bluuebunny/crossref_metadata_2025 huggingface dataset:
The nappe rule: why does it work?
Authors: Ring Uwe , Kassem Osama M.K.
Published: October 2007

The nappe rule stresses that imbrication emplaces nappes with higher metamorphic grade above those with lower grade. This means that the overriding nappes must be exhuming during nappe stacking; otherwise metamorphic grade would increase structurally downwards. The high-grade metamorphic internides of many orogens are characterized by a pervasive nappe-emplacement-related subhorizontal foliation indicative of vertical ductile shortening (thinning). By quantifying finite strain in the Gran Paradiso Massif, Italian Alps, we show that vertical ductile thinning associated with a nappe-emplacement-related subhorizontal foliation caused sufficient exhumation of the overriding nappes and can thus explain the occurrence of higher-grade rocks above lower-grade ones.
Combined IFN-γ and retinoic acid treatment targets the N-Myc/Max/Mad1 network resulting in repression of N-Myc target genes in MYCN-amplified neuroblastoma cells
Authors: Cetinkaya Cihan , Hultquist Anne , Su Yingtao , Wu Siqin , Bahram Fuad , Påhlman Sven , Guzhova Irina , Larsson Lars-Gunnar
Published: October 2007

The MYCN protooncogene is involved in the control of cell proliferation, differentiation, and survival of neuroblasts. Deregulation of MYCN by gene amplification contributes to neuroblastoma development and is strongly correlated to advanced disease and poor outcome, emphasizing the urge for new therapeutic strategies targeting MYCN function. The transcription factor N-Myc, encoded by MYCN, regulates numerous genes together with its partner Max, which also functions as a cofactor for the Mad/Mnt family of Myc antagonists/transcriptional repressors. We and others have previously reported that IFN-γ synergistically potentiates retinoic acid (RA)–induced sympathetic differentiation and growth inhibition in neuroblastoma cells. This study shows that combined treatment of MYCN-amplified neuroblastoma cells with RA+IFN-γ down-regulates N-Myc protein expression through increased protein turnover, up-regulates Mad1 mRNA and protein, and reduces N-Myc/Max heterodimerization. This results in a shift of occupancy at the ornithine decarboxylase N-Myc/Mad1 target promoter in vivo from N-Myc/Max to Mad1/Max predominance, correlating with histone H4 deacetylation, indicative of a chromatin structure typical of a transcriptionally repressed state. This is further supported by data showing that RA+IFN-γ treatment strongly represses expression of N-Myc/Mad1 target genes ornithine decarboxylase and hTERT. Our results suggest that combined IFN-γ and RA signaling can form a basis for new therapeutic strategies targeting N-Myc function for patients with high-risk, MYCN-amplified neuroblastoma. [Mol Cancer Ther 2007;6(10):2634–41]
Epothilones induce human colon cancer SW620 cell apoptosis via the tubulin polymerization–independent activation of the nuclear factor-κB/IκB kinase signal pathway
Authors: Lee Seung Ho , Son Seung Mo , Son Dong Ju , Kim Sun Mi , Kim Tack Joong , Song Sukgil , Moon Dong Cheul , Lee Hyo Won , Ryu Jae Chun , Yoon Do-Young , Hong Jin Tae
Published: October 2007

Molecular mechanisms underlying epothilone-induced apoptotic cell death were investigated in SW620 human colon cancer cells. Treatment with epothilone B and D at different concentrations (1–100 nmol/L) dose-dependently inhibited cell growth and caused cell cycle arrest at G2-M, which was followed by apoptosis. Consistent with this induction of apoptotic cell death, epothilone B and D enhanced the constitutional activation of nuclear factor-κB (NF-κB) via IκB degradation through IκB kinase (IKKα and IKKβ) activation, and this resulted in p50 and p65 translocation to the nucleus. Moreover, cells treated with sodium salicylic acid, an IKK inhibitor, or transiently transfected with mutant IKKα and β did not show epothilone-induced cell growth inhibition or p50 translocation, although p65 was still translocated to the nucleus. Treatment with epothilone B and D also enhanced β-tubulin polymerization and the formation of p50/β-tubulin complex. However, β-tubulin polymerization was not inhibited in the cells treated by sodium salicylic acid or transiently transfected with mutant IKKα and β. Moreover, epothilone B and D increased the expressions of NF-κB–dependent apoptotic cell death regulatory genes, i.e., Bax, p53, and the active form of caspase-3, but reduced Bcl-2 expression, and these actions were partially reversed by salicylic acid. In addition, caspase-3 inhibitor reduced epothilone B–induced cell death and NF-κB activation. These findings suggest that the activation of NF-κB/IKK signals plays an important role in the epothilone-induced apoptotic cell death of SW620 colon cancer cells in a tubulin polymerization–independent manner. [Mol Cancer Ther 2007;6(10):2786–97]
Treatment of colon cancer cells using the cytosine deaminase/5-fluorocytosine suicide system induces apoptosis, modulation of the proteome, and Hsp90β phosphorylation
Authors: Negroni Luc , Samson Michel , Guigonis Jean-Marie , Rossi Bernard , Pierrefite-Carle Valérie , Baudoin Christian
Published: October 2007

