance liquid chromatography–μESI+–tandem mass spectrometry methods for two DEB-specific DNA-DNA cross-links, 1,4-bis-(guan-7-yl)-2,3-butanediol (bis-N7G-BD) and 1-(guan-7-yl)-4-(aden-1-yl)-2,3-butanediol (N7G-N1A-BD). This report describes molecular dosimetry analysis of these adducts in tissues of B6C3F1 mice and F344 rats exposed to a range of BD concentrations (0–625 ppm). Much higher (4- to 10-fold) levels of DEB-DNA cross-links were observed in mice compared with rats exposed to the same BD concentrations. In both species, bis-N7G-BD levels were 1.5- to 4-fold higher in the liver than in other tissues examined. Interestingly, tissues of female animals exposed to BD contained higher concentrations of bis-N7G-BD adducts than tissues of male animals, which is in accord with previously reported differences in tumor incidence. The molecular dosimetry data presented herein suggest that species and gender differences observed in BD-induced cancer are directly related to differences in the extent of BD metabolism to DEB. Furthermore, a rat model of sensitivity to BD may be more appropriate than a mouse model for assessing human risk associated with BD exposure, because rats and humans seem to be similar with respect to DEB formation. [Cancer Res 2009;69(6):2479–8]
The Novel Role of Tyrosine Kinase Inhibitor in the Reversal of Immune Suppression and Modulation of Tumor Microenvironment for Immune-Based Cancer Therapies
Authors: Ozao-Choy Junko , Ma Ge , Kao Johnny , Wang George X. , Meseck Marcia , Sung Max , Schwartz Myron , Divino Celia M. , Pan Ping-Ying , Chen Shu-Hsia
Published: March 2009

In tumor-bearing hosts, myeloid-derived suppressor cells (MDSC) and T regulatory cells (Treg) play important roles in immune suppression, the reversal of which is vitally important for the success of immune therapy. We have shown that ckit ligand is required for MDSC accumulation and Treg development. We hypothesized that sunitinib malate, a receptor tyrosine kinase inhibitor, could reverse MDSC-mediated immune suppression and modulate the tumor microenvironment, thereby improving the efficacy of immune-based therapies. Treatment with sunitinib decreased the number of MDSC and Treg in advanced tumor-bearing animals. Furthermore, it not only reduced the suppressive function of MDSCs but also prevented tumor-specific T-cell anergy and Treg development. Interestingly, sunitinib treatment resulted in reduced expression of interleukin (IL)-10, transforming growth factor-β, and Foxp3 but enhanced expression of Th1 cytokine IFN-γ and increased CTL responses in isolated tumor-infiltrating leukocytes. A significantly higher percentage and infiltration of CD8 and CD4 cells was detected in tumors of sunitinib-treated mice when compared with control-treated mice. More importantly, the expression of negative costimulatory molecules CTLA4 and PD-1 in both CD4 and CD8 T cells, and PDL-1 expression on MDSC and plasmacytoid dendritic cells, was also significantly decreased by sunitinib treatment. Finally, sunitinib in combination with our immune therapy protocol (IL-12 and 4-1BB activation) significantly improves the long-term survival rate of large tumor-bearing mice. These data suggest that sunitinib can be used to reverse immune suppression and as a potentially useful adjunct for enhancing the efficacy of immune-based cancer therapy for advanced malignancies. [Cancer Res 2009;69(6):2514–22]
Tumor-Initiating Cells of HER2-Positive Carcinoma Cell Lines Express the Highest Oncoprotein Levels and Are Sensitive to Trastuzumab
Authors: Magnifico Alessandra , Albano Luisa , Campaner Stefano , Delia Domenico , Castiglioni Fabio , Gasparini Patrizia , Sozzi Gabriella , Fontanella Enrico , Menard Sylvie , Tagliabue Elda
Published: March 2009

Purpose: The existence of tumor-initiating cells in breast cancer has profound implications for cancer therapy. In this study, we investigated the sensitivity of tumor-initiating cells isolated from human epidermal growth factor receptor type 2 (HER2)-overexpressing carcinoma cell lines to trastuzumab, a compound used for the targeted therapy of breast cancer.

Experimental Design: Spheres were analyzed by indirect immunofluorescence for HER2 cell surface expression and by real-time PCR for HER2 mRNA expression in the presence or absence of the Notch1 signaling inhibitor (GSI) or Notch1 small interfering RNA. Xenografts of HER2-overexpressing breast tumor cells were treated with trastuzumab or doxorubicin. The sphere-forming efficiency (SFE) and serial transplantability of tumors were assessed.

