bluuebunny/crossref_metadata_2025_split huggingface dataset:
Amphiregulin Contributes to the Transformed Phenotype of Human Hepatocellular Carcinoma Cells
Authors: Castillo Josefa , Erroba Elena , Perugorría María J. , Santamaría Mónica , Lee David C. , Prieto Jesús , Avila Matías A. , Berasain Carmen 
Published: June 2006

Abstract
Hepatocellular carcinoma is a major cause of cancer-related deaths. Current treatments are not effective, and the identification of relevant pathways and novel therapeutic targets are much needed. Increasing evidences point to the activation of the epidermal growth factor receptor (EGFR) as an important mechanism in the development of hepatocarcinoma. We previously described that amphiregulin (AR), a ligand of the EGFR, is not expressed in healthy liver but is up-regulated during chronic liver injury, the background on which most liver tumors develop. Now, we have studied the expression and role of AR in human hepatocarcinoma. AR expression and function was studied in human liver tumors and cell lines. AR is expressed in human hepatocellular carcinoma tissues and cell lines and behaves as a mitogenic and antiapoptotic growth factor for hepatocarcinoma cells. We provide several lines of evidence, including AR silencing by small interfering RNAs and inhibition of amphiregulin by neutralizing antibodies, showing the existence of an AR-mediated autocrine loop that contributes to the transformed phenotype. Indeed, interference with endogenous AR production resulted in reduced constitutive EGFR signaling, inhibition of cell proliferation, anchorage-independent growth, and enhanced apoptosis. Moreover, knockdown of AR potentiated transforming growth factor-β and doxorubicin-induced apoptosis. Conversely, overexpression of AR in SK-Hep1 cells enhanced their proliferation rate, anchorage-independent growth, drug resistance, and in vivo tumorigenic potential. These observations suggest that AR is involved in the acquisition of neoplastic traits in the liver and thus constitutes a novel therapeutic target in human hepatocarcinoma. (Cancer Res 2006; 66(12): 6129-38)
Ras Stimulation of E2F Activity and a Consequent E2F Regulation of Integrin α6β4 Promote the Invasion of Breast Carcinoma Cells
Authors: Yoon Sang-Oh , Shin Sejeong , Mercurio Arthur M. 
Published: June 2006

Abstract
Active Ras proteins contribute to breast carcinogenesis and progression. Here, we provide evidence that active H-Ras regulates the expression and activity of the E2F family of transcription factors in SUM-159 breast carcinoma cells. In addition, we show by using a DNA-binding mutant of E2F, as well as expression of specific E2Fs that are transcriptionally active, that the active E2Fs1-3 can mediate the H-Ras-dependent invasion of SUM-159 cells. The inhibitory E2Fs4-5, in contrast, do not influence invasion. One mechanism by which the active E2Fs promote H-Ras-dependent invasion seems to be their ability to increase expression of the β4 integrin subunit, a component of the α6β4 integrin that is known to enhance carcinoma invasion. Specifically, expression of E2Fs1-3 increased β4 mRNA, protein, and cell surface expression. The active E2Fs were unable to stimulate invasion in cells that expressed a β4 short hairpin RNA. This effect of the active E2Fs on β4 expression does not seem to result from E2F-mediated β4 transcription because the β4 promoter lacks known E2F binding motifs. In summary, the data reported here indicate a novel mechanism by which H-Ras can promote the invasion of breast carcinoma cells. This mechanism links active H-Ras, transcriptionally active E2F, and the α6β4 integrin in a common pathway that culminates in enhanced α6β4-dependent invasion. (Cancer Res 2006; 66(12): 6288-95)
Tal1 Transgenic Expression Reveals Absence of B Lymphocytes
Authors: Palamarchuk Alexey , Zanesi Nicola , Aqeilan Rami I. , Efanov Alexey , Maximov Vadim , Santanam Urmila , Hagan John P. , Croce Carlo M. , Pekarsky Yuri 
Published: June 2006

