bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gene expression profiles in breast tumors regarding the presence or absence of estrogen and progesterone receptors
Authors: Nagai Maria Aparecida , da Rós Nancy , Neto Mário Mourão , de Faria Junior Silvio Rodrigues , Brentani Maria Mitzi , Hirata Roberto , Neves Eduardo Jordão 
Published: May 2004

AbstractEstrogen acts via its receptor (ER) to stimulate cell growth and differentiation in the mammary gland. ER and progesterone receptor (PR), which is regulated by estrogen via ER, have been used as prognostic markers in clinical management of breast cancer patients. Patients with ER− breast tumors have a poorer prognosis than patients with ER+ tumors. The aim of the present study was the identification of tumor‐associated genes differentially expressed in breast tumors regarding the presence or absence of ER and PR hybridized with cDNA microarrays containing 4,500 tumor‐derived expressed sequence tags generated using the ORESTES technique. Samples of human primary breast carcinomas from 38 patients were analyzed. The experiments were performed in triplicates and data from each element were acquired by phosphoimage scanning. Data acquisition was performed using the ArrayVision software. After normalization statistical analysis was applied. In a preliminary analysis, 98 differentially expressed transcripts were identified, 46 were found to be more expressed in ER+/PR+ and 52 were found to be more expressed in ER−/PR− breast tumors. The biochemical functions of the genes in the reported expression profile are diverse and include metabolic enzymes, protein kinases, helicases, transcription factors, cell cycle regulators and apoptotic factors. ER−/PR− breast tumors displayed increased levels of transcripts of genes associated with neurodegeneration and genes associated with proliferation were found in ER+/PR+ tumors. © 2004 Wiley‐Liss, Inc.
Use of adenoviruses encoding CD40L or IL‐2 against B cell lymphoma
Authors: Meziane El Kahina , Bhattacharyya Tapan , Armstrong Anne C. , Qian Cheng , Hawkins Robert E. , Stern Peter L. , Dermime Said 
Published: May 2004

AbstractSome B cell lymphomas lack important costimulatory properties that could prevent them from being used as cell based vaccines. Infection of A20 B lymphoma cells with a replication‐defective adenovirus encoding murine (m) CD40L, but not mIL‐2, produces an antigen presentation phenotype with upregulation of MHC Class I/II, induction of B7‐1/2 molecules and production of MIL‐12 and MIP‐1α. Subcutaneous vaccination with irradiated Ad‐mCD40L‐infected‐ or Ad‐mIL‐2‐infected‐A20 cells generated A20‐specific CD8+ T cell responses and cross reactive A20 Ig antibodies. Only vaccination with Ad‐mCD40L‐infected A20 cells produced a significant delay in tumor growth and long‐term survival (p = 0.0039). Stronger protective immunity to A20 challenge was generated by intravenous priming with A20 cells infected with Ad‐mCD40L, Ad‐mIL‐2 or their combination followed by a boost immunization with A20 cells activated with syngeneic fibroblasts expressing CD40L. Compared to Ad‐LacZ‐infected A20 priming, the combination priming was most effective followed by Ad‐mCD40L and Ad‐mIL‐2 (p = 0.0027, p = 0.0027, p = 0.0163 respectively). Significant A20‐specific CD8+ T cell‐mediated cytotoxicity was only demonstrated in splenocytes from these groups of vaccinated animals. By contrast, ELISPOT assay of splenocytes from all A20 prime/boosted vaccinated groups demonstrated increases in γ‐interferon release by T cells elicited by in vitro stimulation either with A20 cells or another syngeneic 2PK‐3 lymphoma, indicating the presence of cross reactive immunity. Similarly anti‐A20 immunoglobulin antibodies generated after vaccination were not necessarily A20 idiotype‐specific. Direct therapy of pre‐established tumors was achieved with the combination of Ad‐mCD40L and Ad‐mIL‐2 given at Days 4 and 8 at the tumor site with a significant long‐term survival of 85% of tumor‐bearing mice (p = 0.0001). Our study strongly supports the use of Ad‐CD40L and Ad‐IL‐2 combination therapy for the treatment of patients with B cell lymphoma. © 2004 Wiley‐Liss, Inc.
Inhibition of growth and survival of human head and neck squamous cell carcinoma cells by curcumin via modulation of nuclear factor‐κB signaling
Authors: Aggarwal Sita , Takada Yasunari , Singh Sujay , Myers Jeffrey N. , Aggarwal Bharat B. 
Published: May 2004

