bluuebunny/crossref_metadata_2025 huggingface dataset:
On the Limits of Ellipsoidal Models when Analyzing Dielectric Behavior of Living Cells Emphasis on Red Blood Cells
Authors: GHEORGHIU EUGEN
Published: February 2006

Abstract: The dielectric behavior of red blood cells is simulated by taking into account the real shape (consistent with microscopic observations) and the ellipsoids (prolate and oblate spheroids) having the same surface and volume. We have pointed out that the spectra of the imaginary versus the real part of polarizability, which can be directly derived from the measured data, provide quantitative insight to cell morphology. We emphasize that ellipsoidal approximation is fairly good for random oriented cells, but rather poor whenever oriented cells are measured. This fact is assumed to be the reason for the differences between the reported parameters derived from measurements on single cells and those from observations on (random oriented) cells in suspension.
New Light‐Scattering and Field‐Trapping Methods Access the Internal Electric Structure of Submicron Particles, like Influenza Virusesa
Authors: GIMSA JAN
Published: February 2006

Abstract: A variety of AC‐electrokinetic field effects can be exploited for handling or electric characterization of microscopic and submicroscopic particles, like cells, organelles, supramolecular structures, and artificial colloids. Despite the fact that dielectric spectroscopy methods by AC‐electrokinetics, like common impedance methods, are based on the impedance properties of the different constituents of the particles, the first methods yield higher parameter resolutions. A drawback of the electrokinetic methods was that they required microscopic observability of field‐induced particle movements. New AC‐electrokinetic methods like electrorotational light scattering (ERLS), dielectrophoretic phase‐analysis light scattering (DPALS), and dielectrophoretic field trapping (DFT) solve this problem and access the submicroscopic particle range. This paper gives an introduction to the new methods and presents measurements on influenza viruses. To develop a dielectric virus model, experiments of ERLS were combined with DFT of viruses in microstructured electric‐field cages. The model assumes a spherical virus with a radius of 50 nm and a single‐shell dielectric structure. The shell thickness of 18 nm summarizes the dimensions of the lipid and viral surface protein layers. For this model, the conductivities of core and shell of 0.1 mS/m and 0.1 μS/m, respectively, and the relative permittivities of 30 and 80, respectively, were obtained.
Improvement of a Front End for Bioimpedance Spectroscopya
Authors: YÉLAMOS DAVID , CASAS ÓSCAR , BRAGÓS RAMON , ROSELL JAVIER
Published: February 2006

Abstract: This paper describes the main changes that have been introduced into the design of a new front end to be used with commercial impedance analyzers for the measurement of biological samples. This bioimpedance adapter has been specially designed to improve the accuracy at low frequencies and to increase the frequency range. The use of very accurate current conveyor circuits, together with the use of common‐mode negative feedback, leads to an improvement in the impedance measurements at low frequencies, reducing the effect of electrode impedance.
Virtual Biopsies in Barrett's Esophagus Using an Impedance Probe
Authors: GONZÁLEZ‐CORREA C. A. , BROWN B. H. , SMALLWOOD R. H. , KALIA N. , STODDARD C. J. , STEPHENSON T. J. , HAGGIE S. J. , SLATTER D. N. , BARDHAN K. D.
Published: February 2006

Abstract: Preliminary results of electrical impedance measurements in squamous and columnar epithelia in rat and human tissues are presented. The aim of this work is to show the possibility of differentiating these two types of epithelia in terms of their electrical characteristics. For the measurements, we employed a 1.95m‐long, 3.2‐mm‐diameter, four‐electrode probe designed to be used transendoscopically in the diagnosis of Barrett's esophagus (BE). BE is a condition in which the normal squamous epithelium of the esophagus is replaced by columnar epithelium of the intestinal type. This metaplasia is considered as a premalignant condition that puts patients at a 30‐125‐fold risk of developing adenocarcinoma of the esophagus. The diagnosis and surveillance of BE involve taking multiple biopsies, an expensive and time‐consuming procedure. This study constitutes the first stage in the replacement of tissue biopsy by “virtual biopsies”.
Progress in Realization of Magnetic Induction Tomography
Authors: KORJENEVSKY ALEXANDER V. , CHEREPENIN VLADIMIR A.
Published: February 2006

Abstract: The method enabling one to obtain tomographic images of an electrically conductive or dielectric object by the excitation of the variable magnetic field inside it and by measuring the resulting field around the object is described. The main equations and theoretical estimations are given. It is shown that phasesensitive measurements should be used in magnetic induction tomography. The measuring system providing the data set necessary for the image reconstruction is discussed. Under the conditions of the measurements discussed in this paper, image reconstruction is possible with the use of a simple method of convolution and back‐projection along magnetic lines. Computer simulation demonstrates the visualization of the conductivity distribution by the method of magnetic induction tomography with phase measurements.
Evaluation of Impedance Technique for Detecting Breast Carcinoma Using a 2‐D Numerical Model of the Torso
Authors: RADAI MICHAL M. , ABBOUD SHIMON , ROSENFELD MOSHE
Published: February 2006

