bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification and characterization of Birt–Hogg–Dubé associated renal carcinoma
Authors: Murakami T , Sano F , Huang Y , Komiya A , Baba M , Osada Y , Nagashima Y , Kondo K , Nakaigawa N , Miura T , Kubota Y , Yao M , Kishida T
Published: February 2007

The Birt–Hogg–Dubé (BHD) gene is responsible for BHD syndrome, a rare autosomal dominant disease, characterized by benign hair follicle tumours, spontaneous pneumothorax and renal neoplasms with diverse histology. To elucidate its involvement in the development of renal neoplasms, we examined a total of 100 sporadic renal tumours with various histological subtypes for BHD mutation by SSCP‐sequencing analyses. We found one germline insertion mutation in the C8 hotspot of exon 11 (c.1733insC), which is known to have a strong association with renal tumour occurrence. The germline‐mutated patient suffered from solitary renal cell carcinoma (RCC) but did not have any other BHD manifestations or family history. The tumour revealed heterogeneous cytomorphology, mainly a mixture of eosinophilic and focally clear cells with tubulopapillary architecture. In this tumour, both BHD alleles were inactivated by germline mutation concomitant with loss of heterozygosity, and the amount of BHD mRNA detected by real‐time quantitative PCR (RQ‐PCR) was very low. Renal tumour subtype/nephron segment‐specific gene expression detected by RQ‐PCR demonstrated that the tumour expressed relatively high amounts of α‐methylacyl‐CoA racemase (AMACR) and the KIT oncogene, but relatively low amounts of carbonic anhydrase IX (CA9), aquaporin 1 (AQP1), claudin 7 (CLDN7), parvalbumin (PVALB), chloride channel Kb (CLCNKB) and 11‐β‐hydroxysteroid dehydrogenase 2 (HSD11B2), suggesting diverse mRNA signatures. Further clustering analysis of 88 renal tumours based on expression of these eight genes sub‐classified the tumour as close to oncocytomas and chromophobe RCCs, which are considered distal nephron‐associated tumours. These data suggest that somatic mutation of BHD is relatively rare in Japanese patients. The BHD‐mutated RCC identified in this study, which exhibits heterogeneous biological features in both morphology and gene expression signatures, seems to deviate from our current understanding of renal tumour classification. Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Human osteosarcoma cells express functional receptor activator of nuclear factor‐kappa B
Authors: Mori K , Le Goff B , Berreur M , Riet A , Moreau A , Blanchard F , Chevalier C , Guisle‐Marsollier I , Léger J , Guicheux J , Masson M , Gouin F , Rédini F , Heymann D
Published: February 2007

RANK, RANK ligand (RANKL) and osteoprotegerin (OPG) are the key regulators of bone metabolism, both in normal and pathological conditions. Previous data have demonstrated that human osteosarcoma biopsies express RANKL as well as OPG, and functional RANK is expressed in a murine osteosarcoma cell line. As RANK expression in human osteosarcoma remains controversial, the aim of the present study was to analyse its expression in vitro in human osteosarcoma cell lines, ex vivo using pathological tissues, and then to determine its functionality in terms of signal transduction pathways modulated by RANKL. RT‐PCR analysis and immunohistochemistry experiments revealed that RANK is expressed at both transcriptional and protein levels in MNNG/HOS, Saos‐2 and MG‐63 human osteosarcoma cell lines, in contrast to the U‐2 OS osteosarcoma cell line and human osteoblasts, which were negative. RANK was also expressed in 57% of osteosarcoma biopsies. Furthermore, western blot experiments clearly demonstrated the functionality of RANK. Thus, RANKL significantly induced the phosphorylation of ERK1/2, p38 and IκB in RANK‐positive osteosarcoma cells. This study is the first report of functional RANK expression in human osteosarcoma cells: this strengthens the involvement of the RANK–RANKL–OPG axis in primary bone tumour biology and identifies novel therapeutic approaches targeting RANK‐positive osteosarcoma. Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Comparison of the effects of diclofenac or other non‐steroidal anti‐inflammatory drugs (NSAIDs) and diclofenac or other NSAIDs in combination with proton pump inhibitors (PPI) on hospitalisation due to peptic ulcer disease
Authors: Höer Ariane , Gothe Holger , Schiffhorst Guido , Sterzel Astrid , Grass Ulrich , Häussler Bertram
Published: February 2007

Purpose

Up to 25% of patients taking non‐steroidal anti‐inflammatory drugs (NSAIDs) chronically experience gastrointestinal side effects. This report aims to determine the gastroprotective effects of proton pump inhibitors (PPI) in patients taking NSAIDs, especially diclofenac.

Methods

From the claims database of a German sickness fund with 1.4 million beneficiaries, we used data from patients enrolled in the health plan continuously from 2000 until 2004 with an inpatient diagnosis of peptic ulcer disease in 2003 and 2004. For our nested case‐control study, we matched these cases for calendar time with up to 10 controls per case. Our main outcome measure were the adjusted odds ratios (ORs) for peptic ulcer disease associated with diclofenac and other NSAIDs.

Results

In the study population of 752 613 beneficiaries, 979 cases and 10 319 controls were identified. A stratified analysis according to the prescription of diclofenac alone or in combination with PPI showed that diclofenac prescriptions increased the risk for hospitalisation due to peptic ulcer significantly (adjusted OR 2.4 [95%CI 1.94, 3.05]). If PPI were prescribed concomitantly with diclofenac, we observed a risk reduction (OR 1.3 [95%CI 0.7, 2.3]). The significance of the PPI effect was shown using an interaction term in a regression model without stratification, where a risk reduction of 60% (OR 0.4 [95%CI 0.2, 0.7], p < 0.05) was found.