The bacterial cytosine deaminase (CD) gene, associated with the 5-fluorocytosine (5FC) prodrug, is one of the most widely used suicide systems in gene therapy. Introduction of the CD gene within a tumor induces, after 5FC treatment of the animal, a local production of 5-fluorouracil resulting in intratumor chemotherapy. Destruction of the gene-modified tumor is then followed by the triggering of an antitumor immune reaction resulting in the regression of distant wild-type metastasis. The global effects of 5FC on colorectal adenocarcinoma cells expressing the CD gene were analyzed using the proteomic method. Application of 5FC induced apoptosis and 19 proteins showed a significant change in 5FC-treated cells compared with control cells. The up-regulated and down-regulated proteins include cytoskeletal proteins, chaperones, and proteins involved in protein synthesis, the antioxidative network, and detoxification. Most of these proteins are involved in resistance to anticancer drugs and resistance to apoptosis. In addition, we show that the heat shock protein Hsp90β is phosphorylated on serine 254 upon 5FC treatment. Our results suggest that activation of Hsp90β by phosphorylation might contribute to tumor regression and tumor immunogenicity. Our findings bring new insights into the mechanism of the anticancer effects induced by CD/5FC treatment. [Mol Cancer Ther 2007;6(10):2747–56]
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6-Methylguanine-DNA-methyltransferase promoter demethylation is involved in basic fibroblast growth factor–induced resistance against temozolomide in human melanoma cells
Authors: Fontijn Dennis , Adema Auke D. , Bhakat Kishor K. , Pinedo Herbert M. , Peters Godefridus J. , Boven Epie
Published: October 2007

Basic fibroblast growth factor (bFGF) is a multifunctional protein and one of the most important growth factors in cutaneous melanoma development and progression. We hypothesized that high bFGF expression might be responsible for chemoresistance in advanced melanoma. M14 human melanoma cells expressing low levels of bFGF were successfully transfected with vectors encoding either the 18 kDa or all isoform proteins of bFGF. M14 cells and bFGF-overexpressing clones had a similar growth rate in vitro. Overexpression of 18 kDa or all isoform proteins of bFGF resulted in, respectively, 2.9- and 6.9-fold resistance against temozolomide. O6-Alkylguanine-DNA-alkyltransferase (AGT) protein levels were highly elevated. Specific inhibition of AGT with O6-benzylguanine completely reversed the resistance in the 18 kDa clone, and partially in the clone overexpressing all isoforms. A methylation-specific PCR showed that at least in the 18 kDa overexpressing clone, increased AGT expression was the result of demethylation of the O6-methylguanine-DNA-methyltransferase promoter. In parental M14 cells, the demethylating agent 5-azacytidine generated AGT expression resulting in temozolomide resistance. Overexpression of all isoform proteins of bFGF, but not the 18 kDa isoform alone, resulted in 2.9-fold resistance against cisplatin, which could not be reversed by O6-benzylguanine. The expression levels of the mismatch repair proteins MSH2, MSH6, and MLH1 were not decreased, which likely excludes a defective mismatch repair system as a cause for cisplatin resistance. There were no changes in sensitivity to docetaxel and doxorubicin. In conclusion, bFGF overexpression can result in resistance against temozolomide mediated by demethylation of the O6-methylguanine-DNA-methyltransferase promoter. [Mol Cancer Ther 2007;6(10):2807–15]
Response to trastuzumab, erlotinib, and bevacizumab, alone and in combination, is correlated with the level of human epidermal growth factor receptor-2 expression in human breast cancer cell lines
Authors: Emlet David R. , Brown Kathryn A. , Kociban Deborah L. , Pollice Agnese A. , Smith Charles A. , Ong Ben Brian L. , Shackney Stanley E.
Published: October 2007

Human epidermal growth factor receptor-2 (HER2) and epidermal growth factor receptor (EGFR) heterodimerize to activate mitogenic signaling pathways. We have shown previously, using MCF7 subcloned cell lines with graded levels of HER2 expression, that responsiveness to trastuzumab and AG1478 (an anti-EGFR agent), varied directly with levels of HER2 expression. HER2 and EGFR up-regulate vascular endothelial growth factor (VEGF), a growth factor that promotes angiogenesis and participates in autocrine growth-stimulatory pathways that might be active in vitro. Here, we show that trastuzumab, erlotinib, and bevacizumab, individually and in combination, inhibit cell proliferation in a panel of unrelated human breast cancer cell lines, in proportion to their levels of HER2 expression. The combination of all three drugs provided a greater suppression of growth than any single drug or two-drug combination in the high HER2–expressing cell lines (P < 0.001). Combination index analysis suggested that the effects of these drugs in combination were additive. The pretreatment net level of VEGF production in each cell line was correlated with the level of HER2 expression (r = 0.883, P = 0.016). Trastuzumab and erlotinib each reduced total net VEGF production in all cell lines. Multiparameter flow cytometry studies indicated that erlotinib alone and the triple drug combination produced a prolonged but reversible blockade of cells in G1, but did not increase apoptosis substantially. These studies suggest that the effects of two and three-drug combinations of trastuzumab, erlotinib, and bevacizumab might offer potential therapeutic advantages in HER2-overexpressing breast cancers, although these effects are of low magnitude, and are likely to be transient. [Mol Cancer Ther 2007;6(10):2664–74]
p21 and p27 induction by silibinin is essential for its cell cycle arrest effect in prostate carcinoma cells
Authors: Roy Srirupa , Kaur Manjinder , Agarwal Chapla , Tecklenburg Marianne , Sclafani Robert A. , Agarwal Rajesh
Published: October 2007