AbstractIncreased expression of proinflammatory and proangiogenic factors are associated with aggressive tumor growth and decreased survival of patients with head and neck squamous cell carcinoma (HNSCC). In as much as genes that are regulated by nuclear factor NF‐κB suppress apoptosis, induce proliferation, and mediate inflammation, angiogenesis and tumor metastasis, agents that suppress NF‐κB activation have potential as treatment for various cancers including HNSCC. We demonstrate that all HNSCC cell lines expressed constitutively active NF‐κB and IκBα kinase (IKK), which is needed for NF‐κB activation. Treatment of MDA 686LN cells with curcumin (diferuloylmethane), a pharmacologically safe chemopreventive agent, inhibited NF‐κB activation through abrogation of IKK. As a result expression of various cell survival and cell proliferative genes including Bcl‐2, cyclin D1, IL‐6, COX‐2 and MMP‐9 was suppressed. This, in turn, inhibits proliferation of all HNSCC cell lines, arrests cell cycle in G1/S phase (MDA 686LN) and induces apoptosis as indicated by upstream and downstream caspase activation, PARP cleavage, annexin V staining in MDA 686LN cells. Suppression of NF‐κB by cell‐permeable p65‐based peptide and NBD peptide also inhibited the proliferation and induced apoptosis in these cells. Our results indicate that curcumin is a potent inhibitor of cell proliferation and an inducer of apoptosis in HNSCC through suppression of IKK‐mediated NF‐κB activation and of NF‐κB‐regulated gene expression. © 2004 Wiley‐Liss, Inc.
Treatment with siRNA and antisense oligonucleotides targeted to HIF‐1α induced apoptosis in human tongue squamous cell carcinomas
Authors: Zhang Qunzhou , Zhang Zuo‐Feng , Rao Jian Y. , Sato J. Denry , Brown Jimmy , Messadi Diana V. , Le Anh D. 
Published: May 2004

AbstractOverexpression of hypoxia inducible factor‐1α (HIF‐1α) in cancers has been correlated to a more aggressive tumor phenotype. We investigated the effect of HIF‐1α knockout on the in vitro survival and death of human tongue squamous cell carcinomas (SCC‐4 and SCC‐9). Under normoxic condition, a basal level of HIF‐1α protein was constitutively expressed in SCC‐9 cells, albeit an undetectable level of HIF‐1α messages. Exposure to hypoxia induced only a transient increase in mRNA transcript but a prolonged elevation of HIF‐1α protein and its immediate downstream target gene product, VEGF. Under normoxic or hypoxic conditions, treatment of SCC‐9 cells with AS‐HIF‐1α ODN suppressed both constitutive and hypoxia‐induced HIF‐1α expression at both mRNA and protein levels. Knockout of HIF‐1α gene expression via either AS‐HIF‐1α ODN or siRNA (siRNAHIF‐1α) treatment resulted in inhibition of cell proliferation and induced apoptosis in SCC‐4 and SCC‐9 cells. We also demonstrated that exposure of SCC‐9 cells to hypoxia led to a time‐dependent increase in the expression of bcl‐2 and IAP‐2, but not p53. The attenuated levels of bcl‐2 and IAP‐2, and the enhanced activity of caspase‐3 after treatment with AS‐HIF‐1α ODN may contribute partly to the effects of HIF‐1α blockade on SCC‐9 cell death. Collectively, our data suggest that a constitutive or hypoxia‐induced expression of HIF‐1α in SCC‐9 and SCC‐4 cells is sufficient to confer target genes expression essential for tumor proliferation and survival. As a result, interfering with HIF‐1α pathways by antisense or siRNA strategy may provide a therapeutic target for human tongue squamous cell carcinomas. © 2004 Wiley‐Liss, Inc.
Addition of integrin binding sequence to a mutant human endostatin improves inhibition of tumor growth
Authors: Yokoyama Yumi , Ramakrishnan S. 
Published: May 2004

