bluuebunny/crossref_metadata_2025 huggingface dataset:
Baryte and calcite cements in the ‘breccias' of Ogmore‐by‐Sea, South Wales
Authors: LEE CHRIS W.
Published: January 2008

Each year many hundreds, if not thousands, of Earth‐science students visit the coastline at Ogmore‐by‐Sea, mid‐Glamorgan. They study the excellent exposures of Lower Carboniferous Limestone, with their well‐preserved coral and other shelly faunas, together with the presumed late Triassic ‘breccias’* that rest unconformably on top. A study of the cements within the breccias may give an insight into syndepositional mineralization and the formation of sedimentary basins linked to the opening of the Atlantic in early Mesozoic times.
Low‐grade metamorphism
Authors: BEVINS RICHARD E. , ROBINSON DOUG
Published: January 2008

Diagenesis refers to those changes which take place in sediments after sedimentation but before lithification (the conversion to solid rock), while metamorphism is defined as the process whereby alterations to the composition, texture or mineralogy take place in consolidated rocks. However, the boundary between diagenesis and metamorphism is gradual/transitional and somewhat arbitrary; it cannot be sharply defined. A consequence of this is that studies of rocks affected by alteration at low temperatures and pressures have been neglected. Within the last decade, however, more attention has been focused on this type of alteration and significant advances have been made in the field of low‐grade metamorphism, particularly over the last five years or so. The Caledonide rocks of Wales have been at the forefront of such investigations.
The trilobite Angelina unstretched
Authors: FORTEY RICHARD A. , OWENS ROBERT M.
Published: January 2008

The early Ordovician trilobite Angelina sedgwickii has hitherto been known only from stretched and squeezed specimens from North Wales. As a classic example of a deformed fossil, it has featured not only in palaeontological but also in structural geology textbooks, and various methodologies have been employed to attempt to restore it to its original shape. Recently discovered specimens from Shropshire, although flattened, are not sheared and preserve the original bilateral symmetry, affording for the first time an opportunity to find out what this trilobite might really have looked like.
Mineralization of the South Pennines
Authors: & TREVOR D. FORD , QUIRK DAVID G.
Published: January 2008

The lead and fluorspar mining area of the Peak District, otherwise known as the South Pennine Orefield, includes much of Derbyshire and a small part of Staffordshire. There are some 2000 named mineral veins and related strata‐bound deposits, containing galena, sphalerite, fluorite, baryte and calcite, hosted in Lower Carboniferous (Dinantian) limestones and dolomites. Small amounts of pyrite and chalcopyrite, and traces of many other minerals and hydrocarbons, are also present. Here we offer an explanation of how the minerals of the South Pennine Orefield were emplaced within the host rock.
PHOTOPROCESSES IN THE ORGANIC SOLID STATE*
Authors: Hochstrasser Robin M.
Published: January 2008

Summary The various known photo‐relaxation phenomena in organic crystals are reviewed. The discussion is confined to molecular crystals, and aggregates of organic molecules, in which the low‐lying excited electronic states are either πpgr;*, nπ*, or electron‐transfer type. The pathways for excitation in isolated molecules with these types of electronic states are compared with the corresponding process in solids.

Particular emphasis is placed on the possible roles of intersystem crossing, triplet‐triplet energy transfer and annihilation in solid state photochemistry. Free and localized excitons, energy migration between impurity traps, and some aspects of photoconduction in organic materials are discussed.
PHOTOCHEMISTRY AND SPECTROSCOPY OF CHLOROPHYLL, BACTERIOCHLOROPHYLL AND BACTERIOVIRIDIN IN MODEL SYSTEMS AND PHOTOSYNTHETIZING ORGANISMS
Authors: Krasnovsky A. A.
Published: January 2008

Abstract— In the system (electron donor—pigment—electron acceptor), the photosensitising pigment transfers an electron (hydrogen) from the donor to the acceptor by converting light energy, absorbed by the pigment, into the potential chemical energy of the products. The dependence of the reaction of excited pigments with electron donors or acceptors on the magnitude of the electron affinity of the reacting molecules, the nature of the medium, and the experimental conditions was observed. The initial photo‐process was seen to involve the formation of free radicals, with the subsequent formation of compounds with saturated valencies. The reverse reaction of the photoproducts was accompanied by chemiluminescence. The study of systems containing pyridinenucleotides showed the possibility of photosensitised oxidation—reduction of these compounds by a pigment, and of direct photooxidation of reduced pyridinenucleotides by an electron acceptor of a different kind. In order to understand the specific photo‐transfer of an electron in organisms, the spectral properties of pigments in organisms were compared with the properties of model pigments in monomeric and aggregated forms. It was established that the main role in the spectroscopic properties shown by bacteriochlorophyll, bacterioviridin and chloropyll in organisms is played by various types of intermolecular interactions (aggregations). Different forms of pigment may be involved in different stages of the phototransfer of an electron.
THE EFFECT OF LIGHT ON HALOGENATED SALICYLANILIDE IONS
Authors: Coxon J. A. , Jenkins F. P. , Welti D.
Published: January 2008

Abstract— Irradiation of the anions of halogenated salicylanilides with near ultraviolet light causes the halogen atoms substituted in the 3– or 5– positions to be replaced by hydrogen. With 3, 5 substituted salicylanilides the halogen substituted on the 3 position is lost; 5‐substituted bromosalicylanilides lose the 5‐bromo substituent. 5‐substituted chlorosali‐cylanilides do not lose the 5‐chloro substituent. A free radical mechanism for the reaction is suggested.
DIFFERENTIAL GENE ACTIVATION AS A MODE OF ACTION OF PHYTOCHROME 730
Authors: Mohr H.
Published: January 2008

