bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of midbrain in the control of breathing in anuran amphibians
Authors: Gargaglioni Luciane H. , Meier Janice T. , Branco Luiz G. S. , Milsom William K.
Published: April 2007

The present study was designed to explore systematically the midbrain of unanesthetized, decerebrate anuran amphibians (bullfrogs), using chemical and electrical stimulation and midbrain transections to identify sites capable of exciting and inhibiting breathing. Ventilation was measured as fictive motor output from the mandibular branch of the trigeminal nerve and the laryngeal branch of the vagus nerve. The results of our transection studies suggest that, under resting conditions, the net effect of inputs from sites within the rostral half of the midbrain is to increase fictive breathing frequency, whereas inputs from sites within the caudal half of the midbrain have no net effect on fictive breathing frequency but appear to act on the medullary central rhythm generator to produce episodic breathing. The results of our stimulation experiments indicate that the principal sites in the midbrain that are capable of exciting or inhibiting the fictive frequency of lung ventilation, and potentially clustering breaths into episodes, appear to be those primarily involved in visual and auditory integration, motor functions, and attentional state.
Activated protein C ameliorates LPS-induced acute kidney injury and downregulates renal INOS and angiotensin 2
Authors: Gupta Akanksha , Rhodes George J. , Berg David T. , Gerlitz Bruce , Molitoris Bruce A. , Grinnell Brian W.
Published: April 2007

Endothelial dysfunction contributes significantly to acute renal failure (ARF) during inflammatory diseases including septic shock. Previous studies have shown that activated protein C (APC) exhibits anti-inflammatory properties and modulates endothelial function. Therefore, we investigated the effect of APC on ARF in a rat model of endotoxemia. Rats subjected to lipopolysaccharide (LPS) treatment exhibited ARF as illustrated by markedly reduced peritubular capillary flow and increased serum blood urea nitrogen (BUN) levels. Using quantitative two-photon intravital microscopy, we observed that at 3 h post-LPS treatment, rat APC (0.1 mg/kg iv bolus) significantly improved peritubular capillary flow [288 ± 15 μm/s (LPS) vs. 734 ± 59 μm/s (LPS+APC), P = 0.0009, n = 6], and reduced leukocyte adhesion ( P = 0.003) and rolling ( P = 0.01) compared with the LPS-treated group. Additional experiments demonstrated that APC treatment significantly improved renal blood flow and reduced serum BUN levels compared with 24-h post-LPS treatment. Biochemical analysis revealed that APC downregulated inducible nitric oxide synthase (iNOS) mRNA levels and NO by-products in the kidney. In addition, APC modulated the renin-angiotensin system by reducing mRNA expression levels of angiotensin-converting enzyme-1 (ACE1), angiotensinogen, and increasing ACE2 mRNA levels in the kidney. Furthermore, APC significantly reduced ANG II levels in the kidney compared with the LPS-treated group. Taken together, these data suggest that APC can suppress LPS-induced ARF by modulating factors involved in vascular inflammation, including downregulation of renal iNOS and ANG II systems. Furthermore, the data suggest a potential therapeutic role for APC in the treatment of ARF.
Downregulation of renal TonEBP in hypokalemic rats
Authors: Jeon Un Sil , Han Ki-Hwan , Park Soo-Hyun , Lee Sang Do , Sheen Mee Rie , Jung Ju-Young , Kim Wan Young , Sands Jeff M. , Kim Jin , Kwon H. Moo
Published: April 2007

Hypokalemia causes a significant decrease in the tonicity of the renal medullary interstitium in association with reduced expression of sodium transporters in the distal tubule. We asked whether hypokalemia caused downregulation of the tonicity-responsive enhancer binding protein (TonEBP) transcriptional activator in the renal medulla due to the reduced tonicity. We found that the abundance of TonEBP decreased significantly in the outer and inner medullas of hypokalemic rats. Underlying mechanisms appeared different in the two regions because the abundance of TonEBP mRNA was lower in the outer medulla but unchanged in the inner medulla. Immunohistochemical examination of TonEBP revealed cell type-specific differences. TonEBP expression decreased dramatically in the outer and inner medullary collecting ducts, thick ascending limbs, and interstitial cells. In the descending and ascending thin limbs, TonEBP abundance decreased modestly. In the outer medulla, TonEBP shifted to the cytoplasm in the descending thin limbs. As expected, transcription of aldose reductase, a target of TonEBP, was decreased since the abundance of mRNA and protein was reduced. Downregulation of TonEBP appeared to have also contributed to reduced expression of aquaporin-2 and UT-A urea transporters in the renal medulla. In cultured cells, expression and activity of TonEBP were not affected by reduced potassium concentrations in the medium. These data support the view that medullary tonicity regulates expression and nuclear distribution of TonEBP in the renal medulla in cell type-specific manners.
Self-Tuning of Neural Circuits Through Short-Term Synaptic Plasticity
Authors: Sussillo David , Toyoizumi Taro , Maass Wolfgang
Published: April 2007

Numerous experimental data show that cortical networks of neurons are not silent in the absence of external inputs, but rather maintain a low spontaneous firing activity. This aspect of cortical networks is likely to be important for their computational function, but is hard to reproduce in models of cortical circuits of neurons because the low-activity regime is inherently unstable. Here we show—through theoretical analysis and extensive computer simulations—that short-term synaptic plasticity endows models of cortical circuits with a remarkable stability in the low-activity regime. This short-term plasticity works as a homeostatic mechanism that stabilizes the overall activity level in spite of drastic changes in external inputs and internal circuit properties, while preserving reliable transient responses to signals. The contribution of synaptic dynamics to this stability can be predicted on the basis of general principles from control theory.
A Peptide Conjugate of Vitamin E Succinate Targets Breast Cancer Cells with High ErbB2 Expression
Authors: Wang Xiu-Fang , Birringer Marc , Dong Lan-Feng , Veprek Pavel , Low Pauline , Swettenham Emma , Stantic Marina , Yuan Lin-Hong , Zobalova Renata , Wu Kun , Ledvina Miroslav , Ralph Stephen J. , Neuzil Jiri
Published: April 2007