AbstractTumor vasculatures express high levels of αVβ3/αVβ5 and α5β1 integrins. Consequently, peptides containing the RGD (Arg‐Gly‐Asp) sequence, which is present in ligands of integrins, is effective in targeting therapeutic reagents to tumor vascular endothelium. In our study, we investigated whether the biologic activity of endostatin can be enhanced by the addition of an integrin targeting sequence. RGD sequence was added to either the amino or carboxyl terminus of endostatin containing a point mutation, P125A‐endostatin. Earlier we have shown that the P125A mutation did not affect the biologic activity of endostatin but in fact had better antiangiogenic activity when compared to the native molecule. Further modification of P125A‐endostatin with the RGD motif showed specific and increased binding to endothelial cells, and the increased binding coincided with improved antiangiogenic properties. Both amino and carboxyl terminal RGD‐modification of P125A‐endostatin resulted in greater inhibition of endothelial cell migration and proliferation. RGD modification increased tumor localization without affecting the circulatory half‐life of P125A‐endostatin, and RGD‐modified P125A‐endostatin was found to be more effective when compared to the P125A‐endostatin in inhibiting ovarian and colon cancer growth in athymic mice. Complete inhibition of ovarian tumor growth was observed when P125A‐endostatin‐RGD was encapsulated into alginate beads. These studies demonstrate that addition of a vascular targeting sequence can enhance the biologic activity of an antiangiogenic molecule. © 2004 Wiley‐Liss, Inc.
Association of DNA repair gene XRCC1 polymorphisms with head and neck cancer in Korean population
Authors: Tae Kyung , Lee Hyung Seok , Park Bum Jung , Park Chul Won , Kim Kyung Rae , Cho Hye Young , Kim Lyoung Hyo , Park Byung Lae , Shin Hyoung Doo 
Published: May 2004

AbstractSquamous cell carcinoma of the head and neck (SCCHN), which is relatively prevalent in Korea, is believed to be induced by environmental carcinogens and host genetic factors. Accumulating evidence has shown that genetic differences in DNA repair capacity resulting from genetic polymorphism influence the risk of environmental carcinogenesis. We therefore examined the associations of genetic polymorphisms in the DNA repair genes XRCC1 with the risk of SCCHN in a Korean population (hospital‐based, case‐control study; 147 cases and 168 controls). Three known polymorphisms in the XRCC1 gene were genotyped: R194W(C>T) in exon 6, R280H(G>A) in exon 9 and R399G(G>A) in exon 10. Although no significant associations were apparent with R280H(G>A) and R399G(G>A), a highly significant association (p = 0.0005) of R194W(C>T) with the increased risk (OR = 2.61; 95% CI 1.53–4.46) of SCCHN was detected among patients and normal controls under dominant model. The frequency of minor allele‐containing genotypes (TT and CT) was much higher in SCCHN patients (51.8%) compared to that in normal controls (30.3%) (p = 0. 0005). When considering a relatively small number of cases (n = 147) and controls (n = 168) in our study, larger studies are needed to validate the genetic effects of XRCC1 polymorphisms in Asian populations. In conclusion, the result from our study provides additional evidence of an association of the XRCC1 polymorphism (Arg194Trp) with SCCHN as markers of genetic susceptibility in the Korean population. © 2004 Wiley‐Liss, Inc.
Suppression of malignant growth of human breast cancer cells by ectopic expression of integrin‐linked kinase
Authors: Chen Ping , Shen Wei‐Zhen , Karnik Pratima 
Published: May 2004