Abstract— Phytochrome‐induced photomorphogenesis in the mustard seedling (Sinapis alba L.) which can be regarded as being representative of the dicotyledonous seedlings has been analysed. In the present paper a number of arguments are presented, including data on RNA and protein synthesis and on the effects of actinomycin D and puromycin, which support the hypothesis that the ‘positive’ photoresponses of the seedling can be explained by a differential gene activation through P,30. ‘Positive’ photoresponses are those which are characterized by an initiation or an increase of biosynthetic or growth processes (e.g. biosynthesis of anthocyanin; growth of cotyledons). The lag‐phase of this type of photoresponse is rather long, ‘Negative’ photoresponses are those which are characterized by an inhibition of growth processes or other physiological processes like translocation. Here the lag‐phase is short. Inhibition of hypocotyl lengthening is a typical response of this sort. The concept of differential gene repression through P730 may serve as a working hypothesis to approach the causal analysis of phytochrome‐induced ‘negative’ photoresponses.
THE RELATION BETWEEN REPAIR OF RADIATION DAMAGE AND MUTATION INDUCTION*
Authors: Kimball R. F.
Published: January 2008

Abstract— This essay, written in honor of Alexander Hollaender's seventieth birthday, reviews the development of the concept of repair of premutational damage at both the biological and molecular levels. It stresses the important hut not exclusive role that repair processes play in determining the mutation yield, with emphasis on mutations induced by ultraviolet radiation. It points out that under special circumstances repair may be sufficiently efficient to almost completely eliminate premutational damage.
MECHANISMS AND RATES OF RADIATIONLESS ENERGY TRANSFER
Authors: BENNETT R. O. , KELLOGG R. E.
Published: January 2008

Abstract— Radiationless energy transfer between large molecules has been studied in samples in which a coulombic interaction can be expected to dominate other processes. Measurement of the effect of energy transfer on the lifetime of the donor yields information on the distance dependence of the interaction. The “Forster” formulation of energy transfer due to a coulombic dipole‐dipole interaction has been found to describe accurately the results of both singlet‐singlet and triplet‐singlet transfer. In the latter case, the experimental data are sufficiently precise to be analyzed in a manner suggested by Inokuti and Hirayama, leading to the conclusion that a pure dipole–dipole interaction induces the transfer.

Se ha estudiado la transferencia no radiativa de energía de moleculas grandes en sistemas en los que la interacción electrostática domina otros procesos. La medición del efecto de la transferencia de energía en la vida media del donor da información sobre la dependencia de distancia de la interacción. La teoria de Förster para la transferencia de energía debida a interacciones electrostaticas dipolo–dipolo se encontró que describe con gran exactitud los resultados obtenidos en el caso de transferencia singulete‐singulete y triplete‐singulete, en este último los datos experimentales son suficientemente precisos como para ser analizados mediante el procedimiento surgerido por Inokuti y Hirayama, Ilevando a la conclusión de que la interacción dipolo–dipolo induce transferencia de energía.
STUDIES ON MUTAGENESIS INDUCED IN VITRO*
Authors: GROSSMAN LAWRENCE
Published: January 2008

Abstract— The effective reducción of cytosine, whether in polymer form as a template or in monomer form as a substrate, is recognized in the RN A polymerase system as uracil or thymine. reducción can be brought about by photohydration to form cytosine hydrate, reaction with hydroxylamine to form a 5,6‐reduced monoadduct, or by direct chemical reduction.

A novel tautomeric intermediate is postulated which has permitted the assay of cytosine hydrates in native and denatured DNA.

It is suggested that the most probable u.v. photoproduct responsible for the mutagenesis of DNA is the cytosine hydrate.

Similar modification of uracil or thymine results in loss of recognition at both polymer and monomer levels. Reiteration is observed when polyuridylic acid is either chemically reduced or irradiated with u.v.

La reducción efectiva de la citosina en forma de polímero, como “template” o en forma de monómero como sustrato, puede reconocerse en el sistema RNA polimerasa como uracilo o timina. La reducción puede ocurrir por fotohidratación para formar hidrato de citosina puede reaccionar con hidroxilamina, o puede sufrir una reducción química directa. Se postula un nuevo intermediario que ha permitido ensayar hidratos de la citosina en DNA nativo y desnaturalizado. Se sugiere que el fotoproducto más probable responsable por esta mutagénesis del DNA es el hidrato de citosina. Modificaciones similares del uracilo o la timina resulta de una pérdida de reconocimiento a nivel de polimero o monomero.
An independent algorithm to check the monitor units calculation in radiosurgery
Authors: Ramos Luis Isaac , Monge Rafael Martínez , Aristu José Javier , Moreno Leire Arbea
Published: January 2008

Double checking of the monitor units (MU) is an important step in the quality assurance (QA) process in radiosurgery. In this paper we propose the use of an independent algorithm constructed using the ellipsoid which best fits the measurements taken with the bubble head frame. The monitor units calculated by this independent algorithm and the commercial planning system were compared in 40 patients treated with radiosurgery (57 isocenters, 320 arcs). The average relative difference was . These results are better for the variance, , when all the depths of the bubble head frame are measured and no arcs are calculated by extrapolation or when only one of these factors appear. If there are missing values in the bubble head frame measurements and the model is extrapolated, the variance of the results is greater, . The algorithm is reliable as a QA tool for linac radiosurgery.
A simple fixed‐point approach to invert a deformation fielda)
Authors: Chen Mingli , Lu Weiguo , Chen Quan , Ruchala Kenneth J. , Olivera Gustavo H.
Published: January 2008