Abstract
TAL1 oncogene encodes a helix-loop-helix transcription factor, Tal1, which is required for blood cell development, and its activation is a frequent event in T-cell acute lymphoblastic leukemia. Tal1 interacts and inhibits other helix-loop-helix factors such as E47 and HEB. To investigate the function of Tal1 in B cells, we generated Eμ-TAL1 transgenic mouse line, expressing Tal1 in mouse B-cell lineage. Fluorescence-activated cell sorting (FACS) analysis of lymphocytes isolated from spleens of five out of five founders reveals complete absence of IgM- or CD19-expressing cells. Only 2% to 3% of these cells were B220+ and 100% of B220+ cells were CD43+, indicating that these mice were able to make pro-B cells. Similarly, FACS analysis of bone marrow cells in Eμ-TAL1 mice revealed complete absence of B220+IgM+ and B220+CD19+ cells. Analysis of the recombination status of IgH genes revealed the presence of D-J but absence or drastic reduction of V-D-J rearrangements. Our results suggest that Tal1 overexpression in B cells results in a phenotype similar to that of B cells of E47/E2A knockout animals. This represents first in vivo evidence that Tal1 can completely inhibit E47/E2A function. (Cancer Res 2006; 66(12): 6014-7)
R-253 Disrupts Microtubule Networks in Multiple Tumor Cell Lines
Authors: Gururaja Tarikere L. , Goff Dane , Kinoshita Taisei , Goldstein Eileen , Yung Stephanie , McLaughlin John , Pali Erlina , Huang Jianing , Singh Rajinder , Daniel-Issakani Sarkiz , Hitoshi Yasumichi , Cooper R.D.G. , Payan Donald G. 
Published: June 2006

Abstract
Purpose: The design and development of synthetic small molecules to disrupt microtubule dynamics is an attractive therapeutic strategy for anticancer drug discovery research. Loss of clinical efficacy of many useful drugs due to drug resistance in tumor cells seems to be a major hurdle in this endeavor. Thus, a search for new chemical entities that bind tubulin, but neither are a substrate of efflux pump, P-glycoprotein 170/MDR1, nor cause undesired side effects, would potentially increase the therapeutic index in certain cancer treatments.
Experimental Design: A high-content cell-based screen of a compound library led to the identification of a new class of compounds belonging to a thienopyrimidine series, which exhibited significant antitumor activities. On structure-activity relationship analysis, R-253 [N-cyclopropyl-2-(6-(3,5-dimethylphenyl)thieno[3,2-d]pyrimidin-4-yl)hydrazine carbothioamide] emerged as a potent antiproliferative agent (average EC50, 20 nmol/L) when examined in a spectrum of tumor cell lines.
Results: R-253 is structurally unique and destabilizes microtubules both in vivo and in vitro. Standard fluorescence-activated cell sorting and Western analyses revealed that the effect of R-253 on cell growth was associated with cell cycle arrest in mitosis, increased select G2-M checkpoint proteins, and apoptosis. On-target activity of R-253 on microtubules was further substantiated by immunofluorescence studies and selected counter assays. R-253 competed with fluorescent-labeled colchicine for binding to tubulin, indicating that its binding site on tubulin could be similar to that of colchicine. R-253 neither is a substrate of P-glycoprotein 170/MDR1 nor is cytotoxic to nondividing human hepatocytes.
Conclusion: Both biochemical and cellular mechanistic studies indicate that R-253 could become a promising new tubulin-binding drug candidate for treating various malignancies.
Parthenolide Cooperates with NS398 to Inhibit Growth of Human Hepatocellular Carcinoma Cells through Effects on Apoptosis and G0-G1 Cell Cycle Arrest
Authors: Ralstin Matthew C. , Gage Earl A. , Yip-Schneider Michele T. , Klein Patrick J. , Wiebke Eric A. , Schmidt C. Max 
Published: June 2006

