bluuebunny/crossref_metadata_2025_split huggingface dataset:
Down-regulated nucleoside diphosphate kinasenm23-H1expression is unrelated to high-risk human papillomavirus but associated with progression of cervical intraepithelial neoplasia and unfavourable prognosis in cervical cancer
Authors: Branca M , Giorgi C , Ciotti M , Santini D , Di Bonito L , Costa S , Benedetto A , Bonifacio D , Di Bonito P , Paba P , Accardi L , Mariani L , Ruutu M , Favalli C , Syrjänen K 
Published: March 2006

Objective:One of the factors leading to an invasive phenotype is thenm23family of metastases-associated genes. Of the six known members,nm23-H1is the most frequently studied potential anti-metastatic gene in cervical cancer. However, the possible molecular links to oncogenic human papillomavirus (HPV) are completely unexplored as yet.Materials and methods:As a part of the HPV-Pathogen Istituto Superiore di Sanità study, a series of 150 squamous cell carcinomas (SCCs) and 152 cervical intraepithelial neoplasia (CIN) lesions were examined by immunohistochemical staining fornm23-H1, and tested for HPV by polymerase chain reaction (PCR) with three sets of primers (MY09/11, GP5+/GP6+and short PCR fragment). Follow-up data were available on all patients with SCC, and 67 CIN lesions were monitored by serial PCR for clearance or persistence of HPV after cone treatment.Results:A linear decrease (p = 0.001) was observed innm23-H1expression, starting from CIN1 (85% with normal expression), with the most dramatic down regulation on transition from CIN2 (70% normal) to CIN3 (39%) and further to SCC (25%). Reduced expression was associated with CIN3 or cancer at an odds ratio 8.72 (95% confidence interval 4.13 to 18.41).Nm23-H1was of no use as a marker of the high-risk human papillomavirus (HR-HPV) type, and it did not predict clearance or persistence of HR-HPV after treatment of CIN. Importantly,nm23-H1expression was a significant prognostic factor in cervical cancer, reduced expression being associated with lower survival (p = 0.022) in univariate analysis. In the multivariate (Cox) regression model, however, only the International Federation of Gynecology and Obstetrics stage (p = 0.001) and age (p = 0.011) remained independent prognostic predictors.Conclusions:Down-regulatednm23-H1expression is markedly associated with progression from CIN2 to CIN3, and predicts poor prognosis in cervical cancer.Nm23-H1down regulation is probably orchestrated by mechanisms independent of HR-HPV oncoproteins and is possibly related to the emergence of a proteolytic phenotype.
Crystalline plasma cell inclusions in helicobacter-associated gastritis
Authors: Stewart C J R , Spagnolo D V 
Published: March 2006

Background:Crystalline cytoplasmic inclusions are well documented in B cell lymphomas but have rarely been described in reactive plasmacytic infiltrates.Aim:Three cases of Lelicobacter-associated gastritis are described in which plasma cells focally contained rhomboid and needle-shaped crystalline inclusions.Methods:Crystalline inclusions were identified in the gastric biopsy specimens from three patients undergoing routine upper gastrointestinal endoscopy. The cells were characterised immunohistochemically using the following antisera: cytokeratin, leucocyte common antigen, desmin, CD20, CD68, CD79a, CD138, immunoglobulin (Ig)G, IgA and IgM heavy chains, and κ and λ Ig light chains. Clinical follow-up data were obtained.Results:All biopsies showed a Lelicobacter-associated active chronic gastritis. Variable numbers of plasma cells with intracytoplasmic crystalline inclusions in the superficial lamina propria were seen. The crystals were not stained with any of the antisera tested, but the cells containing the crystals expressed CD79a and CD138 and, in the two assessable cases, showed IgA and λ light chain immunoreactivity. The more numerous morphologically normal plasma cells in each patient were polytypic, and there were no histological features to suggest lymphoma. Crystals were not identified in the plasma cells in mucosal biopsy specimens from other sites in any of the patients.Conclusions:Crystalline inclusions in plasma cells can occur in association with Lelicobacter gastritis. Although light chain restriction was shown in two patients, the overall histological and clinical findings indicated a reactive process. The presence of plasma cell crystals in isolation should not be considered to be diagnostic of lymphoma.
THEORETICAL AND NUMERICAL STUDY OF AN IMPLICIT DISCRETIZATION OF A 1D INVISCID MODEL FOR RIVER FLOWS
Authors: BERMÚDEZ A. , MUÑOZ-SOLA R. , RODRÍGUEZ C. , VILAR M. A. 
Published: March 2006

