bluuebunny/crossref_metadata_2025 huggingface dataset:
GAPPI: IDENTIFYING IMPORTANT PROTEIN MODULES THROUGH PROTEIN-PROTEIN INTERACTION GRAPHS
Authors: MOSCHOPOULOS CHARALAMPOS , FYTROS MARIOS , ALATSATHIANOS STAMATIS , LIKOTHANASSIS SPIRIDON , KOSSIDA SOPHIA
Published: May 2012

In this paper a new Genetic Algorithm is proposed, called GAppi, which performs clustering in protein-protein interaction networks to identify protein complexes. The algorithm has been tested exhaustively with experimental datasets coming from online protein interaction databases and individual experiments and it has been compared with five other effective techniques in order to demonstrate its efficiency and superior performance. Results showed that GAppi produces feasible and very efficient solutions compared to other techniques. Except from that, due to its adaptive behavior, each time it is used it can satisfy different constraints, thus meeting the different needs of each user. Furthermore, a user friendly interface has been implemented that hosts the proposed algorithmic strategy.
THE EFFECT OF TEMPERATURE ON BIPOLAR ELECTRICAL FATIGUE BEHAVIOR OF LEAD ZIRCONATE TITANATE CERAMICS
Authors: POJPRAPAI SOODKHET , GLAUM JULIA
Published: May 2012

The ferroelectric fatigue behavior of lead zirconate titanate was investigated under different temperatures (room temperature and 125°C). A bipolar electric field of ±1.5 kV/mm at a frequency of 50 Hz was applied to the samples up to 2 × 105cycles. A markedly different fatigue rate was observed dependent on temperature. The fatigue degradation represented by the loss of polarization and strain increases with the number of cycles and is more pronounced in the case of the lower temperature. Brennan's model based on a logarithmic fatigue rate is applied to explain the temperature effect on fatigue behavior due to the pinning effect.
The subsurface record of the Late Palaeozoic glaciation in the Chaco Basin, Bolivia
Authors: Bache F. , Moreau J. , Rubino J. L. , Gorini C. , Van-Vliet Lanoë B.
Published: May 2012

The Late Palaeozoic glaciation was the longest of the Phanerozoic era. It is recorded in numerous Gondwanan basins, with some, such as the Chaco Basin, having a high petroleum potential. In this basin, the quality of the available seismic, well and outcrop data permits us to characterize the Late Palaeozoic glacial record. Palaeovalleys that are
c
. 500 m deep and
c
. 7 km wide have been analysed here. Focusing on the glaciogenic Carboniferous deposits, seismic data with well ties and outcrop analogues provide new sedimentological insights. The palaeovalley infill is imaged as a chaotic seismic facies overlain by an aggrading–prograding prism, interpreted as tillites covered by a fluvio-deltaic system. Tillites form both under the ice and during rapid ice recession, whereas fluvio-deltaic systems can only originate from a stable ice margin and last until the ice sheets withdraw inland. These two depositional modes are repeated several times, generating a progressive burial of the Carboniferous palaeovalleys. This succession of erosions and fills records major glacial stages, including a series of glacial and interglacial phases from the Late Devonian to the Early Permian. Depicting the Late Palaeozoic glacial history of the Chaco Basin seems crucial for the localization of potential good reservoirs.
Genome-Enabled Insights into Legume Biology
Authors: Young Nevin D. , Bharti Arvind K.
Published: May 2012

Legumes are the third-largest family of angiosperms, the second-most-important crop family, and a key source of biological nitrogen in agriculture. Recently, the genome sequences of Glycine max (soybean), Medicago truncatula, and Lotus japonicus were substantially completed. Comparisons among legume genomes reveal a key role for duplication, especially a whole-genome duplication event approximately 58 Mya that is shared by most agriculturally important legumes. A second and more recent genome duplication occurred only in the lineage leading to soybean. Outcomes of genome duplication, including gene fractionation and sub- and neofunctionalization, have played key roles in shaping legume genomes and in the evolution of legume-specific traits. Analysis of legume genome sequences also enables the discovery of legume-specific gene families and provides a framework for genome-wide association mapping that will target phenotypes of special importance in legumes. Translating genomic resources from sequenced species to less studied but still important “orphan” legumes will enhance prospects for world food production.
Plasmodesmata Paradigm Shift: Regulation from Without Versus Within
Authors: Burch-Smith Tessa M. , Zambryski Patricia C.
Published: May 2012

Plant cells are surrounded by cellulosic cell walls, creating a potential challenge to resource sharing and information exchange between individual cells. To overcome this, plants have evolved channels called plasmodesmata that provide cytoplasmic continuity between each cell and its immediate neighbors. We first review plasmodesmata basics—their architecture, their origin, the types of cargo they transport, and their molecular components. The bulk of this review discusses the regulation of plasmodesmata formation and function. Historically, plasmodesmata research has focused intensely on uncovering regulatory or structural proteins that reside within or immediately adjacent to plasmodesmata. Recent findings, however, underscore that plasmodesmata are exquisitely sensitive to signals far removed from the plasmodesmal channel itself. Signals originating from molecules and pathways that regulate cellular homeostasis—such as reactive oxygen species, organelle-organelle signaling, and organelle-nucleus signaling—lead to astonishing alterations in gene expression that affect plasmodesmata formation and function.
Control of Arabidopsis Root Development
Authors: Petricka Jalean J. , Winter Cara M. , Benfey Philip N.
Published: May 2012

