bluuebunny/crossref_metadata_2025_split huggingface dataset:
Analysis of ISG Expression in Chronic Hepatitis C Identifies Viperin as a Potential Antiviral Effector *
Authors: Helbig Karla J. , Lau Daryl T.-Y. , Semendric Ljiljana , Harley Hugh A. J. , Beard Michael R. 
Published: August 2005

Abstract

Interferon (IFN) α inhibits hepatitis C virus (HCV) replication both clinically and

in vitro

; however, the complete spectrum of interferon-stimulated genes (ISGs) expressed in the HCV-infected liver or the genes responsible for control of HCV replication have not been defined. To better define ISG expression in the chronically infected HCV liver, DNA microarray analysis was performed on 9 individuals with chronic hepatitis C (CHC). A total of 232 messenger RNAs were differentially regulated in CHC compared with nondiseased liver controls. A significant proportion of these were potential ISGs that were transcriptionally elevated, suggesting an ongoing response to endogenous IFN and/or double-stranded RNA. One ISG significantly elevated in all patients was viperin, an evolutionary conserved ISG that has antiviral activity against human cytomegalovirus. Stimulation of Huh-7 and HepG2 cells with IFN-α or -γ revealed viperin is predominantly a type I ISG. Furthermore, viperin expression could also be induced following transfection of Huh-7 cells with either poly(I:C) or HCV RNA. Transient expression of viperin in cells harboring the HCV genomic replicon resulted in a significant decrease in HCV replication, suggesting that viperin has anti-HCV activity.
In conclusion
, even in the face of a persistent HCV infection, there is an active ISG antiviral cellular response, highlighting the complexity of the host viral relationship. Furthermore, ISG viperin has anti-HCV activity

in vitro

; we postulate that viperin, along with other ISGs, acts to limit HCV replication. (Hepatology 2005.)
Theta oscillation‐coupled dendritic spiking integrates inputs on a long time scale
Authors: Huhn Zsófia , Orbán Gergő , Érdi Péter , Lengyel Máté 
Published: August 2005

AbstractPersistent neural activity lasting for seconds after transient stimulation has been observed in several brain areas. This activity has been taken to be indicative of the integration of inputs on long time scales. Passive membrane properties render neural time constants to be on the order of milliseconds. Intense synaptic bombardment, characteristic of in vivo states, was previously shown to further reduce the time scale of effective integration. We explored how long‐term integration in single cells could be supported by dendritic spikes coupled with the theta oscillation, a prominent brain rhythm often observed during working memory tasks. We used a two‐compartmental conductance‐based model of a hippocampal pyramidal cell to study the interplay of intrinsic dynamics with periodic inputs in the theta frequency band. We show that periodic dendritic spiking integrates inputs by shifting the phase relative to an external oscillation, since spiking frequency is quasi‐linearly modulated by current injection. The time‐constant of this integration process is practically infinite for input intensities above a threshold (the integration threshold) and can be still several hundred milliseconds long below the integration threshold. The somatic compartment received theta frequency stimulation in antiphase with the dendritic oscillation. Consequently, dendritic spikes could only elicit somatic action potentials when they were sufficiently phase‐shifted and thus coincided with somatic depolarization. Somatic depolarization modulated the frequency but not the phase of firing, endowing the cell with the capability to code for two different variables at the same time. Inputs to the dendrite shifted the phase of dendritic spiking, while somatic input was modulating its firing rate. This mechanism resulted in firing patterns that closely matched experimental data from hippocampal place cells of freely behaving rats. We discuss the plausibility of our proposed mechanism and its potential to account for the firing pattern of cells outside the hippocampus during working memory tasks. © 2005 Wiley‐Liss, Inc.
Small interfering RNA targeting survivin sensitizes lung cancer cell with mutant p53 to adriamycin
Authors: Yonesaka Kimio , Tamura Kenji , Kurata Takayasu , Satoh Taroh , Ikeda Masato , Fukuoka Masahiro , Nakagawa Kazuhiko 
Published: August 2005