In this paper, we consider a 1D inviscid model to simulate river flows whose unknown are the water elevation, the flow rate and the wet area. We rewrite this model in terms of the wet area and the flow rate. Next, by using a weak formulation and a discretization by characteristics, we derive an implicit semidiscretized scheme that involves a variational inequality. Under suitable hypothesis, we prove that this scheme has at least one solution. We present an algorithm for the numerical solution of the fully discretized problem and the numerical results obtained for channels with parabolic and rectangular sections and variable depth. Finally, we perform a stability analysis for the semidiscretized scheme applied to a similar problem where the convection term has been omitted.
Cancer Cell Mitochondria Are Direct Proapoptotic Targets for the Marine Antitumor Drug Lamellarin D
Authors: Kluza Jérôme , Gallego Miguel-Angel , Loyens Anne , Beauvillain Jean-Claude , Sousa-Faro José-Maria Fernandez , Cuevas Carmen , Marchetti Philippe , Bailly Christian 
Published: March 2006

Abstract
Lamellarin D is a marine alkaloid with a pronounced cytotoxicity against a large panel of cancer cell lines and is a potent inhibitor of topoisomerase I. However, lamellarin D maintains a marked cytotoxicity toward cell lines resistant to the reference topoisomerase I poison camptothecin. We therefore hypothesized that topoisomerase I is not the only cellular target for the drug. Using complementary cell-based assays, we provide evidence that lamellarin D acts on cancer cell mitochondria to induce apoptosis. Lamellarin D, unlike camptothecin, induces early disruption of the inner mitochondrial transmembrane potential (Δψm) in the P388 leukemia cell line. The functional alterations are largely prevented by cyclosporin A, an inhibitor of the mitochondrial permeability transition (MPT), but not by the inhibitor of caspases, benzyloxycarbonyl-Val-Ala-Asp(Ome)-fluoromethylketone. Δψm disruption is associated with mitochondrial swelling and cytochrome c leakage. Using a reliable real-time flow cytometric monitoring of Δψm and swelling of mitochondria isolated from leukemia cells, we show that lamellarin D has a direct MPT-inducing effect. Furthermore, mitochondria are required in a cell-free system to mediate lamellarin D–induced nuclear apoptosis. The direct mitochondrial effect of lamellarin D accounts for the sensitivity of topoisomerase I–mutated P388CPT5 cells resistant to camptothecin. Interestingly, a tumor-active analogue of lamellarin D, designated PM031379, also exerts a direct proapoptotic action on mitochondria, with a more pronounced activity toward mitochondria of tumor cell lines compared with nontumor cell lines. Altogether, this work reinforces the pharmacologic interest of the lamellarins and defines lamellarin D as a lead in the search for treatments against chemoresistant cancer cells. (Cancer Res 2006; 66(6): 3177-87)
Tumor Susceptibility and Apoptosis Defect in a Mouse Strain Expressing a Human p53 Transgene
Authors: Dudgeon Crissy , Kek Calvina , Demidov Oleg N. , Saito Shin-ichi , Fernandes Kenneth , Diot Alexandra , Bourdon Jean-Christophe , Lane David P. , Appella Ettore , Fornace Albert J. , Bulavin Dmitry V. 
Published: March 2006

Abstract
Activation of apoptosis is believed to be critical for the role of p53 as a tumor suppressor. Here, we report a new mouse strain carrying a human p53 transgene in the mouse p53-null background. Expression of human p53 in these mice was comparable with wild-type murine p53; however, transactivation, induction of apoptosis, and G1-S checkpoint, but not transrepression or regulation of a centrosomal checkpoint, were deregulated. Although multiple functions of p53 were abrogated, mice carrying the human p53 transgene did not show early onset of tumors as typically seen for p53-null mice. In contrast, human p53 in the p53-null background did not prevent accelerated tumor development after genotoxic or oncogenic stress. Such behavior of human p53 expressed at physiologic levels in transgenic cells could be explained by unexpectedly high binding with Mdm2. By using Nutlin-3a, an inhibitor of the interaction between Mdm2 and p53, we were able to partially reconstitute p53 transactivation and apoptosis in transgenic cells. Our findings indicate that the interaction between p53 and Mdm2 controls p53 transcriptional activity in homeostatic tissues and regulates DNA damage– and oncogene-induced, but not spontaneous, tumorigenesis.(Cancer Res 2006; 66(6): 2928-36)
Overexpression of the Oncoprotein Prothymosin α Triggers a p53 Response that Involves p53 Acetylation
Authors: Kobayashi Takahiko , Wang Ting , Maezawa Masaji , Kobayashi Masanobu , Ohnishi Shunsuke , Hatanaka Kazuteru , Hige Shuhei , Shimizu Yuichi , Kato Mototsugu , Asaka Masahiro , Tanaka Junji , Imamura Masahiro , Hasegawa Kiminori , Tanaka Yoshiyuki , Brachmann Rainer K. 
Published: March 2006