Abstract: Previous experimental studies showed that significant changes occur in the electrical properties of breast cancer tissue compared to the surrounding normal tissue. This phenomenon motivated studies on cancer detection using electrical impedance techniques. In the present study, a two‐dimensional model of the torso and a numerical method were used to investigate the changes in the potential distribution as a result of a malignant tissue present in the breast. A transverse MRI image of the woman's torso was scanned. Noise reduction and contour‐following algorithms were applied to differentiate between eight compartments in the torso. The extracted tissue types were lungs, blood, ribs, bone marrow of the cord, breast fat, skin, skeletal muscle, and heart muscle. Isotropic homogeneous conductivity was assigned to each one of these compartments. The volume conductor problem was solved numerically using the finite volume method to determine the potential distribution developed due to the dipole source. Cases without and with artificially inserted malignant region with realistic sizes were examined to investigate the sensitivity of impedance techniques to detect breast cancer. Significant changes were detected in the potential distribution inside the volume conductor as a result of the realistic size of breast tumors. A linear relation was found between the surface potential in the vicinity of the tumor region and the size of the tumor. For a small malignant area of 0.22 cm2, the surface potential near the tumor region decreased only slightly from a value of 13.81 mV in the normal case to 13.67 mV (0.14 mV change; 1.0%). For a larger malignant area of 5.43 cm2, the potential decrease was more pronounced, 11.29 mV (2.52 mV change; 18.3%), indicating that realistic sizes of breast tumor result in significant changes in the surface potential. Thus, impedance techniques employed in the present study show very good promise in detecting breast cancer.
A Comparison of the Siconolfi and Cole‐Cole Procedures for Multifrequency Impedance Data Analysis
Authors: WARD LEIGH , FULLER NIGEL , CORNISH BRUCE , ELIA MARINOS , THOMAS BRIAN
Published: February 2006

Abstract: The established Cole‐Cole and newer Siconolfi methods for analysis of multifrequency impedance data were compared in a group of normal healthy individuals studied under bedside conditions. Impedance quotients derived from each procedure were similarly well correlated with independent dilutional estimates of total body water. Although both methods estimated resistance at zero frequency, were highly correlated, and provided impedance quotients with very similar correlations with extracellular water, these estimates were significantly different and thus may not be used interchangeably. The Siconolfi procedure demonstrated no significant advantage over the Cole‐Cole method. In view of the sound theoretical basis for the latter, it is concluded that analysis of MFBIA data by the Cole‐Cole method is to be preferred.
Practical Limits of the Kramers‐Kronig Relationships Applied to Experimental Bioimpedance Data
Authors: RIU PERE J. , LAPAZ CRISTINA
Published: February 2006

Abstract: Use of the Kramers‐Kronig integral relationships has been proposed by several authors as a means to qualify the validity of experimental impedance data or to obtain the imaginary part of the impedance (or the permittivity) when only the real part is available. Few works are found in the literature where these relationships are applied. The goal of the present work is to investigate the practical limits on the applicability of these mathematical expressions when real factors such as a limited number of measurement frequencies or instrumentation errors are taken into account. We use simulated and real data to perform calculations and conclude that those expressions are practically applicable in almost every experimental situation, including the detection of measurement errors.
Experimental Assessment of Phase Magnitude Imaging in Multifrequency EIT by Simulation and Saline Tank Studies
Authors: FITZGERALD ANTHONY , HOLDER DAVID , GRIFFITHS HUW
Published: February 2006

Abstract: Multifrequency EIT (MFEIT) data can be used to form dual‐frequency images that display the change of complex resistivity with frequency relative to a selected reference frequency. It has only been possible to calculate the complex resistivity at the image frequency from MFEIT images by assuming some a priori information, such as a homogeneous, resistive reference or a resistivity described by a single dispersion Cole model. The purpose of this paper is to introduce an alternative method of image formation, referred to as “phase magnitude imaging”, which enables the complex resistivity of tissue to be obtained independently of the tissue model and without the need for a homogeneous reference. It was expected that the major obstacle to practical application of this technique would be instrumentation errors that affect the measurement of phase. To assess these effects, a cucumber cortex was imaged in a saline‐filled tank using an HP4284A impedance analyzer. Cole parameters determined from the phase magnitude images differed by up to 300% from results of the simulation. These errors were reduced to less than 15% by using reciprocity data to partially correct for the influence of stray capacitance on the voltage measurement.
Impedance Modulation by Pulsed Ultrasound
Authors: JOSSINET JACQUES , LAVANDIER BERNARD , CATHIGNOL DOMINIQUE
Published: February 2006

Abstract: The propagation of an acoustic wave in an electrolyte solution produces local and periodic conductivity changes. This acousto‐electrical interaction is due to the variations of the parameters controlling ionic conductivity against pressure and temperature. The overall effect is about 10−7% Pa−1 for solutions of physiological ions and is practically independent of the ionic species involved. The bulk compressibility of the medium is responsible for about 47% of the effect, the change in viscosity due to pressure changes is responsible for about 18%, and the changes of ionic mobility against temperature are responsible for about 35%. Detectable impedance changes were produced in the focal zone of a 500‐kHz focused transducer using moderate intensity ultrasound (peak pressure < 1 MPa). This technique potentially enables the association of the spatial resolution of pulsed ultrasound and impedance measurement, although technical improvements and feasibility studies are still needed prior to practical applications.
Impedance Parameter Characterizing Apple Bruise
Authors: VOZÁRY ESZTER , LÁSLÓ PÉTER , ZSIVÁNOVITS GÁBOR
Published: February 2006