Conclusions

The concomitant prescription of PPI and diclofenac decreases the hospitalisation risk due to peptic ulcer significantly. The results support the use of PPI as gastroprotective agents in patients who receive NSAIDs. Copyright © 2007 John Wiley & Sons, Ltd.
Das Labor auf dem Chip: Mikrofluidik
Authors: Franke Thomas , Wixforth Achim
Published: February 2007

Das Labor auf dem Chip bietet viele Vorteile, weil es nur Mikro‐ oder Nanolitermengen benötigt. Es ermöglicht zum Beispiel sehr empfindliche gentechnische Analysen. Allerdings dominieren andere physikalische Kräfte das Verhalten mikro‐ und nanoskopischer Flüssigkeitsmengen als in der makroskopischen Welt. Eine besondere Herausforderung der Mikro‐ und Nanofluidik ist der Transport und die Manipulation der winzigen Flüssigkeitsmengen. Neben dreidimensionalen Chiparchitekturen richtet sich das Forschungsinteresse auf planare Strukturen, deren Oberflächeneigenschaften chemisch moduliert sind. Auf ihnen lassen sich die Fluide in Form winziger Tröpfchen manipulieren, besonders elegant sind dafür akustische Oberflächenwellen. Die erste Generation solcher Laborchips ist bereits auf dem Markt.
Tropfen säubern Blätter. Spielwiese
Authors: Schlichting Hans Joachim
Published: February 2007

Wassertropfen auf Pflanzenblättern befreien die Oberfläche von Staub. Das ist als Lotuseffekt bekannt. Auf liegenbleibenden Tropfen sammeln sich die Staubteilchen an der höchsten Stelle in Form eines kleinen runden Floßes. Dieser Vorgang lässt sich im Rahmen der klassischen Thermodynamik als Ergebnis der Maximierung der Energiedissipation erklären, was auf eine Minimierung der Grenzflächenenergie hinausläuft.
Akustische Oberflächenwellen schalten Lichtstrahlen
Authors: Beck Markus , de Lima Maurício M. , Santos Paulo
Published: February 2007

An der Nahtstelle zwischen Elektronik und Glasfaserkommunikation wird eine Vielzahl optoelektronischer Komponenten benötigt, die Licht erzeugen, elektrische Signale in optische umwandeln, schalten, verstärken, weiterleiten und verarbeiten. Am Paul‐Drude‐Institut für Festkörperelektronik in Berlin wurde ein neuartiges, einfach realisierbares Konzept demonstriert, das die Übertragung elektrischer in optische Signale in sehr kompakten integrierten Bauelementen ermöglicht.
Incorporation of Accessible Functionalities in Nanoscaled Coatings on Textiles Characterized by Coloration
Authors: Hossain M. Mokbul , Herrmann Axel S. , Hegemann Dirk
Published: February 2007

The plasma‐assisted process presented in this paper facilitates the deposition of nitrogen containing functional coatings on textiles. Low pressure RF plasma was used to deposit multi‐functional thin films, which have a high amine content. Either acetylene or ethylene were mixed with ammonia to obtain a crosslinked structure that contained functional groups, which were accessible for dye molecules throughout the film volume. Varying deposition conditions were used in order to compare hydrocarbon gas mixtures in terms of deposition rates, water contact angles, aging, dyeability, yellowness index, and rub/wash fastnesses. The deposition rates were found to be higher for the acetylene discharges, but decreased with increasing ammonia‐to‐hydrocarbon ratios for both gas mixtures. Although this indicates etching effects, a permanent hydrophilization could still be obtained. These findings demonstrate that plasma polymerization provides an eco‐friendly multi‐functionalized surface modification, since the use of chemicals, waste water etc. can be eliminated. Dyeing of the plasma coatings by acid dyestuffs showed that the relative color strength value, i.e. amine functionalities, can be noticeably enhanced, while being strongly influenced by the energy input and by the gas ratio. It was evident that the coating quality could be improved significantly using an ammonia/ethylene plasma due to reduced unsaturated bonds, the latter being investigated by the CIELAB color spaces. A high dyeing fastness indicated a strong dye‐molecule bonding, which in turn, is an indication of permanency of the amine groups. A pilot‐scale web coater at Empa was used to demonstrate the feasibility of industrial scale‐up.

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Field instrumentation for real‐time monitoring of periglacial solifluction
Authors: Harris Charles , Luetschg Martina , Davies Michael C. R. , Smith Fraser , Christiansen Hanne H. , Isaksen Ketil
Published: February 2007

Here we describe new field instrumentation recently installed on a non‐permafrost solifluction slope in Dovrefjell, Norway, and a continuous permafrost solifluction slope in Svalbard. The equipment is designed to provide continuous data on soil thermal status, hydraulic condition, phase change, soil volume strain and soil shear strain. Supporting frames were constructed from steel scaffolding tubes and provide a stable mounting for two LVDT displacement transducers. These are arranged in an inverted triangular configuration with the triangle apex linked to a small steel footplate embedded in the ground surface, allowing continuous monitoring of frost heave, thaw settlement and downslope surface displacements. In addition, thermistors and Druck PDCR 81 miniature pore pressure transducers were installed to a depth of 0.8 m in Dovrefjell and 1.2 m (approximately 20 cm below the permafrost table) in Svalbard. Thermistors were also mounted above the ground surface to 2 m to measure air temperature. All instrumentation was logged at 1 h intervals using a Campbell CR23X logger and multiplexer. In Svalbard an automatic digital camera recording one image per day was installed adjacent to the site in order to monitor snow depth. Simple Rudberg columns will be excavated after several years to observe the profiles of soil movement. Copyright © 2007 John Wiley & Sons, Ltd.
Periglacial Appalachia: palaeoclimatic significance of blockfield elevation gradients, eastern USA
Authors: Nelson Kim J. Park , Nelson Frederick E. , Walegur Michael T.
Published: February 2007

