bluuebunny/crossref_metadata_2025 huggingface dataset:
SU‐FF‐T‐433: TMR Ratio Method to Correct for SSD Changes in Prostate IGRT with IMRT Delivery
Authors: Li T , Szal M , Grant D , Tapen E , Farhangi E , Kim T , Chu K
Published: July 2006

Purpose: In IGRT, couch shifts are needed to align the target to account for organ motion. In some rare cases treatment SSD may differ significantly (up to 1.0 cm) from the plan after these shifts. TMR ratio method is proposed to correct SSD changes so dosimetric accuracy of IGRT with IMRT delivery can be preserved. Method and Materials: A prostate patient CT was contoured in Eclipse TPS (Varian Medical Systems, v7.3) as test body. A bolus was added surrounding the body with either 1.0 cm or 2.0 cm thick bolus, (simulating 1.0 cm and 2.0 cm SSD change, respectively). An IMRT prostate clinical plan using 18 MV photons was exported to each of the three test bodies to create verification plans. TMRs were then read from our clinical data table according to different depths in the three test bodies. The TMR ratios were generated based on the non‐bolus plan. To apply the TMR ratio to the beams, the prescription percent isodose line in each plan was lowered by the corresponding TMR ratios to increase MUs. By doing this, all other treatment parameters, including dynamic MLC configuration were kept the same. The corrected plans were exported to corresponding bodies and doses were calculated. The DVHs of prostate and critical organs were then compared. Results: DVHs for prostate and critical organs were identical for all three scenarios after TMR ratio correction. Conclusion: The TMR ratio method was applicable for IMRT plans to correct for small SSD changes in IGRT. For regular IMRT plans, if SSD changes are caused by other reasons like weight loss, this method is still valid assuming PTV does not change. However, if SSD change is larger than 1.0 cm, it is prudent to re‐CT scan the patient and re‐calculate plan because the PTV might have changed.
SU‐FF‐T‐457: Whole‐Body Dose for Helical Tomotherapy
Authors: Goddu S , Mutic S , Grigsby J , Santanam L , Low D
Published: July 2006

Purpose: Tomotherapy is a form of intensity modulated radiation therapy (IMRT) that utilizes rotating fan beams modulated by a binary‐multileaf collimator. The radiation is delivered either serially or helically as the patient is moved in a craniocaudal sequence for tumor coverage. While Tomotherapy can deliver highly conformal dose distributions, it yields the lowest delivery efficiency (tumor dose per MU) of current IMRT‐delivery options. This relatively low efficiency has the potential for delivering high total‐body doses due to head leakage, so a quantitative evaluation of the whole‐body dose is warranted. Methods and Materials: We conducted this evaluation for a dedicated helical Tomotherapy delivery device (Hi‐Art System®, Tomotherapy Inc) and compared the results against the previously published serial Tomotherapy system (Corvus, NOMOS Corporation) and traditional IMRT whole‐body data. A typical head‐and‐neck treatment plan (2Gy per fraction, 6622MU) was prepared and delivered to a large water‐equivalent phantom. An ADCL‐calibrated large‐volume ionization chamber (A17 Exradin) was used to measure the low doses. The dose was measured at both 1.5cm (dmax) and at the center of the phantom. Results: From 10cm to 48cm from the inferior target edge (the most proximal serial tomotherapy point was at 10 cm), the helical tomotherapy dose was less than 0.5% of the target dose, and was between 20% and 30% of the serial tomotherapy leakage dose. This study showed that the whole‐body dose for the 70Gy is approximately 140mSv. This dose is less than the 560mSv for a 70Gy treatment as published by Followill, et al. (Int.J.Radiat.Oncol.Biol.Phys. 38, 667). Conclusions: This study indicates that the commercial helical Tomotherapy system provides less whole‐body dose than serial Tomotherapy or conventional IMRT. This is probably due to the internal linear accelerator shielding design and the use of 6 MV photons.

This work was supported in part by funding from Tomotherapy, Inc.
SU‐FF‐P‐04: New Stereotactic Radiosurgery CPT Codes for 2006
Authors: Hevezi J
Published: July 2006

Purpose: To identify the new planning codes for stereotactic radiosurgery (SRS) and stereotactic body radiation therapy (SBRT) beginning January 1, 2006. Methods & Materials: On Jan. 1, 2006, CMS promulgated new procedure codes for SRS and SBRT planning. Previously, G0338 was to be used to cover this work in the hospital setting for Medicare patients. After this date, the CPT radiation therapy planning codes available in the 77XXX series are to be used to cover the work of SRS and SBRT planning. Results: The CPT code for 3D planning, CPT 77295 will now be used to cover the work previously covered under the temporary G0338 code in the hospital setting. All of the applicable CPT codes that cover additional work for a course of radiation therapy (77300, 77336, 77370, 77470, etc) will still be available to cover work associated with the treatment course. The new stereoscopic guidance code, 77421, is however bundled into the G codes used for delivery, at present. Suggested codes will be presented. Conclusions: SRS and SBRT users will need to use CPT codes to cover the work of planning for these procedures after Jan 1, 2006. Other carriers will likely follow CMS' recommendation, but they should be queried for their policy on this coverage, lest denial of payments ensue.
TU‐C‐330A‐03: Sulci Density Map to Aid in the Use of Apparent Diffusion Coefficient for Therapy Evaluation
Authors: Ewell L , Watchman C
Published: July 2006

Purpose: To quantify the density and spatial variation of sulci in the human brain so as to more accurately calculate Apparent Diffusion Coefficients (ADCs) for use in radiotherapy evaluation. Methods and Materials: ADCs are calculated for Volumes Of Interest (VOI) using Diffusion Weighted Magnetic Resonance Imaging (DWMRI).