AbstractAllelic loss at the short arm of chromosome 11 is one of the most common and potent events in the progression and metastasis of breast cancer. Here, we present evidence that the Integrin‐Linked Kinase (ILK) gene maps to the commonly deleted chromosome 11p15.5 and suppresses malignant growth of human breast cancer cells both in vitro and in vivo. ILK is expressed in normal breast tissue but is downregulated in metastatic breast cancer cell lines and in advanced breast cancers. Transfection of wild‐type ILK into the MDA‐MB‐435 mammary carcinoma cells potently suppressed their growth and invasiveness in vitro and reduced the cells' ability to induce tumors and metastasize in athymic nude mice. Conversely, expression of the ankyrin repeat or catalytic domain mutants of ILK failed to suppress the growth of these cells. Growth suppression by ILK is not due to apoptosis but is mediated by its ability to block cell‐cycle progression in the G1 phase and by modulating the levels of integrins. These findings directly demonstrate that ILK deficiency facilitates neoplastic growth and invasion and suggest a novel role for the ILK gene in the suppression of tumor metastasis. © 2004 Wiley‐Liss, Inc.
Poly(ADP‐ribosyl)ation inhibitors: Promising drug candidates for a wide variety of pathophysiologic conditions
Authors: Beneke Sascha , Diefenbach Joerg , Bürkle Alexander 
Published: May 2004

AbstractPoly(ADP‐ribose) polymerases are involved in many aspects of regulation of cellular functions. Using NAD+ as a substrate, they catalyse the covalent transfer of ADP‐ribose units onto several acceptor proteins to form a branched ADP‐ribose polymer. The best characterised and first discovered member of this multiprotein family is PARP‐1. Its catalytic activity is markedly stimulated upon binding to DNA strand interruptions, and the resulting polymer is thought to function in chromatin relaxation as well as in signalling the presence of damage to DNA repair complexes and in regulating enzyme activities. Moderate activation of PARP‐1 facilitates the efficient repair of DNA damage arising from monofunctional alkylating agents, reactive oxygen species or ionising radiation, but severe genotoxic stress leads to rapid energy consumption and subsequently to necrotic cell death. The latter aspect of PARP‐1 activity has been implicated in the pathogenesis of various clinical conditions such as shock, ischaemia‐reperfusion and diabetes. Inhibition of ADP‐ribose polymer formation has been shown to be effective, on the one hand, in the treatment of cancer in combination with alkylating agents by suppressing DNA repair and thus driving tumour cells into apoptosis, and on the other hand it appears to be a promising drug target for the treatment of pathologic conditions involving oxidative stress. In view of the existence of several members of the PARP family in mammalian cells, one has to be aware of possible side effects but also of a wide spectrum of potential clinical applications, which calls for the development of more specific inhibitors. © 2004 Wiley‐Liss, Inc.
Molecular detection of circulating tumor cells is an independent prognostic factor in patients with high‐risk cutaneous melanoma
Authors: Mocellin Simone , Del Fiore Paolo , Guarnieri Laura , Scalerta Romano , Foletto Mirto , Chiarion Vanna , Pilati Pierluigi , Nitti Donato , Lise Mario , Rossi Carlo R. 
Published: May 2004

