bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic and Epigenetic Alterations in the von Hippel-Lindau Gene: the Influence on Renal Cancer Prognosis
Authors: Smits Kim M. , Schouten Leo J. , van Dijk Boukje A.C. , Hulsbergen-van de Kaa Christina A. , Wouters Kim A.D. , Oosterwijk Egbert , van Engeland Manon , van den Brandt Piet A. 
Published: February 2008

Abstract
Background: Inactivation of the von Hippel-Lindau (VHL) gene is considered as an early event in renal cancer tumorigenesis. The prognostic relevance of these changes, however, is not clear and previous results are contradictory. We have evaluated the influence of (epi)genetic alterations in VHL on cause-specific survival in clear-cell renal cell cancer (ccRCC) in a large, population-based group of cases.
Methods: One hundred and eighty-five cases of ccRCC, identified in the Netherlands Cohort Study on diet and cancer diagnosed in the period 1986 to 1997, were included in the analyses. Mortality information until December 2005, including causes of death, were obtained for all cases through linkage with the Central Bureau of Statistics. VHL mutations were determined with PCR single-strand conformational polymorphism and direct sequencing. VHL methylation was determined with methylation-specific PCR. Kaplan-Meier analyses and Cox proportional hazards models were used to assess associations between VHL alterations and cause-specific mortality.
Results: Median follow-up in our population was 6 years. The frequency of loss of function mutations and methylation, separately or combined, did not differ statistically significant between different cancer stages or between tumors with different sizes. We observed no influence of loss of function mutations or methylation of the VHL gene on cause-specific mortality (hazard ratio, 1.08; 95% confidence interval, 0.69-1.68, P = 0.735) as compared with patients with a wild-type or silent mutation in VHL.
Discussion: Our results indicate that (epi)genetic alterations in the VHL gene do not have prognostic value in ccRCC.
Endogenous Vascular Endothelial Growth Factor-C Expression Is Associated with Decreased Drug Responsiveness in Childhood Acute Myeloid Leukemia
Authors: de Jonge Hendrik J.M. , Weidenaar Alida C. , ter Elst Arja , Boezen H. Marike , Scherpen Frank J.G. , Bouma-ter Steege Jessica C.A. , Kaspers Gertjan J.L. , Goemans Bianca F. , Creutzig Ursula , Zimmermann Martin , Kamps Willem A. , de Bont Eveline S.J.M. 
Published: February 2008

Abstract
Purpose: We hypothesized that downstream effects of endogenous vascular endothelial growth factor (VEGF)/VEGF receptor signaling on acute myelogenous leukemia (AML) cell survival resulted in increased in vitro cellular drug resistance and a longer time to kill most leukemic cells in vivo upon drug exposure.
Experimental Design: In primary AML cells from pediatric patients, VEGFA and VEGFC mRNA expression and in vitro cellular resistance to nine cytotoxic drugs were studied. As in vivo equivalents for in vitro drug resistance, in vivo AML blast reduction upon drug exposure, measured as blast cell reduction on day 15 in the bone marrow and as time in days from diagnosis to complete remission (CR) were used.
Results: Increased endogenous VEGFC levels significantly correlated with increased in vitro resistance for six typical AML drugs in primary AML cells from pediatric patients. Patients with &gt;5% blasts on day 15 showed a 12.9-fold increase in the median VEGFC level compared with patients with ≤5% blasts (P = 0.002). Time to reach CR was studied using linear regression analysis with VEGFC, age at diagnosis, sex, treatment protocol, FAB type, cytogenetic risk profile, and WBC counts as variables. There was a significant positive independent association between VEGFC levels and time to CR (b = 6.02, SE = 1.58, P ≤ 0.0001, n = 72).
Conclusions: These results suggest for the first time that higher endogenous VEGFC levels of AML cells are related to decreased in vitro and in vivo drug responsiveness.
In vitro and In vivo Radiosensitization Induced by the DNA Methylating Agent Temozolomide
Authors: Kil Whoon Jong , Cerna David , Burgan William E. , Beam Katie , Carter Donna , Steeg Patricia S. , Tofilon Philip J. , Camphausen Kevin 
Published: February 2008

