bluuebunny/crossref_metadata_2025 huggingface dataset:
Antagonism of Sphingosine-1-Phosphate Receptors by FTY720 Inhibits Angiogenesis and Tumor Vascularization
Authors: LaMontagne Kenneth , Littlewood-Evans Amanda , Schnell Christian , O'Reilly Terence , Wyder Lorenza , Sanchez Teresa , Probst Beatrice , Butler Jeannene , Wood Alexander , Liau Gene , Billy Eric , Theuer Andreas , Hla Timothy , Wood Jeanette
Published: January 2006

FTY720, a potent immunomodulator, becomes phosphorylated in vivo (FTY-P) and interacts with sphingosine-1-phosphate (S1P) receptors. Recent studies showed that FTY-P affects vascular endothelial growth factor (VEGF)–induced vascular permeability, an important aspect of angiogenesis. We show here that FTY720 has antiangiogenic activity, potently abrogating VEGF- and S1P-induced angiogenesis in vivo in growth factor implant and corneal models. FTY720 administration tended to inhibit primary and significantly inhibited metastatic tumor growth in a mouse model of melanoma growth. In combination with a VEGFR tyrosine kinase inhibitor PTK787/ZK222584, FTY720 showed some additional benefit. FTY720 markedly inhibited tumor-associated angiogenesis, and this was accompanied by decreased tumor cell proliferation and increased apoptosis. In transfected HEK293 cells, FTY-P internalized S1P1 receptors, inhibited their recycling to the cell surface, and desensitized S1P receptor function. Both FTY720 and FTY-P apparently failed to impede VEGF-produced increases in mitogen-activated protein kinase activity in human umbilical vascular endothelial cells (HUVEC), and unlike its activity in causing S1PR internalization, FTY-P did not result in a decrease of surface VEGFR2 levels in HUVEC cells. Pretreatment with FTY720 or FTY-P prevented S1P-induced Ca2+ mobilization and migration in vascular endothelial cells. These data show that functional antagonism of vascular S1P receptors by FTY720 potently inhibits angiogenesis; therefore, this may provide a novel therapeutic approach for pathologic conditions with dysregulated angiogenesis. (Cancer Res 2006; 66(1): 221-31)
Activation of RhoB by Hypoxia Controls Hypoxia-Inducible Factor-1α Stabilization through Glycogen Synthase Kinase-3 in U87 Glioblastoma Cells
Authors: Skuli Nicolas , Monferran Sylvie , Delmas Caroline , Lajoie-Mazenc Isabelle , Favre Gilles , Toulas Christine , Cohen-Jonathan-Moyal Elizabeth
Published: January 2006

Hypoxia is a crucial factor in tumor aggressiveness and resistance to treatment, particularly in glioma. Our previous results have shown that inhibiting the small GTPase RhoB increased oxygenation of U87 human glioblastoma xenografts, in part, by regulating angiogenesis. We investigated here whether RhoB might also control a signaling pathway that would permit glioma cells to adapt to hypoxia. We first showed that silencing RhoB with siRNA induced degradation and inhibition of the transcriptional activity of the hypoxia-inducible factor by the proteasome in U87 hypoxic cells. This RhoB-dependent degradation of hypoxia-inducible factor-1α in hypoxic conditions was mediated by the Akt/glycogen synthase kinase-3β pathway. While investigating how hypoxia could activate this signaling pathway, using the GST-Rhotekin RBD pulldown assay, we showed the early activation of RhoB by reactive oxygen species under hypoxic conditions and, subsequently, its participation in the ensuing cellular adaptation to hypoxia. Overall, therefore, our results have not only highlighted a new signaling pathway for hypoxia controlled by the small GTPase RhoB, but they also strongly implicate RhoB as a potentially important therapeutic target for decreasing tumor hypoxia. (Cancer Res 2006; 66(1): 482-9)
Preferential Dependence of Breast Cancer Cells versus Normal Cells on Integrin-Linked Kinase for Protein Kinase B/Akt Activation and Cell Survival
Authors: Troussard Armelle A. , McDonald Paul C. , Wederell Elizabeth D. , Mawji Nasrin M. , Filipenko Nolan R. , Gelmon Karen A. , Kucab Jill E. , Dunn Sandra E. , Emerman Joanne T. , Bally Marcel B. , Dedhar Shoukat
Published: January 2006

The emerging paradigm of “oncogene addiction” has been called an Achilles' heel of cancer that can be exploited therapeutically. Here, we show that integrin-linked kinase (ILK), which is either activated or overexpressed in many types of cancers, is a critical regulator of breast cancer cell survival through the protein kinase B (PKB)/Akt pathway but is largely dispensable for the survival of normal breast epithelial cells and mesenchymal cells. We show that inhibition of ILK activity with a pharmacologic ILK inhibitor, QLT-0267, results in the inhibition of PKB/Akt Ser473 phosphorylation, stimulation of apoptosis, and a decrease in mammalian target of rapamycin (mTOR) expression in human breast cancer cells. In contrast, QLT-0267 treatment has no effect on PKB/Akt Ser473 phosphorylation or apoptosis in normal human breast epithelial, mouse fibroblast, or vascular smooth muscle cells. The inhibition of PKB/Akt Ser473 phosphorylation by QLT-0267 in breast cancer cells was rescued by a kinase-active ILK mutant but not by a kinase-dead ILK mutant. Furthermore, a dominant-negative ILK mutant increased apoptosis in the MDA-MB-231 breast cancer cell line but not in normal human breast epithelial cells. The inhibitor was active against ILK isolated from all cell types but did not have any effect on cell attachment and spreading. Our data point to an “ILK addiction” of breast cancer cells whereby they become dependent on ILK for cell survival through the mTOR-PKB/Akt signaling pathway and show that ILK is a promising target for the treatment of breast cancer. (Cancer Res 2006; 66(1): 393-403)
Natural Killer Cells Produce T Cell–Recruiting Chemokines in Response to Antibody-Coated Tumor Cells
Authors: Roda Julie M. , Parihar Robin , Magro Cynthia , Nuovo Gerard J. , Tridandapani Susheela , Carson William E.
Published: January 2006