Abstract: The electrical impedance spectra of Jonathan apples exposed to different pressing force were measured in the frequency range from 1 kHz to 1 MHz with an HP 4284A precision RLC meter. The apoplasmic resistance (Ra), the symplasmic resistance (Rs), and the Ra/Rs ratio were determined as a function of the force and the deformation. Below the bioyield deformation, there was no observable change in the value of Ra/Rs. Above the bioyield, the Ra/Rs ratio markedly decreased in consequence of the Ra decrease due to both the increased ion concentration in the apoplasmic part and the decrease of cell membrane resistance as a result of cell membrane rupture.
A Parametric Method to Resolve the Ill‐Posed Nature of the EIT Reconstruction Problem: A Simulation Study
Authors: DE MUNCK J. C. , FAES TH. J. C. , HERMANS A. J. , HEETHAAR R. M.
Published: February 2006

Abstract: The reconstruction problem of electrical impedance tomography (EIT) is to estimate the distribution of the conductivity inside an object from measured potential distributions on the circumference caused by injected current patterns. Mathematically, this reconstruction problem is an ill‐posed nonlinear inverse problem, with many unknowns. In this paper, the ill‐posed nature is demonstrated by analyzing the condition of the sensitivity matrix; the associated inverse problem can only be solved on a very coarse grid. To circumvent the ill‐posed nature of the EIT reconstruction problem, we present a new parametric formulation. In this formulation, it is assumed that the object consists of compartments with homogeneous conductivity. The position, orientation, size, and conductivity of these compartments are treated as unknown parameters, which are determined by solving the forward problem (using the boundary element method) and optimizing the parameters (using Powell's or the simplex method) in order to fit the parameters to the EIT data. Simulations show that the parametric method is stable and adequately solves the EIT problem.
Uniqueness, Shape, and Dimension in EIT
Authors: LIONHEART WILLIAM R. B.
Published: February 2006

Abstract: We briefly review the known mathematical results on uniqueness of solution in electrical impedance tomography (EIT). Generally, a real or complex conductivity is determined uniquely by complete boundary data. Uniqueness results are also known for planar resistor networks. However, it is common to make gross errors in the forward modeling of the electrical fields and this may result in no consistent solution. In particular, a two‐dimensional model is often used when data are collected from a three‐dimensional domain. The boundary shape is often inaccurately known, and commonly modeled by a circle. No model conductivity consistent with measured data exists when the dimension or the boundary shape is wrong.
Development of a Reconstruction Algorithm for Imaging Impedance Changes in the Human Head
Authors: GIBSON A. , BAYFORD R. H. , HOLDER D. S.
Published: February 2006

Abstract:Accurate imaging of impedance changes in the brain with EIT using scalp electrodes ideally requires an algorithm designed for a 3D hemispherical object that is capable of imaging through the skull. A 2D algorithm is presented, intended as the first step towards a full 3D version. It is based on a sensitivity matrix approach and allows images to be reconstructed from any electrode positions. Its performance was assessed using a 2D circular tank with a simulated skull. The findings suggested the following: if polar current drive was used with no explicit skull compensation, a feature in the image would be placed 25% closer to the center and would be around one‐third the amplitude of an identical perturbation in a homogeneous medium.
Monitoring Regional Lung Ventilation by Functional Electrical Impedance Tomography during Assisted Ventilationa
Authors: FRERICHS INÉZ , HAHN GNTER , SCHIFFMANN HOLGER , BERGER CORD , HELLIGE GERHARD
Published: February 2006

Abstract: A new approach in discriminating the regional air volume changes in the lungs associated with either spontaneous or mechanical ventilation during assisted ventilation is presented. Impedance data are obtained by conventional electrical impedance tomography (EIT). The data are filtered in the range of either the spontaneous or the ventilator rate and processed by the functional EIT (f‐EIT) evaluation technique, whereby the variation of the respective EIT data with time is determined and imaged. EIT measurements performed in an infant during synchronized intermittent mandatory ventilation were evaluated with this method and indicated that the specific local lung volume swings related to spontaneous and mechanical inhalations can be separated and imaged as tomograms. This noninvasive approach may become useful in optimizing the ventilatory pattern during advanced forms of artificial ventilation and may help the clinician in the therapy management of individual patients.
Gastric Emptying in Patients with Type I Diabetes Mellitus
Authors: VAISMAN NACHUM , WEINTROB NOAMI , BLUMENTAL ALEXANDER , YOSEFSBERG ZEEV , VARDI PNINA
Published: February 2006