Abstract
Purpose: Temozolomide, a DNA methylating agent, is currently undergoing clinical evaluation for cancer therapy. Because temozolomide has been shown to increase survival rates of patients with malignant gliomas when given combined with radiation, and there is conflicting preclinical data concerning the radiosensitizing effects of temozolomide, we further investigated the possible temozolomide-induced enhancement of radiosensitivity.
Experimental Design: The effects of temozolomide on the in vitro radiosensitivity of U251 (a human glioma) and MDA-MB231BR (a brain-seeking variant of a human breast tumor) cell lines was evaluated using clonogenic assay. DNA damage and repair were evaluated using phosphorylated histone H2AX (γH2AX), and mitotic catastrophe was measured using nuclear fragmentation. Growth delay was used to evaluate the effects of temozolomide on in vivo (U251) tumor radiosensitivity.
Results: Exposure of each cell line to temozolomide for 1 h before irradiation resulted in an increase in radiosensitivity with dose enhancement factors at a surviving fraction of 0.1 ranging from 1.30 to 1.32. Temozolomide had no effect on radiation-induced apoptosis or on the activation of the G2 cell cycle checkpoint. As a measure of DNA double strand breaks, γH2AX foci were determined as a function of time after the temozolomide + irradiation combination. The number of γH2AX foci per cell was significantly greater at 24 h after the combined modality compared with the individual treatments. Mitotic catastrophe, measured at 72 h, was also significantly increased in cells receiving the temozolomide + irradiation combination compared with the single treatments. In vivo studies revealed that temozolomide administration to mice bearing U251 tumor xenografts resulted in a greater than additive increase in radiation-induced tumor growth delay with a dose enhancement factor of 2.8.
Conclusions: These results indicate that temozolomide can enhance tumor cell radiosensitivity in vitro and in vivo and suggest that this effect involves an inhibition of DNA repair leading to an increase in mitotic catastrophe.
Suppression of Lung Tumor Growth and Metastasis in Mice by Adeno-Associated Virus-Mediated Expression of Vasostatin
Authors: Cai Ke Xia , Tse Lai Ying , Leung Carly , Tam Paul K.H. , Xu Ruian , Sham Mai Har 
Published: February 2008

Abstract
Purpose: Angiogenesis inhibitors have strong therapeutic potential as antitumor agents in suppressing tumor growth and metastatic progression. Vasostatin, the N-terminal domain of calreticulin, is a potent angiogenesis inhibitor. In this study, we determined the effectiveness of vasostatin delivered by recombinant pseudotype adeno-associated virus 2/5 (rAAV2/5-VAS) as a gene therapy approach for lung cancer treatment.
Experimental Design: We used rAAV2/5 to deliver vasostatin intratumorally or systemically in different mouse lung tumor models — subcutaneous, orthotopic xenograft, and spontaneous metastasis lung tumor models. The therapeutic efficacy of rAAV2/5-VAS was determined by monitoring tumor volume, survival rate, and degree of neovascularization after treatment in these models.
Results: Mice bearing subcutaneous tumor of rAAV2/5-VAS pretreated Lewis lung carcinoma cells showed &gt;50% reduction in primary tumor volume and reduced spontaneous pulmonary metastases. The tumor-suppressive action of rAAV2/5-VAS in subcutaneous human lung tumor A549 xenograft correlated with a reduced number of capillary vessels in tumors. In the orthotopic xenograft model, rAAV2/5-VAS suppressed metastasis of A549 tumors to mediastinal lymph nodes and contralateral lung. Furthermore, treatment of immunocompetent mice in the spontaneous lung metastases model with rAAV2/5-VAS after primary tumor excision prolonged their median survival from 21 to 51.5 days.
Conclusion: Our results show the effectiveness of rAAV2/5-VAS as an angiogenesis inhibitor in suppressing tumor growth during different stages of tumor progression, validating the application of rAAV2/5-VAS gene therapy in treatment against lung cancer.
Activation of CCR9/CCL25 in Cutaneous Melanoma Mediates Preferential Metastasis to the Small Intestine
Authors: Amersi Farin F. , Terando Alicia M. , Goto Yasufumi , Scolyer Richard A. , Thompson John F. , Tran Andy N. , Faries Mark B. , Morton Donald L. , Hoon Dave S.B. 
Published: February 2008