The Arabidopsis root has been the subject of intense research over the past decades. This research has led to significantly improved understanding of the molecular mechanisms underlying root development. Key insights into the specification of individual cell types, cell patterning, growth and differentiation, branching of the primary root, and responses of the root to the environment have been achieved. Transcription factors and plant hormones play key regulatory roles. Recently, mechanisms involving protein movement and the oscillation of gene expression have also been uncovered. Root gene regulatory networks controlling root development have been reconstructed from genome-wide profiling experiments, revealing novel molecular connections and models. Future refinement of these models will lead to a more complete description of the complex molecular interactions that give rise to a simple growing root.
Epigenetic Mechanisms Underlying Genomic Imprinting in Plants
Authors: Köhler Claudia , Wolff Philip , Spillane Charles
Published: May 2012

Genomic imprinting, the differential expression of an autosomal gene that is dependent on its parent of origin, has independently evolved in flowering plants and mammals. In both of these organism classes, imprinting occurs in embryo-nourishing tissues—the placenta and the endosperm, respectively. It has been proposed that some imprinted genes control nutrient flow from the mother to the offspring. Genome-wide analyses of imprinted genes in plants have revealed that many imprinted genes are located in the vicinity of transposon or repeat sequences, implying that transposon insertions are associated with the evolution of imprinted loci. Imprinted expression of a number of genes is conserved between monocots and dicots, suggesting that long-term selection can maintain imprinted expression at some loci. In terms of epigenetic mechanisms, imprinted expression is largely controlled by an antagonistic action of DNA methylation and Polycomb group–mediated histone methylation in the vicinity of imprinted genes, whereby the position of such epigenetic modifications can determine whether a gene will be expressed mainly from either the maternally or paternally inherited alleles.
The Evolution of Flavin-Binding Photoreceptors: An Ancient Chromophore Serving Trendy Blue-Light Sensors
Authors: Losi Aba , Gärtner Wolfgang
Published: May 2012

Photoreceptor flavoproteins of the LOV, BLUF, and cryptochrome families are ubiquitous among the three domains of life and are configured as UVA/blue-light systems not only in plants—their original arena—but also in prokaryotes and microscopic algae. Here, we review these proteins' structure and function, their biological roles, and their evolution and impact in the living world, and underline their growing application in biotechnologies. We present novel developments such as the interplay of light and redox stimuli, emerging enzymatic and biological functions, lessons on evolution from picoalgae, metagenomics analysis, and optogenetics applications.
Plant Stem Cell Niches
Authors: Aichinger Ernst , Kornet Noortje , Friedrich Thomas , Laux Thomas
Published: May 2012

Multicellular organisms possess pluripotent stem cells to form new organs, replenish the daily loss of cells, or regenerate organs after injury. Stem cells are maintained in specific environments, the stem cell niches, that provide signals to block differentiation. In plants, stem cell niches are situated in the shoot, root, and vascular meristems—self-perpetuating units of organ formation. Plants' lifelong activity—which, as in the case of trees, can extend over more than a thousand years—requires that a robust regulatory network keep the balance between pluripotent stem cells and differentiating descendants. In this review, we focus on current models in plant stem cell research elaborated during the past two decades, mainly in the model plant Arabidopsis thaliana. We address the roles of mobile signals on transcriptional modules involved in balancing cell fates. In addition, we discuss shared features of and differences between the distinct stem cell niches of Arabidopsis.
An intermediate-conductance Ca2+-activated K+ channel is important for secretion in pancreatic duct cells
Authors: Hayashi Mikio , Wang Jing , Hede Susanne E. , Novak Ivana
Published: May 2012

Potassium channels play a vital role in maintaining the membrane potential and the driving force for anion secretion in epithelia. In pancreatic ducts, which secrete bicarbonate-rich fluid, the identity of K+ channels has not been extensively investigated. In this study, we investigated the molecular basis of functional K+ channels in rodent and human pancreatic ducts (Capan-1, PANC-1, and CFPAC-1) using molecular and electrophysiological techniques. RT-PCR analysis revealed mRNAs for KCNQ1, KCNH2, KCNH5, KCNT1, and KCNT2, as well as KCNN4 coding for the following channels: KVLQT1; HERG; EAG2; Slack; Slick; and an intermediate-conductance Ca2+-activated K+ (IK) channel (KCa3.1). The following functional studies were focused on the IK channel. 5,6-Dichloro-1-ethyl-1,3-dihydro-2 H-benzimidazole-2-one (DC-EBIO), an activator of IK channel, increased equivalent short-circuit current ( Isc) in Capan-1 monolayer, consistent with a secretory response. Clotrimazole, a blocker of IK channel, inhibited Isc. IK channel blockers depolarized the membrane potential of cells in microperfused ducts dissected from rodent pancreas. Cell-attached patch-clamp single-channel recordings revealed IK channels with an average conductance of 80 pS in freshly isolated rodent duct cells. These results indicated that the IK channels may, at least in part, be involved in setting the resting membrane potential. Furthermore, the IK channels are involved in anion and potassium transport in stimulated pancreatic ducts.
eNOS knockout mouse as a model of fetal growth restriction with an impaired uterine artery function and placental transport phenotype
Authors: Kusinski Laura C. , Stanley Joanna L. , Dilworth Mark R. , Hirt Cassandra J. , Andersson Irene J. , Renshall Lewis J. , Baker Bernadette C. , Baker Philip N. , Sibley Colin P. , Wareing Mark , Glazier Jocelyn D.
Published: May 2012