AbstractDetection of circulating tumor cells (CTCs) might improve current staging procedures by identifying a subgroup of patients with minimal residual disease and thus a higher risk of disease recurrence. Forty patients with ≥2‐mm‐thick cutaneous melanoma with or without lymph node metastasis were enrolled. After standard radical surgery and adjuvant therapy in case of lymph node metastasis, patients were followed up with routine physical and radiologic assessments as well as serial PCR‐based analysis of CTCs using 2 melanoma markers (tyrosinase and Melan‐A/Mart‐1). After a median follow‐up of 30 months, 18 patients had disease recurrence and 28 were PCR‐positive before the disease became clinically evident. The sensitivity of the molecular test was 83%. Median time to PCR positivity and median PCR‐to‐relapse time were 12 and 8 months, respectively. At multivariate analysis, PCR positivity was an independent predictor of disease recurrence (hazard ratio = 2.06, 95% CI 1.07–3.35; p = 0.03). Among high‐risk melanoma patients, serial PCR‐based analysis of CTCs can identify a subgroup at higher risk of disease recurrence, with clinically significant advance. Therefore, CTC detection might be employed for the selection of patients for adjuvant treatment and during follow‐up for early indication of therapeutic failure. © 2004 Wiley‐Liss, Inc.
Gelsolin gene silencing involving unusual hypersensitivities to dimethylsulfate and KMnO4in vivo footprinting on its promoter region
Authors: Haga Kazunori , Fujita Hisakazu , Nomoto Minoru , Sazawa Ataru , Nakagawa Koji , Harabayashi Toru , Shinohara Nobuo , Takimoto Masato , Nonomura Katsuya , Kuzumaki Noboru 
Published: May 2004

AbstractWe previously reported that gelsolin gene expression is reduced in various tumors. In an effort to gain further insights into the mechanism of gelsolin downregulation in tumors, we examined the in vivo properties of the gelsolin promoter in urinary bladder cancer cell lines. Neither mutation nor hypermethylation was responsible for gene silencing at the promoter. After exposure to trichostatin A (TSA), a histone deacetylase inhibitor, gelsolin promoter activity was markedly enhanced in the cancer cells, not in cells derived from normal tissue. Chromatin immunoprecipitation assays revealed that both histones H3 and H4 were hypoacetylated in the promoter region of the cancer cells, and the accumulation of acetylated histones was detected by TSA treatment. In vivo footprinting analysis revealed the presence of dimethylsulfate (DMS) hypersensitive site in the untranslated region around nucleotide −35 only in the cancer cells but not in cells derived from normal tissue, and analysis of KMnO4 reactive nucleotides showed that the stem loop structure could be formed in vivo of the cancer cells. This novel stem loop structure may play a part in regulating the transcription of the gelsolin gene in the cancer cells. These results suggest that nucleosome accessibility through histone deacetylation and structural changes (DMS hypersensitivity and stem loop structure) in the promoter region form the basis of the mechanism leading to the silencing of gelsolin gene in human bladder cancer. © 2004 Wiley‐Liss, Inc.
Implications of cytokeratin 8/18 filament formation in stratified epithelial cells: Induction of transformed phenotype
Authors: Raul Ujwala , Sawant Sharada , Dange Prerana , Kalraiya Rajiv , Ingle Arvind , Vaidya Milind 
Published: May 2004

AbstractThe cytokeratin (CK) pair 8 and 18 is normally expressed in all simple epithelia. This pair is not normally seen in stratified epithelial cells. Squamous cell carcinomas derived from stratified epithelia show anomalous expression of this CK pair. It is not known whether CKs 8 and 18 in any way contribute to the malignant phenotype of these cells. We used an immortalised, nontransformed human foetal buccal mucosa (FBM) cell line that expresses significantly higher amounts of CK18 compared to CK8. FBM cells were transfected with the full‐length CK8 gene to study the role of CKs 8 and 18 in malignant transformation. Clones with higher expression of CK8 compared to untransfected FBM cells were studied for changes in their phenotypic characteristics. Immunofluorescence studies using antibodies to CKs 8 and 18 revealed well‐decorated filaments throughout the cytoplasm in CK8 gene–transfected cells vs. untransfected FBM cells. Transmission images showed that FBM cells were isolated while transfected cells were in groups of well‐spread cells with cellular projections. Transfected cells were independent of growth supplement requirements and showed anchorage‐independent growth in soft agar assay and significantly reduced doubling time compared to nontransfected FBM cells. DNA flow‐cytometric studies revealed increased DNA content and prolonged S phase in transfected clones vs. FBM cells. Injection of cells s.c. obtained from soft agar colonies developed from 2 of the clones resulted in tumour formation at the site of injection. In both cases, lung metastasis was also seen. Thus, in conclusion, it appears that increased expression of CK8 in some way changes the phenotypic characteristics of stratified epithelial cells, resulting in malignant transformation. © 2004 Wiley‐Liss, Inc.
Suppression of thymic lymphomas and increased nonthymic lymphomagenesis in Trp53‐deficient mice lacking inducible nitric oxide synthase gene
Authors: Tatemichi Masayuki , Tazawa Hiroshi , Masuda Mitsuharu , Saleem Mohammad , Wada Sayori , Donehower Lawrence A. , Ohgaki Hiroko , Ohshima Hiroshi 
Published: May 2004