Recent studies have shown that silibinin induces p21/Cip1 and p27/Kip1 and G1 arrest in different prostate cancer cells irrespective of p53 status; however, biological significance and mechanism of such induction have not been studied. Here, using two different prostate cancer cell lines DU145 and 22Rv1, representing androgen-independent and androgen-dependent stages of malignancy, first we investigated the importance of p21 and p27 induction in silibinin-mediated G1 arrest. Silencing p21 and p27 individually by RNA interference showed marked reversal in G1 arrest; however, their simultaneous ablation showed additional reversal of G1 arrest in 22Rv1 but not DU145 cells. These results suggest that whereas relative importance of these molecules might be cell line specific, their induction by silibinin is essential for its G1 arrest effect. Next, studies were done to examine mechanisms of their induction where cycloheximide-chase experiments showed that silibinin increases p21 and p27 protein half-life. This effect was accompanied by strong reduction in Skp2 level and its binding with p21 and p27 together with strong decrease in phosphorylated Thr187 p27 without considerable change in proteasomal activity, suggesting a posttranslational mechanism. Skp2 role was further elucidated using Skp2-small interfering RNA–transfected cells, where decreased G1 arrest and attenuated Cip/Kip induction were observed with silibinin treatment. Further, silibinin caused a marked increase in p21 and p27 mRNA levels together with an increase in their promoter activity, also indicating a transcriptional mechanism. Together, our results for the first time identify a central role of p21 and p27 induction and their regulatory mechanism in silibinin-mediated cell cycle arrest. [Mol Cancer Ther 2007;6(10):2696–707]
IB05204, a dichloropyridodithienotriazine, inhibits angiogenesis in vitro and in vivo
Authors: Martínez-Poveda Beatriz , Muñoz-Chápuli Ramón , Rodríguez-Nieto Salvador , Quintela José M. , Fernández Antonio , Medina Miguel-Ángel , Quesada Ana R.
Published: October 2007

In the course of a blind screening program for inhibitors of angiogenesis, IB05204 (4,8-dichloro-12-phenylpyrido[5′,6′:4″,5″;3′,2′:4,5]dithieno[3″,2″−d′:3,2−d]-1,2,3-ditriazine) was selected for its ability to inhibit endothelial tubule-like network formation on Matrigel. IB05204 inhibits the in vivo angiogenesis in the chorioallantoic membrane (CAM) and the mouse Matrigel plug assays. Antiangiogenic activity seems to be highly dependent on the chloro substituents because their removal results in a complete loss of the in vitro inhibitory activity of endothelial differentiation and in vivo antiangiogenic activity in CAM assay. Although IB05204 inhibits the growth of endothelial and tumor cells in culture, its antiangiogenic activity seems to be mainly dependent on the prevention of endothelial capillary-like tube formation and inhibition of endothelial migration because these effects are recorded at lower concentrations. IB05204 treatment inhibits matrix metalloproteinase-2 (MMP-2) production in endothelial and tumor cells, down-regulates endothelial cyclooxygenase-2 expression, and represses phosphorylation of endothelial Akt in response to serum stimulation, suggesting that IB05204 interferes with molecular mechanisms of cell migration and survival. IB05204 induces apoptosis in endothelial cells through cytochrome c release and caspase activation. Data here shown altogether indicate that IB05204 is a compound that interferes with several key steps of angiogenesis, making it a promising drug for further evaluation in the treatment of angiogenesis-related pathologies. [Mol Cancer Ther 2007;6(10):2675–85]
Anti-CD166 single chain antibody-mediated intracellular delivery of liposomal drugs to prostate cancer cells
Authors: Roth Audrey , Drummond Daryl C. , Conrad Fraser , Hayes Mark E. , Kirpotin Dmitri B. , Benz Christopher C. , Marks James D. , Liu Bin
Published: October 2007

Targeted delivery of small-molecule drugs has the potential to enhance selective killing of tumor cells. We have identified previously an internalizing single chain [single chain variable fragment (scFv)] antibody that targets prostate cancer cells and identified the target antigen as CD166. We report here the development of immunoliposomes using this anti-CD166 scFv (H3). We studied the effects of a panel of intracellularly delivered, anti-CD166 immunoliposomal small-molecule drugs on prostate cancer cells. Immunoliposomal formulations of topotecan, vinorelbine, and doxorubicin each showed efficient and targeted uptake by three prostate cancer cell lines (Du-145, PC3, and LNCaP). H3-immunoliposomal topotecan was the most effective in cytotoxicity assays on all three tumor cell lines, showing improved cytotoxic activity compared with nontargeted liposomal topotecan. Other drugs such as liposomal doxorubicin were highly effective against LNCaP but not PC3 or Du-145 cells, despite efficient intracellular delivery. Post-internalization events thus modulate the overall efficacy of intracellulary delivered liposomal drugs, contributing in some cases to the lower than expected activity in a cell line–dependent manner. Further studies on intracellular tracking of endocytosed liposomal drugs will help identify and overcome the barriers limiting the potency of liposomal drugs. [Mol Cancer Ther 2007;6(10):2737–46]
Thioredoxin-like domains required for glucose regulatory protein 58–mediated reductive activation of mitomycin C leading to DNA cross-linking
Authors: Adikesavan Anbu Karani , Jaiswal Anil K.
Published: October 2007