Fetal growth restriction (FGR) is the inability of a fetus to reach its genetically predetermined growth potential. In the absence of a genetic anomaly or maternal undernutrition, FGR is attributable to “placental insufficiency”: inappropriate maternal/fetal blood flow, reduced nutrient transport or morphological abnormalities of the placenta (e.g., altered barrier thickness). It is not known whether these diverse factors act singly, or in combination, having additive effects that may lead to greater FGR severity. We suggest that multiplicity of such dysfunction might underlie the diverse FGR phenotypes seen in humans. Pregnant endothelial nitric oxide synthase knockout (eNOS−/−) dams exhibit dysregulated vascular adaptations to pregnancy, and eNOS−/− fetuses of such dams display FGR. We investigated the hypothesis that both altered vascular function and placental nutrient transport contribute to the FGR phenotype. eNOS−/− dams were hypertensive prior to and during pregnancy and at embryonic day (E) 18.5 were proteinuric. Isolated uterine artery constriction was significantly increased, and endothelium-dependent relaxation significantly reduced, compared with wild-type (WT) mice. eNOS−/− fetal weight and abdominal circumference were significantly reduced compared with WT. Unidirectional maternofetal 14C-methylaminoisobutyric acid (MeAIB) clearance and sodium-dependent 14C-MeAIB uptake into mouse placental vesicles were both significantly lower in eNOS−/− fetuses, indicating diminished placental nutrient transport. eNOS−/− mouse placentas demonstrated increased hypoxia at E17.5, with elevated superoxide compared with WT. We propose that aberrant uterine artery reactivity in eNOS−/− mice promotes placental hypoxia with free radical formation, reducing placental nutrient transport capacity and fetal growth. We further postulate that this mouse model demonstrates “uteroplacental hypoxia,” providing a new framework for understanding the etiology of FGR in human pregnancy.
Syntheses, Magnetic and Spectral Studies on the Coordination Compounds of the Polystyrene‐anchored Thiazolidin‐4‐one
Authors: Kumar Dinesh , Kumar Amit
Published: May 2012

The reaction between polystyrene 3‐formylsalicylate and thiophene‐2‐carboxylic acid hydrazide in DMF in the presence of ethyl acetate results in the formation of polystyrene N‐(2‐carbamoylthienyl)‐3′‐carboxy‐2′‐hydroxybenzylideneimine (I). A benzene suspension of I reacts with mercaptoacetic acid and forms the polystyrene N‐(2‐carbamoylthienyl)‐C‐(3′‐carboxy‐2′‐hydroxyphenyl) thiazolidin‐4‐one, PSCH2–LH2 (II). A DMF suspension of II reacts with Zn(II), Co(II), Cu(II), Zr(OH)2(IV) and MoO2(VI) ions and forms the corresponding polystyrene‐anchored coordination compounds, [PSCH2–LZn(DMF)] (III), [PSCH2–LCo(DMF)3] (IV), [PSCH2–LHCu(OAc)] (V), [PSCH2–LH2Zr(OH)2(OAc)2] (VI) and [PSCH2–LHMoO2(acac)] (VII) respectively. The polystyrene‐anchored coordination compounds have been characterized on the basis of elemental analyses, spectral (IR, reflectance, ESR) studies and magnetic susceptibility measurements. II acts as a neutral tridentate ONS donor ligand in VI, a monobasic bidentate OS donor ligand in VII, a monobasic tridentate ONS donor ligand in V and a dibasic tridentate ONO donor ligand in III and IV. The acetato groups behave as monodentate ligands in V and VI. A square‐planar structure for V, a tetrahedral structure for III, an octahedral structure for IV and VII and a pentagonal‐bipyramidal structure for VI are suggested.
On the Global Well‐Posedness of the Viscous Two‐Component Camassa‐Holm System
Authors: Li Xiuming
Published: May 2012

We establish the local well‐posedness for the viscous two‐component Camassa‐Holm system. Moreover, applying the energy identity, we obtain a global
existence result for the system with (u0, η0) ∈ H1(ℝ) × L2(ℝ).
Frequency-Dependent Streaming Potential of Porous Media—Part 1: Experimental Approaches and Apparatus Design
Authors: Glover P. W. J. , Ruel J. , Tardif E. , Walker E.
Published: May 2012

Electrokinetic phenomena link fluid flow and electrical flow in porous and fractured media such that a hydraulic flow will generate an electrical current andvice versa. Such a link is likely to be extremely useful, especially in the development of the electroseismic method. However, surprisingly few experimental measurements have been carried out, particularly as a function of frequency because of their difficulty. Here we have considered six different approaches to make laboratory determinations of the frequency-dependent streaming potential coefficient. In each case, we have analyzed the mechanical, electrical, and other technical difficulties involved in each method. We conclude that the electromagnetic drive is currently the only approach that is practicable, while the piezoelectric drive may be useful for low permeability samples and at specified high frequencies. We have used the electro-magnetic drive approach to design, build, and test an apparatus for measuring the streaming potential coefficient of unconsolidated and disaggregated samples such as sands, gravels, and soils with a diameter of 25.4 mm and lengths between 50 mm and 300 mm.
HSP DNAJB8 Controls Tumor-Initiating Ability in Renal Cancer Stem–like Cells
Authors: Nishizawa Satoshi , Hirohashi Yoshihiko , Torigoe Toshihiko , Takahashi Akari , Tamura Yasuaki , Mori Takashi , Kanaseki Takayuki , Kamiguchi Kenjiro , Asanuma Hiroko , Morita Rena , Sokolovskaya Alice , Matsuzaki Junichi , Yamada Ren , Fujii Reona , Kampinga Harm H. , Kondo Toru , Hasegawa Tadashi , Hara Isao , Sato Noriyuki
Published: May 2012