Abstract
Activation of the tumor suppressor protein p53 is a critical cellular response to various stress stimuli and to inappropriate activity of growth-promoting proteins, such as Myc, Ras, E2F, and β-catenin. Protein stability and transcriptional activity of p53 are modulated by protein-protein interactions and post-translational modifications, including acetylation. Here, we show that inappropriate activity of prothymosin α (PTMA), an oncoprotein overexpressed in human cancers, triggers a p53 response. Overexpression of PTMA enhanced p53 transcriptional activity in reporter gene assays for p53 target gene promoters hdm2, p21, and cyclin G. Overexpressed PTMA resulted in increased mRNA and protein levels for endogenous p53 target genes, hdm2 and p21, and in growth suppression. In contrast, reduction of endogenous PTMA through RNA interference decreased p53 transcriptional activity. Histone acetyltransferases (HATs) act as p53 coactivators and acetylate p53. PTMA, known to interact with HATs, led to increased levels of acetylated p53. PTMA did not increase the transcriptional activity of an acetylation-deficient p53 mutant, suggesting that p53 acetylation is an indispensable part of the p53 response to PTMA. Chromatin immunoprecipitation assays showed that excess PTMA associates with the p21 promoter and results in increased levels of acetylated p53 at the p21 promoter. Our findings indicate that overexpressed PTMA elicits a p53 response that involves p53 acetylation. (Cancer Res 2006; 66(6): 3137-44)
Dynamic Interactions of Cortactin and Membrane Type 1 Matrix Metalloproteinase at Invadopodia: Defining the Stages of Invadopodia Formation and Function
Authors: Artym Vira V. , Zhang Ying , Seillier-Moiseiwitsch Françoise , Yamada Kenneth M. , Mueller Susette C. 
Published: March 2006

Abstract
Metastatic tumor cells that actively migrate and invade surrounding tissues rely on invadopodia to degrade extracellular matrix (ECM) barriers. Invadopodia are membrane protrusions that localize enzymes required for ECM degradation. Little is known about the formation, function, and regulation of invadopodia. Here, we show that invadopodia have two distinct aspects: (a) structural for organizing the cellular actin cytoskeleton to form membrane protrusions and (b) functional for using proteolytic enzyme(s) for ECM degradation. Small interfering RNA (siRNA) inhibition established that organization of invadopodia structure requires cortactin, whereas protease inhibitor studies identified membrane type 1 matrix metalloproteinase (MT1-MMP) as the key invadopodial enzyme responsible for gelatin matrix degradation in the breast carcinoma cell line MDA-MB-231. The inhibition of invadopodial structure assembly by cortactin depletion resulted in a block of matrix degradation due to failure of invadopodia formation. Either protease inhibition or MT1-MMP siRNA depletion moderately decreased the formation of invadopodial structures that were identified as actin-cortactin accumulations at the ventral cell membrane adherent to matrix. The invadopodia that were able to form upon MT1-MMP inhibition or depletion retained actin-cortactin accumulations but were unable to degrade matrix. Examination of cells at different time points as well as live-cell imaging revealed four distinct invadopodial stages: membrane cortactin aggregation at membranes adherent to matrix, MT1-MMP accumulation at the region of cortactin accumulation, matrix degradation at the invadopodia region, and subsequent cortactin dissociation from the area of continued MT1-MMP accumulation associated with foci of degraded matrix. Based on these results, we propose a stepwise model of invadopodia formation and function. (Cancer Res 2006; 66(6): 3034-43)
Delocalization and Destabilization of the Arf Tumor Suppressor by the Leukemia-Associated NPM Mutant
Authors: Colombo Emanuela , Martinelli Paola , Zamponi Raffaella , Shing Danielle C. , Bonetti Paola , Luzi Lucilla , Volorio Sara , Bernard Loris , Pruneri Giancarlo , Alcalay Myriam , Pelicci Pier Giuseppe 
Published: March 2006