Abstract: Diabetic autonomic neuropathy is a known complication of long‐standing diabetes. The present study was designed to study the prevalence of asymptomatic prolonged gastric emptying (GE) in young patients with IDDM and its correlations with disease duration and autonomic nerve function. The study population included 40 poorly controlled patients, mean age 17.6 ± 4.6 years, with a disease duration of 1‐17.5 years, and 20 age‐ and sex‐matched controls. Autonomic nerve functions were assessed by standard cardiovascular reflexes, and gastrointestinal (GI) symptoms were assessed by a detailed questionnaire. GE was assessed by electrical impedence tomography (EIT), at 2 hours after a standard semisolid meal. Mean half‐time gastric emptying was significantly prolonged in diabetic patients, 54.80 ± 26.63 versus 40.37 ± 8.62 min (p < 0.05), with a higher prevalence in the first 3 years and after 10 years of disease duration. No differences were found between diabetics and controls regarding cardiovascular tests. No correlations were found between age, GI scores, cardiovascular tests, and GE. Patients with IDDM may suffer from prolonged GE. This is not always accompanied by autonomic impairments. As impaired gastric emptying may involve poor glycemic control and early satiety, patients with difficulties in metabolic control or poor caloric intake should be studied for the possibility of delayed gastric emptying.
Assessment and Calibration of a Low‐Frequency System for Electrical Impedance Tomography (EIT), Optimized for Use in Imaging Brain Function in Ambulant Human Subjects
Authors: HOLDER D. S. , GONZÁLEZ‐CORREA C. A. , TIDSWELL T. , GIBSON A. , CUSICK G. , BAYFORD R. H.
Published: February 2006

Abstract: An EIT system has been produced that has been optimized for imaging impedance changes with scalp electrodes during brain activity in ambulant subjects. It can record from 225 Hz to 65 kHz, has a small headbox on a lead 10 m long, and has software programmable electrode selection. In calibration experiments in a small cylindrical tank filled with potassium chloride solution and samples of cucumber, noise was less than 1% with averaging, and acceptable images were produced at frequencies down to 1800 Hz. This suggests that EIT can be performed at low frequencies, which are likely to give larger signals during brain activity. Future work will include trials in humans and improvement of the current source and isolation.
Can We Optimize Electrode Placement for Impedance Pneumography?
Authors: KHAMBETE N. , METHERALL P. , BROWN B. , SMALLWOOD R. , HOSE R.
Published: February 2006

Abstract: In this paper, we discuss issues involved in defining an optimum placement of four electrodes for impedance pneumography. We observed a general trend where the change in impedance (ΔZ) decreased while the sensitivity (ΔZ/Z) increased with distance between the drive and receive electrode pairs. However, the theoretical study indicated that ΔZ/Z should decrease with distance. The scatter of points in the plots indicated that sensitivity was influenced by factors other than distance. The correlation coefficient between the theoretical and measured ΔZ/Z was low, but significant. This suggested that the best electrode configuration can be derived from the theoretical data. High ΔZ/Z was obtained when the drive and receive electrode pairs were placed close to the lungs and in different horizontal planes.
Gene Expression in Pancreatic Adenocarcinoma
Authors: FRAZIER MARSHA L.
Published: February 2006

Abstract: Both acinar and duct cell‐specific gene products are expressed by pancreatic adenocarcinoma. In order to begin to understand the mechanisms by which genes of both cell types are expressed in pancreatic adenocarcinoma, an understanding of the underlying transcription factors is important. PDX1 plays an important role in the development of the pancreas and is also expressed in the adult pancreas; it is known to be involved in the regulation of expression of both acinar and islet cell‐specific gene products. We have examined pancreatic adenocarcinoma cell lines and have determined that they also express PDX1, making it a candidate transcription factor for the abnormal regulation of these acinar and duc cell gene products.
Carbonic Anhydrase in Human Pancreas: Hypotheses for the Pathophysiological Roles of CA Isozymes
Authors: NISHIMORI ISAO , FUJIKAWA‐ADACHI KIYOMI , ONISHI SABURO , HOLLINGSWORTH MICHAEL A.
Published: February 2006

Abstract: Among more than ten isozymes of the carbonic anhydrase (CA) family, only cytoplasmic CA II and membrane‐bound CA IX have been reported to be expressed in human pancreas. To study the mRNA expression of CA isozymes in human pancreas, reverse transcriptase‐polymerase chain reaction (RT‐PCR)‐Southern blot analysis and cDNA sequencing following RT‐PCR were employed. CA II, IV, VI, IX, and XII were clearly identified in polyA+ RNA from normal human pancreas by RT‐PCR‐Southern blotting. Results with cultured pancreatic tumor cell lines suggest that CA II, IV, IX, and XII are expressed in the ductal cells, and CA VI is expressed in the acinar cells. We propose a hypothesis for the pathophysiological function of CA isozymes in human pancreas; (1) the intraluminal CA isozymes (CA IV, VI, and possibly XII) form a mutually complementary system with cytoplasmic CA II to regulate the luminal pH of the pancreatic duct system and work as a self‐defense mechanism against pancreatitis; (2) CA II and other CA isozymes play a pathological role in the autoimmune process of idiopathic chronic pancreatitis.
Proteins Expressed by Pancreatic Duct Cellsand Their Relatives
Authors: HOLLINGSWORTH MICHAEL A.
Published: February 2006

Abstract: Significant progress has been made in the characterization of the structure and function of pancreatic ductal cells. Our understanding at this point in time extends to knowledge of specific molecules that provide for the structural composition of the ductal cells, their interactions with the local environment, and the regulation of their growth and properties of differentiation. Knowledge of the molecular composition and structure of the secretory products of epithelial cells in the pancreas also has increased so that we now understand the individual contributions of several secretory products to the overall function of pancreatic juice. Further study of these parameters will give us important insight into the normal function of the ductal cells and into how these processes are altered during the development and progression of diseases of the pancreas such as pancreatitis and cancer.
Immortalized Pancreatic Duct Cells in vitro and in vivo
Authors: JESNOWSKI R. , MÜLLER P. , SCHARECK W. , LIEBE S. , LÖHR M.
Published: February 2006