AbstractChemotherapy to date has not been effective in the treatment of human hepatocellular carcinoma. More effective treatment strategies may involve combinations of agents with activity against hepatocellular carcinoma. Parthenolide, a nuclear factor-κB (NF-κB) inhibitor, and NS398, a cyclooxygenase (COX)-2 inhibitor, have been shown to individually suppress the growth of hepatocellular carcinoma cells in vitro. To investigate their effects in combination, three human hepatocellular carcinoma lines (Hep3B, HepG2, and PLC) were treated with parthenolide and/or NS398. Parthenolide (0.1-10 μmol/L) and NS398 (1-100 μmol/L) each caused concentration-dependent growth inhibition in all cell lines. The addition of parthenolide to NS398 reduced the concentration of NS398 required to inhibit hepatocellular carcinoma growth. Because parthenolide and COX-2 inhibitors have been reported to influence NF-κB activity, the effects on this pathway were investigated. The combination of parthenolide/NS398 inhibited phosphorylation of the NF-κB-inhibitory protein IκBα and increased total IκBα levels. NF-κB DNA-binding and transcriptional activities were inhibited more by the combination than the single agents in Hep3B and HepG2 cells but not in PLC cells. The response of PLC cells to NS398 was augmented by p65 small interfering RNA to inhibit NF-κB p65 protein expression. The combination of parthenolide/NS398 increased apoptosis only in PLC cells, suggesting that the combination may decrease the apoptotic threshold in these cells. In Hep3B and HepG2 cells, combination treatment with NS398/parthenolide altered the cell cycle distribution resulting in more G0-G1 accumulation. Cyclin D1 levels were further decreased by combination treatment in all cell lines, correlating with the cell cycle alterations. Our results suggest that parthenolide may be effective in combination with COX-2 inhibitors for the treatment of hepatocellular carcinoma. (Mol Cancer Res 2006;4(6):387–400)
Oxytocin Induces Proliferation and Migration in Immortalized Human Dermal Microvascular Endothelial Cells and Human Breast Tumor-Derived Endothelial Cells
Authors: Cassoni Paola , Marrocco Tiziana , Bussolati Benedetta , Allia Elena , Munaron Luca , Sapino Anna , Bussolati Gianni 
Published: June 2006

Abstract
Oxytocin either increases or inhibits cell growth in different cell subtypes. We tested here the effect of oxytocin on cell proliferation and migration of human dermal microvascular endothelial cells (HMEC) and tumor-associated endothelial cells purified from human breast carcinomas (B-TEC). Oxytocin receptors were expressed in both cell subtypes at mRNA and protein levels. Through oxytocin receptor, oxytocin (1 nmol/L-1 μmol/L) significantly increased cell proliferation and migration in both HMEC and B-TEC, and addition of a selective oxytocin antagonist fully reverted these effects. To verify whether a different expression of adhesion molecule-related genes could be responsible for the oxytocin-induced cell migration, untreated and treated cells were compared applying a microarray technique. In HMEC, oxytocin induced the overexpression of the matrix metalloproteinase (MMP)-17, cathepsin D, and integrin β6 genes. In B-TEC, oxytocin significantly switched on the gene profile of some MMP (MMP-11 and MMP-26) and of integrin β6. The up-regulation of the integrin β6 gene could be involved in the oxytocin-induced cell growth, because this subunit is known to determine activation of mitogen-activated protein kinase-extracellular signal-regulated kinase 2, which is involved in the oxytocin mitogenic effect. In B-TEC, oxytocin also increased the expression of caveolin-1 at gene and protein levels. Because oxytocin receptor localization within caveolin-1-enriched membrane domains is necessary for activation of the proliferative (instead of the inhibitory) response to oxytocin, its enhanced expression can be involved in the oxytocin-induced B-TEC growth as well. Altogether, these data indicate that oxytocin contributes to cell motility and growth in HMEC and B-TEC. (Mol Cancer Res 2006;4(6):351–9)
Dynamics of Biweekly Oscillations in the Equatorial Indian Ocean*
Authors: Miyama Toru , McCreary Julian P. , Sengupta Debasis , Senan Retish 
Published: June 2006