Abstract
Purpose: Specific chemokines and their respective receptors have been implicated in distant tumor cell metastasis. Cutaneous melanoma has a distinct pattern of metastasis, preferentially targeting the submucosa of the small intestine. However, the underlying pathogenic mechanism remains unknown. Migration of CCR9(+) lymphocytes to the small intestine is known to occur in response to the chemoattractant effects of CCL25 (thymus-expressed chemokine). The integrin heterodimers αβ are also known to be important mediators of cellular adhesion. We hypothesize that the mechanism of small intestinal metastasis by melanoma is via the CCR9-CCL25 axis and specific integrins.
Experimental Design: Quantitative reverse transcription-PCR, flow cytometry, and immunohistochemistry were used to assess melanoma tumors for CCR9 and CCL25. Integrin expression was assessed using flow cytometry. CCR9 expression by quantitative reverse transcription-PCR was assessed in primary (n = 23) and metastatic (n = 198) melanomas, and melanoma lines derived from small intestinal metastases (n = 23).
Results: We showed CCR9 expression in 88 of 102 paraffin-embedded metastatic melanomas from the small intestine, 8 of 8 melanoma lines derived from metastases in the small intestine, and 0 of 96 metastatic melanomas from other sites. In vitro migration and invasion studies done on CCR9(+) melanoma lines showed migration in response to CCL25 that was inhibited by anti-CCR9 antibody or by short interfering RNA CCR9. Flow cytometric analysis confirmed CCR9 expression by melanomas to the small intestine and showed concomitant α4β1 integrin expression.
Conclusions: Our findings show that functionally active CCR9 on melanoma cells facilitates metastasis to the small intestine. The CCR9-CCL25 axis may explain the high incidence of melanoma metastasis to this specific location.
Progression and Tumor Heterogeneity Analysis in Early Rectal Cancer
Authors: Lips Esther H. , van Eijk Ronald , de Graaf Eelco J.R. , Doornebosch Pascal G. , de Miranda Noel F.C.C. , Oosting Jan , Karsten Tom , Eilers Paul H.C. , Tollenaar Rob A.E.M. , van Wezel Tom , Morreau Hans 
Published: February 2008

Abstract
Purpose: Adequate preoperative staging of large sessile rectal tumors requires identifying adenomas that already contain an invasive focus, specifically those that are growing in or beyond the submucosa. We systematically compared chromosomal instability patterns in adenoma and carcinoma fractions of the same lesion to assess specific steps in rectal tumor progression.
Experimental Design: We analyzed 36 formalin-fixed, paraffin-embedded tumors. Both the adenoma and carcinoma fractions were typed with single nucleotide polymorphism arrays and compared with 21 previously described pure adenomas. Eighteen cases were included in an intratumor heterogeneity analysis.
Results: Five specific “malignant” events (gain of 8q, 13q, and 20q and loss of 17p and 18q) and aberrant staining for p53 and SMAD4 were all increased in the adenoma fractions of carcinoma cases compared with pure adenomas. Paired analysis revealed that 31% of the samples had an equal amount of malignant aberrations in their adenoma and carcinoma fractions, whereas 25% had one and 33% had two or more extra malignant events in the carcinoma fraction. Analysis of three core biopsies per patient showed a large degree of intratumor heterogeneity. However, the number of malignant aberrations in the biopsy with the most aberrations per tumor correlated with the corresponding adenoma or carcinoma fraction (r = 0.807; P &lt; 0.001).
Conclusion: Five specific chromosomal aberrations, combined with immunohistochemistry for p53 and SMAD4, can predict possible progression of sessile rectal adenomas to early rectal cancer and can, after validation studies, be added to preoperative staging. Preferably, three biopsies should be taken from each tumor to address intratumor heterogeneity.
The Prognostic Significance of Serum β2 Microglobulin Levels in Acute Myeloid Leukemia and Prognostic Scores Predicting Survival: Analysis of 1,180 Patients
Authors: Tsimberidou Apostolia-Maria , Kantarjian Hagop M. , Wen Sijin , O'Brien Susan , Cortes Jorge , Wierda William G. , Koller Charles , Pierce Sherry , Brandt Mark , Freireich Emil J. , Keating Michael J. , Estey Elihu H. 
Published: February 2008

