1. MRI/MRS LABORATORY
Pl:
Goelman, G., PhD
Staff:
Abramovitch, R., PhD
Kippervasser, G., Post Doc
Bick, A., PhD Student
Derei, I., PhD Student
Eshel, A., PhD Student
Harhel, H., PhD Student
Mazuz, A., PhD Student
Motai, M., PhD Student
Rich, R., PhD Student
Shtarkshall, R., PhD Student
Introduction:
The following research projects are currently in progress:
;) Manganese-enhanced MRI (MEMRI) to study the basal ganglia connectivity in healthy and in a rat model of Parkinson’s disease.
Development of new approaches to Functional Neuro-Imaging (fMRI) by synchronization measurements in the functioning brain.
High b values diffusion MRI to study tumor physiology.
Cortical layer mapping using connectivity fMRI – Application to rat barrel field.
Mapping changes in synchronization in Parkinson's disease – Application to rat model and human patients.
Using fMRI to reveal brain representation of morphological processes and the organization of the mental lexicon.
Applying a new non-invasive technique for quantitative assessment of tumor angiogenesis.
Assessment of anti-antigenic therapy using MRI.
Analysis of the angiogenic potential of heparanase in wound healing.
Non-invasive assessment of lever regenerating after partial hepatectomy in normal an cirrhotic liver.
Development of new fMRI approach to measure basal neuronal activity – Application to Parkinson's disease.
Keywords:
Functional MRI. Parkinson’s Disease. Functional Collectivity. Tumor Vascularity.
Recent publications:
Zaroubi S., and Goelman G. (2000) Complex Denoising of MR Data Via Wavelet Analysis: Application for Functional MRI. Magn. Reson. Imaging, 18(1):59-68.
Goelman G. (2000) Fast 3D T2-Weighted MRI with Hadamard Encoding in the Slice Select Direction. Magn. Reson. Imag., 18:939-945.
Pelled G., Bergman H., and Goelman G. (2002) Bilateral overactivation of the sensorimotor cortex in the unilateral rodent model of Parkinson’s disease – a functional magnetic resonance imaging study. European J. of Neuroscience, 15:389-394.
Dor Y., Djonov V., Abramovitch R., Itin A., Fishman G.I., Carmeliet P., Goelman G., Keshet E. (2002) Conditional switching of VEGF provides new insights into adult neovascularization and pro-angiogenic therapy. EMBO J, 21(8):1939-1947.
Roth-Deri I., Zangen A., Aleli M., Goelman G., Pelled G., Nakash R., Gispan-Hermai I., Green T., Shalam Y., Yadid G. (2003) Effect of experimental-delivered and self-administrated cocaine on extracellular beta-endorphin levels in the nucleus accumbens. J. Neurochem. Mar., 84(5):930-938.
Shabat S., Nyska A., Long P.H., Goelman G., Abramovitch R., Ezov N., Levin-Harus T., Peddada S., Redlich M., Yedgar S., and Nyska M. (2004) Osteonecrosis in a Chemically Induced Rat Model of Human Hemolytic Disorders Associated with Thrombosis – A New Model for Avascular Necrosis of Bone. Calcified Tissue International, 74(3):220-228.
Shamir M., Goelman G., and Chai O. (2004) Postanesthetic cerebellar dysfunction in cats. J. Vet. Intern. Med., 18(3):368-369.
Pelled G., and Goelman G. (2004) Different Physiological MRI noise between cortical layers. Magn. Reson. Medicine, 52(4):913-916.
Goelman G. (2004) Radial Correlation Contrast – A functional connectivity MRI contrast to map changes in local neuronal communication. NeuroImage, 23:1432-1439.
Darash-Yahana M., Pikarsky E., Abramovitch R., Karplus R., Kasem S., Pal B., Zeira E., Galun E., and Peled A. (2004) High expression levels of CXCR4 are associated with human prostate growth and metastasis. FASEB J., 18(11):1240-1242.