Abstract
Variability of the wind field over the equatorial Indian Ocean is spread throughout the intraseasonal (10–60 day) band. In contrast, variability of the near-surface υ field in the eastern, equatorial ocean is concentrated at biweekly frequencies and is largely composed of Yanai waves. The excitation of this biweekly variability is investigated using an oceanic GCM and both analytic and numerical versions of a linear, continuously stratified (LCS) model in which solutions are represented as expansions in baroclinic modes. Solutions are forced by Quick Scatterometer (QuikSCAT) winds (the model control runs) and by idealized winds having the form of a propagating wave with frequency σ and wavenumber kw. The GCM and LCS control runs are remarkably similar in the biweekly band, indicating that the dynamics of biweekly variability are fundamentally linear and wind driven. The biweekly response is composed of local (nonradiating) and remote (Yanai wave) parts, with the former spread roughly uniformly along the equator and the latter strengthening to the east. Test runs to the numerical models separately forced by the τx and τy components of the QuikSCAT winds demonstrate that both forcings contribute to the biweekly signal, the response forced by τy being somewhat stronger. Without mixing, the analytic spectrum for Yanai waves forced by idealized winds has a narrowband (resonant) response for each baroclinic mode: Spectral peaks occur whenever the wavenumber of the Yanai wave for mode n is sufficiently close to kw and they shift from biweekly to lower frequencies with increasing modenumber n. With mixing, the higher-order modes are damped so that the largest ocean response is restricted to Yanai waves in the biweekly band. Thus, in the LCS model, resonance and mixing act together to account for the ocean's favoring the biweekly band. Because of the GCM's complexity, it cannot be confirmed that vertical mixing also damps its higher-order modes; other possible processes are nonlinear interactions with near-surface currents, and the model's low vertical resolution below the thermocline. Test runs to the LCS model show that Yanai waves from several modes superpose to form a beam (wave packet) that carries energy downward as well as eastward. Reflections of such beams from the near-surface pycnocline and bottom act to maintain near-surface energy levels, accounting for the eastward intensification of the near-surface, equatorial υ field in the control runs.
Numerical Investigation of Solitary Internal Wave-Induced Global Instability in Shallow Water Benthic Boundary Layers
Authors: Diamessis Peter J. , Redekopp Larry G. 
Published: June 2006

Abstract
The time-dependent boundary layer induced by a weakly nonlinear solitary internal wave in shallow water is examined through direct numerical simulation. Waves of depression and elevation are both considered. The mean density field corresponds to that typical of the coastal ocean and lakes where the lower fraction of the water column is subject to the stabilizing effect of a diffuse stratification. Sufficient resolution of the “inviscid” dynamics of the boundary layer is ensured through use of a Legendre spectral multidomain discretization scheme in the vertical direction. At higher Reynolds numbers, where the simulations become underresolved, because of restrictions in available computational resources, spectral accuracy and numerical stability at the scales of physical interest are preserved through use of a penalty scheme in the vertical and explicit spectral filtering. Thus, a highly accurate description of the qualitative dynamics of the wave-induced global instability is possible and finescale physical mechanisms critical to the appearance of this instability are not smeared out by the high artificial dissipation inherent in lower-order finite-difference schemes. Results indicate that, for a wave amplitude exceeding a critical value, the global instability occurs in regions near the bottom boundary where the wave induces an adverse pressure gradient. The structure of the associated separation bubble is modified through the establishment of coherent and synchronous dynamics, characterized by elevated levels of bottom shear stress and a periodic shedding of coherent vortex structures. Although details of the vortex shedding depend on the particular wave forcing involved, these vortical structures always ascend high into the water column. All findings suggest that this global instability is a potent mechanism for benthic turbulence, mixing, and possible sediment resuspension in shallow waters, presumably even more intense than the nominal turbulent boundary layer.
A Modeling Study of the Impact of Tropical Instability Waves on the Heat Budget of the Eastern Equatorial Pacific
Authors: Menkes Christophe E. R. , Vialard Jérôme G. , Kennan Sean C. , Boulanger Jean-Philippe , Madec Gurvan V. 
Published: June 2006

Abstract
A numerical simulation is used to investigate the mixed layer heat balance of the tropical Pacific Ocean including the equatorial cold tongue and the region of vortices associated with tropical instability waves (TIWs). The study is motivated by a need to quantify the effects that TIWs have on the climatological heat budget of the cold tongue mixed layer; there has been some discrepancy between observations indicating very large equatorward heat transport by TIWs and models that disagree on the full three-dimensional budget. Validation of the model reveals that the TIW-induced circulation patterns are realistic but may have amplitudes about 15% weaker than those in the observations. The SST budget within tropical instabilities is first examined in a frame of reference moving with the associated tropical instability vortices (TIVs). Zonal advection of temperature anomalies and meridional advection of temperature by current anomalies dominate horizontal advection. These effects strongly heat the cold cusps and slightly cool the downwelling areas located at the leading edge of the vortices. Cooling by vertical mixing is structured at the vortex scale and almost compensates for horizontal advective heating in the cold cusps. In contrast to some previous studies, TIW-induced vertical advection is found to be negligible in the SST budget. Cooling by this term is only significant below the mixed layer. The effect of TIWs on the climatological heat budget is then investigated for the region bounded by 2°S–6°N, 160°–90°W, where instabilities are most active. TIW-induced horizontal advection leads to a warming of 0.84°C month−1, which is of the same order as the 0.77°C month−1 warming effect of atmospheric fluxes, while the mean currents and vertical mixing cool the upper ocean by −0.59°C month−1 and −1.06°C month−1, respectively. The cooling effect of TIW-induced vertical advection is also negligible in the long-term surface layer heat budget and only becomes significant below the mixed layer. The results above, and in particular the absence of cancellation between horizontal and vertical TIW-induced eddy advection, are robust in three other sensitivity experiments involving different mixing parameterizations and increased vertical resolution.
Effect of smoking cessation on cough reflex sensitivity
Authors: Dicpinigaitis P. V. , Sitkauskiene B. , Stravinskaite K. , Appel D. W. , Negassa A. , Sakalauskas R. 
Published: June 2006

