42 results on '"Marom H"'
Search Results
2. The contribution of grain boundary scattering versus surface scattering to the resistivity of thin polycrystalline films
- Author
-
Marom, H., Ritterband, M., and Eizenberg, M.
- Published
- 2006
- Full Text
- View/download PDF
3. Decay of elastic waves in alumina
- Author
-
Marom, H., Sherman, D., and Rosenberg, Z.
- Subjects
Aluminum oxide -- Research ,Elastic waves -- Research ,Physics -- Research ,Physics - Abstract
Research describing the dynamic response of alumina subject to shock compression is presented. In particular the relationship between wave decay and the dependence of Hugoniot elastic limit on target thickness is investigated.
- Published
- 2000
4. Particle size effect on the apparent brittle-ductile transition in YBa2Cu3O7−x-Sn composite superconductor
- Author
-
Chaim, R. and Marom, H.
- Published
- 1993
- Full Text
- View/download PDF
5. The effect of surface roughness on the resistivity increase in nanometric dimensions.
- Author
-
Marom, H. and Eizenberg, M.
- Subjects
- *
ELECTRIC resistance , *CONDUCTION electrons , *ELECTRON scattering , *PARTICLES (Nuclear physics) , *COPPER , *METALLIC films - Abstract
Materials with nanometric dimensions exhibit higher electrical resistivity due to additional scattering centers for the conduction electrons, mainly from surfaces and grain boundaries. In this study we focus on the effect of surfaces by implementing an experimental technique in which the resistivity of thin films is measured during and after etching them inside a solution. This technique enables to analyze the contribution of surfaces to the resistivity and gives a unique insight as for the effect of surface roughness. It is shown that the scattering of electrons from annealed copper films with smooth enough surfaces is mostly specular and that the resistivity in this case is dominated by the effect of grain boundaries. However, when the roughness of the surface becomes larger than the de Broglie wavelength of the electrons, a substantial increase in resistivity occurs. This roughness-induced resistivity is analyzed and shown to be much larger in certain cases than the resistivity predicted for a flat surface, even when all electron scatterings are assumed to be completely diffused. [ABSTRACT FROM AUTHOR]
- Published
- 2006
- Full Text
- View/download PDF
6. The temperature dependence of resistivity in thin metal films.
- Author
-
Marom, H. and Eizenberg, M.
- Subjects
- *
THIN films , *CRYSTAL growth , *DISLOCATIONS in crystals , *CRYSTAL grain boundaries , *TWINNING (Crystallography) - Abstract
The dependence of resistivity on temperature in thin metal films is investigated by extending the model of Mayadas and Shatzkes to include temperature dependence. It is shown that previous interpretations of a dominant grain boundary mechanism are not necessarily correct, and that the combined influence of grain boundaries and surfaces should be considered in the analysis of experimental results. The analytical expressions developed enable systematic studies of the different factors influencing the dependence of resistivity on temperature in thin metal films. [ABSTRACT FROM AUTHOR]
- Published
- 2004
- Full Text
- View/download PDF
7. On the inelastic shock profile in alumina.
- Author
-
Marom, H., Sherman, D., Rosenberg, Z., and Murray, N.
- Subjects
- *
ALUMINUM oxide , *ELASTICITY - Abstract
The dynamic response of alumina specimens, above their elastic limits, was studied using planar impact experiments with different tile thickness. Stress-time measurements with manganin gauges show a steady spreading of the inelastic portion of the shock profile with increasing tile thickness. Such behavior is typical of elastic waves moving at a constant speed that depends on their amplitude. This finding supports recent interpretations of the failure ramp, by which the elastic response of these materials should be extended to higher stresses than the initial jump. However, further analysis of these profiles raises some questions regarding the exact determination of the Hugoniot elastic limit. [ABSTRACT FROM AUTHOR]
- Published
- 2002
- Full Text
- View/download PDF
8. The temperature dependence of resistivity in thin metal films
- Author
-
Eizenberg, M. and Marom, H.
- Subjects
Coordination compounds -- Electric properties ,Dielectric films -- Research ,Thin films -- Research ,Physics - Abstract
The dependence of resistivity on temperature in thin films by extending the model of Mayadas and Shatzkes to include temperature dependence is investigated. The investigations show that previous interpretations of a dominant gain boundary mechanism are not necessarily correct, and that the combined influence of grain boundaries and surfaces should be considered in the analysis of experimental results.
- Published
- 2004
9. Size-dependent resistivity of nanometric copper wires
- Author
-
Marom, H., primary, Mullin, J., additional, and Eizenberg, M., additional
- Published
- 2006
- Full Text
- View/download PDF
10. HBM ESD failures caused by a parasitic pre-discharge current spike.
- Author
-
Etherton, M., Axelrod, V., Meuse, T., Miller, J.W., and Marom, H.
- Published
- 2008
11. Study of Transistor and Product NBTI Lifetime Distributions.
- Author
-
Jin Qin, Baoguang Yan, Shoshany, Y., Roy, D., Rahamim, H., Marom, H., and Bernstein, J.B.
- Published
- 2008
- Full Text
- View/download PDF
12. DF-RQA practice for SoC [design for reliability and quality assurance].
- Author
-
Marom, H.
- Published
- 2004
- Full Text
- View/download PDF
13. On the inelastic response of Al[sub 2]O[sub 3] under shock loading.
- Author
-
Marom, H., Sherman, D., and Rosenberg, Z.
- Subjects
- *
ALUMINUM oxide , *MECHANICAL shock , *GAGES - Abstract
The dynamic response of alumina under shock compression was studied using planar impact experiments with different tile thicknesses. Results show steady spreading of the inelastic shock profile with increasing tile width. Further analysis indicates an expected change in failure mechanism in pressures of about twice the Hugoniot Elastic Limit (HEL). HEL decay phenomenon in alumina is probably a measurement artifact, resulting from the relatively slow response times of manganin gauges. [ABSTRACT FROM AUTHOR]
- Published
- 2000
14. DF-RQA practice for SoC
- Author
-
Marom, H., primary
- Full Text
- View/download PDF
15. Extend a helping hand in disaster 6,000 miles away from home - the Israeli Field Hospital in the Philippines.
- Author
-
Dagan, D., Marom, H., and Kreiss, Y.
- Published
- 2013
16. No need to tax the sick: clinical guidelines for rofecoxib as an alternative effective method to the copayment policy in the advent of increasing pharmaceutical expenditures.