Glucose regulatory protein (GRP58) is known to mediate mitomycin C (MMC)–induced DNA cross-linking. However, the mechanism remains elusive. We hypothesized that thioredoxin-like domains, one at NH2 terminus and another at COOH terminus, are required for GRP58-mediated MMC reductive activation leading to DNA cross-linking. Site-directed mutagenesis mutated cysteines in thioredoxin domains to serines. Wild-type (WT) and mutant GRP58 were cloned in pcDNA to produce GRP58 V5-tagged WT and mutant proteins on transfection in mammalian cells. Human colon carcinoma (HCT116) cells transiently expressing and Chinese hamster ovary cells stably expressing WT and mutant GRP58 were analyzed for MMC-induced DNA cross-linking. WT GRP58 was highly efficient in MMC-induced DNA cross-linking. However, both NH2- and COOH-terminal thioredoxin mutants showed significant reduction in MMC-induced DNA cross-linking. The coexpression of GRP58 with thioredoxin reductase 1 and/or treatment of cells with NADPH increased MMC-induced DNA cross-linking from the WT GRP58. In similar experiments, siRNA inhibition of thioredoxin reductase 1 led to decreased MMC-induced DNA cross-linking. Further experiments revealed that mutations in thioredoxin domains led to significant decrease in metabolic reductive activation of MMC. These results led to conclusion that GRP58, through its two thioredoxin-like domains, functions as a reductase leading to bioreductive drug MMC activation and DNA cross-linking. [Mol Cancer Ther 2007;6(10):2719–27]
Honokiol causes G0-G1 phase cell cycle arrest in human prostate cancer cells in association with suppression of retinoblastoma protein level/phosphorylation and inhibition of E2F1 transcriptional activity
Authors: Hahm Eun-Ryeong , Singh Shivendra V.
Published: October 2007

The present study was undertaken to gain insights into the mechanism of cell cycle arrest caused by honokiol, a constituent of oriental herb Magnolia officinalis. The honokiol treatment decreased the viability of PC-3 and LNCaP human prostate cancer cells in a concentration- and time-dependent manner, which correlated with G0-G1 phase cell cycle arrest. The honokiol-mediated cell cycle arrest was associated with a decrease in protein levels of cyclin D1, cyclin-dependent kinase 4 (Cdk4), Cdk6, and/or cyclin E and suppression of complex formation between cyclin D1 and Cdk4 as revealed by immunoprecipitation using anti–cyclin D1 antibody followed by immunoblotting for Cdk4 protein. The honokiol-treated PC-3 and LNCaP cells exhibited a marked decrease in the levels of total and phosphorylated retinoblastoma protein (Rb), which correlated with the suppression of transcriptional activity of E2F1. Exposure of PC-3 and LNCaP cells to honokiol resulted in the induction of p21 (PC-3 and LNCaP) and p53 protein expression (LNCaP). However, small interfering RNA (siRNA)–mediated knockdown of either p21 (PC-3 and LNCaP) or p53 (LNCaP) protein failed to confer any protection against honokiol-induced cell cycle arrest. The honokiol treatment caused the generation of reactive oxygen species (ROS), and the cell cycle arrest caused by honokiol was partially but significantly attenuated in the presence of antioxidant N-acetylcysteine. In conclusion, the present study reveals that the honokiol-mediated G0-G1 phase cell cycle arrest in human prostate cancer cells is associated with the suppression of protein level/phosphorylation of Rb leading to inhibition of transcriptional activity of E2F1. [Mol Cancer Ther 2007;6(10):2686–95]
Molecular Biology of Bone Metastasis
Authors: Kingsley Lauren A. , Fournier Pierrick G.J. , Chirgwin John M. , Guise Theresa A.
Published: October 2007

Metastasis is a final stage of tumor progression. Breast and prostate cancer cells preferentially metastasize to bone, wherein they cause incurable osteolytic and osteoblastic lesions. The bone matrix is rich in factors, such as transforming growth factor-β and insulin-like growth factors, which are released into the tumor microenvironment by osteolysis. These factors stimulate the growth of tumor cells and alter their phenotype, thus promoting a vicious cycle of metastasis and bone pathology. Physical factors within the bone microenvironment, including low oxygen levels, acidic pH, and high extracellular calcium concentrations, may also enhance tumor growth. These elements of the microenvironment are potential targets for chemotherapeutic intervention to halt tumor growth and suppress bone metastasis. [Mol Cancer Ther 2007;6(10):2609–17]
Formyl peptide receptor-like 1–mediated endogenousTRAILgene expression with tumoricidal activity
Authors: Lin Chentao , Wei Wei , Zhang Jinchun , Liu Shilian , Liu Yanxin , Zheng Dexian
Published: October 2007