Abstract: Although pancreatic adenocarcinoma has become one of the best characterized malignant diseases, severe diagnostic and therapeutic problems are still associated with this disease. The establishment of a molecular model of pancreatic carcinogenesis may provide tools that could result in earlier diagnosis of this disease and, in turn, improves prognosis. Since pancreatic adeno‐carcinoma seems to originate in epithelial cells in the pancreatic ducts, cultivation of native pancreatic duct epithelial cells (PDEC) is the initial step in the establishment of an in vitro model of pancreatic carcinogenesis. As these native cells survive only a short period in culture, the aim of this study was to establish a stable pancreatic duct cell line by immortalization with the SV40 large T antigen. Furthermore, initial steps in pancreatic carcinogenesis should possibly be imitated by additional transfections of mutated ki‐ras and/or mutated p53 genes. By optimization of the isolation protocol and the culture medium, yield as well as proliferative activity of isolated PDEC was increased considerably. Transfection of SV40 large T antigen resulted in an increase in the proliferative lifetime of the isolated cells, but no real immortal phenotype was obtained. Moreover, one step in the transformation from the normal to the malignant phenotype was imitated successfully by additional transfection of mutated ki‐ras.
Growth Factors and Cytokines in Pancreatic Carcinogenesis
Authors: FRIESS HELMUT , GUO XIAO‐ZHONG , NAN BI‐CHENG , KLEEFF ÖRG , BÜCHLER MARKUS W.
Published: February 2006

Abstract: Pancreatic cancer is a deadly disease challenging basic and clinical researchers alike in characterizing its pathobiology and finding better treatment options. A number of molecular alterations including gene mutations such as k‐ras, p53, and Smad4 and aberrant expression of a variety of genes have been identified in recent years. This review focuses on two families of growth factors and growth factor receptors which are representative for the molecular alterations observed in pancreatic cancer: the transforming growth factor‐β superfamily of serine‐threonine kinase receptors and their ligands, which usually act as negative growth regulators, and the epidermal growth factor receptor family and their ligands, which have the potential to act as growth promoters in pancreatic cancer. In addition, we will discuss the role of the cytokines TNF‐α, IFN‐γ, and IL‐6 and its effects on pancreatic cancer cell proliferation in vitro and in vivo. Pancreatic cancer cell biology consists of complex interactions of various factors, and a better understanding of the molecular pathogenesis of this disorder might lead to better treatment strategies in the near future.
Strategies for the Detection of Disease Genes in Pancreatic Cancer
Authors: WALLRARR C. , MÜLLER‐PILLASCH F. , MICHA A. , WENGER C. , GENG M. , SOLINAS‐TOLDO S. , LICHTER P. , FROHME M. , HOHEISEL J.D. , ADLER G. , GRESSA T. M.
Published: February 2006

Abstract: The present review summarizes our strategies aimed at identifying and characterizing genetic alterations occurring at the transcriptional and chromosomal level in pancreatic cancer. To study trancriptional alterations we have used a number of techniques including modified versions of differential hybridizations and cDNA RDA (representational difference analysis). These approaches have led to the identification of more than 500 genes with differen tial expression in pancreatic cancer. To study chromosomal aberrations occurring in pancreatic cancer tissues we used comparative genomic hybridization (CGH). This allowed the identification of a number of chromosomal regions containing putative tumor suppressor genes or oncogenes. Genes isolated in both approaches represent potential new disease genes for pancreatic cancer and are at present being characterized by individual or serial analysis.
Protein Tyrosine Dephosphorylation and the Maintenance of Cell Adhesions in the Pancreas
Authors: SCHNEKENBURGER J. , MAYERLE J. , SIMON P. , DOMSCHKE W. , LERCH M. M.
Published: February 2006

Abstract: Cell‐cell contacts are important regulatory elements in tissue development, organ morphogenesis and malignant tumor invasion. In recent in vivo studies we have identified the members of the cadherin/catenin family of cell adhesion proteins that are differentially expressed in the pancreas and have determined their cell biological dynamics during dissociation and repair of adherens junctions. To further characterize these events, epithelial cell culture systems were used and a number of type II protein tyrosine phosphatases (PTPs) were found to colocalize and interact with the cadherin/catenin complex. These observations suggest that tyrosine dephosphorylation in general and PTPs in particular are involved in cell contact formation. Our most recent experiments indicate 1) that inhibition of PTPs alone dissociates pancreatic adherens junctions, 2) that cytosolic and transmembrane PTPs are differentially expressed in acinar cells, and 3) that a subset of them can associate with proteins of the cadherin/catenin complex at pancreatic cell‐cell adhesions.
Pancreatic Cancer: Development of a Unifying Etiologic Concept
Authors: LOWENFELS ALBERT B. , MAISONNEUVE PATRICK
Published: February 2006

Abstract: Our knowledge of the etiology of all forms of cancer including pancreatic cancer has improved dramatically in the second half of this century. The current model describes a gradual change from a normal pancreatic cell to a fully malignant cell requiring several stages with gradual and progressive alterations appearing at the genetic and the tissue level. Although there are many germ line diseases that are associated with pancreatic cancer it is probable that inherited diseases account for only about 10% of the total burden of pancreatic cancer. Avoidance of smoking and dietary modification are the current best strategies for reducing the risk of this tumor. In addition, newer molecular techniques and imaging procedures should provide clinicians with the ability to detect pancreatic cancer at an early, potentially curable stage.
Ki‐Ras Oncogene Mutations in Chronic Pancreatitis: Which Discriminating Ability for Malignant Potential?
Authors: VAN LAETHEM J. L.
Published: February 2006