In the current report, we have examined the ability of natural killer (NK) cells to produce T cell–recruiting chemokines following dual stimulation with interleukin (IL)-2 or IL-12 and human breast cancer cells coated with an antitumor antibody (trastuzumab). NK cells stimulated in this manner secreted an array of T cell–recruiting chemotactic factors, including IL-8, macrophage-derived chemokine, macrophage inflammatory protein 1α (MIP-1α), monocyte chemoattractant protein 1, and regulated on activation, normal T-cell expressed and secreted (RANTES), whereas stimulation of NK cells with either agent alone had minimal effect. Furthermore, these factors were functional for T-cell chemotaxis as culture supernatants derived from costimulated NK cells induced migration of both naïve and activated T cells in an in vitro chemotaxis assay. T-cell migration was significantly reduced when neutralizing antibodies to IL-8, MIP-1α, or RANTES were added to culture supernatants before their use in the chemotaxis assay. In addition, coadministration of trastuzumab-coated tumor cells and IL-12 to mice led to enhanced serum MIP-1α. As a clinical correlate, we examined the chemokine content of serum samples from breast cancer patients enrolled on a phase I trial of trastuzumab and IL-12, and found elevated levels of IL-8, RANTES, IFN-γ inducible protein 10, monokine induced by IFN-γ, and MIP-1α, specifically in those patients that experienced a clinical benefit. Sera from these patients exhibited the ability to direct T-cell migration in a chemotaxis assay, and neutralization of chemokines abrogated this effect. These data are the first to show chemokine production by NK cells, specifically in response to stimulation with antibody-coated tumor cells, and suggest a potential role for NK cell–derived chemokines in patients receiving therapeutic monoclonal antibodies. (Cancer Res 2006; 66(1): 517-26)
Matrix Metalloproteinase-9 from Bone Marrow–Derived Cells Contributes to Survival but not Growth of Tumor Cells in the Lung Microenvironment
Authors: Acuff Heath B. , Carter Kathy J. , Fingleton Barbara , Gorden D. Lee , Matrisian Lynn M.
Published: January 2006

The role of specific stromal-derived matrix metalloproteinases (MMPs) was analyzed in experimental metastasis assays in wild-type and either MMP-9, MMP-7, or MMP-2 null mice. MMP-9 null mice showed an 81% reduction in Lewis lung carcinoma tumor number, whereas MMP-7 null mice showed a 42% increase in tumor number, and there was no difference in tumor number in MMP-2 null mice compared with wild-type controls. Similarly, in an orthotopic model of lung cancer, 50% fewer MMP-9 null mice were able to establish tumors in the lung compared with control mice, although the size of the tumors was not different. The effect of MMP-9 on lung tumor colonization was dependent on the expression of MMP-9 from bone marrow–derived cells and is most likely contributed by neutrophils. To examine temporal effects of stromal MMP-9, bioluminescence imaging from luciferase-expressing human lung cancer–derived A549 cells revealed that there were fewer tumor cells in the lungs of MMP-9 null mice as early as 19 hours after injection compared with control mice, with no difference in subsequent growth rates. Six hours after injection of tumor cells, MMP-9 null mice showed a 4-fold increase in the percent of tumor cells undergoing apoptosis compared with control mice. We conclude that MMP-9 from the bone marrow contributes to the early survival and establishment of tumors in the lung and has no effect on subsequent growth. These results provide insights into the failure of MMP inhibitors in clinical trials in patients with late-stage lung cancer. (Cancer Res 2006; 66(1): 259-66)
Ligand-Directed Surface Profiling of Human Cancer Cells with Combinatorial Peptide Libraries
Authors: Kolonin Mikhail G. , Bover Laura , Sun Jessica , Zurita Amado J. , Do Kim-Anh , Lahdenranta Johanna , Cardó-Vila Marina , Giordano Ricardo J. , Jaalouk Diana E. , Ozawa Michael G. , Moya Catherine A. , Souza Glauco R. , Staquicini Fernanda I. , Kunyiasu Akihiko , Scudiero Dominic A. , Holbeck Susan L. , Sausville Edward A. , Arap Wadih , Pasqualini Renata
Published: January 2006

A collection of 60 cell lines derived from human tumors (NCI-60) has been widely explored as a tool for anticancer drug discovery. Here, we profiled the cell surface of the NCI-60 by high-throughput screening of a phage-displayed random peptide library and classified the cell lines according to the binding selectivity of 26,031 recovered tripeptide motifs. By analyzing selected cell-homing peptide motifs and their NCI-60 recognition patterns, we established that some of these motifs (a) are similar to domains of human proteins known as ligands for tumor cell receptors and (b) segregate among the NCI-60 in a pattern correlating with expression profiles of the corresponding receptors. We biochemically validated some of the motifs as mimic peptides of native ligands for the epidermal growth factor receptor. Our results indicate that ligand-directed profiling of tumor cell lines can select functional peptides from combinatorial libraries based on the expression of tumor cell surface molecules, which in turn could be exploited as “druggable” receptors in specific types of cancer. (Cancer Res 2006; 66(1): 34-40)
The Interaction between Two Radiosensitizers: 5-Iododeoxyuridine and Caffeine
Authors: Seo Yuji , Yan Tao , Schupp Jane E. , Yamane Kazuhiko , Radivoyevitch Tomas , Kinsella Timothy J.
Published: January 2006