In the brain, the sulci are the narrow fissures separating convolutions and are filled with CerbroSpinal Fluid (CSF). Since CSF is free fluid, a VOI that contains a high density of sulci should, in principal, have a higher ADC.

Using ImageJ (http://rsb.info.nih.gov/ij/), we have analyzed sagittal T1 weighted MR images of a number of patients. The images sets were acquired on one of two different GE MRI machines: 1.5T and 3.0T field strength. We have plotted the normalized pixel standard deviation, as a function of distance from a medial point. We have concentrated on the cerebral hemispheres, superior to the corpus callosum so as to focus on sulci and avoid voxel dissimilarities due to variations in other brain anatomy. Results: Relative to the 25% most medial slices, we see a decrease in the normalized standard deviation of pixel intensity of 13.7% ± 5.6% (SD) of the next 25% of the slices. The most lateral 50% of the slices (25% left and right) had about the same normalized standard deviation as the most medial (increase of 1.0% ± 7.1% (SD)). These results are consistent with the fact that near the periphery of each brain hemisphere, there are more sulci. Conclusion: Sulci density, as measured by normalized standard deviation of pixel intensity, has a substantial variation across the hemispheres of the brain. This fact should be considered when assessing variations in ADCs used for radiotherapy evaluation.
TU‐C‐224A‐01: Fast Multifield Optimization of the Biological Effect in IMRT with Ion Beams
Authors: Wilkens J J , Oelfke U
Published: July 2006

Purpose: To investigate a new technique for multifield optimization of the biological effect (relative biological effectiveness times dose) for intensity modulated radiotherapy with scanned ion beams and to compare this method to an existing planning system for ions. Method and Materials: Our approach is based on the mixed irradiation formalism of the linear‐quadratic model using dose averaged mean values of alpha and sqrt(beta). We employ a novel objective function to directly optimize the biological effect rather than the physical dose. It is based on constraints in biologically effective dose for targets and organs at risk in close analogy to inverse planning for photons. The required biological input data are reduced to a minimum and are completely independent from the optimization itself. They can be derived from any radiobiological model or even from directly measured data. The new optimization method is fully integrated into the inverse treatment planning tool KonRad. Results: Comparisons with the TRiP98 treatment planning code are shown for spread‐out Bragg peaks as well as for three‐dimensional treatment plans for carbon ions, where all fields are optimized separately. While the agreement between both planning systems is very good, the calculation time is substantially reduced in KonRad. By enabling the multifield optimization in KonRad, the quality of the treatment plans and the sparing of healthy tissues can be clearly improved, which is demonstrated on several examples. Depending on the number of beam spots used, typical optimization times are between 10 and 60 minutes. Conclusion: The proposed system offers complete and fast inverse treatment planning for ions. Simultaneous multifield optimization of the biological effect can considerably enhance the resulting plans since it makes the best use of all possible degrees of freedom. Conflict of Interest: Research sponsored by Siemens Medical Solutions corporation.
TU‐C‐224A‐07: Multi‐Objective IMRT Planning: A New Algorithm, with Clinical Examples
Authors: Craft D , Bortfeld T , Halabi T
Published: July 2006

Purpose: Intensity modulated radiation treatment planning for difficult cases is typically a time‐consuming manual search for a plan which gives an acceptable tradeoff between tumor coverage and critical structure sparing. We develop a method to calculate the efficient tradeoff surface of a multi‐objective IMRT inverse planning problem. This serves two purposes: to eliminate the time‐consuming manual search process, and to provide the treatment planners with the complete tradeoff information, allowing them to make more informed decisions. Method and Materials: We formulate a linear multi‐objective IMRT treatment planning problem, the solution of which is a set of Pareto optimal treatment plans. Since each Pareto optimal plan involves a lengthy optimization, it is prudent to represent the complete surface with as few points as possible. Given the current set of Pareto surface plans, we use geometric considerations to formulate the optimization problem which computes the next plan. In this way, plans are added to the Pareto database until the surface is well represented. Results: The algorithm is applied to two clinical cases. For the prostate case, we display a tradeoff between the prostate coverage, femoral head sparing, and rectal sparing. For the skull‐based tumor, we display a tradeoff between tumor coverage, and the maximum doses of the chiasm, pituitary, and brainstem. Conclusion: We provide a method to efficiently generate Pareto surfaces for treatment planning, even when the number of organs to be traded off exceeds two or three. The method is applicable to any convex objective functions, including equivalent uniform dose, as well as the more standard quadratic penalty IMRT formulations. We expect that the clinical benefit of being able to visualize the tradeoff information — e.g. exactly how a decrease in critical structure dose degrades the tumor coverage — during the planning process will inspire a surge of research in this field.
TU‐FF‐A1‐02: Estimating Dose to ICD Outside the Treatment Fields Using Skin QED Diode
Authors: Chan M , Song Y , Meli J , Huang Y , Burman C
Published: July 2006