Cancer stem–like cells (CSC) are a small population of cancer cells with superior tumor initiating, self-renewal, and differentiation properties. In this study, we show that the cancer-testis antigen and HSP40 family member DNAJB8 contributes to the CSC phenotype in renal cell carcinoma (RCC). DNAJB8 overexpression increased the percentage of side population (SP) cells representing CSCs in RCC cells, enhancing their tumor-initiating ability. Conversely, attenuation of DNAJB8 decreased SP cells and reduced tumor-initiating ability. The utility of DNAJB8 as an immunologic target was established in DNA vaccination experiments. Compared with immunization with the tumor-associated antigen survivin, which was expressed in both CSCs and non-CSCs in RCC, immunization with Dnajb8 expression plasmids yielded stronger antitumor effects. Together, our findings suggest that DNAJB8 plays a role in CSC maintenance and that it offers a candidate for CSC-targeting immunotherapy in RCC. Cancer Res; 72(11); 2844–54. ©2012 AACR.
Combination Therapy with HSP90 Inhibitor 17-DMAG Reconditions the Tumor Microenvironment to Improve Recruitment of Therapeutic T cells
Authors: Rao Aparna , Taylor Jennifer L. , Chi-Sabins Nina , Kawabe Mayumi , Gooding William E. , Storkus Walter J.
Published: May 2012

Ineffective recognition of tumor cells by CD8+ T cells is a limitation of cancer immunotherapy. Therefore, treatment regimens that coordinately promote enhanced antitumor CD8+ T-cell activation, delivery, and target cell recognition should yield greater clinical benefit. Using an MCA205 sarcoma model, we show that in vitro treatment of tumor cells with the HSP90 inhibitor 17-DMAG results in the transient (proteasome-dependent) degradation of the HSP90 client protein EphA2 and the subsequent increased recognition of tumor cells by Type-1 anti-EphA2 CD8+ T cells. In vivo administration of 17-DMAG to tumor-bearing mice led to slowed tumor growth, enhanced/prolonged recognition of tumor cells by anti-EphA2 CD8+ T cells, reduced levels of myeloid-derived suppressor cells and regulatory T cells in the tumor microenvironment, and activation of tumor-associated vascular endothelial cells in association with elevated levels of Type-1 tumor-infiltrating lymphocytes. When combined with EphA2-specific active vaccination or the adoptive transfer of EphA2-specific CD8+ T cells, 17-DMAG cotreatment yielded a superior tumor therapeutic regimen that was capable of rendering animals free of disease. Taken together, our findings indicate that 17-DMAG functions as an immune adjuvant in the context of vaccines targeting EphA2. Cancer Res; 72(13); 3196–206. ©2012 AACR.
Chemokine (C-X-C Motif) Ligand 12 Is Associated with Gallbladder Carcinoma Progression and Is a Novel Independent Poor Prognostic Factor
Authors: Lee Hyun Jung , Lee Kyungmin , Lee Dong Gwang , Bae Kwang-Hee , Kim Jang-Seong , Liang Zhe Long , Huang Song Mei , Suk Oh Yoon , Kim Ha Yon , Jo Deog Yeon , Min Jeong-Ki , Kim Jin-Man , Lee Hyo Jin
Published: May 2012

Purpose: Although recent studies have suggested that chemokine (C-X-C motif) ligand 12 (CXCL12) is important in the progression of various malignancies, its role in gallbladder carcinoma (GBC) remains unknown. We investigated CXCL12 expression in GBC and its biologic and prognostic role in GBC tumorigenesis.

Experimental Design: We examined CXCL12 expression in tumor specimens from 72 patients with GBC by immunohistochemistry and analyzed the correlation between CXCL12 expression and clinicopathologic factors or survival. The functional significance of CXCL12 expression was investigated by CXCL12 treatment and suppression of CXCR4, a major receptor of CXCL12, as well as by CXCL12 overexpression in in vitro and in vivo studies.

Results: CXCL12 was differentially expressed in GBC tissues. CXCL12 expression was significantly associated with a high histologic grade (P = 0.042) and nodal metastasis (P = 0.015). Multivariate analyses showed that CXCL12 expression (HR, 8.675; P = 0.014) was an independent risk factor for patient survival. CXCL12 significantly increased anchorage-dependent and -independent growth, migration, invasion, adhesiveness, and survival of GBC cells in vitro, and these effects were dependent on CXCR4. Consistent with these results, overexpression of CXCL12 significantly promoted GBC tumorigenicity in a xenograft model.

Conclusions: Our results indicate that GBC cells express both CXCL12 and its receptor CXCR4, and CXCL12 may have a role in GBC progression through an autocrine mechanism. In addition, CXCL12 is a novel independent poor prognostic factor in patients with GBCs. Thus, targeting CXCL12 and CXCR4 may provide a novel therapeutic strategy for GBC treatment. Clin Cancer Res; 18(12); 3270–80. ©2012 AACR.
Paracrine Receptor Activation by Microenvironment Triggers Bypass Survival Signals and ALK Inhibitor Resistance in EML4-ALK Lung Cancer Cells
Authors: Yamada Tadaaki , Takeuchi Shinji , Nakade Junya , Kita Kenji , Nakagawa Takayuki , Nanjo Shigeki , Nakamura Takahiro , Matsumoto Kunio , Soda Manabu , Mano Hiroyuki , Uenaka Toshimitsu , Yano Seiji
Published: May 2012

Purpose: Cancer cell microenvironments, including host cells, can critically affect cancer cell behaviors, including drug sensitivity. Although crizotinib, a dual tyrosine kinase inhibitor (TKI) of ALK and Met, shows dramatic effect against EML4-ALK lung cancer cells, these cells can acquire resistance to crizotinib by several mechanisms, including ALK amplification and gatekeeper mutation. We determined whether microenvironmental factors trigger ALK inhibitor resistance in EML4-ALK lung cancer cells.

Experimental Design: We tested the effects of ligands produced by endothelial cells and fibroblasts, and the cells themselves, on the susceptibility of EML4-ALK lung cancer cell lines to crizotinib and TAE684, a selective ALK inhibitor active against cells with ALK amplification and gatekeeper mutations, both in vitro and in vivo.