AbstractTrp53‐deficient mice spontaneously develop lymphomas, mainly of thymic origin, although the molecular mechanism remains largely unknown. As several interaction effects between p53 and iNOS have been reported, we hypothesized that iNOS activity in the thymus is causally linked to lymphomagenesis in Trp53‐deficient mice. We therefore created mouse strains with different combinations of the Trp53 and iNOS genes. Western blot and histologic analyses showed that the iNOS protein was constitutively expressed in the thymus independently of Trp53 status and its expression was enhanced in Trp53+/– and Trp53–/– mice compared to Trp53+/+ mice. Homozygous disruption of iNOS decreased the incidence of thymic lymphomas by almost 40% (p = 0.087) and 90% (p < 0.05) in Trp53–/– and Trp53+/– mice, respectively, compared to the respective iNOS wild‐type mice but significantly (p < 0.05) increased the development of nonthymic lymphomas in Trp53–/– and Trp53+/– mice. Although iNOS gene disruption did not affect the phenotype of thymic lymphomas, absence of the iNOS gene shifted the spectrum of nonthymic lymphoma from the B‐cell to the T‐cell lineage. RT‐PCR analysis revealed enhanced expression of IL‐10, which could have a promoting effect on lymphomagenesis, even without any stimulation, in the spleen of aging mice with the gene combinations Trp53–/–iNOS–/– and Trp53+/–iNOS–/– but not Trp53–/–iNOS+/+ or Trp53+/–iNOS+/+. These results suggest that iNOS could increase the development of thymic lymphomas in Trp53‐deficient mice. While iNOS may have protective effects against nonthymic lymphomagenesis, the regulation of cytokine production by iNOS may be involved in the underlying mechanism of antilymphomagenesis effects in the peripheral lymphoid organ. © 2004 Wiley‐Liss, Inc.
Test sensitivity of prostate‐specific antigen in the Finnish randomised prostate cancer screening trial
Authors: Auvinen Anssi , Määttänen Liisa , Finne Patrik , Stenman Ulf‐Håkan , Aro Jussi , Juusela Harri , Rannikko Sakari , Tammela Teuvo L.J. , Hakama Matti 
Published: May 2004

AbstractWe estimated the sensitivity of serum prostate‐specific antigen (PSA) as a screening test for prostate cancer in the Finnish randomised, population‐based prostate cancer screening trial. The study population consisted of 80,458 men aged 55–67 years identified from the national population registry and randomised to the screening or control arm of the trial. The screening algorithm was based on determination of serum PSA concentration. Test sensitivity was estimated based on interval cancer incidence during the first 4 years of follow‐up among screening participants with a negative screening test. Interval cancers were defined as those occurring among men with a negative screening test. Altogether, 19 interval cancers were detected among 17,897 men with serum PSA < 3 ng/ml during the first screening interval. A further 5 cases were diagnosed among 811 men with PSA 3.0–3.9 ng/ml with a benign digital rectal examination or free total PSA ratio ≥ 0.16. Test sensitivity based on serum PSA of 3 ng/ml was estimated to be 0.89 (95% confidence interval 0.84–0.93) and that based on PSA of 4 ng/ml combined with an ancillary test (digital rectal examination or free total PSA ratio in the PSA range 3.0–3.9) was 0.87 (0.82–0.92). Test sensitivity achieved with serum PSA in prostate cancer screening appears excellent in the context of a population‐based effectiveness trial. © 2004 Wiley‐Liss, Inc.