Inversion of deformation fields is applied frequently to map images, dose, and contours between the reference frame and the study frame. A prevailing approach that takes the negative of the forward deformation as the inverse deformation is oversimplified and can cause large errors for large deformations or deformations that are composites of several deformations. Other approaches, including Newton's method and scatter data interpolation, either require the first derivative or are very inefficient. Here we propose an iterative approach that is easy to implement, converges quickly to the inverse when it does, and works for a majority of cases in practice. Our approach is rooted in fixed‐point theory. We build a sequence to approximate the inverse deformation through iterative evaluation of the forward deformation. A sufficient but not necessary convergence condition (Lipschitz condition) and its proof are also given. Though this condition guarantees the convergence, it may not be met for an arbitrary deformation field. One should always check whether the inverse exists for the given forward deformation field by calculating its Jacobian. If nonpositive values of the Jacobian occur only for few voxels, this method will usually converge to a pseudoinverse. In case the iteration fails to converge, one should switch to other means of finding the inverse. We tested the proposed method on simulated 2D data and real 3D computed tomography data of a lung patient and compared our method with two implementations in the Insight Segmentation and Registration Toolkit (ITK). Typically less than ten iterations are needed for our method to get an inverse deformation field with clinically relevant accuracy. Based on the test results, our method is about ten times faster and yet ten times more accurate than ITK's iterative method for the same number of iterations. Simulations and real data tests demonstrated the efficacy and the accuracy of the proposed algorithm.
Volumetric modulated arc therapy: IMRT in a single gantry arc
Authors: Otto Karl
Published: January 2008

In this work a novel plan optimization platform is presented where treatment is delivered efficiently and accurately in a single dynamically modulated arc. Improvements in patient care achieved through image‐guided positioning and plan adaptation have resulted in an increase in overall treatment times. Intensity‐modulated radiation therapy (IMRT) has also increased treatment time by requiring a larger number of beam directions, increased monitor units (MU), and, in the case of tomotherapy, a slice‐by‐slice delivery. In order to maintain a similar level of patient throughput it will be necessary to increase the efficiency of treatment delivery. The solution proposed here is a novel aperture‐based algorithm for treatment plan optimization where dose is delivered during a single gantry arc of up to 360 deg. The technique is similar to tomotherapy in that a full 360 deg of beam directions are available for optimization but is fundamentally different in that the entire dose volume is delivered in a single source rotation. The new technique is referred to as volumetric modulated arc therapy (VMAT). Multileaf collimator (MLC) leaf motion and number of MU per degree of gantry rotation is restricted during the optimization so that gantry rotation speed, leaf translation speed, and dose rate maxima do not excessively limit the delivery efficiency. During planning, investigators model continuous gantry motion by a coarse sampling of static gantry positions and fluence maps or MLC aperture shapes. The technique presented here is unique in that gantry and MLC position sampling is progressively increased throughout the optimization. Using the full gantry range will theoretically provide increased flexibility in generating highly conformal treatment plans. In practice, the additional flexibility is somewhat negated by the additional constraints placed on the amount of MLC leaf motion between gantry samples. A series of studies are performed that characterize the relationship between gantry and MLC sampling, dose modeling accuracy, and optimization time. Results show that gantry angle and MLC sample spacing as low as 1 deg and 0.5 cm, respectively, is desirable for accurate dose modeling. It is also shown that reducing the sample spacing dramatically reduces the ability of the optimization to arrive at a solution. The competing benefits of having small and large sample spacing are mutually realized using the progressive sampling technique described here. Preliminary results show that plans generated with VMAT optimization exhibit dose distributions equivalent or superior to static gantry IMRT. Timing studies have shown that the VMAT technique is well suited for on‐line verification and adaptation with delivery times that are reduced to for a 200 cGy fraction.
Temporal radiographic texture analysis in the detection of periprosthetic osteolysis
Authors: Wilkie Joel R. , Giger Maryellen L. , Chinander Michael R. , Engh Charles A. , Hopper Robert H. , Martell John M.
Published: January 2008

Periprosthetic osteolysis is one of the most serious long‐term problems in total hip arthroplasty. It has been primarily attributed to the body's inflammatory response to submicron polyethylene particles worn from the hip implant, and it leads to bone loss and structural deterioration in the surrounding bone. It was previously demonstrated that radiographic texture analysis (RTA) has the ability to distinguish between osteolysis and normal cases at the time of clinical detection of the disease; however, that analysis did not take into account the changes in texture over time. The goal of this preliminary analysis, however, is to assess the ability of temporal radiographic texture analysis (tRTA) to distinguish between patients who develop osteolysis and normal cases. Two tRTA methods were used in the study: the RTA feature change from baseline at various follow‐up intervals and the slope of the best‐fit line to the RTA data series. These tRTA methods included Fourier‐based and fractal‐based features calculated from digitized images of 202 total hip replacement cases, including 70 that developed osteolysis. Results show that separation between the osteolysis and normal groups increased over time for the feature difference method, as the disease progressed, with area under the curve (AUC) values from receiver operating characteristic analysis of 0.65 to 0.72 at 15 years postsurgery. Separation for the slope method was also evident, with AUC values ranging from 0.65 to 0.76 for the task of distinguishing between osteolysis and normal cases. The results suggest that tRTA methods have the ability to measure changes in trabecular structure, and may be useful in the early detection of periprosthetic osteolysis.
WHEN RENORMALIZABILITY MAY BE NOT SUFFICIENT: COULOMB PROBLEM FOR VECTOR BOSONS
Authors: FLAMBAUM VICTOR , KUCHIEV MICHAEL
Published: January 2008