Results: In HER2-overexpressing carcinoma cell lines, cells with tumor-initiating cell properties presented increased HER2 levels compared with the bulk cell population without modification in HER2 gene amplification. HER2 levels were controlled by Notch1 signaling, as shown by the reduction of HER2 cell surface expression and lower SFE following γ-secretase inhibition or Notch1 specific silencing. We also show that trastuzumab was able to effectively target tumor-initiating cells of HER2-positive carcinoma cell lines, as indicated by the significant decrease in SFE and the loss of serial transplantability, following treatment of HER2-overexpressing xenotransplants.

Conclusions: Here, we provide evidence for the therapeutic efficacy of trastuzumab in debulking and in targeting tumor-initiating cells of HER2-overexpressing tumors. We also propose that Notch signaling regulates HER2 expression, thereby representing a critical survival pathway of tumor-initiating cells.
Coassociation of Estrogen Receptor and p160 Proteins Predicts Resistance to Endocrine Treatment; SRC-1 is an Independent Predictor of Breast Cancer Recurrence
Authors: Redmond Aisling M. , Bane Fiona T. , Stafford Anthony T. , McIlroy Marie , Dillon Mary F. , Crotty Thomas B. , Hill Arnold D. , Young Leonie S.
Published: March 2009

Purpose: This study investigates the role of the p160 coactivators AIB1 and SRC-1 independently, and their interactions with the estrogen receptor, in the development of resistance to endocrine treatments.

Experimental Design: The expression of the p160s and the estrogen receptor, and their interactions, was analyzed by immunohistochemistry and quantitative coassociation immunofluorescent microscopy, using cell lines, primary breast tumor cell cultures, and a tissue microarray with breast cancer samples from 560 patients.

Results: Coassociation of the p160s and estrogen receptor α was increased in the LY2 endocrine-resistant cell line following treatment with tamoxifen in comparison with endocrine-sensitive MCF-7 cells. In primary cultures, there was an increase in association of the coactivators with estrogen receptor α following estrogen treatment but dissociation was evident with tamoxifen. Immunohistochemical staining of the tissue microarray revealed that SRC-1 was a strong predictor of reduced disease-free survival (DFS), both in patients receiving adjuvant tamoxifen treatment and untreated patients (P < 0.0001 and P = 0.0111, respectively). SRC-1 was assigned a hazard ratio of 2.12 using a Cox proportional hazards model. Endocrine-treated patients who coexpressed AIB1 with human epidermal growth factor receptor 2 had a significantly shorter DFS compared with all other patients (P = 0.03). Quantitative coassociation analysis in the patient tissue microarray revealed significantly stronger colocalization of AIB1 and SRC-1 with estrogen receptor α in patients who have relapsed in comparison with those patients who did not recur (P = 0.026 and P = 0.00001, respectively).

Conclusions: SRC-1 is a strong independent predictor of reduced DFS, whereas the interactions of the p160 proteins with estrogen receptor α can predict the response of patients to endocrine treatment.
The Antitumor and Immunoadjuvant Effects of IFN-α in Combination with Recombinant Poxvirus Vaccines
Authors: Hance Kenneth W. , Rogers Connie J. , Zaharoff David A. , Canter Daniel , Schlom Jeffrey , Greiner John W.
Published: March 2009

Purpose: IFN-α is a pleiotropic cytokine possessing immunomodulatory properties that may improve the efficacy of therapeutic cancer vaccines. The aim of this study was to evaluate the effectiveness and compatibility of combining recombinant IFN-α with poxvirus vaccines targeting the human carcinoembryonic antigen (CEA) in murine models of colorectal and pancreatic adenocarcinomas, where CEA is a self-antigen.

Experimental Design: The phenotypic and functional effects of IFN-α were evaluated in the draining inguinal lymph nodes of tumor-free mice. We studied the effect of the site of IFN-α administration (local versus distal) on antigen-specific immune responses to poxvirus vaccination. Mechanistic studies were conducted to assess the efficacy of IFN-α and CEA-directed poxvirus vaccines in tumor-bearing CEA transgenic mice.