Locational data for 96 allochthonous blockfields distributed throughout the Appalachian Mountains of eastern USA were obtained using TerraServer, an online resource for viewing air‐photo and satellite imagery. The elevation of Appalachian blockfields south of the Last Glacial Maximum (LGM) border parallels regional gradients of contemporary mean July, summer and annual temperature. Mean July temperature reductions inferred from palaeoecological studies indicate that the median elevation of blockfields throughout the Appalachians lay at or above timberline during the LGM. Palaeotemperatures calculated using known Appalachian lapse rates and published LGM temperature departures indicate that most blockfields in the study area were formed under climatic conditions conducive to permafrost. Allochthonous blockfields in the Appalachians appear to be constituent elements of periglacial ‘form communities’.

Internet‐based map products can be used to create generalised reconnaissance‐level geomorphic data bases over large areas. Complementary use of these resources and spatial‐analytic techniques holds considerable potential for addressing the broad‐scale problems with which traditional climatic geomorphology is concerned. Copyright © 2007 John Wiley & Sons, Ltd.
Avalanche‐derived rock glaciers in Svalbard
Authors: Humlum Ole , Christiansen Hanne H. , Juliussen Håvard
Published: February 2007

Visual year‐round observations have shown that snow avalanches are driving the formation of rock glaciers near the glacier Larsbreen in central Svalbard. Here, avalanches are important suppliers of fresh rock debris, but they also represent the means by which ice is added to the rock glacier interior. During the winter, 1–5 m avalanche snow containing rock debris accumulates, ablating during the following summer, but a gradually accumulating surface layer of released rock debris increasingly reduces the ablation rate. Refreezing of percolating surface water during the ablation season enhances the metamorphosis from avalanche snow into solid ice, assisted by low permafrost temperatures below the avalanche snow. At the end of each summer, a 0–100 cm thick layer consisting of remnant avalanche snow covered by a surface debris layer has been added to the rock glacier permafrost body along the initiation line. Depending upon thickness, slope, relative ice content and temperature, deformation of such thickening layered avalanche deposits eventually leads to the formation of a rock glacier in the run‐out zones of snow avalanches in permafrost regions. Avalanche‐nourished rock glaciers are expected to exhibit a regional downwind preferred orientation. Copyright © 2007 John Wiley & Sons, Ltd.
Patterns of permafrost formation and degradation in relation to climate and ecosystems
Authors: Shur Y. L. , Jorgenson M. T.
Published: February 2007

We develop a permafrost classification system to describe the complex interaction of climatic and ecological processes in permafrost formation and degradation that differentiates five patterns of formation: ‘climate‐driven’; ‘climate‐driven, ecosystem‐modified’; ‘climate‐driven, ecosystem‐protected’; ‘ecosystem‐driven’; and ‘ecosystem‐protected’ permafrost. Climate‐driven permafrost develops in the continuous permafrost zone, where permafrost forms immediately after the surface is exposed to the atmosphere and even under shallow water. Climate‐driven, ecosystem‐modified permafrost occurs in the continuous permafrost zone when vegetation succession and organic‐matter accumulation lead to development of an ice‐rich layer at the top of the permafrost. During warming climates, permafrost that has formed as climate‐driven can occur in the discontinuous permafrost zone, where it can persist for a long time as ecosystem‐protected. Climate‐driven, ecosystem protected permafrost, and its associated ground ice, cannot re‐establish in the discontinuous zone once degraded, although the near surface can recover as ecosystem‐driven permafrost. Ecosystem‐driven permafrost forms in the discontinuous permafrost zone in poorly drained, low‐lying and north‐facing landscape conditions, and under strong ecosystem influence. Finally, ecosystem‐protected permafrost persists as sporadic patches under warmer climates, but cannot be re‐established after disturbance. These distinctions are important because the various types react differently to climate change and surface disturbances. For example, climate‐driven, ecosystem‐modified permafrost can experience thermokarst even under cold conditions because of its ice‐rich layer formed during ecosystem development, and ecosystem‐driven permafrost is unlikely to recover after disturbance, such as fire, if there is sufficient climate warming. Copyright © 2007 John Wiley & Sons, Ltd.
Infrastructure impacts and facility siting issues during hurricanes
Authors: Moore, President and CEO David A. , Kellogg, MPA Dorothy Allen
Published: February 2007

Hurricanes Katrina and Rita affected the U.S. chemical and petroleum industries sectors as they did everyone and everything else along the Gulf, highlighting profoundly the strengths and weaknesses of plans to prepare for and recover from a devastating area‐wide catastrophe. The direct impacts to the industries were more economic; no fatalities or serious injuries occurred from releases at chemical or petroleum facilities during the storms. Hurricane plans and release prevention efforts were largely successful. Nevertheless, the facilities, companies, and their employees were left with significant physical and economic recovery challenges resulting from the impacts on the facilities themselves and the supporting infrastructure.