The Coulomb problem for vector bosons W± incorporates a known difficulty; the boson falls on the center. In QED the fermion vacuum polarization produces a barrier at small distances which solves the problem. In a renormalizable SU(2) theory containing vector triplet (W+, W-, γ) and a heavy fermion doublet F with mass M the W- falls on F+ to distances r ~ 1/M, where M can be made arbitrary large. The collapse may be prevented if the theory contains additional light fermions or scalars, which switch the ultraviolet behavior of the theory from anti-screening to screening. Similar situation can take place in the Standard Model. Thus, the renormalizability of a theory may be not sufficient to guarantee a reasonable behavior at small distances for nonperturbative problems, such as a bound state problem.
Could googling take down a president?
Authors: Conti Gregory
Published: January 2008

Everything we do online is known and knowable and can be combined with everything else that is known and knowable.
Diffusion in Solid Silicates: A Tool to Track Timescales of Processes Comes of Age
Authors: Chakraborty Sumit
Published: January 2008

Understanding how processes occurring on a wide range of temporal and spatial scales combine to produce a stable dynamic Earth is a major goal of the Earth scientist. Determining durations of processes is a key step toward attaining that goal. Records of incomplete diffusive equilibration preserved in minerals are uniquely suited for the purpose of unraveling timescales of a variety of processes. Compositional zoning in minerals is like the tracks of a CD that can be decoded with suitable technology. This review discusses the causes for the limited use of this tool until recently and how these hindrances are being overcome. Examples are presented to illustrate that diffusion modeling can clock processes that last from only a few days to those that last over tens of millions of years, recorded in rocks that range in age from current volcanic eruptions to condensates from the early solar nebula.
Blood Flow in End-to-Side Anastomoses
Authors: Loth Francis , Fischer Paul F. , Bassiouny Hisham S.
Published: January 2008

Blood flow in end-to-side autogenous or prosthetic graft anastomoses is of great interest to biomedical researchers because the biomechanical force profile engendered by blood flow disturbances at such geometric transitions is thought to play a significant role in vascular remodeling and graft failure. Thus, investigators have extensively studied anastomotic blood flow patterns in relation to graft failure with the objective of enabling the design of a more optimal graft anastomotic geometry. In contrast to arterial bifurcations, surgically created anastomoses can be modified to yield a flow environment that improves graft longevity. Understanding blood flow patterns at anastomotic junctions is a challenging problem because of the highly varying and complex three-dimensional nature of the geometry that is subjected to pulsatile and, occasionally, turbulent flow.
Motor Unit Synchronization Is Increased in Biceps Brachii After Exercise-Induced Damage to Elbow Flexor Muscles
Authors: Dartnall Tamara J. , Nordstrom Michael A. , Semmler John G.
Published: January 2008

The purpose of this study was to determine the effect of eccentric exercise on correlated motor unit discharge (motor unit synchronization and coherence) during low-force contractions of the human biceps brachii muscle. Eight subjects (age, 25 ± 7 yr) performed three tasks involving isometric contraction of elbow flexors while EMG (surface and intramuscular) records were obtained from biceps brachii. Tasks were 1) maximum voluntary contraction (MVC); 2) constant-force contraction at various submaximal targets; and 3) sustained discharge of pairs of concurrently active motor units for 2–5 min. These tasks were performed before, immediately after, and 24 h after fatiguing eccentric exercise. MVC force declined 46% immediately after eccentric exercise and remained depressed (31%) 24 h later, which is indicative of muscle damage. For the constant-force task, biceps brachii EMG (∼100% greater) and force fluctuations (∼75% greater) increased immediately after exercise, and both recovered by ∼50% 24 h later. Motor unit synchronization, quantified by cross-correlation of motor unit pairs during low-force (1–26% MVC) contractions, was 30% greater immediately after ( n = 105 pairs) and 24 h after exercise ( n = 92 pairs) compared with before exercise ( n = 99 pairs). Similarly, motor unit coherence at low (0–10 Hz) frequencies was 20% greater immediately after exercise and 34% greater 24 h later. These results indicate that the series of events leading to muscle damage from eccentric exercise alters the correlated behavior of human motor units in biceps brachii muscle for ≥24 h after the exercise.
Representation of Shapes, Edges, and Surfaces Across Multiple Cues in the Human Visual Cortex
Authors: Vinberg Joakim , Grill-Spector Kalanit
Published: January 2008

The lateral occipital complex (LOC) responds preferentially to objects compared with random stimuli or textures independent of the visual cue. However, it is unknown whether the LOC (or other cortical regions) are involved in the processing of edges or global surfaces without shape information. Here, we examined processing of 1) global shape, 2) disconnected edges without a global shape, and 3) global surfaces without edges versus random stimuli across motion and stereo cues. The LOC responded more strongly to global shapes than to edges, surfaces, or random stimuli, for both motion and stereo cues. However, its responses to local edges or global surfaces were not different from random stimuli. This suggests that the LOC processes shapes, not edges or surfaces. LOC also responded more strongly to objects than to holes with the same shape, suggesting sensitivity to border ownership. V7 responded more strongly to edges than to surfaces or random stimuli for both motion and stereo cues, whereas V3a and V4 preferred motion edges. Finally, a region in the caudal intraparietal sulcus (cIPS) responded more strongly to both stereo versus motion and to stereo surfaces versus random stereo (but not to motion surfaces vs. random motion). Thus we found evidence for cue-specific responses to surfaces in the cIPS, both cue-specific and cue-independent responses to edges in intermediate visual areas, and shape-selective responses across multiple cues in the LOC. Overall, these data suggest that integration of visual information across multiple cues is mainly achieved at the level of shape and underscore LOC's role in shape computations.
Conservation of Genetic Alterations in Recurrent Melanoma Supports the Melanoma Stem Cell Hypothesis
Authors: Sabatino Marianna , Zhao Yingdong , Voiculescu Sonia , Monaco Alessandro , Robbins Paul , Karai Laszlo , Nickoloff Brian J. , Maio Michele , Selleri Silvia , Marincola Francesco M. , Wang Ena
Published: January 2008