Results: We identified a dose and schedule of IFN-α that induced a locoregional expansion of the draining inguinal lymph nodes and improved cellular cytotoxicity (natural killer and CD8+) and antigen presentation. Suppression of the vaccinia virus was avoided by administering IFN-α distal to the site of vaccination. The combination of IFN-α and vaccine inhibited tumor growth, improved survival, and elicited CEA-specific CTL responses in mice with CEA+ adenocarcinomas. In mice with pancreatic tumors, IFN-α slowed tumor growth, induced CTL activity, and increased CD8+ tumor-infiltrating lymphocytes.

Conclusions: These data suggest that IFN-α can be used as a biological response modifier with antigen-directed poxvirus vaccines to yield significant therapeutic antitumor immune responses. This study provides the rationale and mechanistic insights to support a clinical trial of this immunotherapeutic strategy in patients with CEA-expressing carcinomas.
Androgen Receptor Levels and Association with PIK3CA Mutations and Prognosis in Breast Cancer
Authors: Gonzalez-Angulo Ana M. , Stemke-Hale Katherine , Palla Shana L. , Carey Mark , Agarwal Roshan , Meric-Berstam Funda , Traina Tiffany A. , Hudis Clifford , Hortobagyi Gabriel N. , Gerald William L. , Mills Gordon B. , Hennessy Bryan T.
Published: March 2009

Purpose: To examine the androgen receptor (AR) levels in breast cancer and to assess the impact of AR expression on patient outcomes.

Experimental Design: Reverse-phase protein arrays were used to measure AR levels and a mass spectroscopy–based approach was used to detect PIK3CA mutations. Means and SDs were generated for AR levels. Linear regression models were used to determine if AR levels differed by tumor subtype and PIK3CA mutation status. Two-sample t tests were used to identify pair-wise differences. Survival probabilities were estimated with the use of the Kaplan-Meier product and log-rank test.

Results: The median age was 59 years (23-89 years). Significant differences in AR levels existed among different breast tumor subtypes (highest in estrogen receptor–positive and/or progesterone receptor–positive tumors) as well as by PIK3CA mutation status (P < 0.0001 for both). AR levels were significantly higher in breast tumors with kinase domain PIK3CA mutations versus tumors that are wild type or with PIK3CA helical mutations (P = 0.017 and P < 0.0001, respectively). In 347 patients, dichotomized AR level by the median was a significant prognostic factor of recurrence-free survival (P = 0.0002) and overall survival (P = 0.004). High AR levels were associated with a significantly improved recurrence-free survival in 207 patients with early-stage estrogen/progesterone receptor–positive tumors after adjuvant hormonal therapy. A trend (P = 0.07) was found toward higher AR expression in PIK3CA mutant versus PIK3CA wild-type triple-negative breast tumors.

Conclusions: AR levels may represent a prognostic marker in breast cancers and may provide a valuable tool for selecting treatment. There was an association of PIK3CA mutation (kinase domain) with increased AR levels.
Considerations for the Use of Imaging Tools for Phase II Treatment Trials in Oncology
Authors: Shankar Lalitha K. , Van den Abbeele Annick , Yap Jeff , Benjamin Robert , Scheutze Scott , FitzGerald T.J.
Published: March 2009

In the context of assessing tumor response, imaging tools have the potential to play a vital role in phase II and III treatment trials. If the imaging test is able to predict potential phase III success in a reliable fashion, it would be a useful tool in phase II trial design as it may provide for a more rapid and timely response assessment. The benefits and challenges of using anatomic imaging measures as well as the promising molecular imaging measures, primarily fluorodeoxyglucose-positron emission tomography, are discussed here. The general issues related to successful implementation of advanced imaging in the context of phase II treatment trials are discussed.
Combining Radiotherapy with APO010 in Cancer Treatment
Authors: Verbrugge Inge , Wissink Esther H.J. , Rooswinkel Rogier W. , Jongsma Johan , Beltraminelli Nicola , Dupuis Marc , Borst Jannie , Verheij Marcel
Published: March 2009

Purpose: Various proapoptotic agents are currently being explored to improve the outcome of radiotherapy. We have evaluated whether APO010—a novel recombinant ligand of the Fas/CD95 death receptor—enhanced the cytotoxic effect of radiation on lymphoid and solid tumor cell types.