The massive scale of the storms highlighted numerous weaknesses in facility as well as government and private sector preparations for such a truly catastrophic emergency—and opportunities for improvement. The lessons from these storms must be leveraged to improve the readiness of the U.S. industry for natural, accidental, and intentional events. This study examines some of the gaps in traditional facility siting considerations and risk assessments and suggest elements that could be added to those activities to better prepare for catastrophic events—whether natural disasters or intentional acts of terrorism.

The lessons learned include:

Improve crisis management planning to minimize the catastrophic facility and business losses; and

Site the facility and equipment to minimize impacts of events.

© 2007 American Institute of Chemical Engineers Process Saf Prog 26:, 2007
Evaluation of Baccharis trimera and Davilla rugosa in tests for adaptogen activity
Authors: Mendes Fúlvio Rieli , Tabach Ricardo , Carlini E. A.
Published: February 2007

Baccharis trimera (Asteraceae) and Davilla rugosa (Dilleniaceae) are used popularly as tonics, aphrodisiacs and for stomach ailments, among other uses. Hydroalcohol extracts of the aerial parts of both plants were investigated with regard to their chemical constitution and their pharmacological activity in tests that evaluate adaptogen activity. Alkaloids, flavonoids, saponins, polyphenols/tannins and coumarins were identified in both extracts, while lignans were found only in the extract of Davilla rugosa. This extract presented also a marked antioxidant activity and exerted a moderate antiulcer effect in rats submitted to cold immobilization stress. It did not, however, inhibit the increase in the levels of ACTH and corticosterone induced by stress. Moreover, the Davilla rugosa did not improve the physical performance of mice submitted to forced exercise and the learning time of old rats in the T‐maze, neither did it reduce the blood viscosity of the old animals. Conversely, the Baccharis trimera extract only presented a moderate antioxidant activity, without any positive effect on the other tests. These results point to the absence of an adaptogen activity of Baccharis trimera, with some effects that could be related to such an activity as regards the Davilla rugosa. Copyright © 2007 John Wiley & Sons, Ltd.
Tropical cyclone forecasting with model‐constrained 3D‐Var. I: Description
Authors: Liang Xudong , Wang Bin , Chan Johnny CL , Duan Yihong , Wang Dongliang , Zeng Zhihua , Leiming Mab
Published: February 2007

A disadvantage of three‐dimensional variational data assimilation (3D‐Var) technique is that it cannot make use of complicated constraints such as the dynamics and physics in a numerical model, which are used in the four‐dimensional variational data assimilation (4D‐Var) technique. On the other hand, using a numerical model and its adjoint in the 4D‐Var technique requires a large amount of computer resources, thus limits its practical application. In this paper, a new 3D‐Var method is proposed by adding a numerical model as a constraint. This method minimizes the distance between observation and model variables and time tendency of model variables, which makes the optimized initial conditions (ICs) that not only fit the observations but also satisfy the constraints of full dynamics and physics in the numerical model. The forward and adjoint models used in this method are as same as those in the 4D‐Var method but are only integrated one time step to calculate the time tendency. Because observations are only used at one time slice and are being constrained by the model, it is called the model‐constrained 3D‐Var (MC‐3DVar) technique.

A set of ideal experiments based on a shallow‐water equation model indicates that the model constraints used in MC‐3DVar can spread the observation information spatially and balance the model variables. Part II employs this method to improve tropical cyclone track forecasting using AMSU‐A, QuikSCAT and cloud‐drift wind data. The study shows that the assimilation of these data with MC‐3DVar improves tropical cyclone forecasts and that more satellite data give better performances. Copyright © 2007 Royal Meteorological Society
Correlation of DNA Transfection and Activation of Human c‐raf‐1, But Not Epidermal Growth Factor Receptor, With Certain Head and Neck Squamous Cell Carcinoma‐Derived Cell Lines
Authors: Kasid U. , Pfeifer A. , Merlino G. , Mark G. E. , Dritschilo A.
Published: February 2007

We have examined the mechanism of activation of c‐raf‐1 and the expression of epidermal growth factor receptor (EGF‐R) gene in the three relatively radiation resistant human squamous cell carcinoma‐derived cell lines (SCC‐35, JSQ‐3, and SQ‐20B). The human c‐raf‐1 sequences were observed in the primary G418r, human Alu+ NIH/3T3 clones transfected with these tumor cell DNAs. The human raf‐1‐related sequences were truncated, rearranged, and amplified in the primary NIH/3T3 transfectants, and a majority of the clones revealed sequences corresponding to the carboxy‐terminus of the protein product of human raf‐1 (Raf‐1). A highly tumorigenic potential of transfectant clones correlated with expression of the new (human) raf‐1‐related sequences. By contrast, the EGF‐R gene was amplified and aberrantly overexpressed in only the SQ‐20B tumor cells. The human EGF‐R‐related sequences were not detected in the human Alu+ NIH/3T3 transfectant clones, including those derived following the SQ‐20B tumor cell DNA transfection. The levels of Raf‐1‐associated serine/threonine kinase activity were comparable in SCC‐35 and SQ‐20B cells. We have previously reported that the antisense c‐raf‐1 cDNA transfection is sufficient for the down regulation of tumorigenicity and radioresistance in SQ‐20B cells. The present data suggest that the role of c‐raf‐1 in the development of the tumor phenotype may be unrelated to the amplification and activation of EGF‐R in these squamous carcinoma‐derived cells. © 1993 Wiley‐Liss, Inc.
Sequence analysis of mutational hot spots in the endogenous and transfected colony stimulating factor 1 receptor in gamma‐irradiation induced factor independent subclones of clonal hematopoietic progenitor cell lines
Authors: Romanik Elizabeth A. , Leif Jean , Sakakeeny Mary Ann , Greenberger Joel S.
Published: February 2007