Recent studies have shown that cigarette smokers have diminished cough reflex sensitivity compared with nonsmokers. The current authors proposed a mechanism of chronic cigarette smoke-induced desensitisation of airway cough receptors.To investigate this hypothesis, cough sensitivity to inhaled capsaicin (C5) in chronic smokers was measured both while they were actively smoking and 2, 6, 12 and 24 weeks after smoking cessation.In total, 29 subjects underwent baseline capsaicin challenge while smoking and 2 weeks after smoking cessation. Mean±semlog C5fell from 1.86±0.12 to 1.60±0.12, demonstrating significant enhancement of cough reflex sensitivity. Of the total, 20, 18 and 14 subjects successfully abstained from smoking for 6, 12 and 24 weeks, respectively. Mean log C5values after 12 and 24 weeks of smoking cessation were significantly diminished from baseline. In a control group of smokers, mean log C5did not decrease from baseline after 6, 12 and 24 weeks. Overall, the log C5profile of the smoking cessation group showed a clear, linearly decreasing trend over time compared with the control group.Even after many years of smoking, cough sensitivity is enhanced as early as 2 weeks after smoking cessation. Given the importance of an intact cough reflex, these changes may provide clinical benefit.
Transcriptome analysis of Deinagkistrodon acutus venomous gland focusing on cellular structure and functional aspects using expressed sequence tags
Authors: Zhang Bing , Liu Qinghua , Yin Wei , Zhang Xiaowei , Huang Yijun , Luo Yingfeng , Qiu Pengxin , Su Xingwen , Yu Jun , Hu Songnian , Yan Guangmei 
Published: June 2006

Abstract

Background
The snake venom gland is a specialized organ, which synthesizes and secretes the complex and abundant toxin proteins. Though gene expression in the snake venom gland has been extensively studied, the focus has been on the components of the venom. As far as the molecular mechanism of toxin secretion and metabolism is concerned, we still knew a little. Therefore, a fundamental question being arisen is what genes are expressed in the snake venom glands besides many toxin components?

Results
To examine extensively the transcripts expressed in the venom gland of Deinagkistrodon acutus and unveil the potential of its products on cellular structure and functional aspects, we generated 8696 expressed sequence tags (ESTs) from a non-normalized cDNA library. All ESTs were clustered into 3416 clusters, of which 40.16% of total ESTs belong to recognized toxin-coding sequences; 39.85% are similar to cellular transcripts; and 20.00% have no significant similarity to any known sequences. By analyzing cellular functional transcripts, we found high expression of some venom related genes and gland-specific genes, such as calglandulin EF-hand protein gene and protein disulfide isomerase gene. The transcripts of creatine kinase and NADH dehydrogenase were also identified at high level. Moreover, abundant cellular structural proteins similar to mammalian muscle tissues were also identified. The phylogenetic analysis of two snake venom toxin families of group III metalloproteinase and serine protease in suborder Colubroidea showed an early single recruitment event in the viperids evolutionary process.

Conclusion
Gene cataloguing and profiling of the venom gland of Deinagkistrodon acutus is an essential requisite to provide molecular reagents for functional genomic studies needed for elucidating mechanisms of action of toxins and surveying physiological events taking place in the very specialized secretory tissue. So this study provides a first global view of the genetic programs for the venom gland of Deinagkistrodon acutus described so far and an insight into molecular mechanism of toxin secreting.
All sequences data reported in this paper have been submitted into the public database [GenBank: DV556511-DV565206].