Abramovitch R., Itzik A., Harel H., Nagler A., Vlodavsky I., and Siegal T. (2004) MRI analysis of the effect of halofuginone on metastatic rat brain tumor model. Neoplasia, 6(5):480-489.
Abramovitch R., Tavor E., Jacob-Hirsch J., Zeira E., Amariglio N., Pappo O., Rechavi G., Galun E., and Honigman A. (2004) A pivotal role of cyclic AMP-responsive element binding protein in tumor progression. Cancer Research, 64(4): 1338-1346.
Pikarsky E., Porat R.M., Stein I., Abramovitch R., Amit S., Kasem S., Gutkovich-Pyest E., Simcha Urieli-Shoval S., Galun E., and Ben-Neriah Y. (2004) NF-kappaB functions as a tumor promoter in a mouse model of inflammation-associated liver cancer. Nature, 431(7007):461-466.
Zcharia E., Zilka R., Yaar A., Yacoby-Zeevi O., Zetser A., Metzger S., Sarid R., Naggi A., Casu B., Ilan N., Vlodavsky I., and Abramovitch R. (2005) Heparanase accelerates wound angiogenesis and wound healing in mouse and rat models. FASEB J., 19(2):211-221.
Pelled G., Bergman H., Ben-Hur T., and Goelman G. (2005) Reduced basal-activity and increased functional homogeneity in sensorimotor and striatum of Parkinson’s disease rat model– a functional MRI study. European J. of Neuroscience (in press).
2. P E T
Pl:
Chisin, R., MD
Staff:
Freedman, N., PhD
Lester, H., PhD
Bocher, M., MD
Klein, M., MD
Krausz, Y., MD
Rubinstein, R., MD
Karger, H., MSc
Introduction:
The PET camera, the first to be installed in Israel in July 95, began to generate cardiac scintigraphies using Rubidium generators. In July 97, PET imaging was possible with cyclotron-produced radiotracers: first 18-FluoroDeoxyglucose and then 0-15-labelled water, C-11-Deprenyl, C-11-Choline and 18-F-FluoroDopa.
PET research projects are pursued in Cardiology, Oncology, Pulmonology, Neurology and Psychiatry through active collaboration of the Department of Medical Biophysics and Nuclear Medicine, which runs the PET facility, with the physicans of these departments.
Keywords:
PET. SUV. Patlak. Oncology. Melanoma. Lung cancer. Thyroid. Nasopharyngeal carcinoma. Neck. Rb-82. 150-H2O activation.
Recent publications:
Klein M., Freedman N., Mishani E., Gimon Z., Lotem M., Chisin R. (2000) PET and lymphoscintigraphic evaluation of malignant melanomas. Nuklear Medizin, 39:56-61.
Freedman N., Schechter D., Klein M., Marciano R., Rozenman Y., Chisin R. (2000) Retrospective Comparison between Rb-82 PET and Tl-201 SPECT Myocardial Perfusion Imaging: Insights into SPECT Attenuation Artifacts in Normal and Overweight Subjects. Clin. Nucl. Med., 25:1019-1023.
Nunez R., Yeung H., and Chisin R. (2000) Fluorine-18 FDG Positron Emission Tomography in Advanced Nasopharyngeal Carcinoma. Clin. Nucl. Med., 25:731-733.
Akhurst T., and Chisin R. (2000) Hybrid PET/CT machines: optimized PET machines for the new millennium? Letter to the Editor. J. Nucl. Med., 41:961-962.
Chisin R. and Macapinlac H.A. (2000) The Indications of FDG-PET in Neck Oncology. Radiological Clinics of North America, 38:999-1011.
Bocher M., Mishani E. (2000) The contribution of Positron Emission Tomography-PET to patient management in oncology. Harefuah, 139:64-67.
Rubinstein R., Broier R., Chisin R. (2001) The Contribution of FDG-PET to Diagnosis and Management of Lung Cancer - First Results. Harefuah, 140:100-103.