Overexpression of erbB2 is associated with resistance to apoptosis. We explored whether high level of erbB2 expression by cancer cells allows their targeting using an erbB2-binding peptide (LTVSPWY) attached to the proapoptotic α-tocopheryl succinate (α-TOS). Treating erbB2-low or erbB2-high cells with α-TOS induced similar levels of apoptosis, whereas α-TOS-LTVSPWY induced greater levels of apoptosis in erbB2-high cells. α-TOS rapidly accumulated in erbB2-high cells exposed to α-TOS-LTVSPWY. The extent of apoptosis induced in erbB2-high cells by α-TOS-LTVSPWY was suppressed by erbB2 RNA interference as well as by inhibition of either endocytotic or lysosomal function. α-TOS-LTVSPWY reduced erbB2-high breast carcinomas in FVB/N c-neu transgenic mice. We conclude that a conjugate of a peptide targeting α-TOS to erbB2-overexpressing cancer cells induces rapid apoptosis and efficiently suppresses erbB2-positive breast tumors. [Cancer Res 2007;67(7):3337–44]
Enhanced Expression of Asparagine Synthetase under Glucose-Deprived Conditions Protects Pancreatic Cancer Cells from Apoptosis Induced by Glucose Deprivation and Cisplatin
Authors: Cui Hongyan , Darmanin Stephanie , Natsuisaka Mitsuteru , Kondo Takeshi , Asaka Masahiro , Shindoh Masanobu , Higashino Fumihiro , Hamuro Junji , Okada Futoshi , Kobayashi Masataka , Nakagawa Koji , Koide Hideyuki , Kobayashi Masanobu
Published: April 2007

Although hypovasculature is an outstanding characteristic of pancreatic cancers, the tumor cells survive and proliferate under severe hypoxic, glucose-deprived conditions caused by low blood supply. It is well known that the hypoxia-inducible factor-1 pathway is essential for the survival of pancreatic cancer cells under hypoxic conditions. To discover how pancreatic cancer cells adapt to glucose deprivation as well as hypoxia, we sought glucose deprivation–inducible genes by means of a DNA microarray system. We identified 63 genes whose expression was enhanced under glucose-deprived conditions at >2-fold higher levels than under normal glucose conditions. Among these genes, asparagine synthetase (ASNS) was studied in detail. Although it is known to be associated with drug resistance in leukemia and oncogenesis triggered by mutated p53, its function is yet to be determined. In this study, we found that glucose deprivation induced the overexpression of ASNS through an AMP-activated protein kinase–independent and activating transcription factor-4–dependent manner and that ASNS protects pancreatic cancer cells from apoptosis induced by glucose deprivation itself. ASNS overexpression also induced resistance to apoptosis triggered by cisplatin [cis-diammine-dichloroplatinum (CDDP)] and carboplatin, but not by 5-fluorouracil, paclitaxel, etoposide, or gemcitabine. We show that glucose deprivation induces the activation of c-jun NH2-terminal kinase (JNK)/stress-activated protein kinase (SAPK) in a mock transfectant but not in an ASNS transfectant. Consequently, an inhibitor of JNK/SAPK decreased the sensitivity of pancreatic cancer cells to apoptosis by glucose deprivation and CDDP. These results strongly suggest that ASNS is induced by glucose deprivation and may play a pivotal role in the survival of pancreatic cancer cells under glucose-deprived conditions. [Cancer Res 2007;67(7):3345–55]
Mitogen-Activated Protein Kinase Kinase Inhibition Enhances Nuclear Proapoptotic Function of p53 in Acute Myelogenous Leukemia Cells
Authors: Kojima Kensuke , Konopleva Marina , Samudio Ismael J. , Ruvolo Vivian , Andreeff Michael
Published: April 2007

Activation of the Raf/MEK/ERK pathway and inactivation of wild-type p53 by Mdm2 overexpression are frequent molecular events in acute myelogenous leukemia (AML). We investigated the interaction of Raf/MEK/ERK and p53 pathways after their simultaneous blockades using a selective small-molecule antagonist of Mdm2, Nutlin-3a, and a pharmacologic MEK-specific inhibitor, PD98059. We found that PD98059, which itself has minimal apoptogenic activity, acts synergistically with Nutlin-3a to induce apoptosis in wild-type p53 AML cell lines OCI-AML-3 and MOLM-13. Interestingly, PD98059 enhanced nuclear proapototic function of p53 in these cells. In accordance with the activation of transcription-dependent apoptosis, PD98059 treatment promoted the translocation of p53 from the cytoplasm to the nucleus in OCI-AML-3 cells, in which p53 primarily initiates transcription-independent apoptosis when cells are treated with Nutlin-3a alone. The critical role of p53 localization in cells with increased p53 levels was supported by enhanced apoptosis induction in cells cotreated with Nutlin-3a and the nuclear export inhibitor leptomycin B. PD98059 prevented p53-mediated induction of p21 at the transcriptional level. The repressed expression of antiapototic p21 also seemed to contribute to synergism between PD98059 and Nutlin-3a because (a) the synergistic apoptogenic effect was preserved in G1 cells, (b) p53-mediated induction of p21 was preferentially seen in G1 cells, (c) PD98059 strongly antagonized p21 induction by Nutlin-3a, and (d) cells with high p21 levels were resistant to apoptosis. This is the first report showing that the Raf/MEK/ERK pathway regulates the subcellular localization of p53 and the relative contribution of transcription-dependent and transcription-independent pathways in p53-mediated apoptosis. [Cancer Res 2007;67(7):3210–9]
Nuclear Factor-κB and Manganese Superoxide Dismutase Mediate Adaptive Radioresistance in Low-Dose Irradiated Mouse Skin Epithelial Cells
Authors: Fan Ming , Ahmed Kazi Mokim , Coleman Mitchell C. , Spitz Douglas R. , Li Jian Jian
Published: April 2007

