P. Antich

The Role of Cdk5 in Neuroendocrine Thyroid Cancer

Medullary thyroid carcinoma (MTC) is a neuroendocrine cancer that originates from calcitonin-secreting parafollicular cells, or C cells. We found that Cdk5 and its cofactors p35 and p25 are highly expressed in human MTC and that Cdk5 activity promotes MTC proliferation. A conditional MTC mouse model was generated and corroborated the role of aberrant Cdk5 activation in MTC. C cell-specific overexpression of p25 caused rapid C cell hyperplasia leading to lethal MTC, which was arrested by repressing p25 overexpression. A comparative phosphoproteomic screen between proliferating and arrested MTC identified the retinoblastoma protein (Rb) as a crucial Cdk5 downstream target. Prevention of Rb phosphorylation at Ser807/Ser811 attenuated MTC proliferation. These findings implicate Cdk5 signaling via Rb as critical to MTC tumorigenesis and progression.

Striatal dysregulation of Cdk5 alters locomotor responses to cocaine, motor learning, and dendritic morphology

Motor learning and neuro-adaptations to drugs of abuse rely upon neuronal signaling in the striatum. Cyclin-dependent kinase 5 (Cdk5) regulates striatal dopamine neurotransmission and behavioral responses to cocaine. Although the role for Cdk5 in neurodegeneration in the cortex and hippocampus and in hippocampal-dependent learning has been demonstrated, its dysregulation in the striatum has not been examined. Here we show that strong activation of striatal NMDA receptors produced p25, the truncated form of the Cdk5 co-activator p35. Furthermore, inducible overexpression of p25 in the striatum prevented locomotor sensitization to cocaine and attenuated motor coordination and learning. This corresponded with reduced dendritic spine density, increased neuro-inflammation, altered dopamine signaling, and shifted Cdk5 specificity with regard to physiological and aberrant substrates, but no apparent loss of striatal neurons. Thus, dysregulation of Cdk5 dramatically affects striatal-dependent brain function and may be relevant to non-neurodegenerative disorders involving dopamine neurotransmission.

3D position readout from thick scintillators

AbstractAnoveltechniquehasbeendevelopedandtestedforthethree-dimensionalmeasurementofpositioninSPECT-PETdetectors.Resultsarepresentedfor2and20mmthickNaI(Tl)planarcrystals.Inaplaneofcrystal,acoordinateresolutionofabout1mm(rmserror)isdemonstrated.Thedepthofinteraction(DOI)ismeasuredwithanrmserrorofabout2mmusinglightconeparameters.r 2002ElsevierScienceB.V.Allrightsreserved. PACS: 29.40.Mc;29.40.GxKeywords: Scintillationdetectors;Depthofinteraction;Positionresolution 1. IntroductionThree-dimensionalmeasurementsofinteractionpositions of g-particles or X-rays is a verychallenging task. In high resolution positronemissiontomography(PET),itisveryimportanttoknowthedepthofinteraction(DOI),toavoidthe so-called parallax errors which degrade theimageresolutionfromthecentertotheouteredge.Severalmethodshavebeenproposedtosolvetheproblem. These include the utilization of atemperaturegradientalongthecrystal[1];theuseofaphoswichdesign[2]andtheconnectionoftwoendsofthe crystals toseparatephotosensors[3].Othermethodsincludetheuseofalightabsorbingmaterial around each crystal [4] or drug a lightabsorbing medium between the detector [5].However,allthemethodsrequireeitherextensiveworkwithdetectorcrystalsoradditionalelectro-nics, and the DOI resolution is still not satisfac-tory.Weemployyetanotherapproachtosolvetheproblem.This work is a continuation of the researchdescribed in Ref. [6]. In a search for an optimaldesign of a multi-modality scintillating detector,we have studied several geometries of positionsensitivedevices.Amongcurrentlyavailablecrys-tals, NaI(Tl) crystal is a good candidate for thecombined PET-SPECT modality. It has a highdensity and a good light yield with an emissionwavelengthspectrumwellmatchedtothephoto-cathode of a photomultiplier tube. To avoidhydrophilicdeteriorationofNaI,ourtestcrystalswere packed in metal–glass or glass–glass envel-opes.LimitationsinPETimagingduetoslowlightemission of NaI(Tl) crystals could be overcomeusingasectioneddesignwithtile-typescintillators.

Advances in molecular imaging of pancreatic beta cells.

The development of non-invasive imaging methods for early diagnosis of beta cell associated metabolic diseases, including type 1 and type 2 diabetes (T1D and T2D), has recently drawn interest from the molecular imaging community and clinical investigators. Due to the challenges imposed by the location of the pancreas, the sparsely dispersed beta cell population within the pancreas, and the poor understanding of the pathogenesis of the diseases, clinical diagnosis of beta cell abnormalities is still limited. Current diagnostic methods are invasive, often inaccurate, and usually performed post-onset of the disease. Advances in imaging techniques for probing beta cell mass and function are needed to address this critical health care problem. A variety of imaging techniques have been tested for the assessment of pancreatic beta cell islets. Here we discuss current advances in magnetic resonance imaging (MRI), bioluminescence imaging (BLI), and nuclear imaging for the study of beta cell diseases. Spurred by early successes in nuclear imaging techniques for beta cells, especially positron emission tomography (PET), the need for beta cell specific ligands has expanded. Progress for obtaining such ligands is presented. We report our preliminary efforts of developing such a peptidic ligand for PET imaging of pancreatic beta cells.