5-Iododeoxyuridine (IUdR) and caffeine are recognized as potential radiosensitizers with different mechanisms of interaction with ionizing radiation (IR). To assess the interaction of these two types of radiosensitizers, we compared treatment responses to these drugs alone and in combination with IR in two p53-proficient and p53-deficient pairs of human colon cancer cell lines (HCT116 versus HCT116 p53−/− and RKO versus RKO E6). Based on clonogenic survival, the three single agents (IR, IUdR, and caffeine) as well as IUdR or caffeine combined with IR are less or equally effective in p53-deficient human tumor cells compared with p53-proficient tumor cells. However, using both radiosensitizers, a significantly greater radiosensitization was found in p53-deficient human tumor cells. To better understand the interaction of these two radiosensitizers, additional studies on DNA repair and cell cycle regulation were done. We found that caffeine enhanced IUdR-DNA incorporation and IUdR-mediated radiosensitization by partially inhibiting repair (removal) of IUdR in DNA. The repair of IR-induced DNA double-strand breaks was also inhibited by caffeine. However, these effects of caffeine on IUdR-mediated radiosensitization were not found in p53-proficient cells. Cell cycle analyses also showed a greater abrogation of IR-induced S- and G2-phase arrests by caffeine in p53-deficient cells, particularly when combined with IUdR. Collectively, these data provide the mechanistic bases for combining these two radiosensitizers to enhance tumor cytotoxicity. This differential dual mode of radiosensitization by combining IUdR and caffeine-like drugs (e.g., UCN-01) in p53-deficient human tumors may lead to a greater therapeutic gain. (Cancer Res 2006; 66(1): 490-8)
BRCA1 Mutation Analysis of 41 Human Breast Cancer Cell Lines Reveals Three New Deleterious Mutants
Authors: Elstrodt Fons , Hollestelle Antoinette , Nagel Jord H.A. , Gorin Michael , Wasielewski Marijke , van den Ouweland Ans , Merajver Sofia D. , Ethier Stephen P. , Schutte Mieke
Published: January 2006

Germ line mutations of the BRCA1 gene confer a high risk of breast cancer and ovarian cancer to female mutation carriers. The BRCA1 protein is involved in the regulation of DNA repair. How specific tumor-associated mutations affect the molecular function of BRCA1, however, awaits further elucidation. Cell lines that harbor BRCA1 gene mutations are invaluable tools for such functional studies. Up to now, the HCC1937 cell line was the only human breast cancer cell line with an identified BRCA1 mutation. In this study, we identified three other BRCA1 mutants from among 41 human breast cancer cell lines by sequencing of the complete coding sequence of BRCA1. Cell line MDA-MB-436 had the 5396 + 1G>A mutation in the splice donor site of exon 20. Cell line SUM149PT carried the 2288delT mutation and SUM1315MO2 carried the 185delAG mutation. All three mutations were accompanied by loss of the other BRCA1 allele. The 185delAG and 5396 + 1G>A mutations are both classified as pathogenic mutations. In contrast with wild-type cell lines, none of the BRCA1 mutants expressed nuclear BRCA1 proteins as detected with Ab-1 and Ab-2 anti-BRCA1 monoclonal antibodies. These three new human BRCA1 mutant cell lines thus seem to be representative breast cancer models that could aid in further unraveling of the function of BRCA1. (Cancer Res 2006; 66(1): 41-5)
Dual-Color Imaging of Nuclear-Cytoplasmic Dynamics, Viability, and Proliferation of Cancer Cells in the Portal Vein Area
Authors: Tsuji Kazuhiko , Yamauchi Kensuke , Yang Meng , Jiang Ping , Bouvet Michael , Endo Hitoshi , Kanai Yoshikatsu , Yamashita Koji , Moossa Abdool R. , Hoffman Robert M.
Published: January 2006

We used dual-color in vivo cellular imaging to visualize trafficking, nuclear-cytoplasmic dynamics, and the viability of cancer cells after their injection into the portal vein of mice. For these studies, we used dual-color fluorescent cancer cells that express green fluorescent protein (GFP) linked to histone H2B in the nucleus and retroviral red fluorescent protein (RFP) in the cytoplasm. Human HCT-116-GFP-RFP colon cancer and mouse mammary tumor (MMT) cells were HCT-116-GFP-RFP in the portal vein of nude mice. The cells were observed intravitally in the liver at the single-cell level using the Olympus OV100 whole-mouse imaging system. Most HCT-116-GFP-RFP cells remained in sinusoids near peripheral portal veins. Only a small fraction of the cancer cells invaded the lobular area. Extensive clasmocytosis (destruction of the cytoplasm) of the HCT-116-GFP-RFP cells occurred within 6 hours. The number of apoptotic cells rapidly increased within the portal vein within 12 hours of injection. Apoptosis was readily visualized in the dual-color cells by their altered nuclear morphology. The data suggest rapid death of HCT-116-GFP-RFP cells in the portal vein. In contrast, dual-color MMT-GFP-RFP cells injected into the portal vein mostly survived in the liver of nude mice 24 hours after injection. Many surviving MMT-GFP-RFP cells showed invasive figures with cytoplasmic protrusions. The cells grew aggressively and formed colonies in the liver. However, when the host mice were pretreated with cyclophosphamide, the HCT-116-GFP-RFP cells also survived and formed colonies in the liver after portal vein injection. These results suggest that a cyclophosphamide-sensitive host cellular system attacked the HCT-116-GFP-RFP cells but could not effectively kill the MMT-GFP-RFP cells. (Cancer Res 2006; 66(1): 303-6)
IFN-β Is a Highly Potent Inhibitor of Gastroenteropancreatic Neuroendocrine Tumor Cell GrowthIn vitro
Authors: Vitale Giovanni , de Herder Wouter W. , van Koetsveld Peter M. , Waaijers Marlijn , Schoordijk Wenda , Croze Ed , Colao Annamaria , Lamberts Steven W.J. , Hofland Leo J.
Published: January 2006