Mechanisms governing inducible resistance to ionizing radiation in untransformed epithelial cells pre-exposed to low-dose ionizing radiation (LDIR; ≤10 cGy) are not well understood. The present study provides evidence that pre-exposure to 10 cGy X-rays increases clonogenic survival of mouse skin JB6P+ epithelial cells subsequently exposed to 2 Gy doses of γ-rays. To elucidate the molecular pathways of LDIR-induced adaptive radioresistance, the transcription factor nuclear factor-κB (NF-κB) and a group of NF-κB–related proteins [i.e., p65, manganese superoxide dismutase (MnSOD), phosphorylated extracellular signal-regulated kinase, cyclin B1, and 14-3-3ζ] were identified to be activated as early as 15 min after LDIR. Further analysis revealed that a substantial amount of both 14-3-3ζ and cyclin B1 accumulated in the cytoplasm at 4 to 8 h when cell survival was enhanced. The nuclear 14-3-3ζ and cyclin B1 were reduced and increased at 4 and 24 h, respectively, after LDIR. Using YFP-fusion gene expression vectors, interaction between 14-3-3ζ and cyclin B1 was visualized in living cells, and LDIR enhanced the nuclear translocation of the 14-3-3ζ/cyclin B1 complex. Treatment of JB6P+ cells with the NF-κB inhibitor IMD-0354 suppressed LDIR-induced expression of MnSOD, 14-3-3ζ, and cyclin B1 and diminished the adaptive radioresistance. In addition, treatment with small interfering RNA against mouse MnSOD was shown to inhibit the development of LDIR-induced radioresistance. Together, these results show that NF-κB, MnSOD, 14-3-3ζ, and cyclin B1 contribute to LDIR-induced adaptive radioresistance in mouse skin epithelial cells. [Cancer Res 2007;67(7):3220–8]
Evidence that in Xeroderma Pigmentosum Variant Cells, which Lack DNA Polymerase η, DNA Polymerase ι Causes the Very High Frequency and Unique Spectrum of UV-Induced Mutations
Authors: Wang Yun , Woodgate Roger , McManus Terrence P. , Mead Samantha , McCormick J. Justin , Maher Veronica M.
Published: April 2007

Xeroderma pigmentosum variant (XPV) patients have normal DNA excision repair, yet are predisposed to develop sunlight-induced cancer. They exhibit a 25-fold higher than normal frequency of UV-induced mutations and very unusual kinds (spectrum), mainly transversions. The primary defect in XPV cells is the lack of functional DNA polymerase (Pol) η, the translesion synthesis DNA polymerase that readily inserts adenine nucleotides opposite photoproducts involving thymine. The high frequency and striking difference in kinds of UV-induced mutations in XPV cells strongly suggest that, in the absence of Pol η, an abnormally error-prone polymerase substitutes. In vitro replication studies of Pol ι show that it replicates past 5′T-T3′ and 5′T-U3′ cyclobutane pyrimidine dimers, incorporating G or T nucleotides opposite the 3′ nucleotide. To test the hypothesis that Pol ι causes the high frequency and abnormal spectrum of UV-induced mutations in XPV cells, we identified an unlimited lifespan XPV cell line expressing two forms of Pol ι, whose frequency of UV-induced mutations is twice that of XPV cells expressing one form. We eliminated expression of one form and compared the parental cells and derivatives for the frequency and kinds of UV-induced mutations. All exhibited similar sensitivity to the cytotoxicity of UV(254 nm), and the kinds of mutations induced were identical, but the frequency of mutations induced in the derivatives was reduced to ≤50% that of the parent. These data strongly support the hypothesis that in cells lacking Pol η, Pol ι is responsible for the high frequency and abnormal spectrum of UV-induced mutations, and ultimately their malignant transformation. [Cancer Res 2007;67(7):3018–26]
E-Cadherin Cell-Cell Adhesion in Ewing Tumor Cells Mediates Suppression of Anoikis through Activation of the ErbB4 Tyrosine Kinase
Authors: Kang Hyung-Gyoo , Jenabi Jasmine M. , Zhang Jingsong , Keshelava Nino , Shimada Hiroyuki , May William A. , Ng Tony , Reynolds C. Patrick , Triche Timothy J. , Sorensen Poul H.B.
Published: April 2007