Ramos C.D., Erdi Y.E., Gonen M., Riedel E., Yeung H.W.D., Macapinlac H.A., Chisin R., Larson S.M. (2001) FDG-PET standardized uptake values in normal anatomical structures using iterative reconstruction segmented attenuation correction and filtered back projection. Eur. J. Nucl.Med., 28:155-164..
Ramos C.D., Chisin R., Yeung H.W.D., Larson S.M., Macapinlac H.A. (2001) Incidental focal thyroid uptake on FDG-PET scans should not be overlooked. Clin. Nucl. Med., 26:193-197.
Bocher M., Chisin R., Parag Y., Freedman N., Meir-Weil Y., Lester H., Mishani E., and Bonne O. (2001) Cerebral Activation Associated with Sexual Arousal in Response to a Pornographic Clip: A 15O-H2O PET Study in Heterosexual Men. Neuroimage, 14:105-117.
Freedman N.M.T., Sundaram S.K., Kurdziel K., Carrasquillo J.A., Whatley M., Carson J.M., Sellers D., Libutti S.K., Yang J.C., Bacharach S.L. (2003). Comparison of SUV and Patlak Slope to Monitor Cancer Therapy Using Serial PET Scans. Eur. J. Nucl. Med., 30:46-53.
3. CYCLOTRON
PI:
Mishani, E., PhD
Staff:
Ben-Daniel, R., PhD
Abourbeh, G., PhD Student
Cohen, N, PhD Student
Dissoki, S., PhD Student
Jacobson, O., PhD Student
Laky, D., MSc
Litchi, A., MA
Introduction:
The aim of the research activities is to non-invasively study human biology, using PET, and to promote the development and utilization of cyclotron-produced radiopharmaceuticals by 1) conducting basic research allowing for the development of new labeling agents , new labeling methods, design, synthesis, and biological evaluation of novel PET biomarkers with high “chemical resolution” 2) ameliorating existing methods in order to study physiological, biochemical and pharmacological functions at a molecular level, whether in healthy subjects or in patients 3) prompting technical developments supporting the above-mentioned activities, such as: targetry development for the production of radioisotopes, automation of radiochemical processes, etc.
The following research projects are carried out:
PET and EGFR (Epidermal Growth Factor Receptor); PET and MAO-B (Monoamineoxidase-B); Dopamine and PET; C-11Choline; Technical Developments; PET and Agiogenesis.
Keywords:
PET. Carbon-11. Fluorine-18. EGFR-TK (Tyrosine Kinase). Isotopes.
Recent publications:
Mishani E., Bocher M., Ben David I., Rozen Y., Laki D., Marciano M., Chisin R. (2001) [C-11]Choline – automated preparation and clinical utilization. J. Labl. Comp. Radiopharm., 44S:379-381.
Bonasera T.A., Ortu G., Rozen Y., Krais R., Freedman N.M.T., Chisin R., Gazit A., Levitzki A., and Mishani E. (2001) Potential 18F-Labeled Biomarkers for Epidermal Growth Factor Receptor Tyrosine Kinase. J. of Nucl. Med. and Biol., 28(4):359-374.
Mishani E., Ben David I., Rozen Y., Ortu G., Levitzki A. (2001) Carbon-11 Labeled Irreversible Inhibitors for Mapping Epidermal Growth Factor Receptor Tyrosine Kinase (EGFR-TK). J. Labl. Comp. Radiopharm., 44S:94-96.
Mishani E., Ben David I. (2001) [C-11] Acryloyl Chloride- A Fully Automated Preparation and Reaction with Model Amine. J. Labl. Comp. Radiopharm., 44S:475-476.
Ortu G., Ben-David I., Rozen Y., Levitzki A., Mishani E. (2001) Biological Evaluation of A Novel C-11 Labelled Irreversible EGFRTK Inhibitor. The Quar. J. of Nucl. Med., 45S:7.
Ortu G., Ben-David I., Rozen Y., Freedman N.M.T., Chisin R., Levitzki, A., Mishani E. (2002) In-vitro and In-vivo investigation of an irreversible labeled EGFr inhibitor (ML03) and its potential as PET biomarker in cancer and feasibility as an anticancer drug. Int. J. of Cancer, 101:360-370.