- Author
-
Bar-Dayan Y, Yachelevich N, Benedek P, Grotto I, Goldberg A, Morad Y, Marom H, Ohana N, Rosen, Yitzhak, Yachelevich, Naomi, Benedek, Paul, Grotto, Itamar, Goldberg, Avishy, Morad, Yair, Marom, Hadar, Ohana, Nissim, and Bar-Dayan, Yaron
- Abstract
Background: Over the last few years, major health care systems have been trying to control increasing pharmaceutical expenditures by a variety of methods, such as the controversial copayment policy, as essential health expenditures were being jeopardized.Objective: To analyze the regulatory intervention of preauthorization on a rofecoxib model in the medical corps of the Israeli Defense Forces (IDF) in terms of indications for prescription, consumption, and cost.Interventions: Guidelines established by the medical services branch based on current literature and communication with diverse specialists and hospitals were implemented by a general practitioner who checked each rofecoxib prescription that was written for IDF personnel by a specialist. The intervention was initiated in November 2000 and continued until August 2001 and after the study.Design: The study was divided into two parts. The first part was a retrospective monthly, preintervention analysis of computerized medical records of IDF personnel (N = 247) for whom rofecoxib was prescribed. The second was a prospective monthly, postintervention analysis of filled-out guideline forms (N = 250) of approved rofecoxib prescriptions.Participants: Patients, were IDF personnel, age 18 to 45, treated in military and civilian outpatient clinics for whom rofecoxib was prescribed.Setting: The study took place at the Medical Service Branch of the IDF between August 2000 and August 2001.Results: We demonstrated a significant decrease in average monthly consumption (43.0%) and estimated monthly expenditures (40.84%) of rofecoxib, as well as significant shifts (p < 0.001) in indications for whom rofecoxib was approved. These shifts (from pre- to postintervention) include the following: others/nonspecified (80 to 12%), known peptic disorder (7 to 32%), peptic complaints (4 to 22%), and rheumatic (8 to 19%).Conclusion: This type of intervention can be cost-effective, can provide quality care, and may be a viable alternative to the controversial and problematic copayment policy. [ABSTRACT FROM AUTHOR]- Published
- 2004
17. Successful phage-antibiotic therapy of P. aeruginosa implant-associated infection in a Siamese cat.
- Author
-
Braunstein R, Hubanic G, Yerushalmy O, Oren-Alkalay S, Rimon A, Coppenhagen-Glazer S, Niv O, Marom H, Barsheshet A, and Hazan R
- Subjects
- Animals, Cats, Ceftazidime therapeutic use, Drug Resistance, Multiple, Bacterial, Bacteriophages, Phage Therapy veterinary, Pseudomonas Infections veterinary, Pseudomonas Infections drug therapy, Pseudomonas Infections therapy, Cat Diseases therapy, Cat Diseases drug therapy, Cat Diseases microbiology, Pseudomonas aeruginosa drug effects, Anti-Bacterial Agents therapeutic use
- Abstract
Antibiotic-resistant pathogens are a growing global issue, leading to untreatable infectious diseases in both humans and animals. Personalized bacteriophage (phage) therapy, the use of specific anti-bacterial viruses, is currently a leading approach to combat antibiotic-resistant infections. The implementation of phage therapy has primarily been focused on humans, almost neglecting the impact of such infections on the health and welfare of companion animals. Pets also have the potential to spread resistant infections to their owners or the veterinary staff through zoonotic transmission. Here, we showcase personalized phage-antibiotic treatment of a cat with a multidrug-resistant Pseudomonas aeruginosa implant-associated infection post-arthrodesis surgery. The treatment encompassed a tailored combination of an anti- P. aeruginosa phage and ceftazidime, precisely matched to the pathogen. The phage was topically applied to the surgical wound while the antibiotic was administered intramuscularly. After two treatment courses spanning 7 and 3 weeks, the surgical wound, which had previously remained open for five months, fully closed. To the best of our knowledge, this is the first case of personalized phage therapy application in felines, which provides further evidence of the effectiveness of this approach. The successful outcome paves the way for personalized phage-antibiotic treatments against persistent infections therapy in veterinary practice.
- Published
- 2024
- Full Text
- View/download PDF
18. Genetic Modification of Tumor-Infiltrating Lymphocytes, Peripheral T Cells, and T-Cell Model Cell Lines.
- Author
-
Weinstein-Marom H, Blokon-Kogan D, Levi-Mann M, Katzman C, Shalev S, Zaitsev M, Besser MJ, Shapira-Frommer R, Gross G, Itzhaki O, and Nissim L
- Subjects
- Transfection, Receptors, Antigen, T-Cell genetics, Receptors, Antigen, T-Cell metabolism, RNA, Messenger genetics, RNA, Messenger metabolism, Cell Line, CD8-Positive T-Lymphocytes, Immunotherapy, Adoptive methods, Lymphocytes, Tumor-Infiltrating metabolism, T-Lymphocytes metabolism
- Abstract
Genetic modification of tumor-infiltrating lymphocytes (TILs) or circulating T cells has become an important avenue in cancer therapy. Here we describe a comprehensive method for establishing and expanding TIL cultures and genetically modifying them with a gene of interest (GOI) via retroviral transduction or mRNA transfection. The method includes all the important steps starting with TIL extraction from tumors through to the maintenance of the genetically modified TILs. The protocol includes instructions for retroviral transduction and mRNA transfection of circulating T cells or T-cell lines. The GOIs most commonly introduced into the target cells are chimeric antigen receptors (CARs); genetic adjuvants, such as membrane-bound interleukins; and antitumor T-cell receptors (TCRs)., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)
- Published
- 2024
- Full Text
- View/download PDF
19. Novel engineered B lymphocytes targeting islet-specific T cells inhibit the development of type 1 diabetes in non-obese diabetic Scid mice.
- Author
-
Chen D, Kakabadse D, Fishman S, Weinstein-Marom H, Davies J, Boldison J, Thayer TC, Wen L, Gross G, and Wong FS
- Subjects
- Mice, Animals, Mice, Inbred NOD, Mice, SCID, Histocompatibility Antigens Class II, Diabetes Mellitus, Type 1 prevention & control, Islets of Langerhans, Severe Combined Immunodeficiency, B-Lymphocytes, Regulatory
- Abstract
Introduction: In this study, we report a novel therapeutic approach using B lymphocytes to attract islet-specific T cells in the non-obese diabetic (NOD) mouse model and prevent the development of autoimmune diabetes. Rather than using the antibody receptor of B cells, this approach utilizes their properties as antigen-presenting cells to T cells., Methods: Purified splenic B cells were treated with lipopolysaccharide, which increases regulatory B (Breg) cell function, then electroporated with mRNA encoding either chimeric MHC-I or MHC-II molecules covalently linked to antigenic peptides. Immunoregulatory functions of these engineered B cells (e-B cells) were tested by in vitro assays and in vivo co-transfer experiments with beta-cell-antigen-specific CD8
+ or CD4+ T cells in NOD.Scid mice, respectively., Results: The e-B cells expressing chimeric MHC-I-peptide inhibited antigen-specific CD8+ T-cell cytotoxicity in vitro . The e-B cells expressing chimeric MHC-II-peptide induced antigen-specific CD4+ T cells to express the regulatory markers, PD-1, ICOS, CTLA-4, Lag3, and Nrp1. Furthermore, e-B cells encoding the chimeric MHC-I and MHC-II peptide constructs protected NOD.Scid mice from autoimmune diabetes induced by transfer of antigen-specific CD8+ and CD4+ T cells., Discussion: MHC-peptide chimeric e-B cells interacted with pathogenic T cells, and protected the host from autoimmune diabetes, in a mouse model. Thus, we have successfully expressed MHC-peptide constructs in B cells that selectively targeted antigen-specific cells, raising the possibility that this strategy could be used to endow different protective cell types to specifically regulate/remove pathogenic cells., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Chen, Kakabadse, Fishman, Weinstein-Marom, Davies, Boldison, Thayer, Wen, Gross and Wong.)- Published