AbstractPurpose: Serum β2 microglobulin (β2M) is prognostic in other hematologic malignancies; therefore, we evaluated its prognostic significance in acute myeloid leukemia (AML).Experimental Design: Multivariate analyses were used to examine the effect of pretreatment serum β2M levels on clinical outcomes in patients with AML. β2M was associated with poorer survival in older but not younger patients. We thus fit separate Cox survival models in patients above and below age 60 years treated with remission induction therapy containing high-dose cytarabine (n = 1,280). In each age group, 50% of the patients were used to develop the model, which was tested in the other 50%. Resampling methods were also used to validate the independent prognostic significance of covariates.Results: In patients 60 years or older (n = 591), poorer risk cytogenetics; poorer performance status; and higher levels of β2M, uric acid, and lactate dehydrogenase were each found to independently predict shorter survival and formed the basis of a scoring system. A similar approach was used in patients younger than 60 years (n = 589), with poorer risk cytogenetics, poorer performance status, older age, higher hemoglobin level, and higher leukocyte count predicting a shorter survival and forming the basis of the scoring system. Higher β2M levels were an adverse independent factor for response, survival, relapse-free survival, and event-free survival in older but not in younger patients.Conclusions: Serum β2M levels can help predict outcome in patients ≥60 years with untreated AML, and their use is strongly encouraged.
Focal Adhesion Kinase: Targeting Adhesion Signaling Pathways for Therapeutic Intervention
Authors: Parsons J. Thomas , Slack-Davis Jill , Tilghman Robert , Roberts W. Gregory 
Published: February 2008

Abstract
The tumor microenvironment plays a central role in cancer progression and metastasis. Within this environment, cancer cells respond to a host of signals including growth factors and chemotactic factors, as well as signals from adjacent cells, cells in the surrounding stroma, and signals from the extracellular matrix. Targeting the pathways that mediate many of these signals has been a major goal in the effort to develop therapeutics.
Jesus der Jude Die jüdische Leben-Jesu-Forschung von Abraham Geiger bis Ernst Ludwig Ehrlich
Authors: Homolka Walter 
Published: February 2008

AbstractThe article provides an overview of Jewish Life-of-Jesus research from Abraham Geiger to Ernst Ludwig Ehrlich. Julius Wellhausen's assessment that Jesus was not Christian but Jewish encountered a Jewish community that was striving for civic equality in the course of the Enlightenment and that saw itself impaired by the idea of the ,,Christian state". The ensuing Jewish concern with the central figure of the New Testament was not of fundamental nature, but rather followed from an apologetic impulse: the wish to participate in general society without having to give up Jewish identity. Since then, many Jewish thinkers of the modern era have studied Jesus. The essay outlines the history of ,,bringing Jesus home" to Judaism, which has been observed since the nineteenth century. Jesus returns as exemplary Jew, as hortatory prophet, as revolutionary and freedom fighter, as big brother and messianic Zionist. The foremost intention though was that Jews wanted to remain Jews and nevertheless be part of Christian society. How fortunate, therefore, that Jesus was Jewish.
Monstranz – Gott zeigen Das Fronleichnamsfest aus systemtheoretischer Perspektive
Authors: Hafner Johann EV. 
Published: February 2008

AbstractThe Feast of Corpus Christi was only able to assert itself after it came to be connected with a procession. In this visual rite a host in a monstrance is carried through the streets. The intention is to emphasize the substantial presence of Christ in the "accidental" form of bread. In studying such rites, a scholarly approach to religion does not limit itself to popular custom or sacramental theology, but also asks about the underlying functions of the feast of Corpus Christi. The following article interprets the Corpus Christi procession as a diffusion and expansion of the believer's focused attention. This, in turn, was a reaction to the overly strong emphasis on external appearances of piety when the host was elevated. The host itself may be interpreted as the blind spot of religious observation because it functions as a visible sign of the transcendental that is not further interpreted, but is displayed in silence. It is neither negated nor affirmed, though its meaning is presumed and is operationally repeated.
Jahresringe der Religions- und Geistesgeschichte Jubiläen und Erinnerungen anläßlich des 100. Geburtstages von Hans-Joachim Schoeps, des ,,60sten" der ,,Zeitschrift für Religions- und Geistesgeschichte" und des ,,50sten" der ,,Gesellschaft für Geistesgeschichte"
Authors: Knoll Joachim H. 
Published: February 2008

AbstractIn the near future three anniversaries are to be celebrated: Hans-Joachim Schoeps, German-Jewish scholar and full Professor of Religious and Intellectual History, would have been 100 years old in January 2009. Jointly together with Ernst Benz, full Professor of Theology at the University of Marburg, Hans-Joachim Schoeps launched the Journal of religious and intellectual history (ZRGG), which is now entering its 60th volume. Also, the Scientific Association for religious and intellectual history (GGG), which was as well founded by Hans-Joachim Schoeps, is going to celebrate its 50th anniversary. The article depicts biographical data and scholarly highlights of Schoeps, and combines them with a view to the development of ZRGG and GGG.
Las teorías científicas ante los problemas formativos. Contribución al debate ¿Qué teorías necesitamos en educación?
Authors: Bronckart Jean-Paul , Álvarez Amelia 
Published: February 2008