Mishani E., Ben-David I., Rozen Y. (2002) Improved method for the quality assurance of [C-11]choline. J. of Nucl. Med. and Biol., 29:359-362.
Ben-David I., Rozen Y., Ortu G., and Mishani E. (2003) Radiosynthesis of ML03, a novel positron emission tomography biomarker for targeting epidermal growth factor receptor via the labeling synthon: [C-11]Acryloyl chloride. Appl. Rad. Isotp., 58(2): 209-217.
Even-Sapir E., Metser U., Flusser G., Zuriel L., Kollender Y., Lerman H., Lievshitz G., Ron I., and Mishani E. (2004) Assessment of malignant skeletal disease: Initial experience with 18F-Fluoride PET/CT and comparison between 18F-Fluoride PET and 18F-Fluoride PET/CT. J. Nuc. Med. 45(2):272-278.
Mishani E., Abourbeh G., Rozen Y., Jacobson O., Laky D., Ben-David I., Levitzki A., Shaul M. (2004) Novel Carbon-11 Labeled 4-Dimethylamino-but-2-enoic acid [4-(phenylamino)-quinazoline-6-yl]-amides: Potential PET Bioprobes for Molecular Imaging of EGFR-positive Tumors. J. of Nucl. Med. and Biol., 31(4): 469-476.
Shaul M., Abourbeh G., Jacobson O., Rozen Y., Laky D., Levitzki A., and Mishani E. (2004) Novel Iodine-124 Labeled EGFR Inhibitors as Potential PET Agents for Molecular Imaging in Cancer. Bioorg. Med. Chem., 12:3421-3429.
Barda Y., Cohen N., Lev V., Ben-Aroya N., Koch Y., Mishani E., Fridkin M., Gilon C. (2004) Backbone metal cyclization: novel 99mTc labeled GnRH analog as potential SPECT molecular imaging agent in cancer. J. of Nucl. Med. and Biol., 31(7):921-933.
4. IMMUNOLOGY AND
T-CELL VACCINATION
Pl:
Abulafia-Lapid, R., PhD
Staff:
Abramovitz, J., MSc
Azulay, H., MSc
Haviv, O., BSc
Keren-Zur, Y., BSc
Lanxner, N., MSc
Yachnin, J.,BSc
Introduction:
T-cell Vaccination for HIV-infected Patients
Project 1: A protocol was developed for treating HIV-infected patients using attenuated autologous anti-CD4 auto-reactive T-cells as vaccines.
Project 2: T-Cell and peptide vaccination – a novel therapy for HIV-seropositive patients.
Project 3: Multi site center clinical trials phase II.
T-Cell Responses and auto-antibodies to human hsp70 but not to hsp90 in children with Type 1 diabetes
A new protein involved in Type 1 diabetes autoimmmunity was found. Peptides from this new protein (hsp70) can be used for vaccination therapy for children.
T-Cell Vaccination for patients with Multiple Sclerosis
We perform a phase I/II double-blind controlled clinical trial designed to evaluate the safety and response to autologous T-cell vaccination in MS patients which showed severe progression/deterioration in the functional status. This protocol has been approved by the Helsinki Committee of the Hadassah Medical Center and by the Israeli Health Ministry, 2002 (Abulafia-Lapid R., Schor H., and Karusis D. T-cell Vaccination for Multiple Sclerosis Patients: A Phase I/II Clinical Trial Protocol).
Key words:
Autoimmunity. Diabetes Type 1. MS-Multiple Sclerosis. T-Cell Vaccination. MBP-Myelin Basic Protein. MOG-Myelin Oligodendrocyte Glycoprotein.
Recent Publications:
Abulafia-Lapid R., Elias D., Keren-Zur Y., Raz I., Atlan H., and Cohen I. (1999) T-cell Responses to Human hsp60 and Peptides in IDDM and Healthy Individuals. J. Autoimmunity, 12(2):121-129.