- 2023
- Full Text
- View/download PDF
20. Implementing Logic Gates for Safer Immunotherapy of Cancer.
- Author
-
Savanur MA, Weinstein-Marom H, and Gross G
- Subjects
- Animals, Humans, Immunotherapy, Adoptive methods, Logic, Molecular Targeted Therapy methods, Neoplasms therapy, Precision Medicine methods
- Abstract
Targeting solid tumors with absolute precision is a long-standing challenge in cancer immunotherapy. The identification of antigens, which are expressed by a large fraction of tumors of a given type and, preferably, across various types, but not by normal cells, holds the key to developing safe, off-the-shelf immunotherapies. Although the quest for widely shared, strictly tumor-specific antigens has been the focus of tremendous effort, only few such candidates have been implicated. Almost all antigens that are currently explored as targets for chimeric antigen receptor (CAR) or T cell receptor (TCR)-T cell therapy are also expressed by healthy cells and the risk of on-target off-tumor toxicity has remained a major concern. Recent studies suggest that this risk could be obviated by targeting instead combinations of two or more antigens, which are co-expressed by tumor but not normal cells and, as such, are tumor-specific. Moreover, the expression of a shared tumor antigen along with the lack of a second antigen that is expressed by normal tissues can also be exploited for precise recognition. Additional cues, antigenic or non-antigenic ones, which characterize the tumor microenvironment, could be harnessed to further increase precision. This review focuses on attempts to define the targetable signatures of tumors and assesses different strategies employing advanced synthetic biology for translating such information into safer modes of immunotherapy, implementing the principles of Boolean logic gates., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Savanur, Weinstein-Marom and Gross.)
- Published
- 2021
- Full Text
- View/download PDF
21. The Intracellular Domain of CD40 is a Potent Costimulatory Element in Chimeric Antigen Receptors.
- Author
-
Levin-Piaeda O, Levin N, Pozner S, Danieli A, Weinstein-Marom H, and Gross G
- Subjects
- CD40 Antigens chemistry, CD40 Antigens metabolism, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes metabolism, Cell Line, Genetic Engineering, Humans, Immunotherapy, Adoptive methods, Lymphocyte Activation immunology, Plasmids genetics, Receptors, Antigen, T-Cell genetics, Receptors, Antigen, T-Cell metabolism, Receptors, Chimeric Antigen genetics, Receptors, Chimeric Antigen metabolism, T-Lymphocytes metabolism, CD40 Antigens immunology, Protein Interaction Domains and Motifs immunology, Receptors, Antigen, T-Cell immunology, Receptors, Chimeric Antigen immunology, T-Lymphocytes immunology
- Abstract
The costimulatory domains incorporated into second-generation and third-generation chimeric antigen receptors (CARs) strongly influence CAR-T-cell function. Here, we explored second-generation and third-generation CARs harboring the signaling domain of the CD40 receptor as a new costimulatory element in comparison with similar CARs carrying the 4-1BB domain. In CARs of both generations, CD40 was more potent than 4-1BB in triggering the NF-κB signaling pathway. In human T cells from 2 donors, CD40 was comparable to 4-1BB in upregulating costimulatory and activation markers, inducing proinflammatory cytokine secretion and mediating target cell killing. Interestingly, differences in the response pattern of T cells from the 2 donors with respect to CD40 and 4-1BB were evident. We conclude that in human T cells, the CD40 signaling domain is a potent costimulatory element in both second-generation and third-generation CARs., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)
- Published
- 2021
- Full Text
- View/download PDF
22. Genetic Modification of Tumor-Infiltrating Lymphocytes via Retroviral Transduction.
- Author
-
Weinstein-Marom H, Gross G, Levi M, Brayer H, Schachter J, Itzhaki O, and Besser MJ
- Subjects
- Antigens, CD19 immunology, Cell Line, Tumor, Humans, Immunotherapy, Adoptive methods, Interferon-gamma immunology, K562 Cells, Lymphocyte Activation immunology, Melanoma immunology, Receptors, Chimeric Antigen immunology, Lymphocytes, Tumor-Infiltrating immunology, Retroviridae immunology
- Abstract
Adoptive T cell therapy (ACT) holds great promise for cancer treatment. One approach, which has regained wide interest in recent years, employs antitumor T cells isolated from tumor lesions ("tumor-infiltrating lymphocytes" or TIL). It is now appreciated that a considerable proportion of anti-melanoma TIL recognize new HLA-binding peptides resulting from somatic mutations, which occurred during tumor progression. The clinical efficacy of TIL can potentially be improved via their genetic modification, designed to enhance their survival, homing capacity, resistance to suppression, tumor killing ability and additional properties of clinical relevance. Successful implementation of such gene-based strategies critically depends on efficient and reproducible protocols for gene delivery into clinical TIL preparations. Here we describe an optimized protocol for the retroviral transduction of TIL. As the experimental system we employed anti-melanoma TIL cultures prepared from four patients, recombinant retrovirus encoding an anti-CD19 chimeric antigen receptor (CAR) as a model gene of interest and CD19+ and CD19- human cell lines serving as target cells. Transduction on day 7 of the rapid expansion protocol (REP) resulted in 69 ± 8% CAR positive TIL. Transduced, but not untransduced TIL, from the four patients responded robustly to CD19+, but not CD19- cell lines, as judged by substantial secretion of IFN-γ following co-culture. In light of the rekindled interest in antitumor TIL, this protocol can be incorporated into a broad range of gene-based approaches for improving the in-vivo survival and functionality of TIL in the clinical setting., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Weinstein-Marom, Gross, Levi, Brayer, Schachter, Itzhaki and Besser.)
- Published
- 2021
- Full Text
- View/download PDF
23. In Defense of Secondary Pharmaceutical Patents in Drug Discovery and Development.
- Author
-
Agranat I and Marom H
- Abstract
"An important objective of modern pharmaceutical research is the discovery of new medical uses for known molecules" (UKSC 2018), a component of secondary pharmaceuticals. This Viewpoint's focus is the defense of the vulnerable strategy of secondary pharmaceutical patents (SPPs). Typical claims thereof are new medical uses, dosage, selection, and enatiomer patents. The attacks on secondary pharmaceuticals, including chiral switches, use negative-connotation terms, such as "evergreening", "product hopping", and "pejorative". Most enantiomer patents, including the controversial Nexium patents, were challenged in courts worldwide yet validated. This Viewpoint considers the "teaching away" defense of nonobviousness of Nexium enantiomer patents due to "unexpected results", applying stereochemistry principles. Physical organic chemistry arguments and the prediction of lower energy barriers of epimerization/racemization of benzylic anions of esomeprazole and dexlansoprazole (compared with their uncharged enantiomers) are a basis of the "teaching away". This prediction is verified by DFT computations. "Obvious to try" of many SPPs should not prevail over "unexpected results". A generalized concern about "evergreening" drugs should not be a justification for comprehensive attacks on SPPs. Following UKSC Lyrica decision (2018), plausibility, a condition of patent validity, may enter the arena of enantiomer patents, claiming second medical uses. Secondary pharmaceutical dosage, selection, improvement, and enantiomer patents are not necessarily obvious., Competing Interests: The authors declare no competing financial interest., (Copyright © 2020 American Chemical Society.)