Ability to grow under anchorage-independent conditions is one of the major hallmarks of transformed cells. Key to this is the capacity of cells to suppress anoikis, or programmed cell death induced by detachment from the extracellular matrix. To model this phenomenon in vitro, we plated Ewing tumor cells under anchorage-independent conditions by transferring them to dishes coated with agar to prevent attachment to underlying plastic. This resulted in marked up-regulation of E-cadherin and rapid formation of multicellular spheroids in suspension. Addition of calcium chelators, antibodies to E-cadherin (but not to other cadherins or β1-integrin), or expression of dominant negative E-cadherin led to massive apoptosis of spheroid cultures whereas adherent cultures were unaffected. This correlated with reduced activation of the phosphatidylinositol 3-kinase-Akt pathway but not the Ras-extracellular signal–regulated kinase 1/2 cascade. Furthermore, spheroid cultures showed profound chemoresistance to multiple cytotoxic agents compared with adherent cultures, which could be reversed by α-E-cadherin antibodies or dominant negative E-cadherin. In a screen for potential downstream effectors of spheroid cell survival, we detected E-cadherin–dependent activation of the ErbB4 receptor tyrosine kinase but not of other ErbB family members. Reduction of ErbB4 levels by RNA interference blocked Akt activation and spheroid cell survival and restored chemosensitivity to Ewing sarcoma spheroids. Our results indicate that anchorage-independent Ewing sarcoma cells suppress anoikis through a pathway involving E-cadherin cell-cell adhesion, which leads to ErbB4 activation of the phosphatidylinositol 3-kinase-Akt pathway, and that this is associated with increased resistance of cells to cytotoxic agents. [Cancer Res 2007;67(7):3094–105]
A Common 8q24 Variant in Prostate and Breast Cancer from a Large Nested Case-Control Study
Authors: Schumacher Fredrick R. , Feigelson Heather Spencer , Cox David G. , Haiman Christopher A. , Albanes Demetrius , Buring Julie , Calle Eugenia E. , Chanock Stephen J. , Colditz Graham A. , Diver W. Ryan , Dunning Alison M. , Freedman Matthew L. , Gaziano John M. , Giovannucci Edward , Hankinson Sue E. , Hayes Richard B. , Henderson Brian E. , Hoover Robert N. , Kaaks Rudolf , Key Timothy , Kolonel Laurence N. , Kraft Peter , Le Marchand Loic , Ma Jing , Pike Malcolm C. , Riboli Elio , Stampfer Meir J. , Stram Daniel O. , Thomas Gilles , Thun Michael J. , Travis Ruth , Virtamo Jarmo , Andriole Gerald , Gelmann Edward , Willett Walter C. , Hunter David J.
Published: April 2007

Two recent studies independently identified polymorphisms in the 8q24 region, including a single nucleotide polymorphism (rs1447295), strongly associated with prostate cancer risk. Here, we replicate the overall association in a large nested case-control study from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium using 6,637 prostate cancer cases and 7,361 matched controls. We also examine whether this polymorphism is associated with breast cancer among 2,604 Caucasian breast cancer cases and 3,118 matched controls. The rs1447295 marker was strongly associated with prostate cancer among Caucasians (P = 1.23 × 10−13). When we exclude the Multiethnic Cohort samples, previously reported by Freedman et al., the association remains highly significant (P = 8.64 × 10−13). Compared with wild-type homozygotes, carriers with one copy of the minor allele had an ORAC = 1.34 (99% confidence intervals, 1.19–1.50) and carriers with two copies of the minor allele had an ORAA = 1.86 (99% confidence intervals, 1.30–2.67). Among African Americans, the genotype association was statistically significant in men diagnosed with prostate cancer at an early age (P = 0.011) and nonsignificant for those diagnosed at a later age (P = 0.924). This difference in risk by age at diagnosis was not present among Caucasians. We found no statistically significant difference in risk when tumors were classified by Gleason score, stage, or mortality. We found no association between rs1447295 and breast cancer risk (P = 0.590). Although the gene responsible has yet to be identified, the validation of this marker in this large sample of prostate cancer cases leaves little room for the possibility of a false-positive result. [Cancer Res 2007;67(7):2951–6]
PRL-3 Down-regulates PTEN Expression and Signals through PI3K to Promote Epithelial-Mesenchymal Transition
Authors: Wang Haihe , Quah Samantha Yiling , Dong Jing Ming , Manser Edward , Tang Jing Ping , Zeng Qi
Published: April 2007

PRL-3 is a metastasis-associated phosphatase. We and others have shown that its overexpression increases cell motility and invasiveness. These phenotypic changes are reminiscent of the epithelial-mesenchymal transition (EMT) that occurs during embryonic development and oncogenesis. The EMT is a complex process that converts epithelia into migratory mesenchymal cells. We here attempt to unravel the underlying mechanistic basis of these phenomena. HeLa cells transiently expressing EGFP-PRL-3 (HeLa-PRL-3) exhibit reduced levels of paxillin. Similarly, Chinese hamster ovary cells stably expressing myc-PRL-3 (CHO-PRL-3) also show marked reductions in paxillin, phosphorylated paxillin-Tyr31, and vinculin at focal adhesion complexes and notable reductions in the levels of RhoA-GTP, Rac1-GTP, and filamentous-actin filaments. DLD-1 human colorectal cancer cells engineered to express EGFP-PRL-3 (DLD-1-PRL-3) underwent changes consistent with EMT. In these cells, PRL-3 activates Akt and inactivates glycogen synthase kinase-3β as assessed by phosphospecific antibodies. PRL-3 up-regulates mesenchymal markers fibronectin and Snail and down-regulates epithelial markers E-cadherin, γ-catenin (plakoglobin), and integrin β3, which are major effectors in the EMT pathway. The changes in these EMT characteristics brought about by PRL-3 can be abrogated by the phosphoinositide 3-kinase (PI3K) inhibitor LY294002, implying that PRL-3 acts upstream of PI3K and could play an initiating role to trigger the EMT switch during cancer metastasis. In addition, PRL-3 can down-regulate phosphatase and tensin homologue deleted on chromosome 10, which is an important antagonist of PI3K, further reinforcing PI3K/Akt function in PRL-3–triggered EMT. Catalytically inactive PRL-3 (C104S) was impaired in the above PRL-3–mediated events, indicating that these properties require phosphatase activity. Targeting PRL-3 may thus be a useful strategy to impede cancer cell invasion and metastasis. [Cancer Res 2007;67(7):2922–6]
Oncogenic Role of MPHOSPH1, a Cancer-Testis Antigen Specific to Human Bladder Cancer
Authors: Kanehira Mitsugu , Katagiri Toyomasa , Shimo Arata , Takata Ryo , Shuin Taro , Miki Tsuneharu , Fujioka Tomoaki , Nakamura Yusuke
Published: April 2007