Abulafia-Lapid R., Bentwich Z., Keren-Zur Y., Cohen I., and Atlan H. (2000) T-cell vaccination for HIV-1 seropositive patients: a phase I clinical trial. Experimental AIDS Research, 87-93.
Abulafia-Lapid R., Bentwich Z., Keren-Zur Y., Cohen I., and Atlan H. (2000) T-cell vaccination for HIV-1 seropositive patients - a phase I clinical trial. AIDS, 14(supplement 4):207.
Abulafia-Lapid R., Gillis D., Yosef O., Atlan H., and Cohen I. (2003) T-Cell and Autoantibodies to Human hsp70 in children with Type 1 Diabetes. J. Autoimmunity, 20:313-321.
Denisova G.F., Lideman L., Spectorman E., Abulafia-Lapid R., Burke M., Yust I., and Gershoni, J.M. (2003) Characterization of new monoclonal antibodies that discriminate between soluble and membrane CD4 and compete with human anti-CD4 autoimmune sera. Molecular Immunology, 40: 231-239.
Abulafia-Lapid R., Bentwich Z., Keren-Zur Y., Cohen I.R., Atlan H. (2004) Anti-CD4 autoimmunity in HIV-infected patients: an open trial of T-cell vaccination. J. Clinical Virology, 31S: 48-54.
Abulafia-Lapid R., Maayan S., Bentwich Z., Keren-Zur Y., Abramovitz J., Cohen I.R., Atlan H. (2005) T-cell vaccination against anti-CD4 autoimmunity in HIV-1 subtypes B and C infected patients – an extended open trial. Vaccine, 23:2149-2153.
Aldar S., Bourinbaiar, A.S., and Abulafia-Lapid R. (2005) Autoimmunity, alloimmunization and immunotherapy of AIDS. Autoimmunity Reviews (in press).
Abulafia-Lapid R., Bentwich Z., Maayan S., Keren-Zur Y., Cohen I.R., and Atlan H. (2005). Anti-CD4 autoimmunity in HIV-1 subtypes B and C infected patients and healthy donors. Journal of Autoimmunity (accepted for publication).
5. IN VIVO FUNCTIONAL PROTEOMIC
AND EPIGENETIC MEMORY
PI:
Atlan, H., MD, PhD
Staff:
Panet, R., PhD
Bujanover, S., PhD
Taraboulos, A., PhD (Hebrew University, Medical School)
Introduction:
The role of ion-protein interactions in signal transduction has been documented: the bumetanide and furosemide sensitive Na+K+Cl- cotransporter controls cell growth in 3T3 mouse fibroblasts and in primary cultures of human lymphocytes.This finding was supported by studying the effects of overexpression of the transporter gene on cell proliferation and the effects of the cotransporter activity on the signalling pathway in normal and transfected cells under arrest and after stimulation by growth factors.
In vivo changes in protein structures correlated with different cellular states are studied by looking for changes in the hydrophobicity of proteins by means of hydrophobic interaction chromatography (HIC) and for changes in their attachment to cellular membranes by means of a novel CHAPS flotation technique. Such modifications were observed on Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in human lymphocytes two hours after PHA activation.
Keywords:
Na+K+Cl- cotransport. Signal transduction. MAPkinase. GAPDH. HIC. CHAPS flotation.
Recent Publications:
Panet R., Marcus M., and Atlan H. (2000) Over-expression of the Na+K+Cl- cotransporter gene induces cell proliferation and phenotypic transformation in mouse fibroblasts. Journal of Cellular Physiology, 182:109-118.
Atlan H. (2001). Epigenesis and Self-Organization: New Perspectives in Biology and Medicine, in Conformational Diseases – A compendium, B. Solomon, A. Taraboulos, E. Katchalski-Katsir eds., The Center for the Study of Emerging Diseases, Bialik Institute Jerusalem and Karger, Basel, 291-297.
Panet R., Eliash M., Pick M., and Atlan H. (2002) Na+/K+/Cl- Cotransporter Activates Mitogen-Activated Protein Kinase in Fibroblasts and Lymphocytes. J. Cellul. Physiol.,190:227-237.