Results: EML4-ALK lung cancer cells were highly sensitive to ALK inhibitors. EGF receptor (EGFR) ligands, such as EGF, TGF-α, and HB-EGF, activated EGFR and triggered resistance to crizotinib and TAE684 by transducing bypass survival signaling through Erk1/2 and Akt. Hepatocyte growth factor (HGF) activated Met/Gab1 and triggered resistance to TAE684, but not crizotinib, which inhibits Met. Endothelial cells and fibroblasts, which produce the EGFR ligands and HGF, respectively, decreased the sensitivity of EML4-ALK lung cancer cells to crizotinib and TAE684, respectively. EGFR-TKIs resensitized these cells to crizotinib and Met-TKI to TAE684 even in the presence of EGFR ligands and HGF, respectively.

Conclusions: Paracrine receptor activation by ligands from the microenvironment may trigger resistance to ALK inhibitors in EML4-ALK lung cancer cells, suggesting that receptor ligands from microenvironment may be additional targets during treatment with ALK inhibitors. Clin Cancer Res; 18(13); 3592–602. ©2012 AACR.
A Phase II Pharmacodynamic Study of Preoperative Figitumumab in Patients with Localized Prostate Cancer
Authors: Chi Kim N. , Gleave Martin E. , Fazli Ladan , Goldenberg S. Larry , So Alan , Kollmannsberger Christian , Murray Nevin , Tinker Anna , Pollak Michael
Published: May 2012

Purpose: Activation of the insulin-like growth factor 1 receptor (IGF-IR) is implicated in prostate cancer development and progression. This study evaluated biologic and clinical effects of figitumumab, a fully human monoclonal IGF-IR antibody, in patients with localized prostate cancer.

Experimental Design: Eligible patients received figitumumab 20 mg/kg intravenously every 3 weeks for 3 cycles followed by prostatectomy. The primary endpoint was IGF-IR expression inhibition as assessed by immunohistochemistry.

Results: Sixteen patients were accrued. Median age was 63 years, median prostate-specific antigen (PSA) was 7.2 μg/L (range, 2.5–35), clinical stage was T1 in four patients and T2 in 12 patients, Gleason score ≤7 or >7 in 15 and one patients. Two patients received only 1 cycle (patient choice and grade III hyperglycemia). A PSA decline from baseline of ≥25% and ≥50% occurred in 15 (94%) and 5 (31%) of patients. Mean figitumumab concentration was 350.4 μg/mL (range, 26.3–492.8) in plasma and 51.3 μg/g (range, 27.4–79.6) in prostate tissue. Compared with pretreatment biopsies, IGF-IR expression decreased in the prostatectomy specimens in 14 of 16 patients. The mean IGF-IR immunohistochemistry visual score was 2.1 (SD = 0.6) in biopsy and 1.1 (SD = 0.5) in prostatectomy specimens (P < 0.0001). Androgen receptor expression was also decreased and there was a trend for a decrease in downstream IGF-IR signaling components.

Conclusions: Figitumumab is biologically active in prostate cancer. PSA declines in treatment-naive patients were observed, potentially mediated by IGF-IR effects on androgen receptor expression. These results support the clinical relevance of IGF-IR signaling in prostate cancer and justify further clinical trials. Clin Cancer Res; 18(12); 3407–13. ©2012 AACR.
Human Monoclonal Antibodies Targeting Nonoverlapping Epitopes on Insulin-like Growth Factor II as a Novel Type of Candidate Cancer Therapeutics
Authors: Chen Weizao , Feng Yang , Zhao Qi , Zhu Zhongyu , Dimitrov Dimiter S.
Published: May 2012

Soluble ligands are important targets for therapy of cancers and other diseases. Therapeutic monoclonal antibodies (mAb) against such ligands block their interactions with corresponding receptors but do not enhance their removal from the circulation and can increase their half-lives because of the long half-lives of the antibodies. We have hypothesized that mAbs targeting two or more nonoverlapping epitopes on the same ligand could form oligomeric antibody–ligand complexes that can bind to cells expressing Fc gamma receptors (FcγRs) with high avidity leading to their fast and irreversible removal from the circulation. Insulin-like growth factor II (IGF-II) is an example of such ligands and an important target for human cancer therapy. We identified two mAbs, m610.27 and m630.3, which bound to nonoverlapping epitopes on IGF-II with nanomolar affinity, and generated a bispecific antibody, m660. m660 inhibited the interaction of human IGF-II (hIGF-II) with the human breast cancer cell line MCF-7, hIGF-II–mediated IGF receptor type I and insulin receptor phosphorylation, and cell growth. In the presence of hIGF-II, large complexes of m660 were formed that bound to FcγRII-expressing BJAB cells much more efficiently than the monospecific antibody–hIGF-II complexes and were presumably phagocytosed by phorbol 12-myristate 13-acetate–stimulated macrophage-like U937 cells. A mixture of m610.27 and m630.3 exhibited similar properties. To our knowledge, these mAbs are the first reported to target nonoverlapping epitopes on a cancer-related ligand and could represent a novel class of candidate therapeutics against cancers. This approach could also be used to irreversibly eliminate other disease-related soluble ligands. Mol Cancer Ther; 11(7); 1400–10. ©2012 AACR.
Carotid Intima-Media Thickness in Patients with Idiopathic Restless Legs Syndrome
Authors: Park Joong Hyun , Han Sang Won , Baik Jong Sam
Published: May 2012