Purpose: To determine calibration factors for several diodes and TLD as a function of distance from the field edge. These can then be applied to measure dose at any out‐of‐field point. Method and Materials: Skin QED Diode has been used to estimate the radiation dose to patient's ICD outside the treatment fields. The ICDs from three major manufacturers have an outer case made of Titanium (Ti) ranging from 0.4– 0.6 mm thickness. With the correction of mass attenuation coefficients of Ti and tissue at 6‐MeV, it is estimated that 0.5‐ mm Ti is equivalent to 2.4‐mm tissue. The manufacturers recommend that the ICD be implanted subcutaneously underneath skin at 3–4 mm depth. Therefore, a 5‐mm bolus with skin diode 1‐mm inherent buildup is close to the true depth of the electronic device. The responses of the skin diode with and without bolus, an ISORAD photon diode, and TLD were measured per unit dose to water at off‐axis distances up to 10‐cm from the field edge. Dose at each point was measured by an ionization chamber located at 0.5‐cm and 1.5‐cm depth. Results: The calibration factor as a function of distance from the field edge, relative to its central axis value, changed very little for TLD and for the QED skin diode with 0.5‐cm bolus; decreased by a factor as large as 2 for the photon diode; increased by a factor as large as 3.4 for the QED diode without bolus. Conclusions: The use of diodes for out‐of‐field dose measurements requires knowing the calibration factor as a function of off‐axis distance. This can be readily done at each institution or the manufacturer can provide the pertinent relative response data. The skin QED diode is easy to use as an in‐vivo dosimeter, and, with 5‐mm bolus, its behavior is similar to TLD.
WE‐C‐330A‐02: Cone‐Beam CT for Image‐Guided Head and Neck Surgery: Assessment of Dose and Image Quality Using a C‐Arm Prototype
Authors: Daly M , Siewerdsen J , Moseley D , Jaffray D
Published: July 2006

Purpose: To quantify radiation dose to patient and staff during intraoperative cone‐beam CT (CBCT)‐guided head and neck surgery, and investigate 3D imaging performance as a function of dose. Method and Materials: Dose and image quality measurements were acquired on a mobile C‐arm modified at our institution to provide flat‐panel CBCT. Imaging dose was measured in a custom‐built 16 cm cylindrical head phantom at four positions (isocenter, anterior, posterior, and lateral) as a function of kVp (80–120 kVp) and C‐arm trajectory (“tube‐under” and “tube‐over” 180° orbits). In‐room exposure was measured at positions around the operating table and up to 2 m from isocenter. 3D image quality was assessed in CBCT reconstructions of an anthropomorphic head phantom containing contrast‐detail spheres (11–103 HU; 1.6–12.7 mm). The contrast‐to‐noise ratio (CNR) was evaluated across a broad range of dose (0.6–23.3 mGy). Results: Dose in the 16 cm phantom (100 kVp; “tube‐under” orbit) was 0.059 (isocenter), 0.022 (anterior), 0.10 (posterior), and 0.056 (lateral) mGy/mAs. Dose to the eyes (anterior) was reduced by a factor of 10 for “tube‐under” versus “tube‐over” orbits. In‐room exposure for a typical CBCT scan (∼10 mGy to isocenter) ranged from 33 mR at the anesthetist position, to <0.5 mR at 2 m from isocenter. CNR increased as the square root of dose, with excellent visualization of bony and soft‐tissue structures in the anthropomorphic head phantom achieved at ∼3mGy and ∼10mGy, respectively. Conclusion: The prototype C‐arm CBCT system demonstrates excellent visualization of bony and soft‐tissue structures at dose levels low enough for repeat intraoperative imaging. High‐performance image‐guidance with respect to bony and soft‐tissue anatomy was achieved at doses <∼3mGy and <∼10mGy, respectively. For guidance of head and neck surgery, significant dose sparing to the patient's eyes (a factor of 10) is achieved using a “tube‐under” (rather than “tube‐over”) 180deg; orbit.
TH‐E‐224C‐04: MMCTP, a Radiotherapy Research Environment for Monte Carlo and Patient‐Specific Treatment Planning
Authors: Alexander A , DeBlois F , Seuntjens J
Published: July 2006

Purpose: To develop a flexible software package, on low cost hardware with the aim of integrating new patient specific treatment planning with Monte Carlo dose calculation suitable for large‐scale prospective and retrospective treatment planning studies.

Programming Philosophy: The McGill Monte Carlo Treatment Planning system (MMCTP) is designed as a software environment for the research development of patient specific treatment planning. The design includes a workstation GUI for treatment planning tools, and anonymous access to standard low cost hardware for MC dose calculation. Results: Before using MMCTP, treatment plans are converted into the so‐called McGill RT format. This new file structure was designed for saving patient plans on the workstation. The current MMCTP features are: (a) DICOM and RTOG imports; (b) transverse/sagittal/coronal slice viewing for contours, CT scans, dose distributions; (c) contouring tools; (d) colour‐wash and isodose line display; (e) DVH analysis, and dose matrix comparison tools; (f) external beam editing; (g) thumbnail CT navigation tool; (h) EGS/Beam calculation and XVMC patient transport for photon and electron beams. MMCTP uses a two‐step process to generate MC dose distributions. The MC module controls egs/Beam and XVMC calculations. Input files, prepared from the beam geometry, are uploaded and run on the cluster using shell commands. Upon completion of XVMC, the GUI downloads individual dose files. Conclusion: The MMCTP GUI provides a flexible research platform for the development of patient specific MC treatment planning for photon and electron external beam radiation therapy. MMCTP uses an internal storage format that is flexible in that it allows for multi‐instance multi‐modality image information useful in the planning process. The visualization, dose matrix operation and DVH tools offer extensive possibility for plan analysis and comparison to plans imported from commercial treatment planning systems through well‐documented image storage protocols such as DICOM.
Sci‐Fri AM General‐07: Dual Isotope SPECT to Track Transplanted Cells in Canine Myocardium Using Molecular Imaging
Authors: Blackwood K , Stodilka R , Sykes J , Prato F
Published: July 2006

Introduction: Non‐invasive cell tracking techniques that provide repetitive and functional assessments of transplanted cells will be an asset in cell‐based therapies. Specifically, reporter gene (RG) expression may be used to signal certain molecular events as they occur in vivo.