Formyl peptide receptor-like 1 (FPRL1), which is a G protein–coupled receptor of chemoattractant subfamily, plays an important role in the regulation of host defense against pathogenic infection and the chemotactic and activating effects of Aβ42 on mononuclear phagocytes as well as in the elimination of damaged or pathogen-infected cells. In the present study, we showed that stimulation of FPRL1 agonist ligands (W peptide from a synthetic peptide library, N36 peptide from HIV-1 gp41, and F peptide from HIV-1 envelope protein gp120) elevated endogenous tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) expression in human THP-1 monocytes, primary neutrophils, and mouse leukocytes. Activation of nuclear factor κB was required by the FPRL1-mediated TRAIL expression in the human THP-1 cells and primary neutrophils. The increased TRAIL expression in the mice significantly suppressed the growth of transplanted mouse liver tumor cells by inducing apoptotic cell death. Together, these data provide novel evidence for the physiologic role of FPRL1 and TRAIL in tumor immune surveillance and innate immunity, and implicate a novel strategy for cancer therapy by triggering the endogenous TRAIL expression via stimulation of G protein–coupled receptor FPRL1. [Mol Cancer Ther 2007;6(10):2618–25]
DNA sequence–selective adenine alkylation, mechanism of adduct repair, andin vivoantitumor activity of the novel achiralseco-amino-cyclopropylbenz[e]indolone analogue of duocarmycin AS-I-145
Authors: Kiakos Konstantinos , Sato Atsushi , Asao Tetsuji , McHugh Peter J. , Lee Moses , Hartley John A.
Published: October 2007

AS-I-145 is a novel achiral seco-amino-cyclopropylbenz[e]indolone (seco-amino-CBI) analogue of duocarmycin that has evolved from an alternative strategy of designing CC-1065/duocarmycin agents lacking the characteristic chiral center of the natural agents. The sequence specificity of this compound was assessed by a Taq polymerase stop assay, identifying the sites of covalent modification on plasmid DNA. The adenine-N3 adducts were confirmed at AT-rich sequences using a thermally induced strand cleavage assay. These studies reveal that this compound retains the inherent sequence selectivity of the related natural compounds. The AS-I-145 sensitivity of yeast mutants deficient in excision and post-replication repair (PRR) pathways was assessed. The sensitivity profile suggests that the sequence-specific adenine-N3 adducts are substrates for nucleotide excision repair (NER) but not base excision repair (BER). Single-strand ligation PCR was employed to follow the induction and repair of the lesions at nucleotide resolution in yeast cells. Sequence specificity was preserved in intact cells, and adduct elimination occurred in a transcription-coupled manner and was dependent on a functional NER pathway and Rad18. The involvement of NER as the predominant excision pathway was confirmed in mammalian DNA repair mutant cells. AS-I-145 showed good in vivo antitumor activity in the National Cancer Institute standard hollow fiber assay and was active against the human breast MDA-MD-435 xenograft when administered i.v. or p.o. Its novel structure and in vivo activity renders AS-I-145 a new paradigm in the design of novel achiral analogues of CC-1065 and the duocarmycins. [Mol Cancer Ther 2007;6(10):2708–18]
Carcinoma Arising from Brunner’s Gland in the Duodenum after 17 Years of Observation – A Case Report and Literature Review
Authors: Koizumi Masaru , Sata Naohiro , Yoshizawa Koji , Kurihara Katsumi , Yasuda Yoshikazu
Published: October 2007

A 60-year-old man presented with melena and hematemesis in 1984. Esophagogastroduodenoscopy (EGD) detected a small protruding lesion in the duodenal bulb, which was diagnosed as Brunner’s adenoma. No significant change was detected in subsequent annual EGD and biopsies for 10 years, after which the patient was not observed for 7 years. The patient presented with melena again in 2001. The lesion had changed shape to become a 10 mm sessile tumor with a central depression, and following a biopsy was diagnosed as an adenocarcinoma. The patient underwent partial resection of the duodenum. Histopathological assessment showed acidophilic cells with swollen nuclei, and clear cells forming a tubular or papillary tubule in the mucosal lamina propria and submucosal layer. The tumor cells stained positive for lysozyme, indicating that they arose from Brunner’s gland. The patient showed no sign of recurrence and was disease-free for more than 34 months after surgery. The patient died of pneumonia. This is an extremely rare case of primary duodenal carcinoma arising from Brunner’s gland in a patient observed for 17 years.
Pentoxifylline Suppresses Transduction by HIV-1-Based Vectors
Authors: Smith Johanna A. , Nunnari Giuseppe , Preuss Mirjam , Pomerantz Roger J. , Daniel René
Published: October 2007

Pentoxifylline, a caffeine-related compound, was shown to suppress human immunodeficiency virus type 1 (HIV-1) replication. This effect is thought to be mediated by inhibition of tumor necrosis factor-alpha (TNFα)-mediated long-terminal repeat (LTR)-driven expression. We now demonstrate that pentoxifylline efficiently inhibits transduction by HIV-1-based vectors. This latter effect is independent of LTR-driven expression, and correlates with a reduced efficiency of the completion of the integration process in infected cells. Finally, the effect of pentoxifylline is dramatically reduced in cells expressing a dominant negative ATR protein, and in primary human cells that exhibit low level of ATR activity, suggesting that the effect of pentoxifylline on HIV-1 transduction and replication is at least partly mediated by suppression of the ATR kinase.
Neuroimaging and Correlates of Cognitive Function among Patients with Heart Failure
Authors: Vogels Raymond L.C. , Oosterman Joukje M. , van Harten Barbera , Gouw Alida A. , Schroeder-Tanka Jutta M. , Scheltens Philip , van der Flier Wiesje M. , Weinstein Henry C.
Published: October 2007