IFN-α controls hormone secretion and symptoms in human gastroenteropancreatic neuroendocrine tumors (GEP-NET) but it rarely induces a measurable tumor size reduction. The effect of other type I IFNs, e.g., IFN-β, has not been evaluated. We compared the antitumor effects of IFN-α and IFN-β in BON cells, a functioning human GEP-NET cell line. As determined by quantitative reverse transcription-PCR analysis and immunocytochemistry, BON cells expressed the active type I IFN receptor mRNA and protein (IFNAR-1 and IFNAR-2c subunits). After 3 and 6 days of treatment, IFN-β significantly inhibited BON cell growth in a time- and dose-dependent manner. IC50 and maximal inhibitory effect on day 6 were 8 IU/mL and 98%, respectively. In contrast, the effect of IFN-α resulted significantly in a less potent effect (IC50: 44 IU/mL, maximal inhibition: 26%). IFN-α induced only cell cycle arrest, with an accumulation of the cells in S phase. IFN-β, apart from a more potent delay in S-G2-M phase transit of the cell cycle, also induced a strong stimulation of apoptosis, evaluated by flow cytometry (Annexin V and 7-AAD) and measurement of the DNA fragmentation. Besides, only IFN-β severely suppressed chromogranin A levels in the medium from BON cells after 6 days of treatment. In conclusion, IFN-β is much more potent, compared with IFN-α, in its inhibitory effect on GEP-NET cell proliferation in vitro through the induction of apoptosis and cell cycle arrest. Further studies are required to establish whether IFN-β has comparable potent tumor growth inhibitory effects in vivo. (Cancer Res 2006; 66(1): 554-62)
Enprofylline Protects Motor Neurons from in vitro Excitotoxic Challenge
Authors: Mojsilovic-Petrovic Jelena , Arneja Amrita , Kalb Robert G.
Published: January 2006

Background: The death of motor neurons in amyotrophic lateral sclerosis (ALS) is believed to result, in part, from unrestrained activation of glutamate receptors (excitotoxicity). In some in vitro models, excitotoxic death only occurs if motor neurons develop in the presence of the growth factor, brain-derived neurotrophic factor (BDNF). Objective: Since the increased vulnerability of motor neurons evoked by BDNF is mediated by activation of TrkB, we sought to identify pharmacological agents that can block this pathway. Adenosine receptors are known to transactivate Trk receptors, leading us to examine the effects of manipulating of adenosine receptor signaling on Trk signaling and excitotoxic sensitivity. Methods: Spinal cord cultures were treated with adenosine receptor agonists and antagonists. The biochemical effects on Trk signaling and excitotoxic motor neuron death were examined. Results: We show here that adenosine A2a antagonists can reduce activation of Trk receptors and are neuroprotective. Conversely, activating adenosine A2a receptors in the absence of BDNF signaling makes motor neurons vulnerable to excitotoxic challenge. Conclusion: Selective, high-affinity adenosine A2a antagonists merit consideration as therapeutic agents for the treatment of ALS.
Implications for the Kynurenine Pathway and Quinolinic Acid in Amyotrophic Lateral Sclerosis
Authors: Guillemin Gilles J. , Meininger Vincent , Brew Bruce J.
Published: January 2006

The kynurenine pathway (KP) is a major route of L-tryptophan catabolism leading to production of several neurobiologically active molecules. Among them is the excitotoxin quinolinic acid (QUIN) that is known to be involved in the pathogenesis of several major inflammatory neurological diseases. In amyotrophic lateral sclerosis (ALS) degeneration of motor neurons is associated with a chronic and local inflammation (presence of activated microglia and astrocytes). There is emerging evidence that the KP is important in ALS. Recently, we demonstrated that QUIN is significantly increased in serum and CSF of ALS patients. Moreover, most of the factors associated with QUIN toxicity are found in ALS, implying that QUIN may play a substantial role in the neuropathogenesis of ALS. This review details the potential role the KP has in ALS and advances a testable hypothetical model.
Amyotrophic Lateral Sclerosis: New Developments in Diagnostic Markers
Authors: Dengler Reinhard , von Neuhoff Nils , Bufler Johannes , Krampfl Klaus , Peschel Thomas , Grosskreutz Julian
Published: January 2006