Objective: To compare the in vivo kinetics of a radiolabeled reporter probe (RP) specifically targeted by RG expression to a non‐specific radiolabel (NSL) in canine bone marrow cells (BMC). Cells were co‐labeled in vitro, transplanted into normal canine myocardium, and tracked using dual‐isotope SPECT.

Methods: Following canine bone marrow harvest (n=1), BMCs were isolated, transfected with RG, and grown in culture for 4 weeks. Transfected cells (5.4×106) were then incubated with RP and NSL followed by direct injection into the left canine ventricle. The recipient of transplanted cells was also the donor. Forty 1‐hr SPECT images were acquired to obtain washout kinetics of RP and NSL. Time activity curves (TAC) were generated from SPECT region of interest analysis. After sacrifice, ex vivo measurements of RP and NSL activity remaining in the myocardium were made with a high purity germanium gamma‐ray well counter.

Results: Decay‐corrected TACs demonstrated faster washout kinetics for RP compared to NSL with biological half‐lives of 19 and 39 hours, respectively. This suggests that RP loss is greater than that attributed to cell death alone and demonstrates differences in label stability. Ex vivo tissue analysis confirmed these results.

Conclusion: Multispectral SPECT shows potential for monitoring RG stability and expression to follow cell viability and function non‐invasively in large animals.
Farnesyl Diphosphate Synthase Is a Cytosolic Enzyme inLeishmania majorPromastigotes and Its Overexpression Confers Resistance to Risedronate
Authors: Ortiz-Gómez Aurora , Jiménez Carmen , Estévez Antonio M. , Carrero-Lérida Juana , Ruiz-Pérez Luis M. , González-Pacanowska Dolores
Published: July 2006

Farnesyl diphosphate synthase is the most likely molecular target of aminobisphosphonates (e.g., risedronate), a set of compounds that have been shown to have antiprotozoal activity both in vitro and in vivo. This protein, together with other enzymes involved in isoprenoid biosynthesis, is an attractive drug target, yet little is known about the compartmentalization of the biosynthetic pathway. Here we show the intracellular localization of the enzyme in wild-typeLeishmania majorpromastigote cells and in transfectants overexpressing farnesyl diphosphate synthase by using purified antibodies generated towards a homogenous recombinantLeishmania majorfarnesyl diphosphate synthase protein. Indirect immunofluorescence, together with immunoelectron microscopy, indicated that the enzyme is mainly located in the cytoplasm of both wild-type cells and transfectants. Digitonin titration experiments also confirmed this observation. Hence, while the initial step of isoprenoid biosynthesis catalyzed by 3-hydroxy-3-methylglutaryl-coenzyme A reductase is located in the mitochondrion, synthesis of farnesyl diphosphate by farnesyl diphosphate synthase is a cytosolic process.Leishmania majorpromastigote transfectants overexpressing farnesyl diphosphate synthase were highly resistant to risedronate, and the degree of resistance correlated with the increase in enzyme activity. Likewise, when resistance was induced by stepwise selection with the drug, the resulting resistant promastigotes exhibited increased levels of farnesyl diphosphate synthase. The overproduction of protein under different conditions of exposure to risedronate further supports the hypothesis that this enzyme is the main target of aminobisphosphonates inLeishmaniacells.
Synergy among Differentially Regulated Repressors of the Ribonucleotide Diphosphate Reductase Genes of
Saccharomyces cerevisiae
Authors: Klinkenberg Lee G. , Webb Travis , Zitomer Richard S.
Published: July 2006

The Ssn6/Tup1 general repression complex represses transcription of a number of regulons through recruitment by regulon-specific DNA-binding repressors. Rox1 and Mot3 are Ssn6/Tup1-recruiting, DNA-binding proteins that repress the hypoxic genes, and Rfx1 is a Ssn6/Tup1-recruiting, a DNA-binding protein that represses the DNA damage-inducible genes. We previously reported that Rox1 and Mot3 functioned synergistically to repress a subset of the hypoxic genes and that this synergy resulted from an indirect interaction through Ssn6. We report here cross-regulation between Rox1 and Mot3 and Rfx1 in the regulation of the
RNR
genes encoding ribonucleotide diphosphate reductase. Using a set of strains containing single and multiple mutations in the repressor encoding genes and
lacZ
fusions to the
RNR2
to
-4
genes, we demonstrated that Rox1 repressed all three genes and that Mot3 repressed
RNR3
and
RNR4
. Each repressor could act synergistically with the others, and synergy required closely spaced sites. Using artificial constructs containing two repressor sites, we confirmed that all three proteins could function synergistically but that two Rox1 sites or two Rfx1 sites could not. The significance of this synergy lies in the ability to repress gene transcription strongly under normal growth conditions, and yet allow robust induction under conditions that inactivate only one of the repressors. Since the interaction between the proteins is indirect, the evolution of dually regulated genes requires only the acquisition of closely spaced repressor sites.
Calcineurin Controls Growth, Morphology, and Pathogenicity in
Aspergillus fumigatus
Authors: Steinbach William J. , Cramer Robert A. , Perfect B. Zachary , Asfaw Yohannes G. , Sauer Theodor C. , Najvar Laura K. , Kirkpatrick William R. , Patterson Thomas F. , Benjamin Daniel K. , Heitman Joseph , Perfect John R.
Published: July 2006