Experimental Design: A Bcl-2–overexpressing T-leukemic cell line (Jurkat), a colon carcinoma cell line (HCT116), and a mesothelioma cell line were used as model systems in vitro and in a subcutaneous transplant setting in immunodeficient mice. Sensitivity to single and combined treatment was read out by apoptosis hallmarks and clonogenic survival in vitro, and by tumor growth delay using bioluminescence and palpation in vivo.

Results: Whereas the three cell lines resisted apoptosis induction by irradiation and APO010 alone, combined treatment greatly enhanced their apoptotic response. In clonogenic survival assays, APO010 reduced the outgrowth of Jurkat-Bcl-2 and HCT116 cells and sensitized the mesothelioma cell line to radiation. In vivo, systemic treatment with APO010 alone caused tumor growth delay in Jurkat-Bcl-2 and HCT116 cells. However, APO010 did not improve the efficacy of radiotherapy in any of the model systems at the selected single dose, which had moderate and reversible systemic toxicity.

Conclusions: Although APO010 and radiation had a clear combined cytotoxic effect on tumor cells in vitro, a combined therapeutic effect was not achieved on the same cells subcutaneously grafted in mice, at APO010 doses approximating the maximally tolerable level. These findings suggest that it will be difficult to identify a therapeutic window for this combined modality approach in a clinical setting.
Parthenolide promotes the ubiquitination of MDM2 and activates p53 cellular functions
Authors: Gopal Y.N. Vashisht , Chanchorn Ekkawit , Van Dyke Michael W.
Published: March 2009

MDM2 belongs to a class of ring-finger domain–containing ubiquitin ligases that mediate the proteasomal degradation of numerous proteins, including themselves. Arguably, the most important substrate of MDM2 is p53, which controls cell cycle progression and apoptosis. MDM2 and p53 are parts of a feedback regulatory loop whose perturbations are often present in cancer and are targets for anticancer drug development. We found that the natural product, small-molecule anti-inflammatory agent parthenolide (PN), which is actively being investigated as a potential therapeutic for many human cancers, induces ubiquitination of MDM2 in treated cells, resulting in the activation of p53 and other MDM2-regulated tumor-suppressor proteins. Using cells with functional gene deletions and small interfering RNA knockdown studies, we found that these effects required the DNA damage transducer ataxia telangiectasia mutated. The effects of PN on tumor suppressor activation were comparable with that of nutlin-3a, a recently developed small molecule that was designed to interfere with the interaction between MDM2 and p53 but does not promote MDM2 ubiquitination. Our study illustrates an alternative approach for controlling MDM2 and p53 activities and identifies an additional critically important cancer pathway affected by PN. [Mol Cancer Ther 2009;8(3):552–62]
Gravity Waves in Shear and Implications for Organized Convection
Authors: Stechmann Samuel N. , Majda Andrew J.
Published: March 2009

It is known that gravity waves in the troposphere, which are often excited by preexisting convection, can favor or suppress the formation of new convection. Here it is shown that in the presence of wind shear or barotropic wind, the gravity waves can create a more favorable environment on one side of preexisting convection than the other side.

Both the nonlinear and linear analytic models developed here show that the greatest difference in favorability between the two sides is created by jet shears, and little or no difference in favorability is created by wind profiles with shear at low levels and no shear in the upper troposphere. A nonzero barotropic wind (or, equivalently, a propagating heat source) is shown to also affect the favorability on each side of the preexisting convection. It is shown that these main features are captured by linear theory, and advection by the background wind is the main physical mechanism at work. These processes should play an important role in the organization of wave trains of convective systems (i.e., convectively coupled waves); if one side of preexisting convection is repeatedly more favorable in a particular background wind shear, then this should determine the preferred propagation direction of convectively coupled waves in this wind shear.

In addition, these processes are also relevant to individual convective systems: it is shown that a barotropic wind can lead to near-resonant forcing that amplifies the strength of upstream gravity waves, which are known to trigger new convective cells within a single convective system. The barotropic wind is also important in confining the upstream waves to the vicinity of the source, which can help ensure that any new convective cells triggered by the upstream waves are able to merge with the convective system.