- Published
- 2020
- Full Text
- View/download PDF
24. MHC-I presentation of peptides derived from intact protein products of the pioneer round of translation.
- Author
-
Weinstein-Marom H, Hendel L, Laron EA, Sharabi-Nov A, Margalit A, and Gross G
- Subjects
- Animals, COS Cells, Cell Line, Cell Line, Tumor, Chlorocebus aethiops, Codon, Nonsense genetics, Genes, Reporter genetics, Green Fluorescent Proteins genetics, HeLa Cells, Humans, Mice, Nonsense Mediated mRNA Decay genetics, RNA, Messenger genetics, Histocompatibility Antigens Class I genetics, Peptides genetics, Protein Biosynthesis genetics
- Abstract
Among the earliest protein products of most cellular genes are those synthesized during the pioneer round of translation (PRT), a key step in nonsense-mediated mRNA decay (NMD) that allows scanning of new transcripts for the presence of a premature termination codon (PTC). It has been demonstrated that at least some PRT degradation products can be targeted to major histocompatibility (MHC)-I presentation. To gain new insight into this putative PRT-to-MHC-I route, we have assembled 2 pairs of reporter genes so that the 2 genes in each pair encode an identical fusion protein between a model antigenic peptide and enhanced green fluorescent protein (EGFP), one of which harbors a PTC. We expressed these genes in different mouse and human cell lines and confirmed enhanced NMD activity for the PTC(+) gene in each pair by monitoring the effect of cycloheximide on the level of the respective mRNA. We then exploited several strategies for establishing the ratio between level of peptide presentation and total amount of protein product. We consistently observed significantly higher ratios for the PTC(+) mRNAs compared with the PTC(-) ones, pointing to correlation between the turnover of otherwise identical proteins and the fate of their template mRNA. Using confocal microscopy, we showed a clear link between NMD, the presence of misfolded EGFP polypeptides, and enhanced MHC-I peptide presentation. Altogether, these findings imply that identical full-length gene products differing only in 3' noncoding sequences can be differentially degraded and targeted to the MHC-I presentation pathway, suggesting a more general role for the PRT in establishing the MHC-I peptidome.-Weinstein-Marom, H., Hendel, L., Laron, E. A., Sharabi-Nov, A., Margalit, A., Gross, G. MHC-I presentation of peptides derived from intact protein products of the pioneer round of translation.
- Published
- 2019
- Full Text
- View/download PDF
25. Combined Expression of Genetic Adjuvants Via mRNA Electroporation Exerts Multiple Immunostimulatory Effects on Antitumor T Cells.
- Author
-
Weinstein-Marom H, Levin N, Pato A, Shmuel N, Sharabi-Nov A, Peretz T, Eisenberg G, Lotem M, Itzhaki O, Besser MJ, and Gross G
- Subjects
- Adjuvants, Immunologic administration & dosage, Cells, Cultured, Humans, Interferon-gamma, Melanoma therapy, CD8-Positive T-Lymphocytes transplantation, Electroporation, Gene Transfer Techniques, Immunotherapy, Adoptive, Lymphocytes, Tumor-Infiltrating transplantation, RNA, Messenger administration & dosage
- Abstract
Adoptive transfer of tumor-infiltrating lymphocytes (TILs) or gene-modified T cells expressing antitumor TCRs or chimeric antigen receptors often yields a high rate of clinical response in several types of cancer. New approaches for enhancing the functional properties of antitumor T cells could improve the clinical outcome of these treatments. To this end, we created 3 classes of genes, each designed to operate autonomously upon expression in T cells. We recently reported on the enhancing effects of constitutively active toll-like receptor 4 (caTLR4), membrane (mem) interleukin-2, memIL-12, and memIL-15, and self-oligomerizing, constitutively active CD40 (caCD40). Here, we evaluated their combined effects on peripheral blood CD8 T cells and different antimelanoma TIL cultures following mRNA electroporation. Expression in CD8 T cells induced transient production of interferon-γ and prolonged and robust upregulation of CD25, CD69, 4-1BB, and OX40. The adjuvants enhanced cytolytic activity of TILs and production of interferon-γ and TNF-α in the presence of autologous, but not mismatched, melanoma for at least 3 days after electroporation. Expression of the 3 adjuvants in young TILs from different patients markedly increased the expression of CD25, OX40, 4-1BB, CD127, and CD28 and exhibited cooperative and, at times, synergistic effects. Furthermore, predefined mixtures of mRNA encoding these adjuvants markedly enhanced the specific antitumor response of selected TILs and killing of autologous melanoma cells by young TILs. Our findings suggest that combinations of these new genetic adjuvants can substantially improve the functional properties of antitumor T cells, offering a new tool of unique versatility in adoptive cell therapy.
- Published
- 2019
- Full Text
- View/download PDF
26. Potent Activation of Human T Cells by mRNA Encoding Constitutively Active CD40.
- Author
-
Levin N, Weinstein-Marom H, Pato A, Itzhaki O, Besser MJ, Eisenberg G, Peretz T, Lotem M, and Gross G
- Subjects
- Adjuvants, Immunologic, Humans, Immunotherapy, Adoptive methods, Melanoma immunology, RNA, Messenger, Skin Neoplasms immunology, Tumor Cells, Cultured, CD40 Antigens immunology, Lymphocyte Activation immunology, Lymphocytes, Tumor-Infiltrating immunology, T-Lymphocytes immunology
- Abstract
New strategies for augmenting the actual performance of therapeutic T cells in vivo are needed for improving clinical outcome of adoptive cell therapy. Cumulative findings suggest that CD40 plays an intrinsic role in T cell costimulation. Recently, we demonstrated the ability of truncated, auto-oligomerizing CD40 derivatives to induce strong activation of APCs in a ligand-independent manner. We reasoned that constitutively active CD40 (caCD40) can similarly exert enhancing effects on human antitumor T cells. To test this assumption, we transfected human T cells with in vitro-transcribed caCD40 mRNA. In polyclonal T cells, caCD40 triggered IFN-γ secretion and upregulated CD25 and 4-1BB. In antimelanoma tumor-infiltrating lymphocytes (TILs), caCD40 induced massive production of IFN-γ, exerting a pronounced synergistic effect when coexpressed with constitutively active TLR4 devoid of its extracellular ligand binding. In unselected "young" TILs, caCD40 reproducibly increased surface expression of CD25, OX40, 4-1BB, CD127, and CD28. Three days post-mRNA electroporation of CD8 TILs, caCD40 elevated IFN-γ and TNF-α production and cytolytic activity in the presence of autologous but not HLA-I-mismatched melanoma. Enhanced killing of autologous melanoma by young TILs was observed 4 d posttransfection. These findings suggest that caCD40 can function as a potent T cell adjuvant and provide essential guidelines for similar manipulation of other key members of the TNFR family., (Copyright © 2018 by The American Association of Immunologists, Inc.)