Comparison of LSO samples produced by Czochralsky and modified Musatov methods

Abstract This study is based on test results of 30 LSO samples produced by the POLUS Research Institute in Moscow, Russia, for the University of Texas Southwestern Medical Center at Dallas. Samples were produced by the Czochralsky and the modified Musatov methods. Pulse-height spectra from 22 Na positron annihilations were analyzed and conclusions are drawn. After some minor corrections to the modified Musatov technology, samples could be recommended for use in PET systems.

Fluorinated macromolecular probes for non-invasive assessment of pH by Magnetic resonance spectroscopy

Fluorinated polymeric molecular probes have been synthesized and characterized for non invasive assessment of pH with 19F Magnetic Resonance Spectroscopy (19F MRS). 3-Fluorosalicyl-aldehyde (3-FSA) has been employed as a prototype 19F pH indicator to conjugate to carrier molecules (polyamino dextran, polylysine and albumin). These 3-FSA polymer conjugates exhibit single sharp 19F signal, moderate 19F pH sensitivity, and the physiological pKa necessary for in vivo measurement of pH by 19F MRS. Fluorinated polymeric molecular probes have been synthesized and characterized for non invasive assessment of pH with 19F Magnetic Resonance Spectroscopy (19F MRS). 3-Fluorosalicyl-aldehyde has been employed as a prototype 19F pH indicator to conjugate to carrier polymers. These polymer-3-FSA conjugates exhibit a single sharp 19F signal, moderate 19F pH sensitivity, and physiological pKa necessary for in vivo measurement of pH by 19F MRS.

Compact Compton camera design: parameters and imaging algorithms

This study presents results of Monte Carlo simulations of a compact Compton camera design using the GEANT-based computer code. The proposed system is a sensitive SPECT device made of semiconductor detectors capable of providing angular resolutions of about 1 mrad. To accurately model the camera, the GEANT code was modified to take into account pre-collision motion of elections, the so-called Doppler effect. A new algorithm for three-dimensional image reconstruction based on clustering of individual events has been developed and proven on clustering of individual events has been developed and proven with Monte Carlo phantoms for a Compton camera and with phantoms and small animal studies for a PET machine.

Synthesis and evaluation of a new class of technetium-99m monocationic radiotracers from dithienyldiazalkanes☆

Monocationic 99mTc complexes, [99mTcO2 (THEN)]+ and [99mTcO2(THPN)]+ derived from a new class of N2S2 chelators diethienyldiazalkanes, namely 1,6-di(2-thienyl)-2,5-diazahexane (THEN) and 1,7-di- (2-thienyl)-4,4-dimethyl-2,6-diazaheptane (THPN), have been synthesized using Sn(II) tartrate reduction of [99mTc]pertechnetate at pH 9 and extraction of the complexes as ion pairs with trifluoromethane sulfonate anion (CF3SO3-) in high radiochemical yield (approximately 90%). Radiochemical analysis of the 99mTc complexes using chromatography (Whatman Cellulose CEL300 DEAE anion exchange strip, MEK) and paper chromatography (Whatman I, acetone) revealed high radiochemical purity (> 90%). High octanol-saline partition coefficients (> 37) of [99mTcO2(THEN)]+ and [99mTcO2(THPN)]+ indicated a lipophilic nature of the complexes. Relative stability of the 99mTc complex was high as measured by DTPA challenge studies. Biodistribution of [99mTcO2(THEN)]+ and [99mTcO2(THPN)]+ in rats at 15 min post-injection showed heart-to-blood activity ratios of 0.26 and 0.46, respectively, with rapid blood clearance. Further studies involving the variation of substituents on the basic core structure of this new class of 99mTc complexes may provide radiotracers suitable for myocardial imaging.

Micro-SPECT using NaI(Tl) crystals

A NaI(Tl) based micro-SPECT device that uses pinhole collimator geometry to achieve spatial resolution demagnification is proposed. This detector is based on our previous work in which a novel technique for 3-D position measurement within thick scintillators was developed. Properties of the new detector were studied using a collimated /sup 57/Co source and a 6 mm thick NaI(Tl) crystal that was coupled to a Hamamatsu R2486 position-sensitive photo-multiplier tube (PSPMT). All of the crystal surfaces (except the surface in contact with the PSPMT) were blackened so that an undistorted scintillation light cone resulting from total internal reflection would impinge on the photocathode, which is needed for an accurate depth of interaction (DOI) measurement within the crystal. The spatial resolution in the plane of detector was shown to be better than 1 mm FWHM. The DOI could be measured with an error of about 1 mm FWHM using the light cone parameters. 3-D image reconstruction software based on the MLEM algorithm was developed using Monte Carlo events. Applied to the real data obtained in a realistic geometry of the device, MLEM gives a better than 0.8 mm FWHM resolution in the plane of the /sup 57/Co source. In Monte Carlo calculations, for a detector resolution of 1 mm with a 0.5 mm pinhole collimator, the spatial resolution was demonstrated to be about 0.4 mm FWHM for a point-like source.

PET/SPECT detectors with light intensifiers and fiber coding

NaI scintillators for PET/SPECT detectors with light intensifier and fiber readout are considered using a Monte Carlo model. A coding algorithm which uses light detected at both ends of the fibers is proposed and the simulated results are evaluated. The scheme looks very promising.