Background/Aims: We purposed to investigate the relationship between cerebral abnormalities detected by magnetic resonance imaging (MRI) and cognitive performance in nondemented outpatients with heart failure (HF). Methods: In 58 patients with HF neuropsychological assessment was performed including tests of mental speed, executive functions, memory, language and visuospatial functions. Deep, periventricular and total white matter hyperintensities (WMH), lacunar and cortical infarcts, global and medial temporal lobe atrophy (MTA) were investigated on MRI of the brain. Correlations between MRI findings and the cognitive measures were calculated. Results: MTA correlated with memory (r = –0.353, p < 0.01), with executive functions (r = –0.383, p < 0.01) and the Mini Mental State Examination (r = –0.343, p < 0.05). Total WMH and deep WMH were found to correlate with depression and anxiety scores, but not with cognitive measures. Age, estimated premorbid intelligence and MTA were independent predictors of diminished cognitive performance. Conclusions: In HF patients, MTA was related to cognitive dysfunction, involving memory impairment and executive dysfunction, whereas WMH was related to depression and anxiety.
New Insights into the Role of Sigma Factor RpoS as Revealed in Escherichia coli Strains Lacking the Phosphoenolpyruvate:Carbohydrate Phosphotransferase System
Authors: Flores Noemí , Escalante Adelfo , de Anda Ramón , Báez-Viveros José Luis , Merino Enrique , Franco Bernardo , Georgellis Dimitris , Gosset Guillermo , Bolívar Francisco
Published: October 2007

It has been demonstrated that about 10% of the Escherichia coli genes are under direct or indirect control of RpoS. Therefore, Weber et al. [2005] proposed that this sigma subunit should be considered a second vegetative sigma factor under non-optimal growth conditions. In this report we demonstrate that in the phosphoenolpyruvate:carbohydrate phosphotransferase system-deficient (PTS–) derivatives, PB11 and PB12 of strain JM101 that permanently grow slowly on glucose, the inactivation of rpoS resulted in decreased growth rates of 50 and 10%, respectively. Real-time PCR (RT-PCR) analysis confirmed the important role of this sigma factor in the PTS– strains and allowed the identification of 19 genes including almost all the glycolytic genes, not previously reported, to be at least partially dependent on RpoS. The transcription level of gpp, spoT, ppa and ndk whose products are involved in ppGpp metabolism was upregulated in strain PB12 as compared to the parental strains PB11 and JM101. In the PTS– strains, at least three of these genes (gpp, spoT and ppa) were mainly or partially regulated by RpoS which is known to require ppGpp for activation, while only gpp was highly RpoS-dependent in the parental PTS+ strain JM101. The role of RpoS in the transcription of these genes was analyzed and evidence that the expression of this group of genes could be regulated by a common factor in addition to RpoS was discussed.
Subendothelial Lipoprotein Retention as the Initiating Process in Atherosclerosis
Authors: Tabas Ira , Williams Kevin Jon , Borén Jan
Published: October 2007

The key initiating process in atherogenesis is the subendothelial retention of apolipoprotein B–containing lipoproteins. Local biological responses to these retained lipoproteins, including a chronic and maladaptive macrophage- and T-cell–dominated inflammatory response, promote subsequent lesion development. The most effective therapy against atherothrombotic cardiovascular disease to date—low density lipoprotein–lowering drugs—is based on the principle that decreasing circulating apolipoprotein B lipoproteins decreases the probability that they will enter and be retained in the subendothelium. Ongoing improvements in this area include more aggressive lowering of low-density lipoprotein and other atherogenic lipoproteins in the plasma and initiation of low-density lipoprotein–lowering therapy at an earlier age in at-risk individuals. Potential future therapeutic approaches include attempts to block the interaction of apolipoprotein B lipoproteins with the specific subendothelial matrix molecules that mediate retention and to interfere with accessory molecules within the arterial wall that promote retention such as lipoprotein lipase, secretory sphingomyelinase, and secretory phospholipase A
2
. Although not the primary focus of this review, therapeutic strategies that target the proatherogenic responses to retained lipoproteins and that promote the removal of atherogenic components of retained lipoproteins also hold promise. The finding that certain human populations of individuals who maintain lifelong low plasma levels of apolipoprotein B lipoproteins have an ≈90% decreased risk of coronary artery disease gives hope that our further understanding of the pathogenesis of this leading killer could lead to its eradication.
Tropical Cyclone Intensification from Asymmetric Convection: Energetics and Efficiency
Authors: Nolan David S. , Moon Yumin , Stern Daniel P.
Published: October 2007

Prior studies of the linear response to asymmetric heating of a balanced vortex showed that the resulting intensity change could be very closely approximated by computing the purely symmetric response to the azimuthally averaged heating. The symmetric response to the purely asymmetric part of the heating was found to have a very small and most often negative impact on the intensity of the vortex. This result stands in contrast to many previous studies that used asymmetric vorticity perturbations, which suggested that purely asymmetric forcing could lead to vortex intensification.