To disclose the molecular mechanism of bladder cancer, the second most common genitourinary tumor, we had previously done genome-wide expression profile analysis of 26 bladder cancers by means of cDNA microarray representing 27,648 genes. Among genes that were significantly up-regulated in the majority of bladder cancers, we here report identification of M-phase phosphoprotein 1 (MPHOSPH1) as a candidate molecule for drug development for bladder cancer. Northern blot analyses using mRNAs of normal human organs and cancer cell lines indicated this molecule to be a novel cancer-testis antigen. Introduction of MPHOSPH1 into NIH3T3 cells significantly enhanced cell growth at in vitro and in vivo conditions. We subsequently found an interaction between MPHOSPH1 and protein regulator of cytokinesis 1 (PRC1), which was also up-regulated in bladder cancer cells. Immunocytochemical analysis revealed colocalization of endogenous MPHOSPH1 and PRC1 proteins in bladder cancer cells. Interestingly, knockdown of either MPHOSPH1 or PRC1 expression with specific small interfering RNAs caused a significant increase of multinuclear cells and subsequent cell death of bladder cancer cells. Our results imply that the MPHOSPH1/PRC1 complex is likely to play a crucial role in bladder carcinogenesis and that inhibition of the MPHOSPH1/PRC1 expression or their interaction should be novel therapeutic targets for bladder cancers. [Cancer Res 2007;67(7):3276–85]
Active Induction of Tumor-Specific IgE Antibodies by Oral Mimotope Vaccination
Authors: Riemer Angelika B. , Untersmayr Eva , Knittelfelder Regina , Duschl Albert , Pehamberger Hubert , Zielinski Christoph C. , Scheiner Otto , Jensen-Jarolim Erika
Published: April 2007

A role of IgE antibodies in cancer surveillance has been implicated for a long time. Studies dealing with IgE antibodies directly targeted to tumor antigens have shown marked anticancer effects mediated by this antibody class. Thus, the basic function of IgE antibodies may be to control tumor growth. Thus far, cancer-specific IgE has only been applied passively. Consequently, the aim of this study was to establish an active vaccination protocol to induce tumor antigen–specific IgE antibodies, and to evaluate functional properties. We previously generated epitope mimics, so-called mimotopes, for the epitope recognized by the anti-HER-2 antibody trastuzumab. Upon i.p. immunizations, IgG antibodies with trastuzumab-like properties could be elicited. In the present study, we immunized BALB/c mice via the oral route with these trastuzumab mimotopes, under simultaneous neutralization and suppression of gastric acid. As shown in preceding experiments, this feeding regimen effectively induces Th2 immune responses. Oral immunizations with trastuzumab mimotopes under hypoacidic conditions indeed resulted in the formation of IgE antibodies towards the HER-2 antigen. Moreover, anti-HER-2 IgE-sensitized effector cells mediated SK-BR-3 target cell lysis in an antibody-dependent cytotoxicity assay. We conclude that directed and epitope-specific induction of IgE against tumor antigens is feasible with an oral mimotope vaccination regimen, and that these antibodies mediate anticancer effects. [Cancer Res 2007;67(7):3406–11]
Positron Emission Tomography of Herpes Simplex Virus 1 Oncolysis
Authors: Kuruppu Darshini , Brownell Anna-Liisa , Zhu Aijun , Yu Meixiang , Wang Xukui , Kulu Yakup , Fuchs Bryan C. , Kawasaki Hiroshi , Tanabe Kenneth K.
Published: April 2007

Viral oncolysis, the destruction of cancer cells by replicating viruses, is under clinical investigation for cancer therapy. Lytic viral replication in cancer cells both destroys the cells and liberates progeny virion to infect adjacent cancer cells. The safety and efficacy of this approach are dependent on selective and robust viral replication in cancer cells rather than in normal cells. Methods to detect and quantify viral replication in tissues have relied on organ sampling for molecular analyses. Preclinical and clinical studies of viral oncolysis will benefit significantly from development of a noninvasive method to repetitively measure viral replication. We have shown that positron emission tomography (PET) allows for in vivo detection of herpes simplex virus (HSV)-1 replication in tumor cells using 9-(4-[18F]-fluoro-3-[hydroxymethyl]butyl)guanine ([18F]FHBG) as the substrate for HSV thymidine kinase (HSV-TK). As expected, phosphorylated [18F]FHBG is initially trapped within HSV-1–infected tumor cells and is detectable as early as 2 h following virus administration. MicroPET images reveal that [18F]FHBG accumulation in HSV-1–infected tumors peaks at 6 h. However, despite progressive accumulation of HSV-1 titers and HSV-TK protein in the tumor as viral oncolysis proceeds, tumor cell degradation resulting from viral oncolysis increases over time, which limits intracellular retention of [18F]FHBG. These observations have important consequences with regard to strategies to use [18F]FHBG PET for monitoring sites of HSV-TK expression during viral oncolysis. [Cancer Res 2007;67(7):3295–300]
The Regulation of AMPK β1, TSC2, and PTEN Expression by p53: Stress, Cell and Tissue Specificity, and the Role of These Gene Products in Modulating the IGF-1-AKT-mTOR Pathways
Authors: Feng Zhaohui , Hu Wenwei , de Stanchina Elisa , Teresky Angelika K. , Jin Shengkan , Lowe Scott , Levine Arnold J.
Published: April 2007