- Published
- 2018
- Full Text
- View/download PDF
27. Membrane-attached Cytokines Expressed by mRNA Electroporation Act as Potent T-Cell Adjuvants.
- Author
-
Weinstein-Marom H, Pato A, Levin N, Susid K, Itzhaki O, Besser MJ, Peretz T, Margalit A, Lotem M, and Gross G
- Subjects
- Animals, Cell Line, Cytokines genetics, Electroporation, Female, Humans, Lymphocyte Activation, Male, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Protein Engineering, RNA, Messenger genetics, T-Lymphocytes transplantation, Cell Membrane metabolism, Cytokines metabolism, Immunotherapy, Adoptive methods, T-Lymphocytes physiology, Toll-Like Receptor 4 metabolism
- Abstract
Proinflammatory cytokines are widely explored in different adoptive cell therapy protocols for enhancing survival and function of the transferred T cells, but their systemic administration is often associated with severe toxicity which limits their clinical use. To confine cytokine availability to the therapeutic T cells, we expressed 3 key cytokines, IL-2, IL-12, and IL-15, as integral T-cell membrane proteins. To prevent permanent activation of growth signaling pathways, we delivered these genes to T cells through mRNA electroporation. The engineered cytokines could be detected on the surface of mRNA-transfected cells and binding to their cell-surface receptors mainly occurred in cis. The 3 human cytokines supported the ex vivo growth of activated human CD8 and CD4 T cells for at least 6 days posttransfection, comparably to high-dose soluble IL-2. Similarly, membrane IL-2, membrane IL-12, and, to a lesser extent, membrane IL-15, were comparable with their soluble counterparts in supporting proliferation of splenic mouse CD8 T cells. Following electroporation of human CD8 T cells and antimelanoma tumor-infiltrating lymphocytes, membrane cytokines synergized with constitutively active toll-like receptor 4 in inducing interferon-γ secretion. Efficient cooperation with TLR4 was also evident in the upregulation of the activation molecules CD25, CD69, CD137 (4-1BB), and CD134 (OX40). Taken together, membrane cytokines expressed through mRNA transfection emerge as effective tools for enhancing T-cell proliferation and function and may have potential use in adoptive T-cell therapy.
- Published
- 2016
- Full Text
- View/download PDF
28. Efficient peptide recovery from secreted recombinant MHC-I molecules expressed via mRNA transfection.
- Author
-
Lazarus D, Weinstein-Marom H, Fishman S, Yossef R, Zuri D, Barnea E, Admon A, Margalit A, and Gross G
- Subjects
- Animals, Cell Line, Flow Cytometry, Histocompatibility Antigens Class I chemistry, Histocompatibility Antigens Class I isolation & purification, Humans, Mice, Transfection, Gene Expression, Histocompatibility Antigens Class I genetics, Histocompatibility Antigens Class I immunology, Peptides immunology, RNA, Messenger genetics, Recombinant Proteins
- Abstract
Most current methods for identifying peptides that are bound to a distinct MHC-I product in a given cell sample utilize detergent solubilization of membrane proteins followed by immunoaffinity purification. Since detergent traces and cell debris hamper subsequent peptide analysis, exceedingly large cell samples are often required. To avoid the use of detergents, truncated MHC-I heavy chains have recently been expressed by stable DNA transfection or retroviral transduction, resulting in the secretion of soluble MHC-I complexes to the growth medium. The electroporation of in vitro-transcribed mRNA achieves remarkable efficacy and uniformity of gene expression in numerous cell types, exhibiting exceedingly fast kinetics. We reasoned that mRNA transfection offers a simple, fast and widely applicable alternative to current gene delivery protocols for expressing secreted MHC-I products in cells of interest. To test this assumption we used mRNA to express soluble derivatives of HLA-A2 in the human AF10 B cell myeloma and 624mel melanoma and H-2K(d) in the mouse SP2/0 B cell myeloma. The level of MHC-I complexes secreted by these cells peaked within less than 24h post-transfection and they could be affinity-purified directly from the culture medium in considerably greater yields when compared to nonionic detergent lysates on a cell-to-cell basis. Mass-spectrometry analysis of eluted peptides revealed larger pools in the secreted material than in lysates with substantial overlap in composition. Our results introduce mRNA transfection as a powerful tool for determining the cell's MHC-I peptidome, which can be potentially applied to a broad range of cell types., (Copyright © 2015 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF
29. Single enantiomer versus racemate: chiral distinction in the proton pump inhibitors omeprazole and esomeprazole.
- Author
-
Marom H, Pogodin S, and Agranat I
- Subjects
- Dimerization, Esomeprazole pharmacokinetics, Humans, Models, Chemical, Models, Molecular, Omeprazole pharmacokinetics, Proton Pump Inhibitors pharmacokinetics, Stereoisomerism, Water, Esomeprazole chemistry, Omeprazole chemistry, Proton Pump Inhibitors chemistry
- Abstract
Chiral distinction in the proton pump inhibitor drugs omeprazole and in its chiral-switch esomeprazole magnesium was studied employing the Density Functional Theory (DFT) method. At B3LYP/6-311G(d,p), the 6-methoxy∙∙∙6-methoxy and 5-methoxy∙∙∙5-methoxy homochiral and heterochiral dimers were calculated. The chiral distinction free energies (ΔΔG(298,(RS-SS))) between the cyclic C2-(S,S)- and Ci-(R,S)-dimers with two intermolecular hydrogen bonds are 3.8, 1.9 (with BSSE counterpoise correction), and -6.9 (with D3 dispersion and BSSE counterpoise corrections) kJ/mol. Adding water as an implicit solvent (polarized continuum model [PCM] model) resulted in a chiral distinction energy of -3.3 kJ/mol, indicating a reversal of the order of the relative stabilities of C2-(S,S)- and Ci-(R,S)-dimers. The chiral distinction free energies between the corresponding (less stable) C1-dimers with one intermolecular hydrogen bond are -9.3, -5.8 (with BSSE CC), 17.6 (D3 + BSSE CC), and -3.2 (H2O) kJ/mol. The results highlight the contention that omeprazole is not just a superposition of its enantiomer constituents. They are consistent with the pharmacological evidence of enantiomer-enantiomer interactions in omeprazole versus esomeprazole and the differences between the drugs omeprazole and esomeprazole magnesium and support the lodged application for regulatory supplementary protection certificate (SPC) exclusivity for the esomeprazole-related combination drug Vimovo., (Copyright © 2014 Wiley Periodicals, Inc.)
- Published
- 2014
- Full Text
- View/download PDF
30. New biodegradable organic-soluble chelating agents for simultaneous removal of heavy metals and organic pollutants from contaminated media.