Background: There have been no studies of carotid intima-media thickness (IMT) in idiopathic restless legs syndrome (iRLS) patients. The aims of this study were to evaluate the future risk of stroke in iRLS patients using computer software-assisted automated IMT measurement systems. Methods: We measured the carotid IMT by high-resolution B-mode ultrasound with Intimascope software in 38 iRLS patients and 64 controls. Results: The mean value of the maximum IMT in iRLS patients was significantly lower than that in controls (p < 0.05). In multiple linear regression analysis, younger age and the presence of iRLS remained statistically significant. Younger age or the presence of iRLS was highly correlated with a lower value of the maximum IMT (p < 0.001, p < 0.05). Conclusion: We suggest that iRLS patients may have a lower risk of progression of atherosclerosis.
Invariant Natural Killer T Cells Contribute to the Allergic Response in Cow’s Milk Protein-Sensitized Mice
Authors: Schouten Bastiaan , van Esch Betty C.A.M. , Lim Stephanie M. , Hofman Gerard A. , Knippels Léon M.J. , Willemsen Linette E.M. , Vos Arjan P. , Garssen Johan
Published: May 2012

Background: Little is known about the contribution of the invariant natural killer T (iNKT) cells in the onset of food allergy. Using a mouse model for cow’s milk allergy the function of iNKT cells was investigated. Methods: Mice were sensitized orally with casein or whey proteins. One hour before the sensitizations the mice were injected intraperitoneally with α-galactosylceramide (αGalCer) or control. One week after the last sensitization acute allergic skin reactions were measured. Furthermore, in the liver, spleen and mesenteric lymph nodes (MLN) percentages of iNKT cells were analyzed and liver lymphocyte restimulation assays were performed. Results: Whey- or casein-sensitized mice treated with αGalCer showed enhanced acute allergic skin reactions. The percentage of iNKT cells in the liver of sensitized mice was reduced compared to sham-sensitized mice. αGalCer treatment was found to deplete iNKT cells in the liver of sensitized as well as sham-sensitized mice, and these hepatocytes did not respond to ex vivo restimulation with αGalCer. αGalCer treatment did not reduce iNKT cell percentages in the spleen and MLN of sham-sensitized mice but abrogated the increase in iNKT cell percentage in the spleen upon whey sensitization, whereas it enhanced the iNKT cell percentage in the MLN of casein-sensitized mice. Due to the repeated application of αGalCer, livers were functionally depleted of iNKT cells. This resulted in an increased allergic effector response which was most pronounced in whey-sensitized mice and associated with enhanced whey-specific immunoglobulin levels. Conclusion: iNKT cells may suppress cow’s milk allergic symptoms in mice and may differentially regulate oral sensitization for casein and whey.
Timing of Introduction of Gluten and Celiac Disease Risk
Authors: Ludvigsson Jonas F. , Fasano Alessio
Published: May 2012

Breast milk is the natural nutrition for infants, but in the second half of the first year of life, complementary feeding is needed. Many complementary foods contain gluten, but gluten exposure is associated with the risk of developing celiac disease (CD). CD is a disease with considerable morbidity and mortality. Although CD is associated with certain genetic features, carrying the human leukocyte antigen haplotypes DQ2 or DQ8 (a prerequisite for CD development) cannot fully explain who will or who will not develop CD. Potential risk factors for CD include perinatal events and infant feeding practice. With the exception that children who are breastfed at and beyond gluten introduction into the diet probably may be at a lower risk of developing CD, and that heavy gluten load early in life may increase the risk of future CD, data on the impact of infant feeding are inconsistent.
The Relation of Falls to Fatigue, Depression and Daytime Sleepiness in Parkinson’s Disease
Authors: Bryant M.S. , Rintala D.H. , Hou J.G. , Rivas S.P. , Fernandez A.L. , Lai E.C. , Protas E.J.
Published: May 2012

Objective: To characterize non-motor symptoms in individuals with Parkinson’s disease (PD) who experience falls compared to those who do not fall. Methods: Fifty-four individuals with PD were studied. Thirty-six were fallers and 18 were non-fallers. Fatigue was assessed by the Iowa Fatigue Scale. Excessive daytime sleepiness was assessed by the Epworth Sleepiness Scale, and depressive symptomatology was assessed by the short-form Center for Epidemiologic Studies Depression Scale. Results: Compared to non-fallers, fallers had more severe disability, greater general physical fatigue (p = 0.024), lower energy levels (p = 0.042) and less productivity (p = 0.007). Fallers had more depressive symptomatology than the non-fallers (p = 0.01). Excessive daytime sleepiness was not different between the two groups (p = 0.695). Conclusions: Individuals with PD who fell had more severe motor and non-motor symptoms than those who did not fall. These non-motor symptoms included physical fatigue, energy, productivity and depressive symptomatology.
Prognostic Significance of Circulating Levels of Hepatocyte Growth Factor in Patients with Chagas’ Disease and Idiopathic Dilated Cardiomyopathy
Authors: Wang Yong , Moreira Maria da Consolação V. , Khan Adnan , Heringer-Walther Silvia , Schultheiss Heinz-Peter , Wessel Niels , Siems Wolf-Eberhard , Walther Thomas
Published: May 2012

Objectives: Hepatocyte growth factor (HGF) plays an important role in the improvement in cardiac function and remodeling in a variety of cardiovascular diseases. It is also a strong predictor of mortality in some heart failure (HF) patients. However, its prognostic value in patients with Chagas’ disease (CD) or idiopathic dilated cardiomyopathy (DCM) remains to be investigated. Methods and Results: In this prospective cohort study, HGF concentrations were measured in patients with CD (n = 91), DCM (n = 47), and control subjects (n = 25). While no difference was detected for patients with New York Heart Association class I–II, HGF was significantly increased in advanced HF patients (New York Heart Association class III–IV) in both CD and DCM groups, compared with healthy subjects. There was a strong correlation between HGF and left ventricular ejection fraction in CD patients. However, there was no correlation in patients with DCM. Despite its strong correlation with left ventricular ejection fraction in CD patients, HGF failed to predict mortality and necessity for heart transplant in both CD and DCM patients. Conclusions: Although HGF can be significantly increased in advanced HF patients with CD and DCM, its prognostic value for endpoints is minor. Therefore, the formerly described predictive power for HGF in HF might be restricted to specific etiologies of HF.
Detection of Activated Leukocyte Cell Adhesion Molecule in the Serum of Breast Cancer Patients and Implications for Prognosis
Authors: Witzel Isabell , Schröder Christine , Müller Volkmar , Zander Hilke , Tachezy Michael , Ihnen Maike , Jänicke Fritz , Milde-Langosch Karin
Published: May 2012

