bluuebunny/crossref_metadata_2025_split huggingface dataset:
Temporal factors control hippocampal contributions to fear renewal after extinction
Authors: Zelikowsky Moriel , Pham Daniel L. , Fanselow Michael S. 
Published: May 2011

AbstractFear can be extinguished by repeated exposure to a cue that signals threat. However, extinction does not erase fear, as an extinguished cue presented in a context distinct from that of extinction results in renewed fear of that cue. The hippocampus, which is involved in the formation of contextual representations, is a natural candidate structure for investigations into the neural circuitry underlying fear renewal. Thus far, studies examining the necessity of the hippocampus for fear renewal have produced mixed results. We isolated the conditions under which the hippocampus may be required for renewal. Rats received lesions of the dorsal hippocampus either prior to tone fear conditioning or following extinction. Fear renewal was measured using discrete tone presentations or a long, continuous tone. The topography of fear responding at test was assessed by comparing “early” and “sustained” renewal, where early fear was determined by freezing to the first discrete tone or the equivalent initial segment of a continuous tone and sustained fear was determined by freezing averaged across all discrete tones or the entire continuous tone. We found that following pretraining damage of the hippocampus, early renewal remained intact regardless of lesion condition. However, sustained renewal only persisted in discrete, but not continuous, tone‐tested animals. A more extensive analysis of the topography of fear responding revealed that the disruption of renewal was generated when the tone duration at test began to violate that used during extinction, suggesting that the hippocampus is sensitive to mismatches in CS‐duration. Postextinction lesions resulted in an overall reduction of fear renewal. This pattern of results is consistent with those observed for contextual fear conditioning, wherein animals display a resistance to anterograde amnesia despite the presence of a strong retrograde amnesia for the same contextual information. Furthermore, the data support a role for the hippocampus in sustaining renewal when the CS duration at test does not match that used during extinction. © 2011 Wiley Periodicals, Inc.
Proteins linked to spatial memory formation of CD1 mice in the multiple T‐maze
Authors: Patil Sudarshan S. , Li Kongzhao , Heo Seok , Höger Harald , Lubec Gert 
Published: May 2011

AbstractIn own previous work CD1 mice were tested in the Multiple T‐maze (MTM), a robust land maze allowing determination of latency to reach the goal box with food reward and to evaluate correct decisions made on the way to the goal box. Herein, hippocampi of these animals were used for the current study with the aim to investigate differences in protein levels between trained and yoked mice and, moreover, to determine differences in protein levels between trained and yoked mice with and without memory formation in the MTM. Three training sessions were carried out for four training days each, followed by probe trials on Days 5 and 12. Good and no‐performers in the MTM were separated based on means and median of latency to reach the goal box on probe trial Day 12. Six hours following the probe trial on Day 12, animals were sacrificed and hippocampi were taken. Proteins were extracted and run on two‐dimensional gel electrophoresis, spots were quantified and differentially expressed proteins were identified by mass spectrometry using an ion trap. Levels of 17 proteins were significantly different in trained vs. yoked mice. Seven proteins were differentially expressed comparing trained vs. yoked mice from good and no‐performers. A series of proteins were significantly correlated with latency and may link these proteins to spatial memory formation. Differential protein expression in trained vs. yoked mice and in good and no‐performers may allow insight into spatial memory formation as well as represent tentative pharmacological targets. © 2011 Wiley Periodicals, Inc.
Inhibition of VEGF induces cellular senescence in colorectal cancer cells
Authors: Hasan Mohammad R. , Ho Shirley H. Y. , Owen David A. , Tai Isabella T. 
Published: May 2011