Calcineurin is implicated in a myriad of human diseases as well as homeostasis and virulence in several major human pathogenic microorganisms. The fungus
Aspergillus fumigatus
is a leading cause of infectious death in the rapidly expanding immunocompromised patient population. Current antifungal treatments for invasive aspergillosis are often ineffective, and novel therapeutic approaches are urgently needed. We demonstrate that a mutant of
A. fumigatus
lacking the calcineurin A (
cnaA
) catalytic subunit exhibited defective hyphal morphology related to apical extension and polarized growth, which resulted in drastically decreased filamentation. The Δ
cnaA
mutant lacked the extensive lattice of invading hyphae seen with the wild-type and complemented strains. Sporulation was also affected in the Δ
cnaA
mutant, including morphological conidial defects with the absence of surface rodlets and the added presence of disjunctors creating long conidial chains. Infection with the Δ
cnaA
mutant in several distinct animal models with different types of immunosuppression and inoculum delivery led to a profound attenuation of pathogenicity compared to infection with the wild-type and complemented strains. Lung tissue from animals infected with the Δ
cnaA
mutant showed a complete absence of hyphae, in contrast to tissue from animals infected with the wild-type and complemented strains. Quantitative fungal burden and pulmonary infarct scoring confirmed these findings. Our results support the clinical observation that substantially decreasing fungal growth can prevent disease establishment and decrease mortality. Our findings reveal that calcineurin appears to play a globally conserved role in the virulence of several pathogenic fungi and yet plays specialized roles in each and can be an excellent target for therapeutic intervention.
Transcription Factor Nrg1 Mediates Capsule Formation, Stress Response, and Pathogenesis inCryptococcus neoformans
Authors: Cramer Kari L. , Gerrald Quincy D. , Nichols Connie B. , Price Michael S. , Alspaugh J. Andrew
Published: July 2006

TheCryptococcus neoformans NRG1gene was identified using gene microarrays to define putative transcription factor genes regulated by the cyclic AMP (cAMP) signal transduction pathway. Disruption ofNRG1results in delayed capsule formation and mating, two phenotypes that are directly controlled by cAMP signaling. Putative targets of the Nrg1 transcription factor were identified using a second genome microarray to define differences in the transcriptomes of the wild-type andnrg1mutant strains. These experiments implicate Nrg1 in the transcriptional control of multiple genes involved in carbohydrate metabolism and substrate oxidation, as well as theUGD1gene encoding a UDP-glucose dehydrogenase required for polysaccharide capsule production and cell wall integrity. In addition to being under transcriptional control of the cAMP pathway, Nrg1 contains a putative protein kinase A phosphorylation site; mutation of this motif results in reduced Nrg1 activity. Consistent with prior studies in hypocapsular mutants, thenrg1mutant strain is attenuated in an animal model of disseminated cryptococcal disease.
EppA, a Putative Substrate of DdERK2, Regulates Cyclic AMP Relay and Chemotaxis in
Dictyostelium discoideum
Authors: Chen Songyang , Segall Jeffrey E.
Published: July 2006

The
mitogen-activated protein kinase DdERK2 is critical for
cyclic AMP (cAMP) relay and chemotaxis to cAMP and folate, but the
details downstream of DdERK2 are unclear. To search for targets of
DdERK2 in
Dictyostelium discoideum
,
32
PO
4
3−
-labeled protein
samples from wild-type and Dd
erk2
−
cells
were resolved by 2-dimensional electrophoresis. Mass spectrometry was
used to identify a novel 45-kDa protein, named EppA (ERK2-dependent
phosphoprotein A), as a substrate of DdERK2 in
Dictyostelium
.
Mutation of potential DdERK2 phosphorylation sites demonstrated that
phosphorylation on serine 250 of EppA is DdERK2 dependent. Changing
serine 250 to alanine delayed development of
Dictyostelium
and
reduced
Dictyostelium
chemotaxis to cAMP. Although
overexpression of EppA had no significant effect on the development or
chemotaxis of
Dictyostelium
, disruption of the
eppA
gene led to delayed development and reduced chemotactic responses to
both cAMP and folate. Both
eppA
gene disruption and
overexpression of EppA carrying the serine 250-to-alanine mutation led
to inhibition of intracellular cAMP accumulation in response to
chemoattractant cAMP, a pivotal process in
Dictyostelium
chemotaxis and development. Our studies indicate that EppA regulates
extracellular cAMP-induced signal relay and chemotaxis of
Dictyostelium
.
RECIPROCITY AND THE EMERGENCE OF POWER LAWS IN SOCIAL NETWORKS
Authors: SCHNEGG MICHAEL
Published: July 2006

Research in network science has shown that many naturally occurring and technologically constructed networks are scale free, that means a power law degree distribution emerges from a growth model in which each new node attaches to the existing network with a probability proportional to its number of links (= degree). Little is known about whether the same principles of local attachment and global properties apply to societies as well. Empirical evidence from six ethnographic case studies shows that complex social networks have significantly lower scaling exponents γ ~ 1 than have been assumed in the past. Apparently humans do not only look for the most prominent players to play with. Moreover cooperation in humans is characterized through reciprocity, the tendency to give to those from whom one has received in the past. Both variables — reciprocity and the scaling exponent — are negatively correlated (r = -0.767, sig = 0.075). If we include this effect in simulations of growing networks, degree distributions emerge that are much closer to those empirically observed. While the proportion of nodes with small degrees decreases drastically as we introduce reciprocity, the scaling exponent is more robust and changes only when a relatively large proportion of attachment decisions follow this rule. If social networks are less scale free than previously assumed this has far reaching implications for policy makers, public health programs and marketing alike.
STRUCTURAL AND ELECTRONIC PROPERTIES OF THE DPPC MOLECULE
Authors: ERKOÇ ŞAKİR , KORKMAZ FİLİZ
Published: July 2006