The insulin-like growth factor 1 (IGF-1)-AKT-mTOR pathways sense the availability of nutrients and mitogens and respond by signaling for cell growth and division. The p53 pathway senses a variety of stress signals which will reduce the fidelity of cell growth and division, and responds by initiating cell cycle arrest, senescence, or apoptosis. This study explores four p53-regulated gene products, the β1 and β2 subunits of the AMPK, which are shown for the first time to be regulated by the p53 protein, TSC2, PTEN, and IGF-BP3, each of which negatively regulates the IGF-1-AKT-mTOR pathways after stress. These gene products are shown to be expressed under p53 control in a cell type and tissue-specific fashion with the TSC2 and PTEN proteins being coordinately regulated in those tissues that use insulin-dependent energy metabolism (skeletal muscle, heart, white fat, liver, and kidney). In addition, these genes are regulated by p53 in a stress signal–specific fashion. The mTOR pathway also communicates with the p53 pathway. After glucose starvation of mouse embryo fibroblasts, AMPK phosphorylates the p53 protein but does not activate any of the p53 responses. Upon glucose starvation of E1A-transformed mouse embryo fibroblasts, a p53-mediated apoptosis ensues. Thus, there is a great deal of communication between the p53 pathway and the IGF-1-AKT and mTOR pathways. [Cancer Res 2007;67(7):3043–53]
Inhibition of Angiogenesis and Invasion by 3,3′-Diindolylmethane Is Mediated by the Nuclear Factor–κB Downstream Target Genes MMP-9 and uPA that Regulated Bioavailability of Vascular Endothelial Growth Factor in Prostate Cancer
Authors: Kong Dejuan , Li Yiwei , Wang Zhiwei , Banerjee Sanjeev , Sarkar Fazlul H.
Published: April 2007

Progression of prostate cancer is believed to be dependent on angiogenesis induced by tumor cells. 3,3′-Diindolylmethane (DIM) has been shown to repress neovascularization in a Matrigel plug assay and inhibit cell proliferation, migration, invasion, and capillary tube formation of cultured human umbilical vein endothelial cells. However, the molecular mechanism, by which DIM inhibits angiogenesis and invasion, has not been fully elucidated. Therefore, we sought to explore the molecular mechanism by which DIM inhibits angiogenesis and invasion, specifically by investigating the role of angiogenic factors secreted by prostate cancer cells which control all steps of angiogenesis. We found that BioResponse DIM (B-DIM), a formulated DIM with higher bioavailability, inhibited angiogenesis and invasion by reducing the bioavailability of vascular endothelial growth factor (VEGF) via repressing extracellular matrix–degrading proteases, such as matrix metalloproteinase (MMP)-9 and urokinase-type plasminogen activator (uPA), in human prostate cancer cells and reduced vascularity (angiogenesis) in vivo using Matrigel plug assay. We also found that B-DIM treatment inhibited DNA binding activity of nuclear factor-κB (NF-κB), which is known to mediate the expression of many NF-κB downstream target genes, including VEGF, IL-8, uPA, and MMP-9, all of which are involved in angiogenesis, invasion, and metastasis. Our data suggest that inhibition of NF-κB DNA binding activity by B-DIM contributes to the regulated bioavailability of VEGF by MMP-9 and uPA and, in turn, inhibits invasion and angiogenesis, which could be mechanistically linked with the antitumor activity of B-DIM as observed previously by our laboratory in a prostate cancer animal model. [Cancer Res 2007;67(7):3310–9]^
High HSP90 Expression Is Associated with Decreased Survival in Breast Cancer
Authors: Pick Elah , Kluger Yuval , Giltnane Jennifer M. , Moeder Christopher , Camp Robert L. , Rimm David L. , Kluger Harriet M.
Published: April 2007

The heat shock protein HSP90 chaperones proteins implicated in breast cancer progression, including Her2/neu. HSP90-targeting agents are in clinical trials for breast cancer. HSP90 expression is high in breast cancer cell lines, yet no large studies have been conducted on expression in human tumors and the association with clinical/pathologic variables. Tissue microarrays containing 10 cell lines and primary specimens from 655 patients with 10-year follow-up were assessed using our automated quantitative analysis (AQUA) method; we used cytokeratin to define pixels as breast cancer (tumor mask) within the array spot and measured HSP90 expression within the mask using Cy5-conjugated antibodies. We similarly assessed estrogen receptor, progesterone receptor, and Her2/neu expression. HSP90 expression was more variable in human tumors than in cell lines (P < 0.0001). High HSP90 expression was associated with decreased survival (P = 0.0024). On multivariable analysis, high HSP90 expression remained an independent prognostic marker. High HSP90 expression was associated with high Her2/neu and estrogen receptor, large tumors, high nuclear grade, and lymph node involvement. Although HSP90 levels were high in all our cell lines, expression in tumors was more variable. High HSP90 expression in primary breast cancer defines a population of patients with decreased survival. Evaluation of HSP90 expression in early-stage breast cancer may identify a subset of patients requiring more aggressive or pathway-targeted treatment. Prospective studies are needed to confirm the prognostic role of HSP90, as well as the predictive role of HSP90 expression in patients treated with HSP90 inhibitors. [Cancer Res 2007;67(7):2932–7]
Systematic Urokinase-Activated Anthrax Toxin Therapy Produces Regressions of Subcutaneous Human Non–Small Cell Lung Tumor in Athymic Nude Mice
Authors: Su Yunpeng , Ortiz Janelle , Liu Shihui , Bugge Thomas H. , Singh Ravibhushan , Leppla Stephen H. , Frankel Arthur E.
Published: April 2007