The issue is revisited with an improved model and some new methods of analysis. The model equations have been changed to be more consistent with the anelastic approximation, but valid for a radially varying reference state. Expressions for kinetic and available potential energies are presented for both asymmetric and symmetric motions, and these are used to quantify the flow of energy from localized, asymmetric heat sources to kinetic energy of the wind field of the symmetric vortex.

Previous conclusions were based on simulations that used instantaneous temperature perturbations to represent rapid heat release in cumulus updrafts. Purely asymmetric heat sources that evolve over time and move with the local mean wind are shown to also cause vortex weakening. Weakening of the symmetric vortex is due to extraction of energy by the evolving asymmetries that undergo significant transient growth due to downgradient transport of momentum across the radial and vertical shears of the symmetric wind field. While much of this energy is returned during the axisymmetrization of the resulting potential vorticity anomalies, there is typically a net loss of energy for the symmetric vortex. Some variations on the rotation rate and duration of the heat sources can lead to intensification rather than weakening, as does a deeper (more barotropic) vertical structure of the symmetric vortex. However, it is reaffirmed that these asymmetrically forced changes are small compared to the response to the azimuthally averaged heating of an isolated heat source.

Following the work of Hack and Schubert, the efficiency of the intensification process, defined as the ratio of injected heat energy to the kinetic energy change of the symmetric vortex, is computed for vortices of different sizes and strengths. In the limit of small perturbations, the efficiency does not depend on the temporal distribution of the heating. The efficiency is shown to increase with the intensity of the vortex and with the Coriolis parameter, with substantial efficiency increases for weak vortices. Potential applications of these results for predicting tropical cyclone formation and rapid development are discussed.
A Coupled Atmosphere–Ocean Radiative Transfer System Using the Analytic Four-Stream Approximation
Authors: Lee Wei-Liang , Liou K. N.
Published: October 2007

A coupled atmosphere–ocean radiative transfer model based on the analytic four-stream approximation has been developed. It is shown that this radiation model is computationally efficient and at the same time can achieve acceptable accuracy for flux and heating rate calculations in the atmosphere and the oceans. To take into account the reflection and transmission of the wind-blown air–water interface, a Monte Carlo method has been employed to simulate the traveling of photons and to compute the reflectance and transmittance of direct and diffuse solar fluxes at the ocean surface. For the ocean part, existing bio-optical models, which correlate the concentration of chlorophyll and the absorption and scattering coefficients of phytoplankton and other matters, have been integrated into this coupled model. Comparing to the values computed by more discrete streams illustrates that the relative accuracies of the surface albedo and total transmission in the ocean determined from the present model are generally within 5%, except in cases of the solar zenith angle larger than 80°. Observational data have also been used to validate this model and the results show that the relative differences of downward and upward shortwave fluxes and albedo are within 10% of the observed values. This computationally efficient and physically based radiative transfer model is well suited for consistent flux calculations in a coupled atmosphere–ocean dynamic system.
Convectively Coupled Equatorial Waves. Part I: Horizontal and Vertical Structures
Authors: Yang Gui-Ying , Hoskins Brian , Slingo Julia
Published: October 2007

Multilevel 15-yr ECMWF Re-Analysis (ERA-15) and satellite-observed brightness temperature (Tb) data for the period May–October 1992 are used to examine the horizontal and vertical structures of convectively coupled equatorial waves. Dynamical waves are isolated using a methodology developed previously. Composite structures of convectively coupled equatorial waves are obtained using linear regression/correlation between convection (Tb) and dynamical structures. It is found that the relationship depends on the ambient flow and the nature of the convective coupling, and varies between off-equatorial- and equatorial-centered convection, different hemispheres, and seasons.

The Kelvin wave structure in the Western Hemisphere is generally consistent with classic equatorial wave theory and has its convection located in the region of low-level convergence. In the Eastern Hemisphere the Kelvin wave tends to have convection in the region of enhanced lower-tropospheric westerlies and a tilted vertical structure. The Kelvin wave also tends to have a third peak in zonal wind amplitude at 500 hPa and exhibits upward propagation into the lower stratosphere. Lower-tropospheric westward-moving mixed Rossby–gravity (WMRG) and n = 1 Rossby (R1) wave structures and their relationship with convection are consistent with classic equatorial wave theory and the implied lower-tropospheric convergences. In the Eastern Hemisphere the WMRG and R1 waves have first baroclinic mode structures in the vertical. However, in the Western Hemisphere, the R1 wave has a barotropic structure. In the Eastern Hemisphere the R1 wave, like the Kelvin wave, tends to have equatorial convection in the region of enhanced lower-level westerlies, suggesting that enhanced surface energy fluxes associated with these waves may play an important organizing role for equatorial convection in this warm-water hemisphere.