There is an intensive search for diagnostic markers in amyotrophic lateral sclerosis (ALS). Protein analysis (proteomics) of the cerebrospinal fluid (CSF) appears particularly promising using mass spectrometry and 2-D gel electrophoresis to detect low and high molecular weight proteins, respectively. It is open whether protein changes specific for ALS will be found. This also holds true for inflammatory proteins such as the cytokine monocyte chemoattractant protein-1 which has been detected in CSF in ALS and for other cytokines such as interleukin-1β. Increases of the protein Nogo A and B in muscle tissue and decreases of the growth factor vascular endothelial growth factor in blood may also be useful for monitoring the course of ALS. Clinical neurophysiology provides markers for upper and lower motor neuron damage. A very sensitive method to detect early upper motor neuron involvement is the transcranial magnetic stimulation modification ‘triple stimulation technique’ which can show significant changes in patients without clinical upper motor neuron signs. The loss of lower motor neurons can be closely monitored by MUNE techniques (motor unit number estimate). In modern imaging, the MRI technique DTI (diffusion tensor imaging) has the greatest diagnostic potential for ALS. It can separate between normal and ALS in group comparisons and may be improved to be diagnostic in individual patients. Voxel-based morphometry can reliably demonstrate regional cortical atrophy in motor areas and beyond although it is not appropriate for use in individual patients.
Clinical Trials in ALS: What Did We Learn from Recent Trials in Humans?
Authors: Meininger Vincent
Published: January 2006

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease. No treatment is currently able to stop the disease process. In the absence of new active compounds there is an urgent need to develop new strategies based on the neuroprotective activity of available drugs. ALS is a heterogeneous disease. To build up these therapeutic trials, we need to have a better understanding of the prognostic factors in this disease. During the Phase IV Rilutek Trial in France, we developed in a large population of patients a prognostic score based on clinical parameters available at the bedside. The most significant variables are vital capacity, spasticity, fasciculations, swallowing, cough and creatininemia. This score proved to be very useful in daily use in the clinic and for planning disease management in ALS as in the design of therapeutic trials. In ALS clinical trials, efficacy can be evaluated using survival or functional parameters. In phase II trials, function remains the most commonly used. In phase III trials, the gold standard endpoint remains the survival rate at month 18. We analyzed the most recent ALS trials published in the literature. This review suggests that in these trials there is a discrepancy between drug effects on survival versus function. These results suggest that a reappraisal of strategies to identify therapeutic targets for ALS is required.
The Incorporation of Prior Genomic Information Does Not Necessarily Improve the Performance of Bayesian Linkage Methods: An Example Involving Sex-Specific Recombination and the Two-Point PPL
Authors: Logue Mark W. , Vieland Veronica J.
Published: January 2006

Objective: We continue statistical development of the posterior probability of linkage (PPL). We present a two-point PPL allowing for unequal male and female recombination fractions, ΘM and ΘF, and consider alternative priors on ΘM, ΘF. Methods: We compare the sex-averaged PPL (PPLSA), assuming ΘM = ΘF, to the sex-specific PPL (PPLSS) in (ΘM, ΘF), in a series of simulations; we also compute the PPLSS using alternative priors on (ΘM, ΘF). Results: The PPLSS based on a prior that ignores prior genomic information on sex specific recombination rates performs essentially identically to the PPLSA, even in the presence of large ΘM, ΘF differences. Moreover, adaptively skewing the prior, to incorporate (correct) genomic information on ΘM, ΘF differences, actually worsens performance of the PPLSS. We demonstrate that this has little to do with the PPLSS per se, but is rather due to extremely high levels of variability in the location of the maximum likelihood estimates of (ΘM, ΘF) in realistic data sets. Conclusions: Incorporating (correct) prior genomic information is not always helpful. We recommend that the PPLSA be used as the standard form of the PPL regardless of the sex-specific recombination rates in the region of the marker in question.
Dopamine Receptor D1 Gene –48A/G Polymorphism Is Associated with Bipolar Illness but Not with Schizophrenia in a Polish Population
Authors: Dmitrzak-Weglarz Monika , Rybakowski Janusz K. , Slopien Agnieszka , Czerski Piotr M. , Leszczynska-Rodziewicz Anna , Kapelski Pawel , Kaczmarkiewicz-Fass Magdalena , Hauser Joanna
Published: January 2006

Dysregulation of dopaminergic neurotransmission has been implicated in the etiology of major psychoses. The dopamine D1 receptor (DRD1) plays a role in some brain functions and mechanisms of psychotropic drugs. Therefore, the DRD1 gene makes a good candidate gene for molecular genetic studies in schizophrenia and bipolar affective disorder. In the present study, the –48A/G polymorphism of the DRD1 gene was estimated in patients with schizophrenia (n = 407) or bipolar affective disorder (n = 380), and in healthy controls (n = 399). No association was found between the polymorphism studied and schizophrenia, either in the whole group of patients or in subgroups divided by gender, age at onset or predominance of positive or negative symptoms. A statistical trend was obtained for an association between this polymorphism and bipolar affective disorder (p = 0.059 for genotypes, p = 0.073 for alleles). The G/G genotype and G allele were significantly more frequent in patients with bipolar disorder, type II (p = 0.016 for genotypes, p = 0.008 for alleles), especially in the women subgroup (p = 0.054 for genotypes, p = 0.024 for alleles). An association between the G/G genotype and bipolar affective disorder with disease onset after 18 years of age was also found (p = 0.022). These data suggest that the –48A/G polymorphism of the DRD1 gene may be involved in the etiology of bipolar disorder in a Polish population.
"Ten Times More Difficult to Treat": Female Bodies in Medical Texts from Early Imperial China
Authors: Wilms Sabine
Published: January 2006