AbstractSurvivin is a member of the inhibitor of apoptosis protein (IAP) family that is specifically overexpressed in cancer tissues. p53 is one of the tumor suppressor genes; its induction in response to DNA damage causes apoptosis and correlates with drug sensitivity. To investigate the possible regulation of survivin by p53, we examined the level of survivin expression in lung cancer cell lines in response to adriamycin. Levels of survivin mRNA and protein in cell lines with wild‐type p53 decreased dramatically after p53 induction, but no such reduction of survivin was observed in cell lines with mutated or null p53. Inhibition of wild‐type p53 in A549 cells by small interfering (si) RNA significantly upregulated the expression of survivin. Survivin inhibition by siRNA in PC9 cells with mutated p53 significantly depressed cell proliferation. To investigate the sensitivity of cancer cells to adriamycin after inhibition of survivin, we depressed survivin expression using siRNA, and then added adriamycin at an IC50 dose. After a further 48 hr incubation with adriamycin, proliferation was significantly depressed in the cells treated with siRNA targeting survivin, in comparison with siRNA targeting scramble. Furthermore, both TUNEL and pro‐caspase3 expression assay showed a significant increase in apoptosis after combined treatment with adriamycin and siRNA targeting survivin. Our results demonstrate that survivin is downregulated by p53, and that siRNA targeting of survivin increases cell sensitivity to adriamycin and promotes apoptosis. siRNA targeting of survivin could be potentially useful for increasing sensitivity to anticancer drugs, especially in drug‐resistant cells with mutated p53. © 2005 Wiley‐Liss, Inc.
Role of interleukin‐18 and its receptor in hepatocellular carcinoma associated with hepatitis C virus infection
Authors: Asakawa Masami , Kono Hiroshi , Amemiya Hidetake , Matsuda Masanori , Suzuki Tetsuya , Maki Akira , Fujii Hideki 
Published: August 2005

AbstractInterleukin (IL)‐18 is a proinflammatory cytokine that is up‐regulated in patients with hepatitis C virus (HCV) infection, which is the most common underlying disease in hepatocellular carcinoma (HCC). The purpose of our study was to investigate the role of IL‐18 in HCC associated with HCV infection. Sixty‐five patients with HCC and HCV infections who received curative surgical resections were examined in our study. The expression of the IL‐18 receptor was investigated in HCC tissues obtained from these patients and in 2 HCC cell lines. Nuclear factor (NF)‐κB activity and the expression of Bcl‐xL and xIAP mRNA were tested in the cell lines using recombinant human (rh) IL‐18. The IL‐18 receptor was expressed in both the HCC tissues and the cell lines. NF‐κB activation and the expression of Bcl‐xL and xIAP mRNA were increased by rhIL‐18. Moreover, rhIL‐18 suppressed the apoptosis of HCC cells which was induced by etoposide in vitro. The overall survival rate (55.4%) was significantly worse in the IL‐18 receptor‐positive patients than in the IL‐18 receptor‐negative patients (p = 0.015). In a Cox multivariate analysis, the expression of the IL‐18 receptor was found to be a significant predictor of a poor outcome in HCC patients. The expression of the IL‐18 receptor and an antiapoptotic mechanism involving NF‐κB activation in HCC cells may be implicated in a poor patient outcome. © 2005 Wiley‐Liss, Inc.
Lung cancer risks in relation to vegetable and fruit consumption and smoking
Authors: Rylander Ragnar , Axelsson Gösta 
Published: August 2005

AbstractIn a case‐control study on lung cancer, risk was analysed in relation to smoking habits and frequency of vegetable and fruit consumption. Lung cancer cases in West Sweden and population controls were interviewed using a questionnaire where the frequency of consumption of dietary items and smoking habits were assessed. The material presented comprises 177 female and 359 male confirmed cases of lung cancer and 916 population controls. There was a dose‐response relationship in regard to the number of cigarettes smoked and the number of years smoked, the latter factor being more important. After adjustment for number of cigarettes smoked/day and number of years smoked, the risk for those who seldom consumed vegetables was about twice of that among those who consumed vegetables frequently, both among nonsmokers, smokers and former smokers. This risk increase in relation to vegetable consumption also was present for different smoking categories. A similar tendency, although less pronounced, was found for fruit consumption. The results demonstrate that dietary factors are related to the risk for lung cancer, although smoking is the dominant risk factor. © 2005 Wiley‐Liss, Inc.
Occupational factors and risk of adult bone sarcomas: A multicentric case‐control study in Europe
Authors: Merletti Franco , Richiardi Lorenzo , Bertoni Franco , Ahrens Wolfgang , Buemi Antoine , Costa‐Santos Cristina , Eriksson Mikael , Guénel Pascal , Kaerlev Linda , Jöckel Karl‐Heinz , Llopis‐Gonzalez Agustin , Merler Enzo , Miranda Ana , Morales‐Suárez‐Varela Maria M. , Olsson Håkan , Fletcher Tony , Olsen Jorn 
Published: August 2005