It is generally accepted that human cancers derive from a mutated single cell. However, the genetic steps characterizing various stages of progression remain unclear. Studying a unique case of metastatic melanoma, we observed that cell lines derived from metachronous metastases arising over a decade retained a central core of genetic stability in spite of divergent phenotypes. In the present study, we expanded our previous observations comparing these autologous cell lines of clonal derivation with allogeneic ones and correlated array comparative genomic hybridization (aCGH) with gene expression profiling to determine their relative contribution to the dynamics of disease progression. aCGH and gene expression profiling were performed on autologous cell lines and allogeneic melanoma cell lines originating from other patients. A striking correlation existed between total extent of genetic imbalances, global transcriptional patterns, and cellular phenotypes. They did not follow a strict temporal progression but stemmed independently at various time points from a central core of genetic stability best explained according to the cancer stem cell hypothesis. Although their contribution was intertwined, genomic imbalances detectable by aCGH contributed only 25% of the transcriptional traits determining autologous tumor distinctiveness. Our study provides important insights about the dynamics of cancer progression and supports the development of targeted anticancer therapies aimed against stable genetic factors that are maintained throughout the end stage of disease. [Cancer Res 2008;68(1):122–31]
Is B-Raf a Good Therapeutic Target for Melanoma and Other Malignancies?
Authors: Madhunapantula SubbaRao V. , Robertson Gavin P.
Published: January 2008

The RAF family members, A-Raf, B-Raf, and C-Raf (or Raf-1), are intermediate molecules in the mitogen-activated protein (MAP) kinase [Ras/Raf/MAP kinase/extracellular signal–regulated kinase (Erk) kinase (MEK)/Erk] pathway, which relays extracellular signals from the cell membrane to the nucleus via a cascade of phosphorylation events ultimately promoting cancer development. This pathway is activated by mutation in ∼7% of all human cancers. B-Raf is one of the proteins frequently mutated to an active form during tumor development. Therefore, B-Raf is an attractive cancer target but lack of clinical efficacy using agents targeting this protein has raised serious doubts about its therapeutic utility. Design of more effective B-Raf inhibitory agents, targeting other members of the signaling cascade for greater clinical efficacy or inhibiting B-Raf in combination with other targets, is being evaluated to resolve these perplexing issues. Here, we discuss recent progress, using preclinical models and clinical studies, to resolve the controversy of whether B-Raf would be a good therapeutic target for melanoma and other malignancies. [Cancer Res 2008;68(1):5–8]
Therapeutic Window of MuS110, a Single-Chain Antibody Construct Bispecific for Murine EpCAM and Murine CD3
Authors: Amann Maria , Brischwein Klaus , Lutterbuese Petra , Parr Larissa , Petersen Laetitia , Lorenczewski Grit , Krinner Eva , Bruckmeier Sandra , Lippold Sandra , Kischel Roman , Lutterbuese Ralf , Kufer Peter , Baeuerle Patrick A. , Schlereth Bernd
Published: January 2008

EpCAM (CD326) is one of the most frequently and highly expressed tumor-associated antigens known and recently has also been found on cancer stem cells derived from human breast, colon, prostate, and pancreas tumors. However, like many other tumor-associated antigens used for antibody-based immunotherapeutic approaches, EpCAM is expressed on normal tissues including epithelia of pancreas, colon, lung, bile ducts, and breast. To assess the therapeutic window of an EpCAM/CD3-bispecific single-chain antibody construct of the bispecific T-cell engager (BiTE) class, we constructed murine surrogate of MT110 (muS110) from single-chain antibodies specific for murine EpCAM and CD3 antigens. Immunhistochemical analysis showed that, with minor differences, the expression of EpCAM protein on a large variety of tissues from man and mouse was similar with respect to distribution and level. MuS110 exhibited significant antitumor activity at as low as 5 μg/kg in both syngeneic 4T1 orthotopic breast cancer and CT-26 lung cancer mouse models. Dosing of muS110 for several weeks up to 400 μg/kg by intraanimal dose escalation was still tolerated, indicating existence of a significant therapeutic window for an EpCAM-specific BiTE antibody in mice. MuS110 was found to have similar in vitro characteristics and in vivo antitumor activity as MT110, a human EpCAM/human CD3-bispecific BiTE antibody that currently is in formal preclinical development. [Cancer Res 2008;68(1):143–51]
Peripheral T-Cell Tolerance Associated with Prostate Cancer Is Independent from CD4+CD25+ Regulatory T Cells
Authors: Degl'Innocenti Elena , Grioni Matteo , Capuano Giusy , Jachetti Elena , Freschi Massimo , Bertilaccio Maria T.S. , Hess-Michelini Rodrigo , Doglioni Claudio , Bellone Matteo
Published: January 2008