This paper examines the interpretation of female bodies by male medical authors in post-Han China, investigating medical theories and practices as reflected in the applied medical literature of "prescriptions for women." Between the Han and Song periods, this paper argues, the negative association of the female body with the vague category of pathologies "below the girdle," referring most notably to conditions of vaginal discharge, was replaced with a more positive focus on menstruation, which symbolized regular and predictable cycles of generativity and free flow. As male physicians came to recognize the female body as gendered and accepted the need for a specialized treatment of women, menstruation became the window through which they gained access to the hidden processes inside the female body. By "balancing/regulating the menses," they learned to treat and prevent such dreaded chronic conditions as infertility, susceptibility to cold, or general emaciation and weakness, all which were seen as related to the female reproductive processes. Thus, the practice of menstrual regulation ultimately served to ensure female fertility and the continuation of the family line.
Medicine for Women in Early China: A Preliminary Survey
Authors: Yates Robin
Published: January 2006

This study reviews aspects of the history of medicine for women from approximately the third century BCE to the tenth century CE. It focuses on therapies during the months of pregnancy and childbirth as recorded in newly discovered texts, on the developing pharmacopeia, and on ritual procedures. It argues that acupuncture was used only rarely on pregnant women and that many cultural and religious beliefs and practices, including those drawn from the Buddhist, Daoist, and popular traditions, influenced procedures undertaken in preparation for and during the birth process.
Nonlinear Atmospheric Adjustment to Thermal Forcing
Authors: Fanelli Paul F. , Bannon Peter R.
Published: January 2006

A nonlinear, numerical model of a compressible atmosphere is used to simulate the hydrostatic and geostrophic adjustment to a localized prescribed heating applied over five minutes with a size characteristic of an isolated, deep, cumulus cloud. This thermal forcing generates both buoyancy waves and a horizontally propagating Lamb wave packet as well as a steady state rich in potential vorticity. The adjustments in three model atmospheres (an isothermal, a constant lapse rate, and one with a stratosphere) are studied.

The Lamb wave packet and the two lowest-order buoyancy waves are relatively unaffected by nonlinearities but the higher-order modes and the steady state are. The heating generates a vertically stacked dipole of potential vorticity with a cyclonic perturbation below an anticyclonic perturbation. In contrast to the linear results, the nonlinear dipole is severely distorted by vertical and horizontal advections. In addition, the Lamb wave packet contains some weak positive perturbation potential vorticity.

The energetics is examined using traditional and Eulerian available energetics. Traditional energetics consists of kinetic, internal, and potential energies. It is shown that the Lamb wave packet contains more total traditional energy than that input to the atmosphere by the heating. The traditional energy in the packet resides primarily in the form of internal energy and only secondarily in the form of potential energy. The passage of the Lamb wave packet produces an atmosphere that, overall, is cooler, less dense, and with less total traditional energy than the initial atmosphere. Eulerian available energetics consists of kinetic, available potential, and available elastic energies. The heating generates both available elastic and potential energy that is then converted into kinetic energy. Most of the available elastic energy projects onto the Lamb packet, while almost all of the available potential energy is associated with the buoyancy waves and the steady state.

The effects of varying the spatial and temporal scale of the heating, while keeping the net heating the same, are examined. As the duration of the heating decreases, the amount of energy projected onto the waves increases. Increasing the size of the heating decreases the amount of energy projected onto the waves.

The adjustment is kinetically more vigorous in the nonisothermal atmospheres because of the reduction in the base-state static stability. The presence of a stratosphere produces large anomalies at and above the tropopause that are linked to the vertical motions of the buoyancy wave field.
An Equation for Moist Entropy in a Precipitating and Icy Atmosphere
Authors: Zeng Xiping , Tao Wei-Kuo , Simpson Joanne
Published: January 2006

This paper addresses an equation for moist entropy in the framework of cloud-resolving models. After rewriting the energy equation with moist entropy in the place of temperature, an equation for moist entropy is obtained. The equation expresses the internal and external sources of moist entropy explicitly, providing a basis for the use of moist entropy as a prognostic variable in long-term cloud-resolving modeling. In addition, a precise formula for the surface flux of moist entropy from the underlying surface into the air above is derived.

The equation for moist entropy is used to express the Neelin–Held model for the diagnosis of large-scale vertical velocity. After applying the model to a tropical oceanic atmosphere with mean annual soundings, the paper shows the sensitivity of large-scale vertical circulations to the radiative cooling rate and the surface flux of moist entropy, which demonstrates the necessity for a precise equation for moist entropy in the analysis and modeling of large-scale tropical circulations.
The 29 June 2000 Supercell Observed during STEPS. Part I: Kinematics and Microphysics
Authors: Tessendorf Sarah A. , Miller L. Jay , Wiens Kyle C. , Rutledge Steven A.
Published: January 2006

This is a two-part study that addresses the kinematic, microphysical, and electrical aspects of a severe storm that occurred in western Kansas on 29 June 2000 observed during the Severe Thunderstorm Electrification and Precipitation Study (STEPS) field campaign. In this first part, polarimetric and Doppler radar data are used along with a simple particle growth model to examine the evolution of the kinematic and microphysical properties of the storm from its earliest developing phase through its mature and dissipating phases. During its severe stage, the storm exhibited frequent positive cloud-to-ground lightning strikes, very large (∼5 cm) hail, and a tornado.