Abstract
One third of acute myeloid leukemias (AMLs) are characterized by the aberrant cytoplasmic localization of nucleophosmin (NPM) due to mutations within its putative nucleolar localization signal. NPM mutations are mutually exclusive with major AML-associated chromosome rearrangements and are frequently associated with a normal karyotype, suggesting that they are critical during leukemogenesis. The underlying molecular mechanisms are, however, unknown. NPM is a nucleocytoplasmic shuttling protein that has been implicated in several cellular processes, including ribosome biogenesis, centrosome duplication, cell cycle progression, and stress response. It has been recently shown that NPM is required for the stabilization and proper nucleolar localization of the tumor suppressor p19Arf. We report here that the AML-associated NPM mutant localizes mainly in the cytoplasm due to an alteration of its nucleus-cytoplasmic shuttling equilibrium, forms a direct complex with p19Arf, but is unable to protect it from degradation. Consequently, cells or leukemic blasts expressing the NPM mutant have low levels of cytoplasmic Arf. Furthermore, we show that expression of the NPM mutant reduces the ability of Arf to initiate a p53 response and to induce cell cycle arrest. Inactivation of p19Arf, a key regulator of the p53-dependent cellular response to oncogene expression, might therefore contribute to leukemogenesis in AMLs with mutated NPM. (Cancer Res 2006; 66(6): 3044-50)
The Secretory Leukocyte Protease Inhibitor Is a Type 1 Insulin-Like Growth Factor Receptor–Regulated Protein that Protects against Liver Metastasis by Attenuating the Host Proinflammatory Response
Authors: Wang Ni , Thuraisingam Thusanth , Fallavollita Lucia , Ding Aihao , Radzioch Danuta , Brodt Pnina 
Published: March 2006

Abstract
The secretory leukocyte protease inhibitor (SLPI) can attenuate the host proinflammatory response by blocking nuclear factor κB (NF-κB)–mediated tumor necrosis factor α (TNF-α) production in macrophages. We have previously shown that highly metastatic human and mouse carcinoma cells, on their entry into the hepatic microcirculation, trigger a rapid host proinflammatory response by inducing TNF-α production in resident Kupffer cells. Using GeneChip microarray analysis, we found that in mouse Lewis lung carcinoma subclones, SLPI expression was inversely correlated with tumor cell ability to induce a proinflammatory response and metastasize to the liver and with type 1 insulin-like growth factor receptor expression levels. To establish a causal relationship between SLPI expression and the metastatic phenotype, we generated, by transfection, multiple clones of the highly metastatic subline (H-59) that overexpress SLPI. We show here that the ability of these cells to elicit a host proinflammatory response in the liver was markedly decreased, as evidenced by reduced TNF-α production and vascular E-selectin expression, relative to controls. Moreover, these cells formed significantly fewer hepatic metastases (up to 80% reduction) as compared with mock-transfected controls. Our findings show that SLPI can decrease the liver-metastasizing potential of carcinoma cells and that this protective effect correlates with a decrease in the production of hepatic TNF-α and E-selectin. They suggest that factors that attenuate the host proinflammatory response may have a therapeutic potential in the prevention of liver metastasis. (Cancer Res 2006; 66(6): 3062-70)
In vivo Margin Assessment during Partial Mastectomy Breast Surgery Using Raman Spectroscopy
Authors: Haka Abigail S. , Volynskaya Zoya , Gardecki Joseph A. , Nazemi Jon , Lyons Joanne , Hicks David , Fitzmaurice Maryann , Dasari Ramachandra R. , Crowe Joseph P. , Feld Michael S. 
Published: March 2006

