Harvey Herschman

University of California, Los Angeles, Los Angeles, California, United States

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Publications (10)47.21 Total impact

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    ABSTRACT: In human tumors, and in mouse models, cyclooxygenase-2 (COX-2) levels are frequently correlated with tumor development/burden. In addition to intrinsic tumor cell expression, COX-2 is often present in fibroblasts, myofibroblasts and endothelial cells of the tumor microenvironment, and in infiltrating immune cells. Intrinsic cancer cell COX-2 expression is postulated as only one of many sources for prostanoids required for tumor promotion/progression. Although both COX-2 inhibition and global Cox-2 gene deletion ameliorate UVB-induced SKH-1 mouse skin tumorigenesis, neither manipulation can elucidate the cell type(s) in which COX-2 expression is required for tumorigenesis; both eliminate COX-2 activity in all cells. To address this question, we created Cox-2(flox/flox) mice, in which the Cox-2 gene can be eliminated in a cell-type specific fashion by targeted Cre recombinase expression. Cox-2 deletion in skin epithelial cells of SKH-1 Cox-2(flox/flox);K14Cre(+) mice resulted, following UVB-irradiation, in reduced skin hyperplasia and increased apoptosis. Targeted epithelial cell Cox-2 deletion also resulted in reduced tumor incidence, frequency, size and proliferation rate, altered tumor cell differentiation and reduced tumor vascularization. Moreover, Cox-2(flox/flox);K14Cre(+) papillomas did not progress to squamous cell carcinomas. In contrast, Cox-2 deletion in SKH-1 Cox-2(flox/flox);LysMCre(+) myeloid cells had no effect on UVB tumor induction. We conclude that (i) intrinsic epithelial COX-2 activity plays a major role in UVB-induced skin cancer, (ii) macrophage/myeloid COX-2 plays no role in UVB-induced skin cancer and (iii) there may either be another COX-2 dependent prostanoid source(s) that drives UVB skin tumor induction and/or there may exist a COX-2 independent pathway(s) to UVB-induced skin cancer.
    Carcinogenesis 01/2014; · 5.64 Impact Factor
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    ABSTRACT: Sjogren’s syndrome (SS) is characterized by salivary gland leukocytic infiltrates and impaired salivation (xerostomia). Cox-2 (Ptgs2) is located on chromosome 1 within the span of the Aec2 region. In an attempt to demonstrate that COX-2 drives antibody-dependent hyposalivation, NOD.B10 congenic mice bearing a Cox-2flox gene were generated. A congenic line with non-NOD alleles in Cox-2-flanking genes failed manifest xerostomia. Further backcrossing yielded disease-susceptible NOD.B10 Cox-2flox lines; fine genetic mapping determined that critical Aec2 genes lie within a 1.56 to 2.17 Mb span of DNA downstream of Cox-2. Bioinformatics analysis revealed that susceptible and non-susceptible lines exhibit non-synonymous coding SNPs in 8 protein-encoding genes of this region, thereby better delineating candidate Aec2 alleles needed for SS xerostomia.
    Clinical Immunology 01/2014; · 3.77 Impact Factor
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    ABSTRACT: Cyclooxygenase 2 (COX)-2 is induced by bacterial and viral infections and has complex, poorly understood roles in anti-pathogen immunity. Here, we use a knock-in luciferase reporter model to image Cox2 expression across a range of tissues in mice following treatment with the either the prototypical bacterial pathogen-associated molecular pattern (PAMP), LPS, which activates Toll-like receptor (TLR)4, or with poly(I:C), a viral PAMP, which activates TLR3. LPS induced Cox2 expression in all tissues examined. In contrast, poly(I:C) elicited a milder response, limited to a subset of tissues. A panel of cytokines and interferons was measured in plasma of wild-type, Cox1(-/-) and Cox2(-/-) mice treated with LPS, poly(I:C), MALP2 (TLR2/6), Pam3CSK4 (TLR2/1), R-848 (TLR7/8) or CpG ODN (TLR9), to establish whether/how each COX isoform modulates specific PAMP/TLR responses. Only LPS induced notable loss of condition in mice (inactivity, hunching, piloerection). However, all TLR agonists produced