CD4+CD25+Foxp3+ regulatory T cells (Treg) are thought to suppress the natural and vaccine-induced immune response against tumor-associated antigens (TAA). Here, we show that Treg accumulate in tumors and tumor-draining lymph nodes of aging transgenic adenocarcinoma of the mouse prostate (TRAMP) male mice, which spontaneously develop prostate cancer. TAA overexpression and disease progression associate also with induction of TAA-specific tolerance. TAA-specific T cells were found in the lymphoid organs of tumor-bearing mice. However, they had lost the ability to release IFN-γ and kill relevant targets. Neither in vivo depletion of Treg by PC61 monoclonal antibody followed by repeated vaccinations with antigen-pulsed dendritic cells nor the combined treatment with 1-methyl-l-tryptophan inhibitor of the enzyme indoleamine 2,3-dyoxigenase, PC61 antibody, and dendritic cell vaccination restored the TAA-specific immune response. Treg did not seem to control the early phases of tolerance induction, as well. Indeed, depletion of Treg, starting at week 6, the age at which TRAMP mice are not yet tolerant, and prolonged up to week 12, did not avoid tolerance induction. A similar accumulation of Treg was found in the lymph nodes draining the site of dendritic cell vaccination both in TRAMP and wild-type animals. Hence, we conclude that Treg accrual is a phenomenon common to the sites of an ongoing immune response, and in TRAMP mice in particular, Treg are dispensable for induction of tumor-specific tolerance. [Cancer Res 2008;68(1):292–300]
Expression of CDK4 or CDK2 in Mouse Oral Cavity Is Retained in Adult Pituitary with Distinct Effects on Tumorigenesis
Authors: Macias Everardo , Miliani de Marval Paula L. , Senderowicz Adrian , Cullen John , Rodriguez-Puebla Marcelo L.
Published: January 2008

The keratin 5 (K5) promoter drives transgenic expression to the basal cell layer of stratified epithelia. Surprisingly, analysis of K5CDK4 and K5CDK2 transgenic mouse embryos showed CDK4 and CDK2 expression not only in the expected tissues, but also in the adenohypophysis. This organ is derived from an upwards growth of the primitive oropharnyx, a K5-expressing tissue. We show that transgenic expression of CDKs in the embryonic oral ectoderm is specifically retained in undifferentiated cells from the pars intermedia of the adenohypophysis. Interestingly, we found that K5CDK4 mice show a decreased number of pituitary stem cells, even though CDK4 is not expressed in the stem cells but in transit-amplifying (TA)–like cells. Interestingly, CDK4-expressing cells, but not CDK2-expressing cells, strongly synergize with lack of p27Kip1 to generate pituitary carcinomas that appear with shortened latency and are drastically more aggressive than those arising in p27−/− mice. Thus, we show that deregulation of CDK expression in the primitive oral epithelium plays a unique function, providing a selective advantage that gives rise to transgene-positive TA-like pituitary cells. Furthermore, retention of CDK4 in these TA-like pituitary cells synergizes with loss of p27Kip1 to induce pituitary adenocarcinomas. This model suggests that forced expression of CDK4 sensitizes cells and synergizes with a second change resulting in tumor development. [Cancer Res 2008;68(1):162–71]
Genome-Wide Transcriptional Response to 5-Aza-2′-Deoxycytidine and Trichostatin A in Multiple Myeloma Cells
Authors: Heller Gerwin , Schmidt Wolfgang M. , Ziegler Barbara , Holzer Sonja , Müllauer Leonhard , Bilban Martin , Zielinski Christoph C. , Drach Johannes , Zöchbauer-Müller Sabine
Published: January 2008

To identify epigenetically silenced cancer-related genes and to determine molecular effects of 5-aza-2′-deoxycytidine (Aza-dC) and/or trichostatin A (TSA) in multiple myeloma (MM), we analyzed global changes in gene expression profiles of three MM cell lines by microarray analysis. We identified up-regulation of several genes whose epigenetic silencing in MM is well known. However, much more importantly, we identified a large number of epigenetically inactivated cancer-related genes that are involved in various physiologic processes and whose epigenetic regulation in MM was unknown thus far. In addition, drug treatment of MM cell lines resulted in down-regulation of several MM proliferation-associated factors (i.e., MAF, CCND1/2, MYC, FGFR3, MMSET). Ten Aza-dC and/or TSA up-regulated genes (CPEB1, CD9, GJA1, BCL7c, GADD45G, AKAP12, TFPI2, CCNA1, SPARC, and BNIP3) were selected for methylation analysis in six MM cell lines, 24 samples from patients with monoclonal gammopathy of undetermined significance (MGUS), and 111 samples from patients with MM. Methylation frequencies of these genes ranged between 0% and 17% in MGUS samples and between 5% and 50% in MM samples. Interestingly, methylation of SPARC and BNIP3 was statistically significantly associated with a poor overall survival of MM patients (P = 0.003 and P = 0.017, respectively). Moreover, SPARC methylation was associated with loss of SPARC protein expression by immunostaining in a subset of MM patients. In conclusion, we identified new targets for aberrant methylation in monoclonal gammopathies, and our results suggest that DNA methyltransferase and histone deacetylase inhibition might play an important role in the future treatment of patients with MM. [Cancer Res 2008;68(1):44–54]
Circulating Levels of Inflammatory Cytokines and Risk of Colorectal Adenomas
Authors: Kim Sangmi , Keku Temitope O. , Martin Christopher , Galanko Joseph , Woosley John T. , Schroeder Jane C. , Satia Jessie A. , Halabi Susan , Sandler Robert S.
Published: January 2008