The novel recombinant anthrax toxin, PrAgU2/FP59, composed of the urokinase-activated protective antigen and a fusion protein of Pseudomonas exotoxin and lethal factor was tested for anti–lung cancer efficacy in an in vivo human tumor model. Male athymic nude mice (age 4–6 weeks) were inoculated s.c. with 10 million H1299 non–small cell lung cancer (NSCLC) cells in the left flank. When tumor volumes reached 200 mm3 (6–8 days), i.p. injection of 100 μL saline or different ratios and doses of PrAgU2/FP59 in 100 μL saline were given every 3 days for four doses and an additional dose at day 29. Animals were monitored twice daily and tumor measurements were made by calipers. The maximum tolerated doses of PrAgU2/FP59 differed dependent on the ratios of PrAgU2 to FP59 over the range of 3:1 to 25:1, respectively. At tolerated doses, tumor regressions were seen in all animals. Complete histologic remission lasting 60 days occurred in 30% of animals. PrAgU2/FP59 showed dramatic anti-NSCLC efficacy and warrants further clinical development for therapy of patients with advanced NSCLC. [Cancer Res 2007;67(7):3329–36]
Tumor-Released Microvesicles as Vehicles of Immunosuppression
Authors: Valenti Roberta , Huber Veronica , Iero Manuela , Filipazzi Paola , Parmiani Giorgio , Rivoltini Licia
Published: April 2007

Tumor-released microvesicles, or exosomes, which are abundant in the body fluids of patients with cancer, are likely to be involved in tumor progression. We recently showed that microvesicles released by human melanoma and colorectal carcinoma cells can promote the differentiation of monocytes to myeloid-derived suppressor cells which support tumoral growth and immune escape. These findings underscore an important role for these extracellular organelles in remodeling tumor-stromal interactions to promote malignancy. [Cancer Res 2007;67(7):2912–5]
Job and Organizational Characteristics
Authors: Carless Sally A. , Imber Amantha
Published: April 2007

This research aimed to assess the underlying dimensionality of items commonly used to assess applicants' perceptions of job and organizational characteristics. First, exploratory factor analysis (EFA) was used to determine the number of underlying constructs in a job and organizational characteristics scale. The initial sample consisted of 450 applicants for graduate positions with an international bank. A five-factor structure was identified: (a) Challenging Work, (b) Coworkers, (c) Pay and Promotion Opportunities, (d) Reputation, and (e) Location. Confirmatory factor analysis (CFA) was used to confirm that the five-factor model was a good fit to the data. Preselection ratings were used for EFA and postselection ratings for CFA. The five-factor model was confirmed in two additional samples: graduate applicants for a national telecommunications company and applicants for a state police force. Multigroup CFA was used to assess the generalizability of the model across three groups of applicants. The five-factor model was consistent across the groups.
Some Posterior Standard Deviations in Item Response Theory
Authors: Kim Seock-Ho
Published: April 2007

The procedures required to obtain the approximate posterior standard deviations of the parameters in the three commonly used item response models for dichotomous items are described and used to generate values for some common situations. The results were compared with those obtained from maximum likelihood estimation. It is shown that the use of priors may reduce the instability of estimates of the item parameters, assuming the choice of priors is reasonable. The sample size required for acceptable accuracy for the purposes of practical applications of item response theory may be inferred from tables or computer programs. It is suggested that the careful selection of priors be exercised to obtain the required precision when three-parameter models are applied in these situations.
Access to Information in Connective and Communal Transactive Memory Systems
Authors: Yuan Y. Connie , Fulk Janet , Monge Peter R.
Published: April 2007

This research tested a transactive theory model of how individuals allocate and retrieve task-related information in work teams. It extended prior research by exploring the role of communal information repositories in the context of human information resources. Structural equation modeling of six integrated hypotheses revealed several significant results. First, usage of information repositories was significantly related to individual access to information. However, the relationship between individual direct information exchange with team members (the human repositories) and individual access to information was significant only among average-level users of organizational information repositories. Second, development of individual expertise directories significantly influenced individual direct information exchange with team members. Third, perceived usage of organizational information repositories by team members significantly influenced actual usage. Finally, technology-specific competence in using intranets significantly influenced the actual usage of intranets as organizational information repositories.
How Intrinsic and Extrinsic Motivations Interact in Selectivity: Investigating the Moderating Effects of Situational Information Processing Goals in Issue Publics' Web Behavior
Authors: Young Mie Kim
Published: April 2007

By employing a unique methodological tool that combines individual-level Web behavior data with survey data, this study explored the effects of two levels of motivations on online information selection and candidate evaluation in an actual election campaign: the moderating effects of situational information processing goals (i.e., extrinsic motivation) on the selectivity and candidate evaluation of members of issue publics (i.e., intrinsic motivation). The results suggest that both intrinsic and extrinsic motivations, and more importantly the interplay of the two, exert significant influences on online political information consumption and candidate evaluation. When the accuracy goal was promoted, issue publics extended their search beyond the issue domains of their personal concerns and considered diverse issues in candidate evaluation. However, an issue public's extremity in candidate evaluation was heightened, in that issue publics paid little attention to the implications of the information when the preservation goal was introduced. Implications for the field of communication are discussed.
Case Illustrations of Negative Sexual Experiences Among University Women in Japan
Authors: Uji Masayo , Shono Masahiro , Shikai Noriko , Kitamura Toshinori
Published: April 2007