Objective: Conflicting results have been reported about activated leukocyte cell adhesion molecule (ALCAM) expression in breast cancer and its prognostic value. Little is known about the role of ALCAM levels in the serum of breast cancer patients. Methods: We analyzed soluble ALCAM (sALCAM) levels in the serum of 157 primary breast cancer patients and 48 healthy women by ELISA. In addition, we determined ALCAM protein expression by Western blot analysis (n = 120) and mRNA expression by cDNA microarray analysis (n = 115) in the tumor tissue of corresponding patients. Results: sALCAM levels differed between patients and healthy controls (median 24.2 vs. 18.9 ng/ml, p < 0.001). We observed no correlation between serum levels and protein or mRNA expression in corresponding tumors (r < 0.1, p = n.s.). sALCAM levels were not correlated with histological type, grading, tumor stage, or patient age, but elevated sALCAM levels were associated with shorter disease-free survival (HR = 1.97, 95% CI 1.01–3.2, p = 0.043). Conclusions: Our results indicate that sALCAM can be detected in the serum of patients with primary breast cancer. Elevated serum levels might indicate more aggressive tumor behavior as they might be an independent factor for a worse prognosis in breast cancer patients.
Intractable Bile Leakage after Hepatectomy for Hepatocellular Carcinoma in 359 Recent Cases
Authors: Sadamori Hiroshi , Yagi Takahito , Matsuda Hiroaki , Shinoura Susumu , Umeda Yuzo , Fujiwara Toshiyoshi
Published: May 2012

Background/Aims: Bile leakage is still a common cause of major morbidity after hepatectomy for hepatocellular carcinoma (HCC). The purpose of this study was to identify characteristics and risk factors for intractable bile leakage after hepatectomy for HCC. Methods: Risk factors for bile leakage were analyzed in 359 patients who underwent hepatectomy for HCC between 2001 and 2010. The causes, management and outcomes of intractable bile leakage which needed endoscopic therapy or percutaneous transhepatic biliary drainage were investigated. Results: A total of 296 patients (82.5%) underwent an anatomic hepatectomy, and a repeat hepatectomy was carried out in 59 patients (16.4%). The prevalence of bile leakage was 12.8%, and 8 patients had intractable bile leakage. An operative time ≥300 min was an independent risk factor for bile leakage after hepatectomy for HCC. The main causes of intractable bile leakage were a latent stricture of the biliary anatomy caused by previous treatments for HCC and intraoperative injury of the hepatic duct related to repeat hepatectomy. Conclusion: To help prevent intractable bile leakage, a preoperative assessment of the biliary anatomy and surgical procedures to decrease the incidence of major bile leakage should be considered for selected patients with a high risk for intractable bile leakage.
Development of the Cerebellum in the Platypus (Ornithorhynchus anatinus) and Short-Beaked Echidna (Tachyglossus aculeatus)
Authors: Ashwell Ken W.S.
Published: May 2012

The monotremes are a unique group of mammals whose young are incubated in a leathery-shelled egg and fed with milk from teatless areolae after hatching. As soon as they hatch, monotreme young must be able to maneuver around the nest or maternal pouch to locate the areolae and stimulate milk ejection. In the present study, the embryological collections at the Museum für Naturkunde, Berlin, have been used to follow the development of the monotreme cerebellum through incubation and lactational phases, to determine whether cerebellar circuitry is able to contribute to the coordination of locomotion in the monotreme hatchling, and to correlate cerebellar development with behavioral maturation. The structure of the developing monotreme cerebellum and the arrangement of transitory neuronal populations are similar to those reported for fetal and neonatal eutherians, but the time course of the key events of later cerebellar development is spread over a much longer period. Expansion of the rostral rhombic lip and formation of the nuclear and cortical transitory zones occurs by the time of hatching, but it is not until after the end of the first post-hatching week that deep cerebellar neurons begin to settle in their definitive positions and the Purkinje cell layer can be distinguished. Granule cell formation is also prolonged over many post-hatching months and the external granular layer persists for more than 20 weeks after hatching. The findings indicate that cerebellar circuitry is unlikely to contribute to the coordination of movements in the monotreme peri-hatching period. Those activities are most likely controlled by the spinal cord and medullary reticular formation circuitry.
Heterogeneity of Lung Mononuclear Phagocytes in Chronic Obstructive Pulmonary Disease
Authors: Lee Janet S.
Published: May 2012