Amino acid substitutions in several proto‐oncogenes and growth factor receptors may be activating mutations. The macrophage‐colony stimulator factor (M‐CSF) receptor (c‐fms) differs from the transforming v‐fms at several sites in the extracellular domain and contains a tyrosine residue at the carboxy terminus which may be involved in the negative regulation of the receptor kinase activity. The engineering of two point mutations in human c‐fms gene (residue 301, leucine to serine; and residue 969, tyrosine to phenylalanine) induces factor independent growth and malignant transformation when expressed in murine cells. Point mutations have also been detected in c‐fms in marrow cells or peripheral blood from patients with myelodysplastic syndromes or acute myelomonocytic leukemias. We have previously shown that murine factor independent cell lines, derived from cocultivation of clonal interleukin‐3 (IL‐3) dependent hematopoietic progenitor cell lines with the gamma‐irradiated marrow stromal cell line, D2XRII, have an upregulated c‐fms expression during an intermediate stage on the way to factor independence, but that fully factor independent subclones do not have an overexpression of c‐fms. In order to determine whether the factor independent phenotype resulted from an activating mutation in c‐fms during the transient phase of overexpression, we examined both intracellular and extracellular domains of c‐fms in irradiation induced factor independent subclones of FDC‐P1 JL26 or 32D c‐fmsm cells. Polymerase chain reaction (PCR) amplification of the regions flanking residues 301 and 973 with sequence analysis by the dideoxy chain‐termination method revealed no detectable mutations at either site. These data show that the factor independence of these cell lines does not result from activating mutations at 301 or 973 of the c‐fms receptor. Thus, the induction of growth factor independence may be attributable to 1) activating mutations at other sites in c‐fms; 2) activation of sites distal to the CSF‐1 receptor in the signal transduction pathway; or 3) a mechanism independent of the c‐fms/M‐CSF pathway. © 1993 Wiley‐Liss, Inc.
Alternating and concurrent chemotherapy and radiotherapy for unresectable head and neck carcinoma
Authors: McLaughlin Patrick , Urba Susan , Thornton Allan , Forastiere Arlene , Wolf Gregory
Published: February 2007

Between 1987 and 1989, 12 patients with advanced unresectable head and neck carcinoma were entered on a regimen of alternating and concurrent chemotherapy and radiotherapy. During the initial phase, cisplatin (50 mg/m2/day × 3 days) was administered 1 week and alternated with 160 cGy TID radiation week 3. This alternating schedule was repeated once for a total dose of 300 mg/m2 cisplatin and a total radiation dose of 4,800 cGy. Week 9, concurrent cisplatin (20 mg/m2/day × 5 days) was administered with 200 cGy BID radiation to boost ports. In spite of the alternating schedule, acute toxicity from 160 cGy TID was severe and delays secondary to mucositis increased the average duration of therapy to 11 weeks. Unexpected chronic toxicity included 2 of 12 patients with swallowing difficulty due to a sensory neuropathy which was likely a combined modality effect. This had not been reported in previous combined modality studies. A complete response was achieved in 5 of 12 patients and a partial response in 7 of 12 patients. Overall median survival was 17 months. Although the combination of cisplatin and accelerated radiation given in the above dose schedule induced a complete or partial response in all patients, severe toxicity and lack of survival benefit discourage further use of this regimen. © 1993 Wiley‐Liss, Inc.
Functional and morphological damage after local heart irradiation and/or adriamycin in Wistar rats
Authors: Kitahara T. , Liu K. , Solanki K. , Trott K. R.
Published: February 2007

The hearts of Wistar rats were locally irradiated with 15–30 Gy single doses of 300 kV X‐rays or animals were intravenously injected by single doses of 1–3 mg/kg body weight of adriamycin. Animals were followed until death or for between 320 and 710 days. After irradiation, congestive heart failure occurred with a dose‐dependent latency, which was significantly longer if the atria were excluded from the irradiation field. Cardiac output started to decrease after about 3 months, well before myocardial degeneration was noted, but it did not depend on radiation dose. After adriamycin, cardiac output showed a dose‐dependent drop within 2 weeks to plateau and never recovered to the control values. Capillary density 400 days after treatment was reduced both after irradiation and after adriamycin. Irradiation with 20 Gy 6 months after adriamycin decreased capillary density even further. © 1993 Wiley‐Liss, Inc.
Proliferative assays for the assessment of radiosensitivity of tumor cell lines using 96‐well microcultures
Authors: Cross Peter , Marshall Elaine S. , Baguley Bruce C. , Finlay Graeme J. , Matthews John H. L. , Wilson William R.
Published: February 2007

We have compared the effectiveness of three short‐term proliferative assays [3(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) reduction, methylene blue staining, and [3H]‐thymidine incorporation] in predicting the results of clonogenic assay of radiosensitivity in five mammalian cell lines (SCCVII, AA8, V3, FME, and MM‐96). Cells were cultured in 96‐well microculture plates and a lead wedge was employed to provide a range of radiation doses (60Co source) up to 10 Gy. Radiation dosimetry was determined by a novel modification of the Fricke/thiocyanate dosimetry technique to allow direct determination in 96‐well plates. Cells were cultured following irradiation to determine clonogenic survival curves and to calculate the survival at 2 Gy (SF2), the initial slope of the fitted linear quadratic function (α), and the mean inactivation dose (D). A broad range of radiosensitivity was obtained (SF2 = 0.14–0.92) with the clonogenic assay. All three proliferation assays provided measures of radiosensitivity which correlated with clonogenicity at low radiation dose. The thymidine incorporation assay, which provided excellent linear correlation (r = 0.98) with clonogenicity for SF2 and D, used semiautomated methods for harvesting and scintillation counting to give sample processing times comparable to the colorimetric methods. It offered the advantages of superior assay linearity and dynamic range, and reduced interference by non‐proliferating cells at high radiation dose. © 1994 Wiley‐Liss, Inc.
5‐iodo‐2‐deoxyuridine as cytotoxic chemotherapy and as a possible radiosensitizer in a mouse ovarian ascites tumor model
Authors: Epperly Michael W. , Deutsch Melvin
Published: February 2007