A retrospective study of negative sexual experiences (NSEs) was conducted among 532 Japanese university women. More than one third of the respondents reported having experienced at least one NSE, and two thirds were victimized by strangers. When the woman knew the perpetrator well, the NSE was more likely to be repeated. One sixth of victims did not disclose the incident. Older children disclosed incidents more frequently than did younger children. Women in the total disclosure group disclosed the incidents more quickly than did those in the partial disclosure group. Women victimized by strangers were more likely to disclose the incident completely. Less than 10% of women were disappointed with the reaction of the first-disclosure receiver. Unlike results obtained in previous studies, the victims did not necessarily regard it negatively when the incident was viewed less seriously or they were criticized by first-disclosure receivers. On the other hand, instrumental support was not always supportive.
Septic Arthritis of the Knee after Anterior Cruciate Ligament Surgery
Authors: Schulz Arndt P. , Götze Sebastian , Schmidt Hergo G. K. , Jürgens Christian , Faschingbauer Maximilian
Published: March 2007

Background

Septic arthritis is a rare complication after anterior cruciate ligament surgery. All case series reported so far have been retrospective, and case numbers of septic arthritis have ranged from 4 to 11.

Hypothesis

A stage-adapted treatment regimen for septic arthritis after anterior cruciate ligament surgery can provide reliable results.

Study Design

Case series; Level of evidence, 4.

Methods

From June 1993 to May 2003, 24 patients met the inclusion criteria for this study. The average age at trauma was 32.5 years. Treatment protocol was based on the grade of infection. Options included transarthroscopic treatment for Gaechter grades 1 and 2 infections or medial and lateral arthrotomy for grades 3 and 4 infections. Graft retention was decided based on clinical findings. The setting was a specialized trauma hospital. Follow-up included International Knee Documentation Committee forms, radiographs, and the Tegner and Lysholm scores at a mean of 66 months (range, 11-142) after treatment.

Results

In all cases, treatment of infection was successful; overall, a mean of 2.2 operations were required. In 7 cases, it was possible to salvage the graft. The Tegner activity level before the knee injury was 6.1 points. At follow-up, the average score was 3.8 points. The postoperative subjective International Knee Documentation Committee score averaged 64. The mean Lysholm score was 65.6. On clinical examination, a mean extension deficit of 3° and a mean maximum flexion of 120° were found. In the single-legged hop test, a mean capacity of 63% compared with the uninjured side was measured.

Conclusion

The described treatment regimen gives reliable results for this complication. There were no recurrences of septic arthritis or bone infection. Early infection can be managed arthroscopically with satisfactory results regarding the treatment of infection. In advanced or chronic infection, a more radical approach seems favorable. Results in these cases are overall only fair compared with patients with an uncomplicated anterior cruciate ligament reconstruction.
An Analysis of Soft Tissue Allograft Anterior Cruciate Ligament Reconstruction in a Rabbit Model
Authors: Soon Michael Y. H. , Hassan Afizah , Hui James H. P. , Goh James C. H. , Lee E.H.
Published: March 2007

Background

Soft tissue allografts are essential for revision and multiple ligament surgeries in the knee, where donor-site morbidity is an issue. However, the use of allografts is associated with a higher failure rate of osteointegration. Mesenchymal stem cells (MSCs) are investigated as potential agents to enhance bone tunnel and tendon healing.

Purpose

This study was conducted to analyze the effect of coating allografts with MSCs on the quality and rate of osteointegration at the allograft tendon and bone interface, and the biomechanical properties of these enhanced anterior cruciate ligament (ACL) grafts compared with controls.

Study Design

Descriptive laboratory study.

Methods

Bilateral ACL reconstructions using Achilles tendon allografts were performed in 36 rabbits. On 1 limb, the graft was coated with autogenous MSCs in a fibrin glue carrier, while the contralateral limb served as a control with no MSCs. The reconstructions were assessed histologically and biomechanically at 2, 4, and 8 weeks.

Results

At 8 weeks, histologic analysis of the controls revealed the development of mature scar tissue resembling Sharpey fibers spanning the tendon-bone interface. In contrast, the MSC-enhanced reconstructions showed a mature zone of fibrocartilage blending from bone to the allograft, strongly resembling a normal ACL insertion. On biomechanical testing, the MSC-enhanced grafts had significantly higher load-to-failure rates than controls. However, the stiffness and Young's modulus were lower in the treatment group.

Conclusions

The application of MSCs at the allograft tendon-bone interface during ACL reconstruction results in the development of an intervening zone of fibrocartilage. The use of MSCs to enhance allograft osteointegration is a novel method offering the potential of more physiologic and earlier healing, although further investigation must be conducted to improve the biomechanical strength.

Clinical Relevance

Mesenchymal stem cells can improve the biologic properties of soft tissue allograft healing. Combined with the decrease in donor-site morbidity, allografts are a viable choice for the sports medicine surgeon.
Sensory Impairment, Use of Community Support Services, and Quality of Life in Aged Care Clients
Authors: Tay Tien , Jie Jin Wang  , Lindley Richard , Chia Ee-Munn , Landau Peter , Ingham Nicholas , Kifley Annette , Mitchell Paul
Published: April 2007

Objective: To assess influences from visual or hearing impairment on use of community support services and health-related quality of life in aged care clients. Method: The authors sampled 284 frail elderly individuals presenting for assessment in Sydney, Australia. Moderate to severe visual impairment was defined as visual acuity <20/80 (better eye), and moderate to severe hearing loss as hearing thresholds >40 decibels (better ear). Community support services included home-delivered meals, home help, and community nurse visits. Results: After adjusting for age, sex, and two or more comorbid conditions, moderate to severe visual impairment, but not moderate to severe hearing loss, was significantly associated with increased use of community services (adjusted odds ratio 2.8, 95% confidence interval = 1.0—7.8). Conclusion: Moderate to severe visual impairment was associated with an increased likelihood of community service utilization in this aged care client sample.