El problema de las teorías de referencia pertinentes para emprender intervenciones formativas remite al problema más general del estado actual del avance de las ciencias humanas y sociales, así como del lugar y el papel que ocupan los procesos de educación-formación en el seno de esas ciencias. Cualquier toma de postura sobre estas cuestiones reposa necesariamente en orientaciones filosóficas y epistemológicas (o al menos en preconcepciones” de carácter ontológico) relativas al lugar que ocupa lo humano en el universo, así como a las condiciones y desafíos de la formación y del desarrollo de los seres humanos. En este artículo se comienza por plantear un anclaje filosófico centrado en el problema de la hominización, dividido a su vez en dos partes: una aproximación al estatuto del “devenir del universo” y una aproximación a las características de la “ruptura humana” en el transcurrir de ese proceso. Sobre esa base, se aborda el problema de la situación de las teorías de referencia que podrían ser requeridas desde el campo educativo, así como el de la necesaria autonomía de un “pensamiento” de la educación-formación. Finalmente, se intenta proporcionar respuestas, modestas pero comprometidas, a las preguntas de partida.
Seasonal Evolution of the Upwelling Process South of Cape Blanco*
Authors: Ramp Steven R. , Bahr Frederick L. 
Published: February 2008

Abstract
Bursts of upwelling-favorable winds lasting 4–20 days occur year-round south of Cape Blanco, a major headland on the Oregon coast. The ocean’s response to these events was studied using moored current, temperature, and salinity data; satellite SST data; and a few across-shelf sections near the mooring site. The mooring was located at 42°26.49′N, 124°34.47′W, 6 n mi off Gold Beach, Oregon, from May 2000 to October 2003. After the spring transition but before upwelling jet separation, equatorward wind stress produced a steady upwelling response much the same as a long, straight coast. Currents and winds had similar spectral characteristics with a peak near 15 days. After jet separation, upwelling-favorable winds forced a much more variable current consisting of a series of thin equatorward jets that evolved and moved offshore across the mooring, with shorter time scales than the wind stress forcing. During autumn, the equatorward wind stress weakened slightly and a transition period occurred, with the flow often poleward along the bottom. During winter, the water column was unstratified during poleward winds and currents with little variation in SST across the shelf. Winter upwelling restratified the water column from the bottom up by drawing cold, salty water onshore along the bottom, with little or no change in SST. This scenario was modulated by strong intraseasonal and interannual variability in the ocean and atmosphere. A wavelet transform analysis of alongshore wind stress and the first empirical orthogonal mode of the alongshore currents revealed strong energy peaks in the 30–70-day band. These signals were particularly clear in the ocean and were not coherent with the local wind stress, suggesting they were due to Kelvin waves of equatorial origin. The shift toward longer (40–45–60 days) periods from 2000 to 2003 was consistent with decreasing (warming) northern oscillation index, suggesting that the period as well as the energy of the intraseasonal waves may be important in transmitting heat poleward during warm years.
Mesoscale to Submesoscale Transition in the California Current System. Part I: Flow Structure, Eddy Flux, and Observational Tests
Authors: Capet X. , McWilliams J. C. , Molemaker M. J. , Shchepetkin A. F. 
Published: February 2008

Abstract
In computational simulations of an idealized subtropical eastern boundary upwelling current system, similar to the California Current, a submesoscale transition occurs in the eddy variability as the horizontal grid scale is reduced to O(1) km. This first paper (in a series of three) describes the transition in terms of the emergent flow structure and the associated time-averaged eddy fluxes. In addition to the mesoscale eddies that arise from a primary instability of the alongshore, wind-driven currents, significant energy is transferred into submesoscale fronts and vortices in the upper ocean. The submesoscale arises through surface frontogenesis growing off upwelled cold filaments that are pulled offshore and strained in between the mesoscale eddy centers. In turn, some submesoscale fronts become unstable and develop submesoscale meanders and fragment into roll-up vortices. Associated with this phenomenon are a large vertical vorticity and Rossby number, a large vertical velocity, relatively flat horizontal spectra (contrary to the prevailing view of mesoscale dynamics), a large vertical buoyancy flux acting to restratify the upper ocean, a submesoscale energy conversion from potential to kinetic, a significant spatial and temporal intermittency in the upper ocean, and material exchanges between the surface boundary layer and pycnocline. Comparison with available observations indicates that submesoscale fronts and instabilities occur widely in the upper ocean, with characteristics similar to the simulations.