All of these effects are captured in a two-dimensional model that is further simplified by including only the first two vertical baroclinic modes. Numerical results are shown with a nonlinear model, and linear theory results are in good agreement with the nonlinear model for most cases.
Correction of Humidity Biases in Vaisala RS80-H Sondes during NAME
Authors: Ciesielski Paul E. , Johnson Richard H. , Wang Junhong
Published: March 2009

Examination of the upper-air sonde data taken in conjunction with the North American Monsoon Experiment (NAME) revealed that data at several sites in the core monsoon region exhibited a significant dry bias. In this study, a simple, yet effective, statistical correction technique is applied to correct this dry bias. In addition, a second correction is applied to all Vaisala RS80-H sondes to remove a daytime dry bias resulting from solar heating of the humidity sensor. Moisture analyses computed from the corrected sondes compare favorably to those from independent satellite and aircraft estimates. The corrections led to significant improvement in the description of the humidity field and in several convective parameters, such as precipitable water (PW), CAPE, convective inhibition (CIN), and in the diurnal cycle of apparent drying Q2.
Reply
Authors: Kellenbenz David J. , Grafenauer Thomas J. , Davies Jonathan M.
Published: March 2009

Edwards and Thompson have made comprehensive and thorough comments concerning the methods, accuracy, and results in a case study by Kellenbenz et al. These comments questioned the representativeness of model-derived soundings and graphics used, as well as the modification methods employed with soundings presented in the 18 July 2004 case study. Other issues included the application of previous database studies to lifting condensation level (LCL) values found in the 18 July 2004 examination, as well as a focus that emphasized a single tornadic storm. In this response, the authors address problems and oversights with the 18 July 2004 case study, using new data to conduct a reanalysis of the environment on that evening. Additionally, a large independent database of Rapid Update Cycle (RUC) analysis soundings associated with supercell tornadoes is used to provide the context from which to carefully evaluate LCL results from the 18 July 2004 case relative to significant and violent tornadoes. Results indicate that although the LCL height associated with the F4 tornadic supercell in the original case study was probably overestimated, the background LCL environment was still unusually high for a violent tornado. New material presented in this response reinforces the conclusion that, when LCL heights are at the far upper end of empirical study distributions associated with significant tornadoes, undue weight should not be given to LCL as a tornado probability reduction factor when CAPE–storm relative helicity (SRH) combinations and deep-layer shear are also strong.
Using Optical Microscopy to Monitor Anisotropic Oxidation Growth in High-Temperature Polymer Matrix Composites
Authors: Tandon G.P. , Ragland W.R. , Schoeppner G.A.
Published: March 2009

Durability and degradation mechanisms in composites are fundamentally influenced by the fiber, matrix, and interphase regions that constitute the composite domain. In this work, unidirectional G30-500/PMR-15 composite specimens are aged at elevated temperature in air resulting in oxidation propagation parallel and perpendicular to the fibers. The observed anisotropy in composite oxidation is explained by carefully monitoring the development and growth of damage in composite specimens through the use of fluorescence imaging using dye impregnation in conjunction with optical microscopy. Optical micrographs are taken on polished internal sections and viewed in the dark-field mode to measure the degree, depth, and distribution of thermal oxidation development from external surfaces perpendicular and parallel to the fibers. It is shown that alternative pathways for transport of oxygen into the interior of the composite are fiber—matrix debonds and transverse matrix cracks that propagate with the oxidation front for which the oxidation front consistently precedes the debond crack front.
Bring out the counterpoint: exploring the relationship between implied polyphony and rubato in Bach's solo violin music
Authors: Davis Stacey
Published: March 2009

Performers are consistently instructed to use rubato to `bring out' the implied polyphony in Bach's solo string music. But previous research on the perception of this structural feature suggests that Bach's use of implied polyphony often creates a sense of structural expression, which is something that adds interest to the notes themselves and stands in contrast to the expressive nuances that a performer might later supply. If this is the case, performers could refrain from using much rubato in passages that contain structurally expressive types of implied polyphony, thereby allowing the inherent expression to emerge on its own. In order to test this hypothesis, expert performances from commercial recordings were analyzed to determine the relationship between type of implied polyphony and amount of tempo variation. Initial data confirms that violinists generally avoided any extensive use of rubato in passages where the implied polyphony alters the motivic, metric and/or metric structure and creates this structural expression. Performances of passages containing types of implied polyphony that are less structurally complex or disruptive were then characterized by a more extensive use of rubato that served to `bring out' the contrapuntal structure that was not already inherently expressive.
Adaptation Positions and Behavior Among Post—Myocardial Infarction Patients
Authors: Brink Eva
Published: March 2009