The structural and electronic properties of the DPPC molecule have been investigated theoretically by performing semi-empirical self-consistent-field molecular-orbital theory calculations at the PM3 level in its ground state.
COMPUTER MODEL OF BIOPOLYMER CRYSTAL GROWTH AND AGGREGATION BY ADDITION OF MACROMOLECULAR UNITS — A COMPARATIVE STUDY
Authors: SIÓDMIAK J. , GADOMSKI A.
Published: July 2006

We discuss the results of a computer simulation of the biopolymer crystal growth and aggregation based on the 2D lattice Monte Carlo technique and the HP approximation of the biopolymers. As a modeled molecule (growth unit) we comparatively consider the previously studied non-mutant lysozyme protein, Protein Data Bank (PDB) ID: 193L, which forms, under a certain set of thermodynamic-kinetic conditions, the tetragonal crystals, and an amyloidogenic variant of the lysozyme, PDB ID: 1LYY, which is known as fibril-yielding and prone-to-aggregation agent. In our model, the site-dependent attachment, detachment and migration processes are involved. The probability of growth unit motion, attachment and detachment to/from the crystal surface are assumed to be proportional to the orientational factor representing the anisotropy of the molecule. Working within a two-dimensional representation of the truly three-dimensional process, we also argue that the crystal grows in a spiral way, whereby one or more screw dislocations on the crystal surface give rise to a terrace. We interpret the obtained results in terms of known models of crystal growth and aggregation such as B-C-F (Burton-Cabrera-Frank) dislocation driven growth and M-S (Mullins-Sekerka) instability concept, with stochastic aspects supplementing the latter. We discuss the conditions under which crystals vs non-crystalline protein aggregates appear, and how the process depends upon difference in chemical structure of the protein molecule seen as the main building block of the elementary crystal cell.
ON THE REVERSIBILITY OF 150 WOLFRAM CELLULAR AUTOMATA
Authors: DEL REY A. MARTÍN , SÁNCHEZ G. RODRÍGUEZ
Published: July 2006

In this paper, the reversibility problem for 150 Wolfram cellular automata is tackled for null boundary conditions. It is explicitly shown that the reversibility depends on the number of cells of the cellular automaton. The inverse cellular automaton for each case is also computed.
COMMUNITY FINDING IN COMPLEX NETWORKS
Authors: SHEN XIANGJUN , WANG ZENGFU , WU LENAN
Published: July 2006

The investigation of community structures in complex networks is an important issue in many domains and disciplines. In this paper, we propose a novel method to address the problem based on evaluation of the community structure. By testing the proposed algorithm on artificial and real-world networks, experimental results demonstrate that our approach is both accurate and fast. Our algorithm may shed light on uncovering the universal principles of network architectures and topologies.
Axial heterogeneity of vasopressin-receptor subtypes along the human and mouse collecting duct
Authors: Carmosino Monica , Brooks Heddwen L. , Cai Qi , Davis Linda S. , Opalenik Susan , Hao Chuanming , Breyer Matthew D.
Published: July 2006

Vasopressin and vasopressin antagonists are finding expanded use in mouse models of disease and in clinical medicine. To provide further insight into the physiological role of V1a and V2 vasopressin receptors in the human and mouse kidney, intrarenal localization of the receptors mRNA was determined by in situ hybridization. V2-receptor mRNA was predominantly expressed in the medulla, whereas mRNA for V1a receptors predominated in the cortex. The segmental localization of vasopressin-receptor mRNAs was determined using simultaneous in situ hybridization and immunohistochemistry for segment-specific markers, including aquaporin-2, Dolichos biflorus agglutinin, epithelial Na channels, Tamm Horsfall glycoprotein, and thiazide-sensitive Na+-Cl−cotransporter. Notably, V1a receptor expression was exclusively expressed in V-ATPase/anion exchanger-1-labeled alpha-intercalated cells of the medullary collecting duct in both mouse and human kidney. In cortical collecting ducts, V1a mRNA was more widespread and detected in both principal and intercalated cells. V2-receptor mRNA is diffusely expressed along the collecting ducts in both mouse and human kidney, with higher expression levels in the medulla. These results demonstrate heterogenous axial expression of both V1a and V2 vasopressin receptors along the human and mouse collecting duct. The restricted expression of V1a-receptor mRNA in intercalated cells suggests a role for this receptor in acid-base balance. These findings further suggest distinct regulation of renal transport function by AVP through V1a and V2 receptors in the cortex vs. the medulla.
Direct and Indirect Activation of Cortical Neurons by Electrical Microstimulation
Authors: Tehovnik E. J. , Tolias A. S. , Sultan F. , Slocum W. M. , Logothetis N. K.
Published: July 2006

Electrical microstimulation has been used to elucidate cortical function. This review discusses neuronal excitability and effective current spread estimated by using three different methods: 1) single-cell recording, 2) behavioral methods, and 3) functional magnetic resonance imaging (fMRI). The excitability properties of the stimulated elements in neocortex obtained using these methods were found to be comparable. These properties suggested that microstimulation activates the most excitable elements in cortex, that is, by and large the fibers of the pyramidal cells. Effective current spread within neocortex was found to be greater when measured with fMRI compared with measures based on single-cell recording or behavioral methods. The spread of activity based on behavioral methods is in close agreement with the spread based on the direct activation of neurons (as opposed to those activated synaptically). We argue that the greater activation with imaging is attributed to transynaptic spread, which includes subthreshold activation of sites connected to the site of stimulation. The definition of effective current spread therefore depends on the neural event being measured.
Nicotine Suppression of Gustatory Responses of Neurons in the Nucleus of the Solitary Tract
Authors: Simons Christopher T. , Boucher Yves , Carstens Mirela Iodi , Carstens E.
Published: July 2006