AbstractWe investigated the association between occupational factors and risk of bone sarcoma, a rare tumor with a largely unknown aetiology. A multicentric case‐control study was conducted in 7 European countries in 1995–97. Ninety‐six cases aged 35–69 years with a centrally reviewed diagnosis of bone sarcoma (68 chondrosarcomas and 28 osteosarcomas) were compared to 2,632 population (68%) or colon cancer (32%) controls. Subjects were interviewed to obtain information on occupational, medical and reproductive history, smoking and alcohol consumption and selected exposures including use of pesticides. Response proportions were 90% among cases and 66% among controls. Odds ratios (OR) and 95% confidence intervals (CI) were estimated for selected categories of job titles and branches of industry and for use of pesticides. We found an increased OR for bone sarcoma among blacksmiths, toolmakers, machine‐tool operators (OR = 2.14, 95% CI 1.08–4.26), woodworkers (OR = 2.68, 95% CI 1.36–5.29) and construction workers (OR = 1.62, 95% CI 0.92–2.87). Ever users of pesticide had an OR of 2.33 (95% CI 1.31–4.13), with similar risks for exposure to insecticides and exposure to herbicides. Neither duration of employment in any of the analyzed occupational categories nor duration of use of pesticides showed an increasing trend in the risk of bone sarcoma. ORs of bone sarcoma were 1.03 (95% CI 0.23–4.57), 3.13 (95% CI 1.26–7.76) and 1.44 (95% CI 0.43–4.85) for the first, second and third tertile of days of use of pesticides. Our study suggests that novel and previously reported (woodworking) occupational factors play a role in the aetiology of bone sarcomas. © 2005 Wiley‐Liss, Inc.
A tumor vaccine containing anti‐CD3 and anti‐CD28 bispecific antibodies triggers strong and durable antitumor activity in human lymphocytes
Authors: Haas Claudia , Lulei Maria , Fournier Philippe , Arnold Annette , Schirrmacher Volker 
Published: August 2005

AbstractWe recently reported on newly designed virus‐targeted bispecific CD3‐ and CD28‐binding molecules for human T‐cell activation. When bound via one arm to a human virus‐modified tumor cell vaccine, these reagents caused a polyclonal T‐cell response and overcame the potential various T‐cell evasion mechanisms of tumor cells. In our current study, we demonstrated the induction of strong antitumor activity in human lymphocytes upon coincubation with a virus‐modified tumor vaccine containing anti‐CD3 and anti‐CD28 bispecific antibodies. Blood mononuclear cells or purified T cells that were coincubated with such a tumor vaccine for 3 days were able to destroy monolayers of human breast carcinoma and other carcinoma cells. Serial transfer to new tumor cell monolayers revealed antitumor cytotoxic activity in such effector cells that lasted for about 10 days. Nontumor target cells appeared to be much less sensitive to the activated effector cells. Although the bispecific molecules alone did not activate effector cells, their binding to virus‐infected tumor cells was important and more effective than their binding to free virus. Antitumor activity of the activated effector cells was mediated through soluble factors as well as through direct cell contact of effector cells with the nontargeted bystander tumor cells. Since the virus‐modified tumor vaccine is well tolerated and already exhibits a certain effectiveness in cancer patients, the combination with new bispecific molecules has the potential to introduce additional antitumor effects. The reagents can also be combined with Newcastle Disease Virus (NDV)‐based oncolytic virotherapy. © 2005 Wiley‐Liss, Inc.
Distinct regulation and impact of type 1 T‐cell immunity against HPV16 L1, E2 and E6 antigens during HPV16‐induced cervical infection and neoplasia
Authors: van Poelgeest Mariëtte I.E. , Nijhuis Esther R. , Kwappenberg Kitty M.C. , Hamming Ineke E. , Wouter Drijfhout Jan , Fleuren Gert Jan , van der Zee Ate G.J. , Melief Cornelis J.M. , Kenter Gemma G. , Nijman Hans W. , Offringa Rienk , van der Burg Sjoerd H. 
Published: August 2005