AbstractVascular endothelial growth factor (VEGF) inhibitors, such as bevacizumab, have improved outcomes in metastatic colorectal cancer (CRC). Recent studies have suggested that VEGF can delay the onset of cellular senescence in human endothelial cells. As VEGF receptors are known to be upregulated in CRC, we hypothesized that VEGF inhibition may directly influence cellular senescence in this disease. In our study, we observed that treatment with bevacizumab caused a significant increase (p < 0.05) in cellular senescence in vitro in several CRC cells, such as MIP101, RKO, SW620 and SW480 cells, compared to untreated or human IgG‐treated control cells. Similar results were also obtained from cells treated with a VEGFR2 kinase inhibitor Ki8751. In vivo, cellular senescence was detected in MIP101 tumor xenografts from 75% of mice treated with bevacizumab, while cellular senescence was undetectable in xenografts from mice treated with saline or human IgG (p < 0.05). Interestingly, we also observed that the proportion of senescent cells in colon cancer tissues obtained from patients treated with bevacizumab was 4.4‐fold higher (p < 0.01) than those of untreated patients. To understand how VEGF inhibitors may regulate cellular senescence, we noted that among the two important regulators of senescent growth arrest of tumor cells, bevacizumab‐associated increase in cellular senescence coincided with an upregulation of p16 but appeared to be independent of p53. siRNA silencing of p16 gene in MIP101 cells suppressed bevacizumab‐induced cellular senescence, while silencing of p53 had no effect. These findings demonstrate a novel antitumor activity of VEGF inhibitors in CRC, involving p16.
Cetuximab ± chemotherapy enhances dendritic cell‐mediated phagocytosis of colon cancer cells and ignites a highly efficient colon cancer antigen‐specific cytotoxic T‐cell response in vitro
Authors: Correale P. , Botta C. , Cusi M.G. , Del Vecchio M.T. , De Santi M.M. , Gori Savellini G. , Bestoso E. , Apollinari S. , Mannucci S. , Marra M. , Abbruzzese A. , Aquino A. , Turriziani M. , Bonmassar L. , Caraglia M. , Tagliaferri P. 
Published: May 2011

AbstractCetuximab is a human/mouse chimeric IgG1 monoclonal antibody (mAb) to epidermal growth factor receptor, approved for colorectal carcinoma treatment in combination with chemotherapy. The immune‐mediated effects elicited by its human fraction of crystallization moiety might critically contribute to the overall anti‐tumor effectiveness of the antibody. We therefore investigated cetuximab ability to promote colon cancer cell opsonization and phagocytosis by human dendritic cells (DCs) that are subsequently engaged in antigen‐cross presentation to cytotoxic T‐lymphocyte (CTL) precursors. Human colon cancer cell lines were evaluated for susceptibility to DC‐mediated phagocytosis before and after treatment with chemotherapy ± cetuximab in vitro. Human DCs loaded with control or drug‐treated cetuximab‐coated colon cancer cells were used to in vitro generate cytotoxic T cell clones from peripheral blood mononuclear cells of human leucocyte antigen‐A(*)02.01+ donors. T‐cell cultures were characterized for immune‐phenotype and tumor‐antigen specific CTL activity. The results confirmed that treatment of tumor cells with irinotecan + L‐folinate + 5‐flurouracil (ILF) or with gemcitabine + ILF increased tumor antigen expression. Moreover, malignant cells exposed to chemotherapy and cetuximab were highly susceptible to phagocytosis by human DCs and were able to promote their activation. The consequent DC‐mediated cross‐priming of antigens derived from mAb‐covered/drug‐treated cancer cells elicited a robust CTL anti‐tumor response. On the basis of our data, we suggest a possible involvement of CTL‐dependent immunity in cetuximab anti‐cancer effects.
MUC4: A novel prognostic factor of oral squamous cell carcinoma
Authors: Hamada Tomofumi , Wakamatsu Tsunenobu , Miyahara Mayumi , Nagata Satoshi , Nomura Masahiro , Kamikawa Yoshiaki , Yamada Norishige , Batra Surinder K. , Yonezawa Suguru , Sugihara Kazumasa 
Published: May 2011

AbstractMUC4 mucin is now known to be expressed in various normal and cancer tissues. We have previously reported that MUC4 expression is a novel prognostic factor in several malignant tumors; however, it has not been investigated in oral squamous cell carcinoma (OSCC). The aim of our study is to evaluate the prognostic significance of MUC4 expression in OSCC. We examined the expression profile of MUC4 in OSCC tissues from 150 patients using immunohistochemistry. Its prognostic significance in OSCC was statistically analyzed. MUC4 was expressed in 61 of the 150 patients with OSCC. MUC4 expression was significantly correlated with higher T classification (p = 0.0004), positive nodal metastasis (p = 0.049), advanced tumor stage (p = 0.002), diffuse invasion of cancer cells (p = 0.004) and patient's death (p = 0.004) in OSCC. Multivariate analysis showed that MUC4 expression (p = 0.011), tumor location (p = 0.032) and diffuse invasion (p = 0.009) were statistically significant risk factors. Backward stepwise multivariate analysis demonstrated MUC4 expression (p = 0.0015) and diffuse invasion (p = 0.018) to be statistically significant independent risk factors of poor survival in OSCC. The disease‐free and overall survival of patients with MUC4 expression was significantly worse than those without MUC4 expression (p < 0.0001 and p = 0.0001). In addition, the MUC4 expression was a significant risk factor for local recurrence and subsequent nodal metastasis in OSCC (p = 0.017 and p = 0.0001). We first report MUC4 overexpression is an independent factor for poor prognosis of patients with OSCC; therefore, patients with OSCC showing positive MUC4 expression should be followed up carefully.
Expression and pharmacological inhibition of thymidylate synthase and Src kinase in nonsmall cell lung cancer
Authors: Ceppi Paolo , Rapa Ida , Lo Iacono Marco , Righi Luisella , Giorcelli Jessica , Pautasso Marisa , Billè Andrea , Ardissone Francesco , Papotti Mauro , Scagliotti Giorgio V. 
Published: May 2011