The association between obesity and colorectal neoplasia may be mediated by inflammation. Circulating levels of C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) are elevated in the obese. Adipose tissue can produce and release the inflammatory cytokines that are potentially procarcinogenic. We examined circulating levels of CRP, IL-6, and TNF-α in relation to risk factors and the prevalence of colorectal adenomas. Plasma levels of CRP, IL-6, and TNF-α were quantified in 873 participants (242 colorectal adenoma cases and 631 controls) in a colonoscopy-based cross-sectional study conducted between 1998 and 2002. Multivariable logistic regression was used to estimate associations between known risk factors for colorectal neoplasia and circulating levels of inflammatory cytokines and associations between inflammatory cytokines and colorectal adenomas. Several known risk factors for colorectal neoplasia were associated with higher levels of inflammatory cytokines, including older age, current smoking, and increasing adiposity. The prevalence of colorectal adenomas was associated with higher concentrations of IL-6 and TNF-α and, to a lesser degree, with CRP. For IL-6, adjusted odds ratios (OR) for colorectal adenomas were 1.79 [95% confidence interval (CI), 1.19–2.69] for the second highest plasma level and 1.85 (95% CI, 1.24–2.75) for the highest level compared with the reference level. A similar association was found with TNF-α, with adjusted ORs of 1.56 (95% CI, 1.03–2.36) and 1.66 (95% CI, 1.10–2.52), respectively. Our findings indicate that systemic inflammation might be involved in the early development of colorectal neoplasia. [Cancer Res 2008;68(1):323–8]
Insulin, Insulin-like Growth Factor-I, Endogenous Estradiol, and Risk of Colorectal Cancer in Postmenopausal Women
Authors: Gunter Marc J. , Hoover Donald R. , Yu Herbert , Wassertheil-Smoller Sylvia , Rohan Thomas E. , Manson JoAnn E. , Howard Barbara V. , Wylie-Rosett Judith , Anderson Garnet L. , Ho Gloria Y.F. , Kaplan Robert C. , Li Jixin , Xue Xiaonan , Harris Tiffany G. , Burk Robert D. , Strickler Howard D.
Published: January 2008

Obesity is a risk factor for colorectal cancer, and hyperinsulinemia, a common condition in obese patients, may underlie this relationship. Insulin, in addition to its metabolic effects, has promitotic and antiapoptotic activity that may be tumorigenic. Insulin-like growth factor (IGF)-I, a related hormone, shares sequence homology with insulin, and has even stronger mitogenic effects. However, few prospective colorectal cancer studies directly measured fasting insulin, and none evaluated free IGF-I, or endogenous estradiol, a potential cofactor in postmenopausal women. Therefore, we conducted a case-cohort investigation of colorectal cancer among nondiabetic subjects enrolled in the Women's Health Initiative Observational Study, a prospective cohort of 93,676 postmenopausal women. Fasting baseline serum specimens from all incident colorectal cancer cases (n = 438) and a random subcohort (n = 816) of Women's Health Initiative Observational Study subjects were tested for insulin, glucose, total IGF-I, free IGF-I, IGF binding protein-3, and estradiol. Comparing extreme quartiles, insulin [hazard ratio (HR)q4–q1, 1.73; 95% confidence interval (CI), 1.16–2.57; Ptrend = 0.005], waist circumference (HRq4–q1, 1.82; 95% CI, 1.22–2.70; Ptrend = 0.001), and free IGF-I (HRq4–q1, 1.35; 95% CI, 0.92–1.98; Ptrend = 0.05) were each associated with colorectal cancer incidence in multivariate models. However, these associations each became nonsignificant when adjusted for one another. Endogenous estradiol levels, in contrast, were positively associated with risk of colorectal cancer (HR comparing high versus low levels, 1.53; 95% CI, 1.05–2.22), even after control for insulin, free IGF-I, and waist circumference. These data suggest the existence of at least two independent biological pathways that are related to colorectal cancer: one that involves endogenous estradiol, and a second pathway broadly associated with obesity, hyperinsulinemia, and free IGF-I. [Cancer Res 2008;68(1):329–37]
Twist Promotes Tumor Cell Growth through YB-1 Expression
Authors: Shiota Masaki , Izumi Hiroto , Onitsuka Takamitsu , Miyamoto Naoya , Kashiwagi Eiji , Kidani Akihiko , Yokomizo Akira , Naito Seiji , Kohno Kimitoshi
Published: January 2008

YB-1 controls gene expression through both transcriptional and translational mechanisms and is involved in various biological activities such as brain development, chemoresistance, and tumor progression. We have previously shown that YB-1 is overexpressed in cisplatin-resistant cells and is involved in resistance against DNA-damaging agents. Structural analysis of the YB-1 promoter reveals that several E-boxes may participate in the regulation of YB-1 expression. Here, we show that the E-box–binding transcription factor Twist is overexpressed in cisplatin-resistant cells and that YB-1 is a target gene of Twist. Silencing of either Twist or YB-1 expression induces G1 phase cell cycle arrest of tumor cell growth. Significantly, reexpression of YB-1 led to increase colony formation when Twist expression was down-regulated by small interfering RNA. However, cotransfection of Twist expression plasmid could not increase colony formation when YB-1 expression was down-regulated. Collectively, these data suggest that YB-1 is a major downstream target of Twist. Both YB-1 and Twist expression could induce tumor progression, promoting cell growth and driving oncogenesis in various cancers. Thus, both YB-1 and Twist may represent promising molecular targets for cancer therapy. [Cancer Res 2008;68(1):98–105]
Clonogenic Multiple Myeloma Progenitors, Stem Cell Properties, and Drug Resistance
Authors: Matsui William , Wang Qiuju , Barber James P. , Brennan Sarah , Smith B. Douglas , Borrello Ivan , McNiece Ian , Lin Lan , Ambinder Richard F. , Peacock Craig , Watkins D. Neil , Huff Carol Ann , Jones Richard J.
Published: January 2008