- Author
-
Ullmann A, Brauner N, Vazana S, Katz Z, Goikhman R, Seemann B, Marom H, and Gozin M
- Subjects
- Biological Assay, Cadmium chemistry, Environmental Pollution, Environmental Restoration and Remediation methods, Escherichia coli drug effects, Hydrogen-Ion Concentration, Ions, Lead chemistry, Ligands, Metals chemistry, Metals, Heavy chemistry, Nitrogen chemistry, Organic Chemicals chemistry, Sewage, Soil Pollutants chemistry, Solvents chemistry, Water Pollutants, Chemical chemistry, Water Pollution, Chelating Agents chemistry, Metals, Heavy analysis, Organic Chemicals analysis, Water Pollutants, Chemical analysis
- Abstract
Advanced biodegradable and non-toxic organic chelators, which are soluble in organic media, were synthesized on the basis of the S,S-ethylenediamine-disuccinate (S,S-EDDS) ligand. The modifications suggested in this work include attachment of a lipophilic hydrocarbon chain ("tail") to one or both nitrogen atoms of the S,S-EDDS. The new ligands were designed and evaluated for application in the Sediments Remediation Phase Transition Extraction (SR-PTE) process. This novel process is being developed for the simultaneous removal of both heavy metals and organic pollutants from contaminated soils, sediments or sludge. The new chelators were designed to bind various target metal ions, to promote extraction of these ions into organic solvents. Several variations of attached tails were synthesized and tested. The results for one of them, N,N'-bis-dodecyl-S,S-EDDS (C24-EDDS), showed that the metal-ligand complexes are concentrated in the organic-rich phase in the Phase Transition Extraction process (more than 80%). Preliminary applications of the SR-PTE process with the C24-EDDS ligand were conducted also on actually contaminated sludge (field samples). The extraction of five toxic metals, namely, Cd, Cu, Ni, Pb and Zn was examined. In general, the extraction performance of the new ligand was not less than that of S,S-EDDS when a sufficient ligand-to-extracted ion ratio (about 4:1 was applied., (Copyright © 2013 Elsevier B.V. All rights reserved.)
- Published
- 2013
- Full Text
- View/download PDF
31. Toward the development of the direct and selective detection of nitrates by a bioinspired Mo-Cu system.
- Author
-
Marom H, Popowski Y, Antonov S, and Gozin M
- Subjects
- Hydrogen Peroxide chemistry, Molecular Structure, Spectrometry, Fluorescence, Sulfides chemical synthesis, Sulfides chemistry, Sulfones chemical synthesis, Sulfones chemistry, Sulfoxides chemical synthesis, Sulfoxides chemistry, Copper chemistry, Models, Chemical, Molybdenum chemistry, Nitrates analysis
- Abstract
The development of a new platform for the direct and selective detection of nitrates is described. Two thioether-based chemosensors and the corresponding sulfoxides and sulfones were prepared, and their photophysical properties were evaluated. Upon selective sulfoxidation of these thioethers with nitrates via an oxygen-transfer reaction promoted by a bioinspired Mo-Cu system, significant fluorescence shifts were measured. A selective response of these systems, discriminating between nitrate salts and H(2)O(2), was also shown., (© 2011 American Chemical Society)
- Published
- 2011
- Full Text
- View/download PDF
32. Selective sulfoxidation of thioethers and thioaryl boranes with nitrate, promoted by a molybdenum-copper catalytic system.
- Author
-
Marom H, Antonov S, Popowski Y, and Gozin M
- Subjects
- Boranes chemistry, Catalysis, Copper chemistry, Crystallography, X-Ray, Models, Molecular, Molecular Structure, Molybdenum chemistry, Oxidation-Reduction, Safrole chemistry, Sulfides chemistry, Boranes chemical synthesis, Nitrates chemistry, Organometallic Compounds chemistry, Safrole analogs & derivatives, Sulfides chemical synthesis
- Abstract
The catalytic reduction of nitrate by molybdo-enzymes plays a central role in the global biological cycle of nitrogen. However, the use of nitrates as oxidants in synthetic organic chemistry is very limited and typically requires very strong acidic and other extreme reaction conditions. We have developed a highly chemoselective and efficient catalytic process for the sulfoxidation of thioethers and arylthioethers containing boronic acid or boronic ester functional groups, using nitrate salts as oxidants. This homogeneous catalytic reaction was carried out in acetonitrile, where the MoO(2)Cl(2)(OPPh(3))(2) complex 1 or a mixture of complex 1 with Cu(NO(3))(2) were used as catalysts. We examined the reaction mechanism using (1)H, (15)N, and (31)P NMR techniques and (18)O-labeled sodium nitrate (NaN(18)O(3)) and show that the thioethers are oxidized by nitrate, generating nitrite. Our work adds to the existing chemical transformations available for organoboron compounds, providing straightforward accessibility to a variety of new substrates that could be suitable for Suzuki cross-coupling chemistry.
- Published
- 2011
- Full Text
- View/download PDF
33. Racemization of the gastrointestinal antisecretory chiral drug esomeprazole magnesium via the pyramidal inversion mechanism: A theoretical study.
- Author
-
Marom H and Agranat I
- Subjects
- Esomeprazole chemistry, Models, Molecular, Molecular Conformation, Stereoisomerism, Temperature, Thermodynamics, Anti-Ulcer Agents chemistry, Gastrointestinal Tract metabolism, Omeprazole chemistry, Quantum Theory
- Abstract
The pyramidal inversion mechanisms of the 6-methoxy and the 5-methoxy tautomers of (S)-omeprazole were studied, employing ab initio and DFT methods. The conformational space of the model molecule (S)-2-[(3-methyl-2-pyridinyl)methyl]sulfinyl-1H-benzimidazole was calculated, with respect to rotations around single bonds, at the B3LYP/6-311G(d,p) level. All of the resulting conformations were used as starting points for full optimizations of (S)-omeprazole, at B3LYP/6-31G(d), B3LYP/6-311G(d,p), B3LYP/6-311++G(d,p), B3LYP/6-311G(2df,2pd), MP2/6-31G(d), and MP2/6-311G(d,p) levels. Four distinct pathways were found for enantiomerization via the pyramidal inversion mechanism for each of the tautomers of (S)-omeprazole. Each transition state, in which the sulfur, the oxygen and the two carbon atoms connected directly to the sulfur are in one plane, connects two diastereomeric minima. The enantiomerization is completed by free rotation around the sulfur-methylene bond, and around the methylene-pyridine ring bond. The effective Gibbs' free energy barrier for racemization DeltaG(double dagger) (rac) of the two tautomers of (S)-omeprazole are 39.8 kcal/mol (5-methoxy tautomer) and 40.0 kcal/mol (6-methoxy tautomer), indicating that the enantiomers of omeprazole are stable at room temperature (in the gas phase). The 5-methoxy tautomer of (S)-omeprazole was found to be slightly more stable than the 6-methoxy tautomer, in the gas phase. The energy barrier (DeltaG(++)) for the(S,M) <=>(S,P) diastereomerization of (S)-omeprazole due to the rotation around the pyridine chiral axis was very low, 5.8 kcal/mole at B3LYP/6-311G(d,p)., ((c) 2010 Wiley-Liss, Inc.)
- Published
- 2010
- Full Text
- View/download PDF
34. Toward development of targeted nonsteroidal antiandrogen-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-gadolinium complex for prostate cancer diagnostics.