AbstractThe combination of cytotoxic chemotherapy with signaling pathway inhibitors represents a potential strategy to improve the treatment of nonsmall cell lung cancer (NSCLC). Thymidylate synthase (TS) is an enzyme essential for DNA synthesis, and its overexpression has been associated with the reduced sensitivity to antifolate agents. Src is a tyrosine kinase that modulates the cytotoxicity of cancer cells after drug treatment, and in vitro data indicate that its inhibition could revert the resistance to TS‐inhibiting drugs. Our study investigated the significance of TS and Src expression in NSCLC tissues, and the effects of their pharmacological inhibition in cell lines. In tumor and normal tissues from 94 resected NSCLC patients, TS and Src transcript levels were found positively correlated (RS = 0.66), associated with patients smoking history and overall survival. At multivariate analysis, TS gene expression was an independent prognostic factor (relative risk (RR) = 1.78, from 1.16 to 2.72; p < 0.01). Immunohistochemical detection in tumor specimens confirmed that Src kinase activation, evaluated by phospho‐specific antibody, was associated to a higher TS expression. In cell lines, dasatinib, a Src‐inhibiting agent, synergistically enhanced pemetrexed‐cytotoxicity of A549 cells, as evaluated by MTT and apoptosis assays. The biological explanation for this interaction was based on the upregulation of TS messenger RNA and protein levels induced by pemetrexed, which was significantly prevented by dasatinib cotreatment. The data of our study suggest that TS and Src may belong to a common pathway that bears prognostic significance in NSCLC, and that Src represents a potential target to improve the efficacy of TS‐inhibiting agents.
Dark cell change of the cerebellar Purkinje cells induced by terbutaline under transient disruption of the blood–brain barrier in adult rats: morphological evaluation
Authors: Yamada Naoaki , Sasaki Satoshi , Ishii Hiroyuki , Sato Junko , Kanno Takeshi , Wako Yumi , Tsuchitani Minoru 
Published: May 2011

ABSTRACTThis study aimed to establish a cerebellar degeneration animal model and to characterize the dark cell change of Purkinje cells. We hypothesized that terbutaline, a β2‐adrenoceptor agonist, induces cerebellar degeneration not only in neonatal rats, but also in adult rats. Nine‐week‐old adult male Sprague–Dawley rats were anesthetized and infused with 25% mannitol via the left common carotid artery. Thirty seconds later, terbutaline was infused via the same artery. Dark‐stained Purkinje cells were observed in the entire cerebellum on day 3. Prominent Bergmann glial cells accompanied by swelling of the glial processes were present, and were closely associated with the dark‐stained Purkinje cells. These findings were found continuously throughout day 30. Ultrastructurally, dilated Golgi vesicles and/or endoplasmic reticulum and large lamella bodies were present in both severely changed and slightly changed Purkinje cells. Bergmann glial cells in the area of synaptic contacts of the severely changed Purkinje cells showed swelling. The Bergmann glial process in close contact with the slightly changed Purkinje cell dendrite in molecular layer showed slight swelling, and large lamella bodies in the dendrite were observed close to the dendritic spines. These findings may suggest that terbutaline induced a failure of Bergmann glial cell and resulted in dark cell degeneration of the Purkinje cells due to glutamate excitotoxicity. Copyright © 2011 John Wiley & Sons, Ltd.
Hepatocyte growth factor preferentially activates the anti‐inflammatory arm of NF‐κB signaling to induce A20 and protect renal proximal tubular epithelial cells from inflammation
Authors: da Silva Cleide G. , Maccariello Elizabeth R. , Wilson Szuhuei Wu , Putheti Prabhakar , Daniel Soizic , Damrauer Scott M. , Peterson Clayton R. , Siracuse Jeffrey J. , Kaczmarek Elzbieta , Ferran Christiane 
Published: May 2011