Abstract: Ki‐ras mutations are found in the majority of pancreatic adenocarcinomas (85‐100%). Ki‐ras analysis was increasingly used in ERCP samples in order to differentiate between chronic pancreatitis and pancreatic cancer. However, its sensitivity was recently reported to be low due to a high prevalence of ras mutations in patients with chronic pancreatitis (25‐37%). Detection of Ki‐ras mutations in microdissected pancreata confirmed their high frequency (55‐83%) in pancreatic intraductal lesions (PILs) observed in chronic pancreatitis specimens and in the vicinity of invasive pancreatic carcinoma. There is now molecular evidence that PILs can be precursors of invasive carcinoma, since they can harbor genetic alterations identical to those of the adjacent carcinoma. Similarly, we observed 2 patients with chronic pancreatitis who developed pancreatic cancer 18 and 24 months after the evidence of Ki‐ras mutations in pancreatic brushings. However, besides these findings, ras mutations were also identified in nondiseased pancreata coming from autopsy series. The current data on ras analysis in pancreatic juice and brushings or in microdissected pancreata suggest that PILs with Ki‐ras mutations do not inevitably lead toward invasive carcinoma. Ki‐ras mutations probably have a low discriminating ability for malignant potential and their detection in pancreatic juice is not justified routinely for differentiating between benign and malignant pancreatic diseases. However, prospective follow‐up of patients with chronic pancreatitis harboring a mutant ras is probably of major interest by combining the search for other genetic markers that have the ability to characterize patients with the greater risk of malignant transformation.
Single‐Chain Antibodies in Pancreatic Cancer
Authors: COLCHER DAVID , PAVLINKOVA GABRIELA , BERESFORD GUY , BOOTH BARBARA J.M. , BATRA SURINDER K.
Published: February 2006

Abstract: Pancreatic cancer is a therapeutic challenge for surgical and medical oncology. Development of specific molecular tracers for the diagnosis and treatment of this lethal cancer has been one of our major goals. Monoclonal antibodies (MAbs) have been successfully used as selective carriers for delivering radionuclides, toxins or cytotoxic drugs to malignant cell populations; therefore, monoclonal antibody technology has led to a significant amount of research into optimizing targeted therapy. This targeted therapy results in the selective concentration of cytotoxic agents or radionuclides in tumors and should lessen the toxicity to normal tissues, which would normally limit the dosage and effectiveness of systemically administered drugs. The MAb CC49 reacts with a unique disaccharide, Sialyl‐Tn, present on tumor‐associated mucin (TAG‐72) expressed by a majority of human adenocarcinomas. The unique Sialyl‐Tn epitope has provided a potential target for immunotherapy of cancer. A single chain Fv (scFv) recombinant protein from CC49 MAb was prepared by engineering the DNA fragments for coding heavy‐chain and light‐chain variable regions with an appropriate oligonucleotide linker. scFv molecules, when compared to intact MAbs and the more conventional enzymatically derived F(ab′)2 and Fab′ fragments, offer several advantages as carriers for the selective delivery of radionuclides to tumors. The divalent antibody fragments (sc(Fv)2 or (scFv)2) display an affinity constant similar to that of the intact CC49 IgG and are stable with storage, and after radiolabeling. In preclinical studies, both the covalent and the non‐covalent dimeric scFvs exhibit excellent tumor targeting properties with characteristics similar to those of the monomer, e.g., the rapid blood clearance, low kidney uptake and small size suitable for rapid penetration through tumor tissue. Increased tumor targeting of the dimers are probably due to their increased functional affinity attributable to valency, coupled with their higher molecular weight and fewer interactions with normal organs. These properties make these constructs superior to monovalent CC49 scFv. The relatively high tumor uptake, the in vitro and in vivo targeting specificity, and the stability in storage demonstrated by the dimeric CC49 sc(Fv)2 makes it a promising delivery vehicle for therapeutic applications in pancreatic cancer.
p53 in Relation to Therapeutic Outcome of Locoregional Chemotherapy in Pancreatic Cancer
Authors: GANSAUGE FRANK , GANSAUGE SUSANNE , LINK KARL H. , BEGER HANS G.
Published: February 2006