This study investigated effects of nicotine applied to the tongue surface on responses of gustatory neurons in the nucleus of the solitary tract (NTS) in rats. In pentobarbital-anesthetized rats, single-unit recordings were made from NTS units responsive to one or more tastants (sucrose, NaCl, citric acid, monosodium glutamate, quinine). Application of nicotine (0.87, 8.7, or 600 mM) excited gustatory NTS units and significantly attenuated NTS unit responses to their preferred tastant in a dose-dependent manner. The depressant effect of nicotine was equivalent regardless of which tastant best excited the NTS unit. Nicotinic excitation of NTS units and depression of their tastant-evoked responses were both significantly attenuated by the nicotinic antagonist mecamylamine, which itself did not excite NTS units. In rats with bilateral trigeminal ganglionectomy, nicotine still excited nearly all NTS units but no longer depressed tastant-evoked responses. Nicotine did not elicit plasma extravasation when applied to the tongue. The results indicate that nicotine directly excites NTS units by gustatory nerves and inhibits their tastant-evoked responses by a nicotinic acetylcholine receptor-mediated excitation of trigeminal afferents that inhibit NTS units centrally.
Physiological genomics of cardiac disease: quantitative relationships between gene expression and left ventricular hypertrophy
Authors: Mirotsou Maria , Dzau Victor J. , Pratt Richard E. , Weinberg Ellen O.
Published: July 2006

The pathogenesis of cardiac left ventricular hypertrophy and failure is poorly defined due to the complexity of the disease phenotype. To gain a better understanding of the relationship between gene expression and left ventricular hypertrophy, we employed a quantitative approach to identify genes with expression patterns that correlate in a numerically continuous manner with parameters of cardiac structure and function in a mouse model of left ventricular hypertrophy due to transverse aortic constriction. Several genes showed expression patterns that were significantly correlated (Pearson's correlation coefficient) with measurements of left ventricular weight, left ventricular wall thickness, and diastolic dimension. We validated our findings in two independent data sets and in a small subset of genes by real-time RT-PCR. Of genes with significant correlations to numerically continuous measurements of hypertrophy, we found enrichment for genes encoding extracellular matrix, growth-related and secreted proteins in the directly correlated subset, and for genes encoding mitochondria and metabolic/fatty acid oxidation proteins in the inversely correlated subset. The results of this filtering strategy suggest that this subset of transcripts with quantitative relationships between gene expression and left ventricular hypertrophy represents potentially important pathways that contribute to the progression to heart failure and are thus candidates for follow-up and functional analysis.
Reciprocal congenic lines for a major stroke QTL on rat chromosome 1
Authors: Rubattu Speranza , Hubner Norbert , Ganten Ursula , Evangelista Anna , Stanzione Rosita , Angelantonio Emanuele Di , Plehm Ralph , Langanki Reika , Gianazza Elisabetta , Sironi Luigi , D’Amati Giulia , Volpe Massimo
Published: July 2006

We previously identified a quantitative trait locus (QTL) for stroke proneness between the kallikrein ( Klk) and Mt1pa markers on rat chromosome 1. To gain functional insights, we constructed congenic strains by introgressing either the whole or selected chromosomal segments from the stroke-prone (SHRsp) onto the stroke-resistant (SHRsr) spontaneously hypertensive rat genome and vice versa. The phenotype was the latency to develop stroke under a Japanese high-salt, low-potassium diet for 3 mo [known as Japanese diet (JD)]. Blood pressure (BP) was measured by tail cuff throughout the experiment. Urinary protein excretion was monitored in all lines under JD. The SHRsp-derived lines carrying the SHRsr allele, and particularly the D1Rat134- Mt1pa chromosomal segment, had a significant delay of stroke occurrence and improved survival compared with SHRsp ( P < 0.001). On the other hand, a significant occurrence of stroke events (20%) was detected in the reciprocal lines by the end of the 3-mo treatment with JD ( P = 0.003). The stroke phenotype was also associated with increased proteinuria. Our results underscore the functional importance of the Chr 1 stroke QTL. Furthermore, they underscore the utility of stroke/congenic lines in dissecting the genetics of stroke.
Atypia and Ki-67 Expression from Ductal Lavage in Women at Different Risk for Breast Cancer
Authors: Cazzaniga Massimiliano , Severi Gianluca , Casadio Chiara , Chiapparini Laura , Veronesi Umberto , Decensi Andrea
Published: July 2006

Purpose: Ductal lavage provides adequate material and detects atypical cells from ducts in women at increased risk of breast cancer, but the clinical significance of this finding is unclear. We studied the prevalence and predictors of atypia in addition to the proliferation-associated antigen Ki-67 expression in ductal lavage done in women at different risk of breast cancer.

Results: Ductal lavage was attempted in 202 women at increased risk and in 16 at average risk. Lavage could not be done in 20 women at increased risk because of anatomic impediments. Seven average-risk women (44%) had samples with inadequate cytology versus 30 women at higher risk (16%; P = 0.014). Atypia was observed in two average-risk women [22%; 95% confidence interval (95% CI), 3-60%]. The prevalence of atypia was 33% in women with a 5-year risk of ≥1.3% according to the Gail model (25 of 75; 95% CI, 23-45%), 36% in women with an increased probability of or ascertained BRCA mutation (9 of 25; 95% CI, 18-57%), and 52% in women with contralateral breast cancer (27 of 52; 95% CI, 38-66%). Ki-67 expression measured in a consecutive series of 80 women at increased risk was higher in atypical samples (P = 0.0001) and was positively associated with total cell count per slide (P = 0.002).