AbstractInflammation induces the NF‐κB dependent protein A20 in human renal proximal tubular epithelial cells (RPTEC), which secondarily contains inflammation by shutting down NF‐κB activation. We surmised that inducing A20 without engaging the pro‐inflammatory arm of NF‐κB could improve outcomes in kidney disease. We showed that hepatocyte growth factor (HGF) increases A20 mRNA and protein levels in RPTEC without causing inflammation. Upregulation of A20 by HGF was NF‐κB/RelA dependent as it was abolished by overexpressing IκBα or silencing p65/RelA. Unlike TNFα, HGF caused minimal IκBα and p65/RelA phosphorylation, with moderate IκBα degradation. Upstream, HGF led to robust and sustained AKT activation, which was required for p65 phosphorylation and A20 upregulation. While HGF treatment of RPTEC significantly increased A20 mRNA, it failed to induce NF‐κB dependent, pro‐inflammatory MCP‐1, VCAM‐1, and ICAM‐1 mRNA. This indicates that HGF preferentially upregulates protective (A20) over pro‐inflammatory NF‐κB dependent genes. Upregulation of A20 supported the anti‐inflammatory effects of HGF in RPTEC. HGF pretreatment significantly attenuated TNFα‐mediated increase of ICAM‐1, a finding partially reversed by silencing A20. In conclusion, this is the first demonstration that HGF activates an AKT‐p65/RelA pathway to preferentially induce A20 but not inflammatory molecules. This could be highly desirable in acute and chronic renal injury where A20‐based anti‐inflammatory therapies are beneficial. J. Cell. Physiol. 227: 1382–1390, 2012. © 2011 Wiley Periodicals, Inc.
Voltage sensitive phosphoinositide phosphatases of Xenopus: Their tissue distribution and voltage dependence
Authors: Ratzan William J. , Evsikov Alexei V. , Okamura Yasushi , Jaffe Laurinda A. 
Published: May 2011

AbstractVoltage‐sensitive phosphatases (VSPs) are unique proteins in which membrane potential controls enzyme activity. They are comprised of the voltage sensor domain of an ion channel coupled to a lipid phosphatase specific for phosphoinositides, and for ascidian and zebrafish VSPs, the phosphatase activity has been found to be activated by membrane depolarization. The physiological functions of these proteins are unknown, but their expression in testis and embryos suggests a role in fertilization or development. Here we investigate the expression pattern and voltage dependence of VSPs in two frog species, Xenopus laevis and Xenopus tropicalis, that are well suited for experimental studies of these possible functions. X. laevis has two VSP genes (Xl‐VSP1 and Xl‐VSP2), whereas X. tropicalis has only one gene (Xt‐VSP). The highest expression of these genes was observed in testis, ovary, liver, and kidney. Our results show that while Xl‐VSP2 activates only at positive membrane potentials outside of the physiological range, Xl‐VSP1 and Xt‐VSP phosphatase activity is regulated in the voltage range that regulates sperm–egg fusion at fertilization. J. Cell. Physiol. 226: 2740–2746, 2011. © 2011 Wiley‐Liss, Inc.
Mechanisms controlling neurite outgrowth in a pheochromocytoma cell line: The role of TRPC channels
Authors: Kumar Sanjay , Chakraborty Saikat , Barbosa Cindy , Brustovetsky Tatiana , Brustovetsky Nickolay , Obukhov Alexander G. 
Published: May 2011

AbstractTransient Receptor Potential Canonical (TRPC) channels are implicated in modulating neurite outgrowth. The expression pattern of TRPCs changes significantly during brain development, suggesting that fine‐tuning TRPC expression may be important for orchestrating neuritogenesis. To study how alterations in the TRPC expression pattern affect neurite outgrowth, we used nerve growth factor (NGF)‐differentiated rat pheochromocytoma 12 (PC12) cells, a model system for neuritogenesis. In PC12 cells, NGF markedly up‐regulated TRPC1 and TRPC6 expression, but down‐regulated TRPC5 expression while promoting neurite outgrowth. Overexpression of TRPC1 augmented, whereas TRPC5 overexpression decelerated NGF‐induced neurite outgrowth. Conversely, shRNA‐mediated knockdown of TRPC1 decreased, whereas shRNA‐mediated knockdown of TRPC5 increased NGF‐induced neurite extension. Endogenous TRPC1 attenuated the anti‐neuritogenic effect of overexpressed TRPC5 in part by forming the heteromeric TRPC1–TRPC5 channels. Previous reports suggested that TRPC6 may facilitate neurite outgrowth. However, we found that TRPC6 overexpression slowed down neuritogenesis, whereas dominant negative TRPC6 (DN‐TRPC6) facilitated neurite outgrowth in NGF‐differentiated PC12 cells. Consistent with these findings, hyperforin, a neurite outgrowth promoting factor, decreased TRPC6 expression in NGF‐differentiated PC12 cells. Using pharmacological and molecular biological approaches, we determined that NGF up‐regulated TRPC1 and TRPC6 expression via a p75NTR–IKK2‐dependent pathway that did not involve TrkA receptor signaling in PC12 cells. Similarly, NGF up‐regulated TRPC1 and TRPC6 via an IKK2 dependent pathway in primary cultured hippocampal neurons. Thus, our data suggest that a balance of TRPC1, TRPC5, and TRPC6 expression determines neurite extension rate in neural cells, with TRPC6 emerging as an NGF‐dependent “molecular damper” maintaining a submaximal velocity of neurite extension. J. Cell. Physiol. 227: 1408–1419, 2012. © 2011 Wiley Periodicals, Inc.
In ovo feeding of IGF‐1 to ducks influences neonatal skeletal muscle hypertrophy and muscle mass growth upon satellite cell activation
Authors: Liu He‐He , Wang Ji‐Wen , Zhang Rong‐Ping , Chen Xi , Yu Hai‐Yue , Jin Hai‐Bo , Li Liang , Han Chun‐Chun , Xu Feng , Kang Bo , He Hua , Xu Heng‐Yong 
Published: May 2011