Abstract: Since celiac artery infusion (CAI) led to an increase in survival in palliative chemotherapy in pancreatic cancer, we treated 26 patients with adjuvant CAI following resection for advanced pancreatic cancer. Catheters were placed angiographically into the celiac artery and remained there for five consecutive days. One cycle of chemotherapy consisted of mitoxantrone, 5‐fluorouracil (5‐FU), folinic acid, and cis‐platinum. This treatment was repeated five times in monthly intervals. Median survival times in patients who received CAI are 21 months for all patients, whereas in patients who did not receive adjuvant treatment median survival is 10.5 months. In all patients p53 expression of the carcinomas was determined by immunhistochemistry. In 11/26 patients a p53 overexpression was observed. Although p53 overexpression turned out to be associated with poor prognosis in the patients who underwent adjuvant regional cancer treatment, p53 is not a sufficient prognostic parameter in pancreatic carcinoma, since p53 overexpression was more frequent in undifferentiated tumors and in palliative resected tumors.
Injection of Encapsulated Cells Producing an Ifosfamide‐Activating Cytochrome P450 for Targeted Chemotherapy to Pancreatic Tumors
Authors: MÜLLER PETRA , JESNOWSKI RALF , KARLE PETER , RENZ REGINA , SALLER ROBERT , STEIN HARTMUT , PÜSCHEL KATRIN , von ROMBS KERSTIN , NIZZE HORST , LIEBE STEFAN , WAGNER THOMAS , GÜNZBURG WALTER H. , SALMONS BRIAN , LÖHR MATTHIAS
Published: February 2006

Abstract: The prognosis of pancreatic cancer is poor, and current medical treatment is mostly ineffective. The aim of this study was to design a new treatment modality in an animal model system. We describe here a novel treatment strategy employing a mouse model system for pancreatic carcinoma. Embryonal kidney epithelial cells were genetically modified to express the cytochrome P450 subenzyme 2B1 under the control of a cytomegalovirus (CMV) immediate early promoter. This CYP2B1 gene converts ifosfamide to its active cytotoxic compounds, phosphoramide mustard, which alkylates DNA, and acrolein, which alkylates proteins. The cells were then encapsulated in a cellulose sulphate formulation and implanted into preestablished tumors derived from a human pancreatic tumor cell line. Intraperitoneal administration of low‐dose ifosfamide to tumor bearing mice that received the encapsulated cells results in partial or even complete tumor ablation. Such an in situ chemotherapy strategy utilizing genetically modified cells in an immunoprotected environment may prove useful for solid tumor therapy in man.
Ablation of Tumor Cells In Vivo by Direct Injection of HSV‐Thymidine Kinase Retroviral Vector and Ganciclovir Therapy
Authors: HOWARD BRADLEY D. , KALTHOFF HOLGER , FONG TIMOTHY C.
Published: February 2006

Abstract: The introduction of therapeutic genes into proliferating tumor cells in vivo by direct intralesional injection of retroviral vectors can provide an effective and valuable approach for the treatment of a variety of solid tumor types. Efficient transduction of tumor cells in situ by direct injection was demonstrated using a retroviral vector containing the β‐galactosidase (β‐gal) gene. Ablation therapy in vivo was demonstrated using a retroviral vector containing the Herpes simplex virus thymidine kinase gene (HSV‐TK) to deliver the TK gene into the murine colorectal tumor cell line CT26. Ablation of CT26 tumor cells in situ was achieved by directly injecting high‐titer HSV‐TK retroviral vector preparations into the site of tumor cell inoculation followed by intraperitoneal (i.p.) delivery of ganciclovir (GCV). This gene therapy strategy demonstrated a markedly lower rate of tumor progression, with several complete regressions, compared to animals in control groups. We also demonstrated that resistance to subsequent challenges with unmodified CT26 cells and an enhanced cellular immune response is associated with tumor regression in immunocompetent animals. Our results demonstrate the feasibility of direct in situ administration of HSV‐TK retroviral vectors for the treatment of cancer and suggest that a cellular immune response may be elicited by this therapy.
The “Psychic” Neuron of the Cerebral Cortex
Authors: GOLDMAN‐RAKIC PATRICIA S.
Published: February 2006

ABSTRACT: Remarkable advances in the identification, cloning, and localization of ion channels and receptors in the central nervous system have opened up unprecedented possibilities for relating structure to physiological function at the subcellular level of analysis. A singularly advanced property of select central nervous system neurons is their ability to exhibit increases in firing rate in relation to the mnemonic trace of a preceding event, a property that has been referred to as “working memory.” Single‐cell recordings from the prefrontal cortex of nonhuman primates have revealed neurons in the prefrontal cortex that possess “memory fields” analogous to the receptive field properties of sensory neurons. The integrity of these neurons has been shown to be essential for accurate performance in memory tasks performed by trained monkeys (and humans). We can now show that the excitability and/or tuning of these prefrontal neurons are subject to modulatory influences by dopamine, serotonin, GABA, and glutamate among other peptides and conventional neurotransmitters. I will describe the dopaminergic, serotonergic, and GABAergic innervation of pyramidal neurons engaged in working memory and the localization of neurotransmitter receptors through which they exert their actions. The findings reveal a remarkable degree of diversity in the subcellular localization and functionality of the five cloned dopamine receptors (D1, D2, D3, D4, and D5) and two serotonin (5HT2A and 5HT3) receptors that have been examined to date. The potential now exists for linking systems neurobiology with molecular biophysics to comprehend the highest functions of information processing that distinguish our species.
Studies on Conditional Gene Expression in the Brain
Authors: JERECIC JASNA , SINGLE FRANK , KRÜTH ULI , KRESTEL HEINZ , KOLHEKAR ROHINI , STORCK THORSTEN , KASK KALEV , HIGUCHI MIYOKO , SPRENGEL ROLF , SEEBURG PETER H.
Published: February 2006