Rouvinski R., Gahali-Sass I., Stav I., Metzer E., Atlan H., Taraboulos A. (2003) Both raft- and non-raft proteins associate with CHAPS-insoluble complexes: some APP in large complexes. Biochem. Biophys. Res. Commun., 308:750-758.
6. THEORETICAL BIOLOGY AND
PHILOSOPHY OF BIOLOGY
Pl:
Atlan, H., MD, PhD
Staff:
Becker, T., PhD Student
Cohen, I.R., PhD (Weizmann Institute)
Louzoun, Y., PhD Student
Solomon, S., PhD (Hebrew University)
Introduction:
Structural and functional self-organization properties are studied by computer simulations. Different classes of self-organization can be defined according to the degree to which the meaning of their emerging properties is pre-defined. The biological relevance of these top-down, generic models is compared with that of bottom-up modeling of specific data on biological complex systems. The power and limitations of different modeling techniques are exemplified by applications to sets of data on the onset, prevention and treatment of experimental autoimmune diseases.
In addition to technical problems of modeling complexity, the present genomic and post-genomic state of biology creates ethical problems which must be approached at different levels, from viewpoints both internal and external to biological data proper.
Keywords:
Self-organization. Artificial Intelligence. Bio-complexity. Immune Systems. Ethics of Biology.
Recent Publications:
Atlan H. (2000) Self-organizing networks: weak, strong and intentional, the role of their underdetermination, in Self-Organizing Dynamics and Semantic Structures in Cognitive Systems, ed. A. Carsetti, Kluwer Academic Publ. Dordrecht, pp.127-142.
Koppel M., and Atlan H. (2000) Self-Organization and Computability, in Self-Organizing Dynamics and Semantic Structures in Cognitive Systems, ed. A. Carsetti, Kluwer Academic Publ. Dordrecht, pp.201-209.
Atlan H. (2000) Vivere e conscere, Pluriverso, (Milano), 5(2):24-31.
Shnerb N., Louzoun Y., Bettelheim E., Solomon S. (2000) The importance of being discrete - life always wins on the surface. Proc. Natl. Acad. Sci. USA, 97:10322-10324.
Shnerb N., Bettelheim E., Louzoun Y., Agam O., Solomon S. (2000) Adaptation of autocatalytic fluctuations to diffusive noise. Physical Review E 63.
Atlan H. (2001) Genealogy and Levels of Ethics, in Frontiers of Life, Academic Press, N.Y., pp.707-727.
Hershberg U., Louzoun Y., Atlan H., Solomon S. (2001) HIV time hierarchy: winning the war while loosing all the battles. Physica A, 289:178-190.
Louzoun Y., Atlan H., Cohen I.R. (2001) Modeling the influence of TH1 and TH2 type cells in autoimmune diseases. Journal of Autoimmunity, 17(4).
Louzoun Y, Solomon S., Atlan H., Cohen I.R. (2001) The Emergence of Spatial Complexity in the Immune System. Physica A, 297 (1-2):242-252.
Louzoun Y., Solomon S. (2001) Volatility driven markets in a generalized Lotka Voltera formalism. Physica A, 302:220-233.
Beker T., Aharonov-Barki R., and Ruppin R. (2001) Emerging Command Neuron Circuitry in Evolved Autonomous Agents. Neurocomputing, 38-40.
Aharonov-Barki R., Beker T., and Ruppin E. (2001) Emergence of Memory-Driven Command Neurons in Evolved Artificial Agents. Neural Computation, 13(3).
Louzoun Y., Solomon S., Atlan H., Cohen I.R. (2003) Proliferation and competition in discrete biological systems. Bulletin of Mathematical Biology, 65:375-396.
Atlan H. (2003) The Living Cell as a Paradigm for Complex Natural Systems. Complexus. Modeling and Understanding Functional Interactions in Life Sciences and Systems Biology, Karger Pub. 1, 1-3.
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