Doppler-derived winds, radar reflectivity, and hydrometeor classifications from the polarimetric data over a nearly 4-h period are presented. It is shown that updraft velocity and vertical vorticity had to reach magnitudes of at least 10 m s−1 and 10−2 s−1 and occupy major portions of the storm before it could produce most of the observed severe storm characteristics. Furthermore, the establishment of cyclonic horizontal flow around the right flank of the updraft core was essential for hail production. Most of the largest hail grew from near millimeter-sized particles that originated in the mid- to upper-level stagnation region that resulted from obstacle-like flow of environmental air around the divergent outflow from the upper part of the updraft. These recycling embryonic particles descended around the right flank of the updraft core and reentered the updraft, intermingling with other smaller particles that had grown from cloud base along the main low-level updraft stream.
Large-Scale Waves in the Mesosphere and Lower Thermosphere Observed by SABER
Authors: Garcia Rolando R. , Lieberman Ruth , Russell James M. , Mlynczak Martin G.
Published: January 2006

Observations made by the Sounding of the Atmosphere using Broadband Emission Radiometry (SABER) instrument on board NASA’s Thermosphere–Ionosphere–Mesosphere Energetics and Dynamics (TIMED) satellite have been processed using Salby’s fast Fourier synoptic mapping (FFSM) algorithm. The mapped data provide a first synoptic look at the mean structure and traveling waves of the mesosphere and lower thermosphere (MLT) since the launch of the TIMED satellite in December 2001. The results show the presence of various wave modes in the MLT, which reach largest amplitude above the mesopause and include Kelvin and Rossby–gravity waves, eastward-propagating diurnal oscillations (“non-sun-synchronous tides”), and a set of quasi-normal modes associated with the so-called 2-day wave. The latter exhibits marked seasonal variability, attaining large amplitudes during the solstices and all but disappearing at the equinoxes. SABER data also show a strong quasi-stationary Rossby wave signal throughout the middle atmosphere of the winter hemisphere; the signal extends into the Tropics and even into the summer hemisphere in the MLT, suggesting ducting by westerly background zonal winds. At certain times of the year, the 5-day Rossby normal mode and the 4-day wave associated with instability of the polar night jet are also prominent in SABER data.
An Energy-Balance Analysis of Deep Convective Self-Aggregation above Uniform SST
Authors: Bretherton Christopher S. , Blossey Peter N. , Khairoutdinov Marat
Published: January 2006

The spatial organization of deep moist convection in radiative–convective equilibrium over a constant sea surface temperature is studied. A 100-day simulation is performed with a three-dimensional cloud-resolving model over a (576 km)2 domain with no ambient rotation and no mean wind. The convection self-aggregates within 10 days into quasi-stationary mesoscale patches of dry, subsiding and moist, rainy air columns. The patches ultimately merge into a single intensely convecting moist patch surrounded by a broad region of very dry subsiding air.

The self-aggregation is analyzed as an instability of a horizontally homogeneous convecting atmosphere driven by convection–water vapor–radiation feedbacks that systematically dry the drier air columns and moisten the moister air columns. Column-integrated heat, water, and moist static energy budgets over (72 km)2 horizontal blocks show that this instability is primarily initiated by the reduced radiative cooling of air columns in which there is extensive anvil cirrus, augmented by enhanced surface latent and sensible heat fluxes under convectively active regions due to storm-induced gustiness. Mesoscale circulations intensify the later stages of self-aggregation by fluxing moist static energy from the dry to the moist regions. A simple mathematical model of the initial phase of self-aggregation is proposed based on the simulations.

In accordance with this model, the self-aggregation can be suppressed by horizontally homogenizing the radiative cooling or surface fluxes. Lower-tropospheric wind shear leads to slightly slower and less pronounced self-aggregation into bands aligned along the shear vector. Self-aggregation is sensitive to the ice microphysical parameterization, which affects the location and extent of cirrus clouds and their radiative forcing. Self-aggregation is also sensitive to ambient Coriolis parameter f, and can induce spontaneous tropical cyclogenesis for large f. Inclusion of an interactive mixed-layer ocean slows but does not prevent self-aggregation.
Constraints on Wave Drag Parameterization Schemes for Simulating the Quasi-Biennial Oscillation. Part I: Gravity Wave Forcing
Authors: Campbell Lucy J. , Shepherd Theodore G.
Published: January 2006

Parameterization schemes for the drag due to atmospheric gravity waves are discussed and compared in the context of a simple one-dimensional model of the quasi-biennial oscillation (QBO). A number of fundamental issues are examined in detail, with the goal of providing a better understanding of the mechanism by which gravity wave drag can produce an equatorial zonal wind oscillation. The gravity wave–driven QBOs are compared with those obtained from a parameterization of equatorial planetary waves. In all gravity wave cases, it is seen that the inclusion of vertical diffusion is crucial for the descent of the shear zones and the development of the QBO. An important difference between the schemes for the two types of waves is that in the case of equatorial planetary waves, vertical diffusion is needed only at the lowest levels, while for the gravity wave drag schemes it must be included at all levels. The question of whether there is downward propagation of influence in the simulated QBOs is addressed. In the gravity wave drag schemes, the evolution of the wind at a given level depends on the wind above, as well as on the wind below. This is in contrast to the parameterization for the equatorial planetary waves in which there is downward propagation of phase only. The stability of a zero-wind initial state is examined, and it is determined that a small perturbation to such a state will amplify with time to the extent that a zonal wind oscillation is permitted.
Geographical Dependence of Upper-Level Blocking Formation Associated with Intraseasonal Amplification of the Siberian High
Authors: Takaya Koutarou , Nakamura Hisashi
Published: January 2006