The mouse ovarian ascites tumor model was used to evaluate the intraperitoneal (IP) administration of 5‐iodo‐2‐deoxyuridine (IUDR) as a radiosensitizer and tumor cytotoxic agent. A 7 day continuous infusion of IUDR starting on the day of tumor cell implantation (1 × 106 tumor cells) was extremely effective in prolonging survival compared to no treatment or radiation alone. Infusions starting on day 7 after implantation of tumor cells were less effective. Whole abdominal irradiation (either 500 cGy × 2 or 750 cGy × 2) on days 5 and 7 from tumor cell implantation had very little beneficial effect (P = 0.15 and 0.10, respectively). The combination of radiation and IUDR as used in these experiments did not show any benefit over IUDR alone. As yet, an optimum combination of radiation and IUDR which would be superior to IUDR alone has not been demonstrated for this tumor model. However, these results suggest that the IP administration of IUDR alone or possibly with radiotherapy might be beneficial for malignancies such as ovarian cancer which tend to disseminate IP. © 1994 Wiley‐Liss, Inc.
Antiproliferative effects of ionizing radiation, all‐trans‐retinoic acid, and interferon‐α on cultured human squamous cell carcinomas
Authors: Hoffmann W. , Bamberg M. , Rodemann H. P.
Published: February 2007

In the present study we analyzed the antiproliferative effects of irradiation (IR), all‐trans‐retinoic acid (RA), and interferon‐α (IFN‐α) on two established human cell lines of squamous cell carcinoma of the head and neck (cell line HTB43) and of cervical cancer (cell line HTB35). The determination of the radiosensitivity of these cells using the colony formation assay revealed that the Do value, or radiation dose that reduces survival to e−1 of its previous value on the exponential portion of the survival curve, for both cell lines was identical (2 Gy). The surviving fraction at 2 Gy (SF2) could be demonstrated to be approximately 60% for both cell lines. Treatment of these carcinoma cells either with all‐trans‐RA (dose range 1–10 μM) or with IFN‐α (dose range 0.5–500 IU/ml) resulted in a significant inhibition of colony formation. When the cells were treated with a combination of RA and IFN‐α the growth potential was affected in a synergistic manner. Pretreatment of the squamous cell carcinoma cell lines with RA in combination with IFN‐α for 24 hr followed by a single IR dose of 2 Gy led to a significant potentiation of the radiosensitivity in both lines although this effect was much more pronounced in the cervical cancer cells (HTB35). Cytomorphological and cytochemical analyses revealed that the growth inhibitory activity of RA, IFN‐α, and IR may be ascribed in part to the induction of irreversible postmitotic cells with a more normalized state of differentiation. On the basis of these data, experimental strategies could be developed for future treatment concepts employing RA, IFN‐α, and IR for the therapy of squamous cell carcinomas. © Wiley‐Liss, Inc.
Expression of the human BCL‐2 transgene increases the radiation resistance of a hematopoietic progenitor cell line
Authors: Epperly M. W. , Santucci M. A. , Reed J. C. , Shields D. , Halloran A. , Greenberger J. S.
Published: February 2007

We investigated the effect of overexpression of a BCL‐2 transgene on the irradiation survival of the interleukin (IL)‐3‐dependent 32D cl 3 cell line in vitro. The 32D‐BCL‐2 clonal subline was selected by transfection of 32D cl 3 cells with a BCL‐2 and neor‐containing plasmid vector selecting for G418 resistance. Cell line 32D‐BCL‐2 was IL‐3‐dependent and showed detectable BCL‐2 protein expression by Western analysis of cell lysates. The cells expressing BCL‐2 showed the characteristic block of apoptosis by DNA ladder analysis of cells following deprivation of IL‐3, where a decrease in DNA fragmentation of 32D‐BCL‐2 compared to 32D cl 3 DNA was observed after 200 to 1,000 cGy irradiation. The 32D‐BCL‐2 cell line demonstrated increased radioresistance at a dose rate of 110 cGy/min with an ñ and D0 of 8.70 and 130 cGy, respectively, compared to 5.03 and 101 cGy for parent 32D cl 3 cells (P = 0.015 and 0.018, respectively). At the clinical low dose rate of 7.5 cGy/min, the ñ and D0 for 32D‐BCL‐2 were 2.51 and 178 cGy compared to 1.96 and 148 cGy for 32D cl 3 (P = 0.074 and 0.071, respectively). Thus, expression of a BCL‐2 transgene increased the gamma‐irradiation resistance of 32D cl 3 cells in vitro. These data are consistent with recently published evidence for a role of BCL‐2 in reducing intracellular free oxygen radicals. These results may explain the unexpected survival of BCL‐2‐containing tumor cells in bone marrow transplant recipients after low‐dose‐rate total body irradiation. © Wiley‐Liss, Inc.
Stereotactic radiosurgery: Relative biological effect of continuous vs. intermittent radiation exposures
Authors: Benedict S. H. , Lin P.‐S. , Zwicker R. D. , Khandelwal S. R. , Broaddus W. C. , Schmidt‐Ullrich R. K.
Published: February 2007