AbstractCervical cancer is the possible outcome of a genital infection with high‐risk human papillomavirus type 16 (HPV16) and is preceded by a phase of persistent HPV infection during which the host immune system fails to eliminate the virus. Our previous work showed that failure is reflected by the absence of type 1 T‐cell immunity against HPV16 early antigens E2 and E6 in patients with HPV16+ cervical lesions. We now show that a majority of both patients with cervical lesions and healthy subjects display HPV16 L1 peptide‐specific type 1 T‐cell responses with similar magnitude. The T‐cell response in patients was directed at a broad range of peptides within L1, suggesting that during persistent or repeated exposure to HPV16 L1, the immune system maximizes its efforts to counter the viral challenge. Unlike the type 1 T‐cell responses against HPV16 early antigens E2 and E6, type 1 T‐cell immunity against L1 does not correlate with health or disease. This argues that T‐cell responses against early and late HPV16 antigens essentially differ in the manner in which they are induced and regulated, as well as in their impact on the subsequent stages of HPV16‐induced cervical disease. © 2005 Wiley‐Liss, Inc.
Proliferation and Cdk4 expression in microsatellite unstable colon cancers with TGFBR2 mutations
Authors: Grady William M. , Willis Joseph E. , Trobridge Patty , Romero‐Gallo Judith , Munoz Nina , Olechnowicz Joseph , Ferguson Kelly , Gautam Shiva , Markowitz Sanford D. 
Published: August 2005

AbstractApproximately 15% of human colon cancers have microsatellite instability (MSI) and carry frameshift mutations in a polyadenine tract (BAT‐RII) in the type II transforming growth factor β (TGF‐β) receptor (TGFBR2), a required component of the TGF‐β receptor. The BAT‐RII mutations in MSI colon cancers make the tumors resistant to the effects of TGF‐β. In cultured epithelial cells, TGF‐β can inhibit cell proliferation and induce apoptosis, and in vitro it can regulate the expression of a variety of cyclins, cyclin‐dependent kinases (cdks) and cdk inhibitors. These effects are context‐ and tissue type‐dependent, raising questions about which of these in vitro effects of TGF‐β signaling inactivation contribute to the formation of primary colon cancer. Thus, this study sought to determine the pathogenetically relevant effects of TGFBR2 inactivation in primary MSI colon cancers with mutant BAT‐RII. Colon cancers with mutant BAT‐RII were found to have increased proliferation compared to cancers with wild‐type BAT‐RII. Assessment of cdk4, cyclin D1 and p27kip1 expression revealed that only cdk4 expression was increased in the cancers with mutant BAT‐RII. In order to determine if TGFBR2 inactivation was the cause of these changes, TGFBR2 was reconstituted in an MSI colon cancer cell line, resulting in decreased proliferation and decreased cdk4 expression and kinase activity. These results suggest that TGFBR2 mutations in primary colon cancers may be responsible for the increased proliferation and cdk4 expression in these tumors and provide evidence that deregulation of cdk4 is a pathogenic in vivo consequence of TGFBR2 inactivation in primary colon cancer. © 2005 Wiley‐Liss, Inc.
Wnt pathway is involved in pleomorphic adenomas induced by overexpression of PLAG1 in transgenic mice
Authors: Zhao Xudong , Ren Weihua , Yang Wenjun , Wang Yi , Kong Hui , Wang Long , Yan Lanzhen , Xu Guojiang , Fei Jian , Fu Jiliang , Zhang Chenping , Wang Zhugang 
Published: August 2005

AbstractPleomorphic adenoma gene 1 (PLAG1) was found frequently rearranged and activated in human salivary gland pleomorphic adenomas. It encodes a developmentally regulated transcription factor. Ectopic overexpression of PLAG1 has been proposed to play a crucial role in tumorigenesis of salivary gland pleomorphic adenomas. It was reported that PLAG1 can activate the transcription of insulin‐like growth factor 2 (IGF2), functioning as a protooncogene. In this report, we show that the salivary gland tumors developed in PLAG1 transgenic mice share major histopathologic features with human pleomorphic adenomas. It was found that β‐catenin, the key component of Wnt signaling pathway, was upregulated at transcriptional level in tumors developed in 3 independent transgenic mouse lines. Immunohistochemical staining revealed that expression of β‐catenin as well as c‐myc, downstream of β‐catenin in Wnt signaling pathway, was highly upregulated with overexpression of PLAG1 transgene in tumor and normal transgenic salivary gland tissues. Moreover, we found that PLAG1 can activate the transcription of mouse but not human β‐catenin in the 3T3 cells cotransfected with reporter constructs. Sequence analysis shows there are 4 PLAG1 consensus binding sites in mouse β‐catenin promoter region but not in human. Our findings provide the first in vivo evidence for the oncogenic activity of PLAG1 in pleomorphic adenoma tumorigenesis, reveal a valued animal model for human salivary gland tumors and suggest that Wnt signaling pathway may also contribute to the development of pleomorphic adenomas in transgenic mice. © 2005 Wiley‐Liss, Inc.
Inefficient proteasomal‐degradation pathway stabilizes AP‐2α and activates HER‐2/neu gene in breast cancer
Authors: Li Min , Wang Yingqun , Hung Mien‐Chie , Kannan Perry 
Published: August 2005