Intraseasonal amplification events of the surface Siberian high in winter are generally associated with blocking ridge formation in the upper troposphere. Composite analysis applied to the 20 strongest intraseasonal events of upper-level anticyclonic anomalies at every grid point over Siberia reveals that the blocking formation differs fundamentally between the east and west of the climatological upper-level trough over the Far East. To the west, what can be called “wave-train (Atlantic-origin)” type is common, where a blocking ridge develops from anomalies as a component of a quasi-stationary Rossby wave train propagating across the Eurasian continent under modest feedback forcing from transient eddies. To the east of the trough, what can be called “Pacific-origin” type dominates, where a blocking ridge forms in association with westward development of anticyclonic anomalies from the North Pacific under stronger feedback forcing from the Pacific storm track. Regardless of a particular type of blocking formation in the upper troposphere, a cold air outbreak tends to occur once anomalously cold air reaches the northeastern slope of the Tibetan Plateau.
Measuring the Influence of Complexity on Relational Reasoning
Authors: Birney Damian P. , Halford Graeme S. , Andrews Glenda
Published: January 2006

Relational complexity (RC) theory conceptualizes an individual’s processing capacity and a task’s complexity along a common ordinal metric. The authors describe the development of the Latin Square Task (LST) that assesses the influence of RC on reasoning. The LST minimizes the role of knowledge and storage capacity and thus refines the identification of a processing-capacity-related complexity effect in task performance. The LST is novel with one explicit rule that is easily understood by adults and children. In two studies, a test of 18 items encompassing three RC levels was administered to university ( N = 73; 16-33 years) and school ( N = 204; 8-19 years) students. Rasch analyses indicate that the LST scores were psychometrically stable across age groups and provides important diagnostic clues for task development. Consistent with RC theory, the LST is sensitive to parallel and serial (via segmentation) processing demands. The LST provides a strong basis for research on working memory and related constructs (fluid intelligence).
Pharmacokinetics of Otamixaban, a Direct Factor Xa Inhibitor, in Healthy Male Subjects: Pharmacokinetic Model Development for Phase 2/3 Simulation of Exposure
Authors: Paccaly Anne , Frick Annke , Rohatagi Shashank , Liu Jingli , Shukla Umesh , Rosenburg Ronald , Hinder Markus , Jensen Bradford K.
Published: January 2006

The pharmacokinetics of otamixaban was investigated in healthy male subjects over a wide range of intravenous doses, with duration of administration varying between 1‐minute infusions (bolus dose) and 24‐hour infusions, using noncompartmental and multicompartmental methods. A global compartmental analysis (2 and 3 compartments) generated a single set of pharmacokinetic parameters, regardless of infusion rate and duration, and took into account the 30% decrease in clearance and volume of distribution observed over the dose range. The 2‐compartment model was retained to predict bolus plus 3‐hour‐infusion doses of otamixaban for future phase 2/3 studies. Otamixaban exhibited in healthy subjects several interesting pharmacokinetic features in view of its potential therapeutic use in coronary thrombosis: a rapid plasma distribution and elimination, a well‐described dose‐exposure relationship, a low intersubject variability in plasma exposure, and a mixed renal and biliary excretion with constant renal clearance.
A Comparative Study of Sirolimus Tablet Versus Oral Solution for Prophylaxis of Acute Renal Allograft Rejection
Authors: Mathew Timothy H. , Van Buren Charles , Kahan Barry D. , Butt Khalid , Hariharan Sundaram , Zimmerman James J. ,   Rapamune 309 Study Group
Published: January 2006

This multicenter, open‐label study compared the efficacy, safety, and pharmacokinetic parameters of sirolimus (rapamycin) tablet and liquid formulations for prevention of efficacy failure. A total of 477 renal allograft recipients were randomly assigned (1:1) to receive either tablet or solution formulations of sirolimus for 12 months, plus cyclosporine (CsA) and steroids. Pharmacokinetic parameters were analyzed based on trough concentrations and 24‐hour pharmacokinetic profiles. There were no significant differences in efficacy failure at 3 or 12 months between tablet and solution groups. Graft survival, patient survival, rate of first biopsy‐confirmed acute rejection, time to and severity of acute rejection, and laboratory parameters were not significantly different between groups. Mean steady‐state sirolimus and CsA pharmacokinetic parameters on days 30 and 90 were not significantly different by formulation, except for longer sirolimus tmaxafter tablet administration. Multivariate logistic regression analysis indicated that low sirolimus Cmin, TNand more human leukocyte antigen mismatches were predictors of acute rejection. The tablet and solution formulations of sirolimus demonstrated therapeutic equivalence.
The Effect of Mild and Moderate Hepatic Impairment on Pharmacokinetics, Pharmacodynamics, and Safety of Febuxostat, a Novel Nonpurine Selective Inhibitor of Xanthine Oxidase
Authors: Khosravan Reza , Grabowski Brian A. , Mayer Michael D. , Wu Jing‐Tao , Joseph‐Ridge Nancy , Vernillet Laurent
Published: January 2006

To assess the effect of hepatic impairment on the pharmacokinetics, pharmacodynamics, and safety of febuxostat at steady state, multiple once‐daily 80‐mg oral doses of febuxostat were administered to subjects with normal hepatic function and to subjects with mild or moderate hepatic impairment. There were no statistically significant differences in the plasma pharmacokinetic parameters for unbound febuxostat and its active metabolites between subjects with mild or moderate hepatic impairment and those with normal hepatic function. The percentage decrease in serum uric acid appeared to be lower in hepatic impairment groups (49% [mild] and 48% [moderate]) as compared to the normal hepatic group (62%). This lower percentage decrease was minimal and not considered clinically significant. Febuxostat 80 mg once daily appears to be generally safe and well tolerated in mildly and moderately impaired hepatic function groups, and dose adjustment is not required in subjects with mild to moderate hepatic impairment.