This study explores myocardial infarction patients' experiences of adaptation to illness consequences after one year, focusing on experiences of “the self.” The study sample consisted of 19 respondents (10 women, 9 men) who have suffered a first-time myocardial infarction. They were interviewed 1 year after the acute heart attack. A constant comparative method for grounded theory provided the strategies used for data collection and analysis. Codes emerged and memos clarified theoretical reflections. The resulting model was able to illustrate possible mechanisms underlying two different behaviors: self-modifying and self-protecting behavior. Four different adaptation positions were identified: put up with current health, struggle for health, ignore illness , and struggle against illness. These categories were related to two core categories: self-agency and coping with illness consequences . This model may clarify the different adaptive behavior observed among post—myocardial infarction patients.
Is parental coping associated with quality of life in juvenile idiopathic arthritis?
Authors: Cavallo Sabrina , Feldman Debbie Ehrmann , Swaine Bonnie , Meshefedjian Garbis , Malleson Peter N , Duffy Ciarán M
Published: March 2009

Parents of children with a chronic condition such as juvenile arthritis must cope with greater demands than those living with a healthy child. They must adopt different behaviours in order to lessen the impact on the family structure. Parental coping refers to the parent's specific cognitive and behavioural efforts to reduce or manage a demand on the family system. The aims of this study were: to describe coping in a cohort of parents of children with JIA; to determine whether quality of life is associated with parental coping; to explore whether socio-demographic factors such as child's age, family socioeconomic status and family structure are associated with parental coping. One hundred eighty-two parents caring for a child with JIA completed a postal survey at three times over a one-year period, which included the Juvenile Arthritis Quality of Life Questionnaire (JAQQ), the Coping Health Inventory for Parents (CHIP) and questionnaires describing socio-demographic characteristics. Linear mixed models were employed to analyse the association between the child's quality of life and parental coping. Mean total QoL scores (JAQQ) showed that children experienced difficulty in completing specified activities at most just below 25% of the time and results fall off slightly following the 6 month time point. Mean parental coping scores for the CHIP subscales at baseline were 38.4 ± 9.0, 33.4 ± 11.6, 16.5 ± 6.1, for Maintaining Family Integration (maximum score 57), Maintaining Social Support (maximum score 54) and Understanding the Medical Situation (maximum score 24), respectively. Understanding the Medical Situation was deemed most useful. The child's QoL was associated with parental coping. Parents of children with greater psychosocial dysfunction used more coping behaviours related to Understanding the Medical Situation (β coefficient, 0.73; 95% CI, 0.01, 1.45). These findings underscore the importance of helping parents of children with JIA better understand their child's medical situation.
An Ultrasonogram Reporting System for Thyroid Nodules Stratifying Cancer Risk for Clinical Management
Authors: Horvath Eleonora , Majlis Sergio , Rossi Ricardo , Franco Carmen , Niedmann Juan P. , Castro Alex , Dominguez Miguel
Published: March 2009

Context: There is a high prevalence of thyroid nodules on ultrasonographic (US) examination. However, most of them are benign. US criteria may help to decide cost-effective management.

Objective: Our objective was to develop a standardized US characterization and reporting data system of thyroid lesions for clinical management: the Thyroid Imaging Reporting and Data System (TIRADS).

Design: This was a prospective study using the TIRADS, which is based on the concepts of the Breast Imaging Reporting Data System of the American College of Radiology.

Materials: A correlation of the US findings and fine needle aspiration biopsy (FNAB) results in 1959 lesions biopsied under US guidance and studied histologically during an 8-yr period was divided into three stages. In the first stage, 10 US patterns were defined. In the second stage, four TIRADS groups were defined according to risk. The percentages of malignancy defined in the Breast Imaging Reporting and Data System were followed: TIRADS 2 (0% malignancy), TIRADS 3 (<5% malignancy), TIRADS 4 (5–80% malignancy), and TIRADS 5 (>80% malignancy).

Results: The TIRADS classification was evaluated at the third stage of the study in a sample of 1097 nodules (benign: 703; follicular lesions: 238; and carcinoma: 156). Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 88, 49, 49, 88, and 94%, respectively. The ratio of benign to malignant or follicular FNAB results currently is 1.8.