AbstractTo investigate reasons for the muscle increase observed when eggs are treated by IGF‐1 and whether or not satellite cell activation is specific to different types of myofibers, duck eggs were administrated with IGF‐1. After injection, during the neonatal stages, the duck breast muscle and leg muscle were isolated for analysis. The muscle weight, muscle fiber diameter (MFD), cross‐sectional area (CSA), the number of myofibers per unit area (MFN) and frequency of satellite cell activation and mitosis at the embryo stage of 27 days (27E) and the postnatal stage of 2 days after hatching (P2D) were determined. In addition, expression of two important myogenic transcription factors MyoD and Myf5 were detected and compared in the two types of muscle tissues. Results indicated that IGF‐1 administration increased the duck body weight, MFD, CSA, MFN, and quantity of activated satellite cells and mitotic nuclei in the two types of muscle tissues. The MyoD and Myf5 expressed at a higher level in IGF‐1‐treated muscle. IGF‐1 stimulated muscle weight growth more in the leg muscle than in the breast muscle. These results indicate that in ovo feeding of IGF‐1 can stimulate duck growth and, especially, lead to increased muscle hypertrophy. These increases appear to be mainly dependent on the activation of satellite cells, some of which proliferate and fuse to the myofiber, enabling increased muscle mass. IGF‐1 can indirectly affect satellite cells by regulating the expression of two important myogenic transcription factors, MyoD and Myf5, which help activate satellite cells. J. Cell. Physiol. 227: 1465–1475, 2012. © 2011 Wiley Periodicals, Inc.
Neuronal specific βPix‐b stimulates actin‐dependent processes via the interaction between its PRD and WH1 domain of N‐WASP
Authors: Park Joohyun , Kim Yoonju , Park Zee Yong , Park Dongeun , Chang Sunghoe 
Published: May 2011

AbstractβPix, a Pak‐interacting nucleotide exchange factor (Cool‐1/p85SPR), is a Cdc42/Rac1‐specific guanine nucleotide exchange factor (GEF) involved in various actin‐related processes. Many previous studies have focused on ubiquitously expressed βPix‐a, while the role of the neuronal‐specific isoform βPix‐b is still unknown, especially whether its role is distinct from or similar to βPix‐a. Here we show that unlike βPix‐a, overexpression of βPix‐b stimulates actin‐dependent comet formation in BHK21 cells. This effect is attributed to the interaction between its proline‐rich domain (PRD) and the WH1 domain of N‐WASP. In addition, we show that overexpression of βPix‐b stimulates actin‐dependent dendritic spine formation in rat hippocampal neurons in culture, a formation that is blocked by co‐expression of the WH1 domain of N‐WASP or the PRD of βPix‐b. Knocking‐down endogenous expression of βPix‐b by shRNA reduced the number of dendritic spines, which were rescued only by PRD‐containing βPix‐b mutants. GEF activity of βPix‐b is also required for these effects. The results show that neuronal‐specific βPix‐b stimulates actin‐dependent processes in cells via the interaction between its PRD and the WH1 domain of N‐WASP. Our results identify N‐WASP as the first protein shown to interact with the PRD of βPix‐b, raising the possibility that, as an N‐WASP WH1‐binding protein, βPix‐b may regulate N‐WASP's activity in cells. J. Cell. Physiol. 227: 1476–1484, 2012. © 2011 Wiley Periodicals, Inc.