- Author
-
Marom H, Miller K, Bechor-Bar Y, Tsarfaty G, Satchi-Fainaro R, and Gozin M
- Subjects
- Androgen Antagonists chemistry, Androgen Antagonists metabolism, Anilides chemistry, Anilides metabolism, Animals, Coordination Complexes chemistry, Coordination Complexes metabolism, Humans, Magnetic Resonance Imaging, Male, Mice, Mice, Inbred C57BL, Neoplasm Transplantation, Prostatic Neoplasms metabolism, Receptors, Androgen metabolism, Stereoisomerism, Structure-Activity Relationship, Androgen Antagonists chemical synthesis, Anilides chemical synthesis, Coordination Complexes chemical synthesis, Gadolinium, Prostatic Neoplasms diagnosis
- Abstract
Androgen receptors are present in most advanced prostate cancer specimens, having a critical role in development of this type of cancer. For correct prognosis of patient conditions and treatment monitoring, noninvasive imaging techniques have great advantages over surgical procedures. We developed synthetic methodologies for preparation of novel androgen receptor-targeting agents in an attempt to build a versatile platform for prostate cancer imaging and treatment. The structure of these compounds comprises of a lanthanoid metal ion, gadolinium-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (Gd-DOTA)-based binding fragment and, connected to it by a flexible linker, bicalutamide-derived nonsteroidal antiandrogen moiety. A representative gadolinium complex 15 was evaluated as a magnetic resonance imaging (MRI) agent in C57/bl6 male mouse bearing orthotopic TRAMP C2 prostate tumor.
- Published
- 2010
- Full Text
- View/download PDF
35. Three-dimensional vessel analyses provide more accurate length estimations than the gold standard QCA.
- Author
-
Meerkin D, Marom H, Cohen-Biton O, and Einav S
- Subjects
- Humans, Image Processing, Computer-Assisted, Phantoms, Imaging, Coronary Angiography methods, Coronary Angiography standards, Imaging, Three-Dimensional standards
- Abstract
Objectives: The aim of this study was to compare lesion dimensions as determined by a three-dimensional quantitative coronary angiographic (QCA) system to that of a validated two-dimensional QCA system., Background: In an era of drug-eluting stents, device sizing has become an important clinical application of online QCA. The CardiOp-B system integrates two standard angiographic projections to provide a three-dimensional reconstruction of the arterial segment of interest., Methods: Phase 1 - 47 stenoses from consecutive coronary angiograms were assessed in two projections with both systems providing two data sets for the CMS-Medis system and a single data set for CardiOp-B. Phase 2--a perspex phantom with a known lesion length, was analyzed at increasing degrees of foreshortening with acceptance criteria set at 5% from the absolute value., Results: Phase 1 demonstrated an adequate correlation between the CardiOp-B and Medis systems when minimal luminal diameter was measured in the optimal view (1.32 +/- 0.47 mm vs 1.42 +/- 0.49 mm respectively; r = 0.82). A stronger correlation was noted when length was measured (25.27 +/- 10.76 mm and 21.32 +/- 8.08 mm, respectively; r = 0.95); however CardiOp-B provided a consistently longer length (P < 0.0001). On phantom length measurements the mean accuracy result for the CardiOp-B system was -1.3%. This compared favorably with the two-dimensional system where all measures performed at greater than 20 degrees of for shortening were beyond the 5% criteria from the known length., Conclusions: Three-dimensional QCA provides accurate and precise vessel diameter assessments. Length assessments are consistently longer than two-dimensional measures and are significantly less affected by foreshortened projections.
- Published
- 2010
- Full Text
- View/download PDF
36. Multipeak negative-differential-resistance molecular device.
- Author
-
Mentovich ED, Kalifa I, Tsukernik A, Caster A, Rosenberg-Shraga N, Marom H, Gozin M, and Richter S
- Subjects
- Ions chemistry, Microscopy, Electron, Scanning, Models, Molecular, Molecular Structure, Models, Chemical
- Published
- 2008
- Full Text
- View/download PDF
37. Pyramidal inversion mechanism of simple chiral and achiral sulfoxides: a theoretical study.
- Author
-
Marom H, Biedermann PU, and Agranat I
- Subjects
- Models, Molecular, Molecular Conformation, Omeprazole chemistry, Powder Diffraction, Software, Stereoisomerism, Thermodynamics, Sulfoxides chemistry
- Abstract
The pyramidal inversion mechanism of simple sulfoxides was studied, employing ab initio and DFT methods. The convergence of the geometrical and energetic parameters of H2SO and DMSO with respect to the Hamiltonian and basis set was analyzed in order to determine a computational level suitable for methyl phenyl sulfoxide (3), methyl 4-cyanophenyl sulfoxide (4), diphenyl sulfoxide (5), 4,4'-dicyanodiphenyl sulfoxide (6), benzyl methyl sulfoxide (7) and benzyl phenyl sulfoxide (8). The DFT B3LYP/6-311G(d,p) level was chosen for further calculations of larger sulfoxides. The barriers DeltaE calculated for the pyramidal inversion mechanism of sulfoxides 3-8 are in the range of 38.7-47.1 kcal/mol. These values are in good agreement with the experimental barriers for racemization via the pyramidal inversion mechanism. A resonance effect of a phenyl ring selectively stabilizes the transition state conformations, decreasing the energy barrier for pyramidal inversion by about 3 kcal/mol, compared to a similar molecule without a phenyl substituent. Introducing electron withdrawing groups (cyano) at the para positions of the phenyl ring(s) causes a further decrease of the energy barrier., (Copyright (c) 2007 Wiley-Liss, Inc.)
- Published
- 2007
- Full Text
- View/download PDF
38. Bifurcation lesions in the coronary arteries: early experience with a novel 3-dimensional imaging and quantitative analysis before and after stenting.
- Author
-
Dvir D, Marom H, Assali A, and Kornowski R
- Abstract
Aims: The treatment of coronary bifurcation lesions is technically challenging. Conventional 2-dimensional angiography lacks the ability to properly image the true bifurcation geometry or its plaque distribution. The objectives of this study were to reconstruct coronary bifurcation lesions in 3 dimensions (3D) and to analyse the geometric changes that may occur immediately after stenting., Methods and Results: The CardiOp-B system (Paieon Inc.), a novel system for 3D reconstruction of the coronary vessels, was applied in a retrospective evaluation of 121 angiographic images from 27 patients (74% men, age 71+/-13 years) with bifurcation lesions in the coronary arteries treated by angioplasty procedures. Angulations between the bifurcation branches were measured before and after stenting. Side-branch involvement was found in 70% of cases. Comparison of the pre- and post-stenting angulation yielded a significantly lower angulation between the distal main branch and side branch after stenting (71+/-17 degrees versus 58+/-18 degrees , p<0.001)., Conclusions: 3D reconstructions may provide new insight into complex bifurcation lesions in space and may serve as an important tool for planning interventional procedures and evaluating their results. The implications of the demonstrated angulation changes after stenting should be further evaluated.