ABSTRACT: This manuscript summarizes our recent attempts to regulate in vitro and in vivo the expression of genes encoding components and regulators of the postsynaptic machinery along with marker genes such as lacZ and GFP. In particular, we studied tTA‐dependent regulation and utilized Cre in combination with reversible silencing by intron engineering of dominant negative alleles. We further present a “knockin” approach for on‐site artificial regulation of chromosomal genes.
RNA Editing of aDrosophilaSodium Channel Gene
Authors: HANRAHAN CHRISTOPHER J. , PALLADINO MICHAEL J. , BONNEAU LAURIE J. , REENAN ROBERT A.
Published: February 2006

ABSTRACT:Extensive analysis of cDNAs from the para locus inD. melanogasterreveals posttranscriptional modifications indicative of adenosine‐to‐inosine RNA editing. Most of these edits occur in highly conserved regions of the Na+channel, and they occur in distant relatives ofD. melanogasteras well. Sequence comparison between species has identified putativecis‐acting elements important for each RNA editing site. Double‐stranded RNA secondary structures with striking similarity to known RNA editing sites were generated based on these data. In addition, the RNA editing sites appear to be developmentally regulated. We have cloned a potential RNA editase,DRED, with a high degree of homology to the mammalianRED1,2genes. TheDREDlocus itself is highly regulated by transcription from alternative promoters and alternative splicings.
H+‐Gated Cation Channelsa
Authors: WALDMANN RAINER , CHAMPIGNY GUY , LINGUEGLIA ERIC , DE WEILLE JAN R. , HEURTEAUX C. , LAZDUNSKI MICHEL
Published: February 2006

ABSTRACT: H+‐gated cation channels are members of a new family of ionic channels, which includes the epithelial Na+ channel and the FMRFamide‐activated Na+ channel. ASIC, the first member of the H+‐gated Na+ channel subfamily, is expressed in brain and dorsal root ganglion cells (DRGs). It is activated by pHe variations below pH 7. The presence of this channel throughout the brain suggests that the H+ might play an essential role as a neurotransmitter or neuromodulator. The ASIC channel is also present in dorsal root ganglion cells, as is its homolog DRASIC, which is specifically present in DRGs and absent in the brain. Since external acidification is a major factor in pain associated with inflammation, hematomas, cardiac or muscle ischemia, or cancer, these two channel proteins are potentially central players in pain perception. ASIC activates and inactivates rapidly, while DRASIC has both a fast and sustained component. Other members of this family such as MDEG1 and MDEG2 are either H+‐gated Na+ channels by themselves (MDEG1) or modulators of H+‐gated channels formed by ASIC and DRASIC. MDEG1 is of particular interest because the same mutations that produce selective neurodegeneration in C. elegans mechanosensitive neurons, when introduced in MDEG1, also produce neurodegeneration. MDEG2 is selectively expressed in DRGs, where it assembles with DRASIC to radically change its biophysical properties, making it similar to the native H+‐gated channel, which is presently the best candidate for pain perception.
Molecular and Functional Diversity of Voltage‐Gated Calcium Channels
Authors: DAVILA HERMAN MORENO
Published: February 2006

The contributing roles of voltage‐gated calcium channels (VGCC) to the generation of electrical signaling are well documented. VGCCs open in response to depolarization of the plasma membrane and mediate the flux of calcium into excitable cells, which further depolarizes the membrane. But a more relevant role of VGCCs is to serve as highly regulated mechanisms to deliver calcium ions into specific intracellular locales for a variety of calcium‐dependent processes including neurotransmitter release, hormone secretion, neuronal survival, and muscle contraction. Recent biochemical and molecular biological studies have demonstrated that the calcium channel pore‐forming subunit (α1) is not an isolated entity, but in fact interacts physically with a variety of strategically localized proteins. The functional consequences of such interactions as well as other molecular aspects of VGCC will be discussed. Finally, although far from a final conclusion, what is currently known about the molecular composition of native calcium channels will be summarized.
Molecular Characterization of Two Members of the T‐Type Calcium Channel Family
Authors: PEREZ‐REYES EDWARD , LEE JUNG‐HA , CRIBBS LEANNE L.
Published: February 2006

ABSTRACT: In this chapter we review our recent studies on the cloning of two novel cDNAs (α1G and α1H), and present electrophysiological evidence that they encode low voltage‐activated, T‐type calcium channels (CavT.1 and CavT.2, respectively). The nucleotide sequences of these T channels are very different from high voltage‐activated Ca2+ channels, which explains why they were not cloned earlier using homology‐based strategies. We used a bioinformatic approach, cloning the first fragment in silico. We then used this fragment to screen human heart and rat brain λgt10 libraries, leading to the cloning of two full‐length cDNAs derived from distinct genes (CACNA1G and CACNA1H). The deduced amino acid sequences of the T channels (α1G and α1H) are also very different from previously cloned Ca2+ and Na+ channels; however, there are regions of structural similarity. For example, the T channels also contain four repeats, and within each repeat there are six putative membrane‐spanning regions and a pore loop. Expression of these cloned channels in either Xenopus oocytes or HEK‐293 cells leads to the formation of typical T‐type currents. As observed for native T currents, these channels activate at potentials near the resting membrane potential, inactivate rapidly, deactivate slowly, and have a tiny single‐channel conductance. The currents generated by α1G and α1H are nearly identical in terms of their voltage dependence and kinetics. We present preliminary evidence that nickel may serve as a valuable tool in discriminating between these subtypes.