Linear accelerator‐based stereotactic radiosurgery is increasingly used in place of gamma knife equipment. Conforming radiation isodoses to complex volumes requires multiple isocenters and arcs per isocenter and may result in a protracted and intermittent radiation exposure. The experiments in this study were designed to quantitate the difference between continuous and intermittent radiation schedules which are typical for gamma knife and linear accelerator‐based radiosurgery, respectively. Two radiobiologically well‐characterized cell lines, V79 Chinese hamster and U‐87MG human malignant glioma cells, were irradiated in vitro to 12 Gy delivered as a continuous 5 min exposure and an intermittent exposure lasting maximally 112 min. The effect of continuous vs. intermittent irradiation to a dose of 31.5 Gy was also measured in vivo using FSaII fibrosarcomas, implanted into C3Hf/Sed mice, in a tumor growth assay. The in vitro experiments demonstrated a significant reduction in biological radiation effect reflected in 2‐ to 3‐fold increases in cell survival with intermittent vs. continuous irradiation schemes. Similar effects were seen with the FSaII tumors. The reduced effect of the intermittent irradiation schemes is most likely due to repair processes after radiation exposure, such as Potentially Lethal Damage Repair (PLDR) and Sublethal Damage Repair (SLDR), which can occur during 5–15 min intervals between radiation increments of intermittent stereotactic radiosurgery treatments. © 1995 Wiley‐Liss, Inc.
Induction of growth factor genes in endothelial cells by ionizing radiation
Authors: Haimovitz‐Friedman A. , Witte L. , Chaudhuri A. , McLoughlin M. , Fuks Z.
Published: February 2007

This study reports that exposure of endothelial cells [bovine aortic endothelial cells (BAEC) and porcine aortic endothelial cells (PAEC)] to ionizing radiation leads to activation of the basic fibroblast growth factor (bFGF) and platelet‐derived growth factor (PDGF)‐B genes. Nuclear RNA run‐on experiments showed an increase in nuclear RNA of these factors within 90 min after delivery of a dose of 4 Gy. In addition, there was a dose‐and time‐dependent transient increase in bFGF and PDGF‐B mRNA transcripts, although there were differences in the kinetics of these responses between BAEC and PAEC. Radiation‐induced activation of the bFGF and PDGF‐B genes was also manifested by secretion of the corresponding proteins into the culture media of the irradiated endothelial cells. In contrast, the acidic fibroblast growth factor (aFGF), PDGF‐A, and transforming growth factor beta (TGFβ) genes were not concomitantly activated in these cells, as indicated by lack of increase in their mRNA levels. Activation of specific growth factor genes and the extracellular secretion of their products may play an important role in modulating the radidation response via autocrine or paracrine mechanisms. © 1995 Wiley‐Liss, Inc.
Prostate screening programs hosted by radiation oncologists: Feasibility and outcome
Authors: Yoskovitch Adi , Corn Benjamin W. , Bruner Deborah W. , Jacofsky David , Slivjak Anne , Hanks Gerald E.
Published: February 2007

Screening for prostate cancer has improved early detection of the disease and may impact on mortality rates. Since all reported screening programs to date have originated in urology practices, we undertook such an effort in our department of radiation oncology where a comprehensive prostate cancer program exists.

Four annual prostate cancer screening programs were conducted by our department of radiation oncology between 1990–1993. Examiners and supportive personnel included the attending staff, house staff, rotating medical students, and nurses from the department of radiation oncology. Urologists were encouraged, but not required, to assist. Eligible subjects included men ≧ 50 years old and men ≧ 40 if a family history of prostate cancer in a first degree relative was documented. The screening protocol consisted of directed history, measurement of serum prostate specific antigen (PSA), followed by digital rectal examination (DRE) performed by attending physicians. Needle biopsies were carried out on men with abnormal DRE, elevated PSA (>4 ng/mL), or both. Complete follow‐up was obtained by contacting participants and their primary physicians.

During the 4‐year period, 442 men were screened (annual range: 91–202) and a total of 11 cancers were diagnosed. All patients diagnosed with cancer had negative metastatic work‐up. Among those screened, 20% (90/442) had abnormal DRE alone, 8.8% (39/442) had elevated PSA alone, while 9.2% (41/442) had both abnormal DRE and elevated PSA. Adenocarcinoma was diagnosed in 1% (1/90) of patients with abnormal DRE alone, 18% (7/39) of those with abnormal PSA alone, and in 7% (3/41) of men with both abnormalities. Among those with cancer, 63% (7/11) opted for definitive irradiation, 27% (3/11) chose prostatectomy and one patient chose observation. Among those who selected radiotherapy, 86% (6/7) were treated in our department.