- Published
- 2007
39. Prostate cancer PET bioprobes: synthesis of [18F]-radiolabeled hydroxyflutamide derivatives.
- Author
-
Jacobson O, Bechor Y, Icar A, Novak N, Birman A, Marom H, Fadeeva L, Golan E, Leibovitch I, Gutman M, Even-Sapir E, Chisin R, Gozin M, and Mishani E
- Subjects
- Androgen Antagonists chemistry, Flutamide chemistry, Humans, Male, Radionuclide Imaging, Androgen Antagonists chemical synthesis, Fluorine Radioisotopes chemistry, Flutamide analogs & derivatives, Prostatic Neoplasms diagnostic imaging
- Abstract
Approximately 80-90% of prostate cancers are androgen dependent at initial diagnosis. The androgen receptor (AR) is present in most advanced prostate cancer specimens and is believed to have a critical role in its development. Today, treatment of prostate cancer is done by inhibition of AR using antiandrogens such as flutamide (pro-drug of hydroxyflutamide), nilutamide, and bicalutamide. However, there is currently no noninvasive imaging modalities to detect, guide, and monitor specific treatment of AR-positive prostate cancer. (R)-3-Bromo-N-(4-fluoro-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methyl-propanamide [18F]-1 and N-(4-fluoro-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide [18F]-2, derivatives of hydroxyflutamide, were synthesized as a fluorine-containing imaging agent candidates. A three-step fluorine-18 radiosynthesis route was developed, and the compounds were successfully labeled with a 10+/-3% decay corrected radiochemical yield, 95% radiochemical purity, and a specific activity of 1500+/-200 Ci/mmol end of bombardment (n = 10). These labeled biprobes not only may enable for the future quantitative molecular imaging of AR-positive prostate cancer using positron emission tomography but may also allow for image-guided treatment of prostate cancer.
- Published
- 2005
- Full Text
- View/download PDF
40. Three-dimensional coronary reconstruction from routine single-plane coronary angiograms: in vivo quantitative validation.
- Author
-
Dvir D, Marom H, Guetta V, and Kornowski R
- Subjects
- Aged, Aged, 80 and over, Algorithms, Artificial Intelligence, Coronary Artery Disease pathology, Coronary Stenosis diagnostic imaging, Coronary Stenosis pathology, Female, Humans, Male, Middle Aged, Statistics as Topic, Coronary Angiography, Coronary Artery Disease diagnostic imaging, Image Processing, Computer-Assisted, Imaging, Three-Dimensional
- Abstract
Background: Current X-ray technology displays the complex 3-dimensional (3-D) geometry of the coronary arterial tree as 2-dimensional (2-D) images. To overcome this limitation, an algorithm was developed for the reconstruction of the 3-D pathway of the coronary arterial tree using routine single-plane 2-D angiographic imaging. This method provides information in real-time and is suitable for routine use in the cardiovascular catheterization laboratory., Objectives: The purpose of this study was to evaluate the precision of this algorithm and to compare it with 2-D quantitative coronary angiography (QCA) system., Methods: Thirty-eight angiographic images were acquired from 11 randomly selected patients with coronary artery disease undergoing diagnostic cardiac catheterization. The 2-D images were analyzed using QCA software. For the 3-D reconstruction, an algorithm integrating information from at least two single-plane angiographic images taken from different angles was formulated., Results: 3-D acquisition was feasible in all patients and in all selected angiographic frames. Comparison between pairs of values yielded greater precision of the 3-D than the 2-D measurements of the minimal lesion diameter (P<0.005), minimal lesion area (P<0.05) and lesion length (P<0.01)., Conclusions: The study validates the 3-D reconstruction algorithm, which may provide new insights into vessel morphology in 3-D space. This method is a promising clinical tool, making it possible for cardiologists to appreciate the complex curvilinear structure of the coronary arterial tree and to quantify atherosclerotic lesions more precisely.
- Published
- 2005
- Full Text
- View/download PDF
41. No need to tax the sick: clinical guidelines for rofecoxib as an alternative effective method to the copayment policy in the advent of increasing pharmaceutical expenditures.
- Author
-
Rosen Y, Yachelevich N, Benedek P, Grotto I, Goldberg A, Morad Y, Marom H, Ohana N, and Bar-Dayan Y
- Subjects
- Adolescent, Adult, Drug Utilization economics, Drug Utilization standards, Guideline Adherence, Humans, Israel, Lactones economics, Middle Aged, Military Medicine economics, Prospective Studies, Retrospective Studies, Sulfones economics, Cost Sharing, Drug Utilization statistics & numerical data, Lactones therapeutic use, Military Medicine standards, Practice Guidelines as Topic, Sulfones therapeutic use
- Abstract
Background: Over the last few years, major health care systems have been trying to control increasing pharmaceutical expenditures by a variety of methods, such as the controversial copayment policy, as essential health expenditures were being jeopardized., Objective: To analyze the regulatory intervention of preauthorization on a rofecoxib model in the medical corps of the Israeli Defense Forces (IDF) in terms of indications for prescription, consumption, and cost., Interventions: Guidelines established by the medical services branch based on current literature and communication with diverse specialists and hospitals were implemented by a general practitioner who checked each rofecoxib prescription that was written for IDF personnel by a specialist. The intervention was initiated in November 2000 and continued until August 2001 and after the study., Design: The study was divided into two parts. The first part was a retrospective monthly, preintervention analysis of computerized medical records of IDF personnel (N = 247) for whom rofecoxib was prescribed. The second was a prospective monthly, postintervention analysis of filled-out guideline forms (N = 250) of approved rofecoxib prescriptions., Participants: Patients, were IDF personnel, age 18 to 45, treated in military and civilian outpatient clinics for whom rofecoxib was prescribed., Setting: The study took place at the Medical Service Branch of the IDF between August 2000 and August 2001., Results: We demonstrated a significant decrease in average monthly consumption (43.0%) and estimated monthly expenditures (40.84%) of rofecoxib, as well as significant shifts (p < 0.001) in indications for whom rofecoxib was approved. These shifts (from pre- to postintervention) include the following: others/nonspecified (80 to 12%), known peptic disorder (7 to 32%), peptic complaints (4 to 22%), and rheumatic (8 to 19%)., Conclusion: This type of intervention can be cost-effective, can provide quality care, and may be a viable alternative to the controversial and problematic copayment policy.
- Published
- 2004
- Full Text
- View/download PDF
42. The effect of adnexal surgery on the ovarian response to stimulation in in vitro fertilization.
- Author
-
Shulman A, Marom H, Oelsner G, Horowitz A, Ben-Nun I, Mashiach S, and Dor J
- Subjects
- Adult, Case-Control Studies, Embryo Transfer statistics & numerical data, Estradiol blood, Female, Humans, Infertility, Female etiology, Infertility, Female therapy, Laparoscopy adverse effects, Laparotomy adverse effects, Oocytes physiology, Pregnancy, Salpingostomy adverse effects, Adnexa Uteri surgery, Fertilization in Vitro, Ovulation Induction methods
- Abstract
Objectives: The effect of adnexal surgery on ovarian function is a controversial issue of high clinical significance. The purpose of this study was to assess the effect of adnexal surgery on ovarian function., Study Design: All patients who underwent adnexal surgery in our department during an 8-year period (all records were obtained from the hospital database between January 1991 and December 1998) were cross-matched with our in vitro fertilization (IVF) database. We compared the baseline hormonal levels and the patients' response to IVF stimulation (assessed by the total amount of gonadotropins, maximal estradiol (E2) levels, number of retrieved and fertilized oocytes)., Results: Sixty-four consecutive patients who underwent adnexal surgery were compared with 68 matched controls. Neither of the analyzed parameters were affected by the tubal surgery., Conclusions: We conclude from our study adnexal surgery is not detrimental to ovarian function.
- Published
- 2002
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.