Abstract
We present the first demonstration of in vivo collection of Raman spectra of breast tissue. Raman spectroscopy, which analyzes molecular vibrations, is a promising new technique for the diagnosis of breast cancer. We have collected 31 Raman spectra from nine patients undergoing partial mastectomy procedures to show the feasibility of in vivo Raman spectroscopy for intraoperative margin assessment. The data was fit with an established model, resulting in spectral-based tissue characterization in only 1 second. Application of our previously developed diagnostic algorithm resulted in perfect sensitivity and specificity for distinguishing cancerous from normal and benign tissues in our small data set. Significantly, we have detected a grossly invisible cancer that, upon pathologic review, required the patient to undergo a second surgical procedure. Had Raman spectroscopy been used in a real-time fashion to guide tissue excision during the procedure, the additional reexcision surgery might have been avoided. These preliminary findings suggest that Raman spectroscopy has the potential to lessen the need for reexcision surgeries resulting from positive margins and thereby reduce the recurrence rate of breast cancer following partial mastectomy surgeries. (Cancer Res 2006; 66(6): 3317-22)
Spontaneous and UV Radiation–Induced Multiple Metastatic Melanomas in Cdk4R24C/R24C/TPras Mice
Authors: Hacker Elke , Muller H. Konrad , Irwin Nicole , Gabrielli Brian , Lincoln Douglas , Pavey Sandra , Powell Marianne Broome , Malumbres Marcos , Barbacid Mariano , Hayward Nicholas , Walker Graeme 
Published: March 2006

Abstract
Human melanoma susceptibility is often characterized by germ-line inactivating CDKN2A (INK4A/ARF) mutations, or mutations that activate CDK4 by preventing its binding to and inhibition by INK4A. We have previously shown that a single neonatal UV radiation (UVR) dose delivered to mice that carry melanocyte-specific activation of Hras (TPras) increases melanoma penetrance from 0% to 57%. Here, we report that activated Cdk4 cooperates with activated Hras to enhance susceptibility to melanoma in mice. Whereas UVR treatment failed to induce melanomas in Cdk4R24C/R24C mice, it greatly increased the penetrance and decreased the age of onset of melanoma development in Cdk4R24C/R24C/TPras animals compared with TPras alone. This increased penetrance was dependent on the threshold of Cdk4 activation as Cdk4R24C/+/TPras animals did not show an increase in UVR-induced melanoma penetrance compared with TPras alone. In addition, Cdk4R24C/R24C/TPras mice invariably developed multiple lesions, which occurred rarely in TPras mice. These results indicate that germ-line defects abrogating the pRb pathway may enhance UVR-induced melanoma. TPras and Cdk4R24C/R24C/TPras tumors were comparable histopathologically but the latter were larger and more aggressive and cultured cells derived from such melanomas were also larger and had higher levels of nuclear atypia. Moreover, the melanomas in Cdk4R24C/R24C/TPras mice, but not in TPras mice, readily metastasized to regional lymph nodes. Thus, it seems that in the mouse, Hras activation initiates UVR-induced melanoma development whereas the cell cycle defect introduced by mutant Cdk4 contributes to tumor progression, producing more aggressive, metastatic tumors. (Cancer Res 2006; 66(6): 2946-52)
Promoter Hypermethylation of Multiple Genes in Sputum Precedes Lung Cancer Incidence in a High-Risk Cohort
Authors: Belinsky Steven A. , Liechty Kieu C. , Gentry Frederick D. , Wolf Holly J. , Rogers Justin , Vu Kieu , Haney Jerry , Kennedy Tim C. , Hirsch Fred R. , Miller York , Franklin Wilbur A. , Herman James G. , Baylin Stephen B. , Bunn Paul A. , Byers Tim 
Published: March 2006

Abstract
A sensitive screening approach for lung cancer could markedly reduce the high mortality rate for this disease. Previous studies have shown that methylation of gene promoters is present in exfoliated cells within sputum prior to lung cancer diagnosis. The purpose of the current study is to conduct a nested case-control study of incident lung cancer cases from an extremely high-risk cohort for evaluating promoter methylation of 14 genes in sputum. Controls (n = 92) were cohort members matched to cases (n = 98) by gender, age, and month of enrollment. The comparison of proximal sputum collected within 18 months to &gt;18 months prior to diagnosis showed that the prevalence for methylation of gene promoters increased as the time to lung cancer diagnosis decreased. Six of 14 genes were associated with a &gt;50% increased lung cancer risk. The concomitant methylation of three or more of these six genes was associated with a 6.5-fold increased risk and a sensitivity and specificity of 64%. This is the first study to prospectively examine a large panel of genes for their ability to predict lung cancer and shows the promise of gene promoter hypermethylation in sputum as a molecular marker for identifying people at high risk for cancer incidence. (Cancer Res 2006; 66(6): 3338-44)