Prostate screening can be conducted by a radiation oncology practice and provides a valuable contribution to the community. Our screening program succeeded in diagnosing patients with organ‐confined disease. These data extend the evidence of Catalona et al. [N Engl J Med 324:1156–1161, 1991] which suggest that rectal examination can no longer be regarded as the sole or most useful means of detecting prostate cancer. Most (63%) of the patients diagnosed through this effort opted for definitive treatment by radiotherapy. The majority (86%) of patients selecting irradiation were treated at our center. Although screening for prostate cancer is feasible, controlled clinical trials comparing screened to unscreened samples are needed to determine the effect of earlier detection on morbidity and survival. © 1995 Wiley‐Liss, Inc.
Effect of a pure anti‐estrogen, ICI 182,780, on the in vitro radiosensitivity of MCF‐7 breast carcinoma cells
Authors: Noyes William R. , Timothy Mulcahy R. , Craig Bruce A. , Kinsella Timothy J.
Published: February 2007

Use of the anti‐estrogen tamoxifen (TAM) has been demonstrated to contribute a survival advantage in postmenopausal women with early stage or advanced breast cancer. Although conflicting results exist in the literature, some reports have suggested that TAM may exert potential deleterious effects on radiation sensitivity and response of breast cancers to radiotherapy (RT). A new non‐steroidal anti‐estrogen, ICI 182,780, which, unlike TAM, is without any estrogenic properties, has been used in European clinical trials in place of TAM. This study reports the effects of ICI 182,780 on radiation sensitivity and potentially lethal damage repair (PLDR) in estrogen‐receptor positive (ER+) MCF‐7 human breast carcinoma cells irradiated in vitro. At a concentration of 10−7 M, ICI 182,780 can inhibit the growth‐stimulatory effect of 10−10M 17β‐estradiol (E2). Growth‐arrested MCF‐7 cells were divided into four treatment groups: estradiol‐deprived (−E2) and estradiol‐stimulated (+E2) cultures incubated in the presence or absence of ICI 182,780 (10−7 M). Five days later each group was exposed to γ‐irradiation and cell survival was measured by clonogenic assay in complete medium containing E2. In one series of experiments, the cells were harvested immediately after irradiation, while in a second series, the cells were held at 37°C for an additional 24 hr prior to harvesting. No statistically significant survival difference was detected between groups plated immediately after irradiation or 24 hr later, although a trend toward improved survival for the delayed plating groups was routinely observed. ICI 182,780 did not significantly alter radiation sensitivity of MCF‐7 cells regardless of their hormonal status (+/−E2), nor did it change the sensitivity of cells harvested immediately or allowed 24 hr to express PLDR. These results suggest that ICI 182,780 may be used as an adjuvant in the treatment of breast cancer without altering the radiation sensitivity of breast cancer cells to concurrent RT. © 1995 Wiley‐Liss, Inc.
Cloning and sequencing of the cDNA for the cph oncogene from neoplastic hamster fibroblasts reveal partial homology with the dbl exchange factor
Authors: Velasco Juan A. , Avila Matías A. , Cansado José , Notario Vicente
Published: February 2007

The combination of in vitro transformation protocols and transfection assays allowed us to isolate a new transforming gene, cph, from neoplastic Syrian hamster embryo fibroblasts chemically initiated with a single dose of 3‐methylcholanthrene. Cosmid clones encompassing cph genomic sequences were able to transform NIH/3T3 cells and showed a synergistic action with H‐ras in the transformation of the murine fibroblasts. In the present study, we describe the molecular cloning of the hamster cph oncogene cDNA. Nucleotide sequence analysis of a full‐length cDNA clone (pBl‐19), isolated from a cDNA library from neoplastic hamster cells with cph genomic probes demonstrated that the cloned cph cDNA does not show any significant global homology to sequences deposited in established databases, confirming that cph is a novel gene. The cph cDNA contained an open reading frame with coding capacity for a protein of about 26 kDa, which was synthesized from pBl‐19 by using in vitro transcription‐translation assays. The cph protein deduced from the cDNA nucleotide sequence contained a dbl‐homologous (DH) domain. The fact that the DH domain has been found primarily among GDP‐exchange factors suggests that cph may be a new member of this family of proteins. © 1995 Wiley‐Liss, Inc.
Identification of gene(s) involved in carcinogenic progression of ataxia telangiectasia cells
Authors: Jung Mira , Dimtchev Alexandre , Zhang Yin , Dritschilo Anatoly
Published: February 2007

By using vector‐mediated gene transfer and expression cloning, cDNAs of dominantly acting genes have been identified that cause phenotypic conversion of cells from flat, contact‐inhibited growth to focus formation and anchorage‐independent growth. Such morphologic growth changes are consistent with carcinogenic progression steps. Plasmid rescue and polymerase chain reaction amplification have permitted the identification of four candidate cDNAs (two unknown and two known) that are present in these transformed cells. Partial sequence analysis shows that one unknown gene contains sequence homology to the envelope sequences of the human retrovirus (HIV‐1). This characteristic suggests that the isolated cDNA may be a putative oncogene. The model system reported here permits identification and characterization of genes that may be associated with progression steps from the immortal state to anchorage independence and tumorigenicity. © 1995 Wiley‐Liss, Inc.
Telomere loss, telomerase, and cancer
Authors: Villeponteau Bryant
Published: February 2007

Telomeric DNA safeguards chromosomes from genetic damage and rearrangement. Normal somatic cells lose telomeric DNA with each division and during normal human aging. Immortal cancer cells typically express the enzyme telomerase, a ribonucleoprotein polymerase that adds new telomere repeats onto the chromosome ends. To study the role of telomerase in cancer cells, the RNA component of human telomerase (hTR) was recently cloned. HeLa cells expressing antisense hTR exhibited reduced telomerase activity, gradual loss of telomeric DNA, and cell death after 23–26 doublings. These results demonstrate that telomerase is a critical enzyme for the continued proliferation of metastatic tumor cells. Whereas telomere loss occurs in both normal and precancerous cells, telomere shortening with age can lead to genetic damage, which may underlie the age‐related increases in cancer rates. © 1995 Wiley‐Liss, Inc.