Conclusions: The TIRADS has allowed us to improve patient management and cost-effectiveness, avoiding unnecessary FNAB. In addition, we have established standard codes to be used both for radiologists and endocrinologists.
Vascular Pathology in Male Lewis Rats following Short-Term, Low-Dose Rotenone Administration
Authors: Allen A. L. , Luo C. , Montgomery D. L. , Rajput A. H. , Robinson C. A. , Rajput A.
Published: March 2009

The long-term administration of low doses of rotenone has been used to produce a model of Parkinson disease (PD) in rats. However, only about 50% of similarly treated rats develop the PD-like syndrome, with many dying during the first few days of treatment. The lesions in male Lewis rats that became moribund or died after short-term, low-dose rotenone administration are described. Dosed rats had fibrinoid change and acute hemorrhage involving small arteries and arterioles of the brain and lungs. The thalamus, hypothalamus, and medulla oblongata were most frequently and severely affected. Blood vessels in the brain of some male Lewis rats appeared acutely susceptible to the effects of rotenone. Understanding the selective nature of the fibrinoid change and hemorrhage might explain how rotenone produces PD-like signs and lesions in rats, and it might also provide the basis for a model of intraparenchymal hemorrhagic cerebrovascular disease (i.e., hemorrhagic strokes) in humans.
Review Paper: Gene Expression Profiling in Veterinary and Human Medicine: Overview of Applications and Proposed Quality Control Practices
Authors: Kort E. J. , Norton P. , Haak P. , Berghuis B. , Ramirez S. , Resau J.
Published: March 2009

High throughput molecular analysis of veterinary tissue samples is being applied to a wide range of research questions aimed at improving survival, development of diagnostic assays, and improving the economics of commercial production of animal products. Many of these efforts also, implicitly or explicitly, have ramifications for the clinical care of humans and, potentially, animals. Here we provide an overview of applications of gene expression profiling in veterinary research and practice. We then focus on the current state of quality control and quality assurance efforts in gene expression profiling studies, underscoring lessons learned from such analysis of human samples. Finally, we propose practices aimed at ensuring the reliability and reproducibility of such assays. The implementation of quality assurance practices by a trained pathologist is an essential link in the chain of events leading ultimately to reliable and reproducible research findings and appropriate clinical care.
A New Scenario for Negative Functional Magnetic Resonance Imaging Signals: Endogenous Neurotransmission
Authors: Shih Yen-Yu I. , Chen Chiao-Chi V. , Shyu Bai-Chuang , Lin Zi-Jun , Chiang Yun-Chen , Jaw Fu-Shan , Chen You-Yin , Chang Chen
Published: March 2009

Functional magnetic resonance imaging (fMRI) has revolutionized investigations of brain functions. Increases in fMRI signals are usually correlated with neuronal activation, but diverse explanations have been proposed for negative fMRI responses, including decreases in neuronal activity, the vascular-steal effect, and large increases in oxygen consumption. These possible scenarios, although encompassing a wide range of potential neurovascular responses, cannot yet be used to interpret certain types of negative fMRI signals. Recent studies have found that intravenous injection of dopamine D2receptor (D2DR) agonist reduced the hemodynamic responses in the caudate–putamen (CPu); however, whether endogenous dopaminergic neurotransmission contributes to fMRI signals remains obscure. Since it has been suggested that the D2DR is involved in pain modulation, and the CPu shows equivocal fMRI signals during noxious stimulation, the present study established an animal model based on graded electrical stimulation to elicit different levels of nociception, and aimed to determine whether nociception-induced endogenous dopaminergic neurotransmission is sufficient to generate negative fMRI responses. Our results from cerebral blood volume (CBV)-weighted fMRI, Fos immunohistochemistry, and electrophysiological recording demonstrated a salient bilateral CBV decreases associated with heightened neuronal activity in the CPu induced by unilateral noxious electrical stimulation. In addition, preinjection of D2DR antagonist reduced the observed CBV decreases. Our findings reveal the role of the D2DR in regulating striatal vascular responses and suggest that endogenous neurotransmission-induced CBV decreases underlie negative fMRI signals. Hence, the influence of endogenous neurotransmission should be considered when interpreting fMRI data, especially in an area involved in strong vasoactive neurotransmission.
Activation of Extracellular Signal-Regulated Kinase in the Anterior Cingulate Cortex Contributes to the Induction and Expression of Affective Pain
Authors: Cao Hong , Gao Yong-Jing , Ren Wen-Hua , Li Ting-Ting , Duan Kai-Zheng , Cui Yi-Hui , Cao Xiao-Hua , Zhao Zhi-Qi , Ji Ru-Rong , Zhang Yu-Qiu
Published: March 2009