Many agents are active in multiple myeloma, but the majority of patients relapse. This clinical pattern suggests most cancer cells are eliminated, but cells with the clonogenic potential to mediate tumor regrowth are relatively chemoresistant. Our previous data suggested that CD138+ multiple myeloma plasma cells cannot undergo long-term proliferation but rather arise from clonogenic CD138neg B cells. We compared the relative sensitivity of these distinct cell types to clinical antimyeloma agents and found that dexamethasone, lenadilomide, bortezomib, and 4-hydroxycyclophosphamide inhibited CD138+ multiple myeloma plasma cells but had little effect on CD138neg precursors in vitro. We further characterized clonogenic multiple myeloma cells and stained cell lines using the Hoechst side population and Aldefluor assays. Each assay identified CD138neg cells suggesting that they possess high drug efflux capacity and intracellular drug detoxification activity. We also found that multiple myeloma cells expressing the memory B-cell markers CD20 and CD27 could give rise to clonogenic multiple myeloma growth in vitro and engraft immunodeficient nonobese diabetes/severe combined immunodeficient mice during both primary and secondary transplantation. Furthermore, both the side population and Aldefluor assays were capable of identifying circulating clonotypic memory B-cell populations within the peripheral blood of multiple myeloma patients. Our results suggest that circulating clonotypic B-cell populations represent multiple myeloma stem cells, and the relative drug resistance of these cells is mediated by processes that protect normal stem cells from toxic injury. [Cancer Res 2008;68(1):190–7]
LKB1 Deficiency Sensitizes Mice to Carcinogen-Induced Tumorigenesis
Authors: Gurumurthy Sushma , Hezel Aram F. , Berger Justin H. , Bosenberg Marcus W. , Bardeesy Nabeel
Published: January 2008

Lkb1 is a central regulator of cell polarity and energy metabolism through its capacity to activate the AMP-activated protein kinase (AMPK)–related family of protein kinases. Germ line–inactivating mutation of Lkb1 leads to Peutz-Jeghers syndrome, which is characterized by benign hamartomas and a susceptibility to malignant epithelial tumors. Mutations in Lkb1 are also found in sporadic carcinomas, most frequently in lung cancers associated with tobacco carcinogen exposure. The basis for Lkb1-dependent tumor suppression is not defined. Here, we uncover a marked sensitivity of Lkb1 mutant mice to the chemical carcinogen 7,12-dimethylbenz(a)anthracene (DMBA). Lkb1+/− mice are highly prone to DMBA-induced squamous cell carcinoma (SCC) of the skin and lung. Confirming a cell autonomous tumor suppressor role of Lkb1, mice with epidermal-specific Lkb1 deletion are also susceptible to DMBA-induced SCC and develop spontaneous SCC with long latency. Restoration of wild-type Lkb1 causes senescence in tumor-derived cell lines, a process that can be partially bypassed by inactivation of the Rb pathway, but not by inactivation of p53 or AMPK. Our data indicate that Lkb1 is a potent suppressor of carcinogen-induced skin and lung cancers and that downstream targets beyond the AMPK-mTOR pathway are likely mediators of Lkb1-dependent tumor suppression. [Cancer Res 2008;68(1):55–63]
Phase III Prevention Trial of Fenretinide in Patients with Resected Non–Muscle-Invasive Bladder Cancer
Authors: Sabichi Anita L. , Lerner Seth P. , Atkinson E. Neely , Grossman H. Barton , Caraway Nancy P. , Dinney Colin P. , Penson David F. , Matin Surena , Kamat Ashish , Pisters Louis L. , Lin Daniel W. , Katz Ruth L. , Brenner Dean E. , Hemstreet George P. , Wargo Mary , Bleyer Archie , Sanders William H. , Clifford John L. , Parnes Howard L. , Lippman Scott M.
Published: January 2008

Purpose: The study aims to evaluate the efficacy and toxicity of fenretinide in preventing tumor recurrence in patients with transitional cell carcinoma (TCC) of the bladder.

Experimental Design: We conducted a multicenter phase III, randomized, placebo-controlled trial of fenretinide (200 mg/day orally for 12 months) in patients with non–muscle-invasive bladder TCC (stages Ta, Tis, or T1) after transurethral resection with or without adjuvant intravesical Bacillus Calmette-Guerin (BCG). Patients received cystoscopic evaluation and bladder cytology every 3 months during the 1-year on study drug and a final evaluation at 15 months. The primary endpoint was time to recurrence.

Results: A total of 149 patients were enrolled; 137 were evaluable for recurrence. The risk of recurrence was considered to be “low” in 72% (no prior BCG) and intermediate or high in 32% (prior BCG) of the evaluable patients. Of the lower-risk group, 68% had solitary tumors and 32% had multifocal, low-grade papillary (Ta, grade 1 or grade 2) tumors. The 1-year recurrence rates by Kaplan-Meier estimate were 32.3% (placebo) versus 31.5% (fenretinide; P = 0.88 log-rank test). Fenretinide was well tolerated and had no unexpected toxic effects; only elevated serum triglyceride levels were significantly more frequent on fenretinide (versus placebo). The Data Safety and Monitoring Board recommended study closure at 149 patients (before reaching the accrual goal of 160 patients) because an interim review of the data showed a low likelihood of detecting a difference between the two arms, even if the original accrual goal was met.

Conclusions: Although well tolerated, fenretinide did not reduce the time-to-recurrence in patients with Ta, T1, or Tis TCC of the bladder.