In the upper troposphere, eastward-moving Rossby–gravity (EMRG) and n = 1 gravity waves are found in the Eastern Hemisphere, and eastward-moving WMRG and R1 waves are found in the Western Hemisphere, suggestive of Doppler shifting of waves by the ambient flow.
Evidence of Tropical Forcing of the 6.5-Day Wave from Lightning Observations over Africa
Authors: Chronis Themis G. , Williams Earle , Anagnostou Emmanouil N.
Published: October 2007

A study employing observations and climatic reanalysis data is concerned with links between convection and the well-documented 6.5-day stratospheric global wave. Observations from a long-range lightning detection network, known as ZEUS, reveal an in-phase behavior between the maximization of daily lightning activity over Africa and the intensification of the wave. To extend the observations on a climatological basis, the authors make use of the outgoing longwave radiation (OLR) as proxy for convection and the surface level pressure (SLP) as an indicator of atmospheric column forcing. Cross-spectral analysis shows significant peaks in coherency between OLR and SLP, apparent only over equatorial Africa and South America (Amazon basin), while strong coherency in this frequency band is absent over the Maritime Continent.
Reduced Atmospheric Models Using Dynamically Motivated Basis Functions
Authors: Kwasniok Frank
Published: October 2007

Nonlinear deterministic reduced models of large-scale atmospheric dynamics are constructed. The dynamical framework is a quasigeostrophic three-level spectral model with realistic mean state and variability as well as Pacific–North America (PNA) and North Atlantic Oscillation (NAO) patterns. The study addresses the problem of finding appropriate basis functions for efficiently capturing the dynamics and a comparison between different choices of basis functions; it focuses on highly truncated models, keeping only 10–15 modes. The reduced model is obtained by a projection of the equations of motion onto a truncated basis spanned by empirically determined modes. The total energy metric is used in the projection; the nonlinear terms of the low-order model then conserve total energy. Apart from retuning the coefficient of horizontal diffusion, no empirical terms are fitted in the dynamical equations of the low-order model in order to properly preserve the physics of the system. Using the methodology of principal interaction patterns (PIPs), a basis is derived that carefully compromises minimizing tendency error with maximizing explained variance in the resolved modes. A new PIP algorithm is introduced that is more compact and robust than earlier PIP algorithms; a top-down approach is adopted, removing modes from the system one by one.

The mean state and standard deviation of the streamfunction as well as transient momentum fluxes are well reproduced by a PIP model with only 10 modes. Probability density functions are accurately modeled and autocorrelation functions are captured fairly well using 15 modes. Reduced models based on PIPs are substantially superior to reduced models based on empirical orthogonal functions (EOFs). The leading PIPs have a higher projection onto the PNA and NAO teleconnection patterns than the corresponding EOFs. Both with EOFs and PIPs, the interactions between the resolved modes are predominantly linear and the improvement of PIP models on EOF models stems entirely from better modeling these linear interactions although the full nonlinear tendencies are optimized. There is considerable influence of smaller-scale modes on the large-scale modes due to nonlinear coupling that is not well captured by either EOFs or PIPs. This nonlinear backscattering possibly plays a role in generating the low-frequency variability of the model. The results call for a nonlinear and/or stochastic closure scheme in which PIPs may be suitable basis functions.
Dynamics of Orographically Triggered Banded Convection in Sheared Moist Orographic Flows
Authors: Fuhrer Oliver , Schär Christoph
Published: October 2007

Shallow orographic convection embedded in an unstable cap cloud can organize into convective bands. Previous research has highlighted the important role of small-amplitude topographic variations in triggering and organizing banded convection. Here, the underlying dynamical mechanisms are systematically investigated by conducting three-dimensional simulations of moist flows past a two-dimensional mountain ridge using a cloud-resolving numerical model. Most simulations address a sheared environment to account for the observed wind profiles. Results confirm that small-amplitude topographic variations can enhance the development of embedded convection and anchor quasi-stationary convective bands to a fixed location in space. The resulting precipitation patterns exhibit tremendous spatial variability, since regions receiving heavy rainfall can be only kilometers away from regions receiving little or no rain. In addition, the presence of banded convection has important repercussions on the area-mean precipitation amounts.

For the experimental setup here, the gravity wave response to small-amplitude topographic variations close to the upstream edge of the cap cloud (which is forced by the larger-scale topography) is found to be the dominant triggering mechanism. Small-scale variations in the underlying topography are found to force the location and spacing of convective bands over a wide range of scales. Further, a self-sufficient mode of unsteady banded convection is investigated that does not dependent on external perturbations and is able to propagate against the mean flow. Finally, the sensitivity of model simulations of banded convection with respect to horizontal computational resolution is investigated. Consistent with predictions from a linear stability analysis, convective bands of increasingly smaller scales are favored as the horizontal resolution is increased. However, small-amplitude topographic roughness is found to trigger banded convection and to control the spacing and location of the resulting bands. Thereby, the robustness of numerical simulations with respect to an increase in horizontal resolution is increased in the presence of topographic variations.
Forced Annular Mode Patterns in a Simple Atmospheric General Circulation Model
Authors: Ring Michael J. , Plumb R. Alan
Published: October 2007

Previous studies using simplified general circulation models have shown that “annular modes” arise as the dominant mode of variability. A simple GCM is used here to explore to what extent these modes are also the preferred response of the system to generic forcing.

A number of trials are conducted under which the model is subjected to an artificial, zonally symmetric angular momentum forcing, and the climatologies of these trials are compared to that of the control. The forcing location is varied among the several trials. It is found that the changes in the model’s climatology are generally annular mode–like, as long as the imposed forcing projects strongly upon the annular modes of the unforced model.

The role of changes to the eddy–zonal flow feedback versus the action of direct forcing is also considered through the use of a zonally symmetric version of the model. It is found that the direct responses to forcing are insufficient to capture either the strength or the structure of the annular mode responses. Instead, the changes in eddy fluxes are needed to produce the correct responses.