Conclusions: Atypia is frequent in women at increased risk of breast cancer but it can also be found in average-risk women. Ki-67 expression is associated with atypia and cell yield and it might be assessed as a surrogate biomarker in early-phase chemoprevention trials. (Cancer Epidemiol Biomarkers Prev 2006;15(7):1311–5)
Incidence of Non-Hodgkin's Lymphoma in Sweden, Denmark, and Finland from 1960 through 2003: an Epidemic That Was
Authors: Sandin Sven , Hjalgrim Henrik , Glimelius Bengt , Rostgaard Klaus , Pukkala Eero , Askling Johan
Published: July 2006

Background: Reports during the early 1990s indicated non-Hodgkin's lymphoma (NHL) as one of the most rapidly increasing malignancies. More recent trends remain poorly characterized, as do the underlying reasons for NHL time trends, in particular, the effect of changes in classification and registration of lymphoproliferative malignancies. Insights into the descriptive epidemiology of NHL may shed light upon its elusive etiology.

Methods: We used data from the Swedish, Danish, and Finnish national cancer registers to assess the incidences of NHL and other lymphoproliferative malignancies between 1960 and 2004. Using Poisson regression, we estimated the annual rate of change in NHL incidence per decade by sex, age, and country.

Results: In Sweden, Denmark, and Finland, the NHL incidence increased in both genders and all age categories by about 4% every year up until the early 1990s. Thereafter, the incidence increased at a slower rate (ages 60-79 years), stabilized (ages 50-59 and ≥80 years), and decreased (ages 0-49 years), respectively, similarly for males and females in the three countries. Time trends of NHL were not reciprocated and explained by trends for other lymphoproliferative malignancies nor explained by trends in NHL as secondary primaries or NHL diagnosed postmortem.

Conclusions: The epidemic increase of NHL has recently subsided. Changes in the classification of lymphoproliferative malignancies, or occurrence of NHL as second primaries, only offer a marginal explanation. (Cancer Epidemiol Biomarkers Prev 2006;15(7):1295–300)
A Role for XRCC4 in Age at Diagnosis and Breast Cancer Risk
Authors: Allen-Brady Kristina , Cannon-Albright Lisa A. , Neuhausen Susan L. , Camp Nicola J.
Published: July 2006

Genetic variants in DNA repair genes influence the ability to repair damaged DNA. Unrepaired or improperly repaired DNA may lead to genetic instability and carcinogenesis. We evaluated the role of four tagging single nucleotide polymorphisms (tSNP) in the DNA repair gene, XRCC4, and its association with breast cancer risk and age at diagnosis of breast cancer in 464 cases and 576 controls selected to be BRCA1/2 mutation negative from high-risk Utah pedigrees. We observed a significant association for two 4-locus tSNP haplotypes and age at diagnosis. Carriage of one haplotype was associated with later diagnosis (haplotype frequency, 0.039; mean age at diagnosis, 67.17 years; P = 0.001), and carriage of the other was associated with earlier diagnosis (haplotype frequency, 0.214; mean age at diagnosis, 54.04 years; P = 0.0085). For breast cancer risk, two 2-locus tSNP haplotypes explained the observed association as well as extended four-locus haplotypes. The two 2-locus haplotypes were nominally associated with breast cancer risk, one for reduced risk (odds ratio, 0.57; 95% confidence interval, 0.36-0.90; P = 0.014) and one for increased risk (odds ratio, 1.30; 95% confidence interval, 1.02-1.67; P = 0.033). Moreover, one of the tSNPs is in strong linkage disequilibrium (D′ = 1.00) with an XRCC4 SNP found to be significantly associated with breast cancer risk in Taiwan, hence, confirming their findings. Our results suggest that XRCC4 may play a role in the age at diagnosis and risk of breast cancer in non-BRCA1/2, heritable breast cancer cases. (Cancer Epidemiol Biomarkers Prev 2006;15(7):1306–10)
Clinical Use of p53 in Barrett's Esophagus
Authors: Keswani Rajesh N. , Noffsinger Amy , Waxman Irving , Bissonnette Marc
Published: July 2006

Barrett's esophagus is an established precursor to esophageal adenocarcinoma. Whereas most patients with Barrett's esophagus do not progress to adenocarcinoma, patients with progression have a poor prognosis. Current management strategies use frequent endoscopic surveillance and multiple nontargeted biopsies. This approach, however, may miss dysplastic areas. Furthermore, given the relatively high prevalence of Barrett's esophagus but low incidence of progression, this invasive and expensive approach has not been shown to be cost-effective. Thus, there is intense interest in using biomarkers to identify patients at increased risk of progressing to adenocarcinoma. This has included examination of mutations in the tumor suppressor gene, p53. In this report, we discuss the biology of p53 and the incidence of p53 mutations in Barrett's esophagus and review relevant studies regarding the ability of p53 to predict neoplastic progression. Additionally, we report our results of the expression of p53 by immunohistochemistry in a group of 18 patients that have undergone endoscopic esophageal mucosal resection for dysplasia. Although the presence of a p53 mutation increases the risk of neoplastic progression, the absence of this mutation does not abrogate the risk. Continuing efforts, therefore, are needed to define and prospectively validate a panel of biomarkers to risk-stratify patients with Barrett's esophagus. Determination of p53 mutational status may ultimately be a component of such a panel. (Cancer Epidemiol Biomarkers Prev 2006;15(7):1243–9)