The anterior cingulate cortex (ACC) is implicated in the affective response to noxious stimuli. However, little is known about the molecular mechanisms involved. The present study demonstrated that extracellular signal-regulated kinase (ERK) activation in the ACC plays a crucial role in pain-related negative emotion. Intraplantar formalin injection produced a transient ERK activation in laminae V-VI and a persistent ERK activation in laminae II-III of the rostral ACC (rACC) bilaterally. Using formalin-induced conditioned place avoidance (F-CPA) in rats, which is believed to reflect the pain-related negative emotion, we found that blockade of ERK activation in the rACC with MEK inhibitors prevented the induction of F-CPA. Interestingly, this blockade did not affect formalin-induced two-phase spontaneous nociceptive responses and CPA acquisition induced by electric foot-shock or U69,593, an innocuous aversive agent. Upstream, NMDA receptor, adenylyl cyclase (AC) and phosphokinase A (PKA) activators activated ERK in rACC slices. Consistently, intra-rACC microinjection of AC or PKA inhibitors prevented F-CPA induction. Downstream, phosphorylation of cAMP response element binding protein (CREB) was induced in the rACC by formalin injection and by NMDA, AC and PKA activators in brain slices, which was suppressed by MEK inhibitors. Furthermore, ERK also contributed to the expression of pain-related negative emotion. Thus, when rats were re-exposed to the conditioning context for retrieval of pain experience, ERK and CREB were reactivated in the rACC, and inhibiting ERK activation blocked the expression of F-CPA. All together, our results demonstrate that ERK activation in the rACC is required for the induction and expression of pain-related negative affect.
GABA-Induced Intersubunit Conformational Movement in the GABAAReceptor α1M1-β2M3 Transmembrane Subunit Interface: Experimental Basis for Homology Modeling of an Intravenous Anesthetic Binding Site
Authors: Bali Moez , Jansen Michaela , Akabas Myles H.
Published: March 2009

The molecular basis of general anesthetic interactions with GABAAreceptors is uncertain. An accurate homology model would facilitate studies of anesthetic action. Construction of a GABAAmodel based on the 4 Å resolution acetylcholine receptor structure is complicated by alignment uncertainty between the acetylcholine and GABAAreceptor M3 and M4 transmembrane segments. Using disulfide crosslinking we previously established the orientation of M2 and M3 within a single GABAAsubunit. The resultant model predicts that the βM3 residue β2M286, implicated in anesthetic binding, faces the adjacent α1-M1 segment and not into the β2 subunit interior as some models have suggested. To assess the proximity of β2M286 to the α1-M1 segment we expressed β2M286C and γ2 with 10 consecutive α1-M1 cysteine (Cys) mutants, α1I223C to α1L232C, in and flanking the extracellular end of α1-M1. In activated states, β2M286C formed disulfide bonds with α1Y225C and α1Q229C based on electrophysiological assays and dimers on Western blots, but not with other α1-M1 mutants. β2F289, one helical turn below β2M286, formed disulfide bonds with α1I228C, α1Q229C and α1L232C in activated states. The intervening residues, β2G287C and β2C288, did not form disulfide bonds with α1-M1 Cys mutants. We conclude that the β2-M3 residues β2M286 and β2F289 face the intersubunit interface in close proximity to α1-M1 and that channel gating induces a structural rearrangement in the transmembrane subunit interface that reduces the βM3 to αM1 separation by ∼7 Å. This supports the hypothesis that some intravenous anesthetics bind in the βM3-αM1 subunit interface consistent with azi-etomidate photoaffinity labeling.
Identificando os fatores relacionados ao diagnóstico de enfermagem "risco de quedas" entre idosos
Authors: Marin Maria José Sanches , Amaral Fernanda Siqueira , Martins Isabela Bonifácio , Bertassi Vanessa Clivelaro
Published: March 2009

Considerando que as quedas, entre os idosos, representam um importante problema de saúde pública, o presente estudo tem como objetivo identificar os fatores relacionados ao diagnóstico de enfermagem "risco de quedas" entre 51 idosos residentes em uma microárea. Os resultados apontaram que todos os idosos apresentavam o diagnóstico de enfermagem "risco de quedas", relacionados a inúmeros fatores tanto intrínsecos como extrínsecos. O conhecimento das necessidades dessa população deixa claro a importância de adoção de medidas educativas, individuais e coletivas com a finalidade de manter o nível de saúde da mesma.