AbstractHER‐2/neu proto‐oncogene is overexpressed in about one fourth of human breast cancers. AP‐2 transcription factors bind to the HER‐2/neu gene promoter and activate its expression. In a striking concurrence, anomalous abundance of AP‐2α protein or its homolog AP‐2γ is also detected with HER‐2/neu protein in mammary tumor‐derived cell lines. This suggests that the deregulation of AP‐2 is the preceding pathogenic event and probably the pivotal one in this type of mammary carcinogenesis. We examined the process of AP‐2α gene expression in mammary carcinoma cell lines to identify where the aberration had occurred. We found no amplification of the AP‐2α gene. Its promoter was marginally upregulated; however, it did not significantly increase the mRNA levels. When the AP‐2α protein was examined, a remarkable stability was seen in breast cancer cell lines MDA‐MB‐453 and SK‐BR‐3, with a half‐life of over 30 hr. This is sharply higher than the approximate 1 hr observed in mammary epithelial cell line MCF‐10A and murine cell line NIH 3T3. Treatment of MCF‐10A and NIH 3T3 cells with the proteasome inhibitor MG‐132 showed that AP‐2α was ubiquitinated and its level significantly increased. Moreover, this increase was accompanied by elevated levels HER‐2/neu protein. In contrast, weaker ubiquitination of AP‐2α was seen in MDA‐MB‐453 and SK‐BR‐3 cancer cells, and MG‐132 treatment did not raise the AP‐2α level any further. These results uncover that unusual stability is the main mechanism that raises the levels of AP‐2 proteins, and in addition, provide the first clue that defective ubiquitin‐dependent proteasomal‐degradation pathway is possibly the prime cause that affects the HER‐2/neu gene and culminates in breast cancer. © 2005 Wiley‐Liss, Inc.
Cytotoxic effects induced by a combination of cyclopamine and gefitinib, the selective hedgehog and epidermal growth factor receptor signaling inhibitors, in prostate cancer cells
Authors: Mimeault Murielle , Moore Erik , Moniaux Nicolas , Hénichart Jean‐Pierre , Depreux Patrick , Lin Ming‐Fong , Batra Surinder K. 
Published: August 2005

AbstractAlthough the blockade of the hedgehog cascade by using cyclopamine has been reported to inhibit the growth of some cancer cell types, few studies on the mechanism by which this drug alone or in combination with other cytotoxic agents induces its cytotoxic effect have been reported. In our study, we evaluate, for the first time, the antiproliferative and cytotoxic effects induced by a combination of selective SMO inhibitor, cyclopamine and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, gefitinib on metastatic prostate cancer (PC) cells. The results revealed that cyclopamine, alone or at a lower concentration in combination with gefitinib, inhibited the growth of sonic hedgehog‐ (SHH), epidermal growth factor‐ (EGF) and serum‐stimulated androgen‐sensitive LNCaP‐C33 and LNCaP‐LN3 and androgen‐independent LNCaP‐C81, DU145 and PC3 cells. The antiproliferative effect of cyclopamine and gefitinib, alone or in combination, was mediated via a blockade of the PC3 cells in the G1 phase of the cell cycle. Importantly, the combined cyclopamine and gefitinib also caused a higher rate of apoptotic death of PC cells compared to single agents. The cytotoxic effect induced by these drugs in PC3 cells appears to be mediated at least, in part, via the mitochondrial pathway through the depolarization of the mitochondrial membrane and the release of cytochrome c and reactive oxygen species into the cytosol. This was also accompanied by the activation of caspase cascades, PARP cleavage and DNA fragmentation. Additionally, the combined cyclopamine and gefitinib were more effective at suppressing the invasiveness of PC3 cells through matrigel in vitro as the drugs alone. These findings indicate that the simultaneous blockade of SHH–GLI‐1 and EGF–EGFR signaling, which results in the growth arrest and massive rate of apoptotic cell death, represents a promising strategy for a more effective treatment of metastatic PC forms. © 2005 Wiley‐Liss, Inc.