Chronic obstructive pulmonary disease (COPD) is a disease defined by an aberrant inflammatory response to inhaled cigarette smoke and other noxious particles. The factors triggered in the lungs that drive inflammation and lung tissue destruction are not fully understood, but mononuclear phagocytes play a central role by releasing mediators that promote both inflammation and tissue-destructive emphysema. Although conflicting studies on alveolar macrophages exist regarding chronic cigarette smoke exposure and its effects on macrophage polarization patterns, we have recently identified a cell type in mice defined by CX3CR1 expression. The population of this cell type expands in the lungs and elaborates M1 signature cytokines in response to cigarette smoke exposure in vivo. In addition, the absence of functional CX3CR1 provides protection from tissue-destructive emphysema in a murine model of chronic cigarette smoke exposure. The heterogeneity and plasticity of discrete macrophage subsets, in terms of immunophenotype and function, may explain the seemingly disparate findings showing a suppressed inflammatory profile on the one hand and a heightened inflammatory response on the other. This review examines the evidence that discrete mononuclear phagocyte subsets develop in response to cigarette smoke exposure, and that the spatial cues provided by the lung tissue microenvironment in which the mononuclear phagocytes reside may influence the distribution and function of these subsets.
Extensive Homology of Chicken Macrochromosomes in the Karyotypes of Trachemys scripta elegans and Crocodylus niloticus Revealed by Chromosome Painting despite Long Divergence Times
Authors: Kasai F. , O’Brien P.C.M. , Martin S. , Ferguson-Smith M.A.
Published: May 2012

We report extensive chromosome homology revealed by chromosome painting between chicken (Gallus gallus domesticus, GGA, 2n = 78) macrochromosomes (representing 70% of the chicken genome) and the chromosomes of a turtle, the red-eared slider (Trachemys scripta elegans, TSC, 2n = 50), and the Nile crocodile (Crocodylus niloticus, CNI, 2n = 32). Our data show that GGA1–8 arms seem to be conserved in the arms of TSC chromosomes, GGA1–2 arms are separated and homologous to CNI1p, 3q, 4q and 5q. In addition to GGAZ homologues in our previous study, large-scale GGA autosome syntenies have been conserved in turtle and crocodile despite hundreds of millions of years divergence time. Based on phylogenetic hypotheses that crocodiles diverged after the divergence of birds and turtles, our results in CNI suggest that GGA1–2 and TSC1–2 represent the ancestral state and that chromosome fissions followed by fusions have been the mechanisms responsible for the reduction of chromosome number in crocodiles.
A novel function of FoxO transcription factors in thrombin-stimulated vascular smooth muscle cell proliferation
Authors: Mahajan Shailaja , Fender Anke , Meyer-Kirchrath Jutta , Kurt Muhammed , Barth Mareike , Sagban Tolga , Fischer Jens , Schrör Karsten , Hohlfeld Thomas , Rauch Bernhard
Published: May 2012

Thrombin exerts coagulation-independent effects on the proliferation and migration of vascular smooth muscle cells (SMC). Forkhead box-O (FoxO) transcription factors regulate cell proliferation, apoptosis and cell cycle arrest, but a possible functional interaction between thrombin and FoxO factors has not been identified to date. In human cultured vascular SMC, thrombin induced a time-dependent phosphorylation of FoxO1 and FoxO3 but not FoxO4. This effect was mimicked by an activating-peptide (AP) for protease-activated receptor (PAR)-1, and abolished by a PAR-1 antagonist (SCH79797). APs for other PARs were without effect. FoxO1 and FoxO3 phosphorylation were prevented by the PI3 kinase (PI3K) inhibitor LY294002 while inhibitors of ERK1/2 (PD98059) or p38MAPK (SB203580) were ineffective. LY294002 moreover prevented thrombin-stimulated SMC mitogenesis and proliferation. FoxO1 and FoxO3 siRNA augmented basal DNA synthesis and proliferation of SMC. Nuclear content of FoxO proteins decreased time-dependently in response to thrombin, coincided with suppressed expression of the cell cycle regulating genes p21CIP1 and p27kip1 by thrombin. FoxO1 siRNA reduced basal p21CIP1 while FoxO3 siRNA attenuated p27kip1 expression; thrombin did not show additive effects. LY294002 restored p21CIP1 and p27kip1 protein expression. Immunohistochemistry revealed that human native and failed saphenous vein grafts were characterised by the cytosolic presence of p-FoxO factors in co-localisation of p21CIP1 and p27kip1 with SMC. In conclusion, thrombin and FoxO factors functionally interact through PI3K/Akt-dependent FoxO phosphorylation leading to expression of cell cycle regulating genes and ultimately SMC proliferation. This may contribute to remodelling and failure of saphenous vein bypass grafts.
Safety, pharmacokinetics and pharmacodynamics of multiple ascending doses of R1663, an oral factor Xa inhibitor, in healthy young subjects coupled with exploration of influence of gender and age
Authors: Charoin-Pannier Anne , McIntyre Christine , Zandt Hagen , Ciorciaro Cornelia , Winters Katie , Pepper Tom , Schmitt Christophe
Published: May 2012

This study investigated the safety, pharmacokinetics and pharmacodynamics of multiple oral doses of R1663, a factor Xa inhibitor, and explored the influence of age and gender on pharmacokinetics and pharmacodynamics of R1663. This was a single-blind, randomised, placebo-controlled, dose escalation study in 48 healthy male volunteers aged 18 to 44 years. R1663 doses up to 300 mg twice daily or 400 mg once daily were administered for seven days. The exploration of gender and age effect was carried out in separate cohorts of eight male and eight female volunteers aged 45 to 65 years. Multiple oral doses of R1663 were safe and well tolerated. Pharmacokinetics was linear and showed moderate variability. Plasma concentrations peaked at 3 hour. Terminal half-life at steady state was 3–5 hours. Accumulation of R1663 was minimal. R1663 prolonged clotting times, inhibited thrombin generation (peak height and endogenous thrombin potential [ETP]) and anti-factor Xa activity in a concentration-dependent manner without increasing bleeding time. Pharmacodynamic parameters were strongly correlated to R1663 plasma concentrations. The inhibition was more pronounced on peak height (IC50 = 194 ng/ml) than on ETP (2790 ng/ml). Pharmacokinetics and pharmacodynamics of R1663 appeared not to be substantially affected by age or gender but remained to be confirmed in larger clinical trials including older patients. Meanwhile, dose adjustments based on age and gender are not anticipated.