cytokine responses, many of which were modulated in specific fashions by Cox1 or Cox2 gene deletion. Notably we observed opposing effects of Cox2 gene deletion on the responses to the bacterial PAMP, LPS, and the viral PAMP, poly(I:C), consistent with the differing abilities of the PAMPs to induce Cox2 expression. Cox2 gene deletion limited the plasma IL-1β and interferon-γ responses and hypothermia produced by LPS. In contrast, in response to poly(I:C), Cox2(-/-) mice exhibited enhanced plasma interferon (IFNα,β,γ,λ) and related cytokine responses (IP-10,IL-12). These observations suggest that a COX-2 selective inhibitor, given early in infection, may enhance and/or prolong endogenous interferon responses, and thereby increase anti-viral immunity.
    Biochemical and Biophysical Research Communications 07/2013; · 2.41 Impact Factor
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    ABSTRACT: Cyclooxygenase-1 and -2 are rate-limiting enzymes in the formation of a wide array of bioactive lipid mediators collectively known as prostanoids (prostaglandins, prostacyclins, and thromboxanes). Evidence from clinical trials shows that selective inhibition of the second isoenzyme (cyclooxygenase-2, or Cox-2) is associated with increased risk for serious cardiovascular events and findings from animal-based studies have suggested protective roles of Cox-2 for the heart. To further characterize the function of Cox-2 in the heart, mice with loxP sites flanking exons 4 and 5 of Cox-2 were rendered knockout specifically in cardiac myocytes (Cox-2 CKO mice) via cre-mediated recombination. Baseline cardiac performance of CKO mice remained unchanged and closely resembled that of control mice. Furthermore, myocardial infarct size induced after in vivo ischemia/reperfusion (I/R) injury was comparable between CKO and control mice. In addition, cardiac hypertrophy and function four weeks after transverse aortic constriction (TAC) was found to be similar between the two groups. Assessment of Cox-2 expression in purified adult cardiac cells isolated after I/R and TAC suggests that the dominant source of Cox-2 is found in the non-myocyte fraction. In conclusion, our animal-based analyses together with the cell-based observations portray a limited role of cardiomyocyte-produced Cox-2 at baseline and in the context of ischemic or hemodynamic challenge.
    Journal of Molecular and Cellular Cardiology 08/2010; 49(2):196-209. · 5.15 Impact Factor
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    ABSTRACT: Bioluminescence imaging, especially planar bioluminescence imaging, has been extensively applied in in vivo preclinical biological research. Bioluminescence tomography (BLT) has the potential to provide more accurate imaging information due to its 3D reconstruction compared with its planar counterpart. In this work, we introduce a positron emission tomography (PET) radionuclide imaging-based strategy to validate the BLT results. X-ray computed tomography, PET, spectrally resolved bioluminescence imaging, and surgical excision were performed on a tumor xenograft mouse model expressing a bioluminescent reporter gene. With different spectrally resolved measured data, the BLT reconstructions were acquired based on the third-order simplified spherical harmonics (SP3) approximation and the diffusion approximation (DA). The corresponding tomographic images were obtained for validation of bioluminescence source reconstruction. Our results show the strength of PET imaging compared with other validation methods for BLT and improved source localization accuracy based on the SP(3) approximation compared with the diffusion approximation.
    Molecular imaging and biology: MIB: the official publication of the Academy of Molecular Imaging 05/2010; 13(1):53-8. · 2.47 Impact Factor
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    John M Streicher, Shuxun Ren, Harvey Herschman, Yibin Wang
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    ABSTRACT: Activation of p38 mitogen-activated protein kinase (MAPK) has a significant impact on cardiac gene expression, contractility, extracellular matrix remodeling, and inflammatory response in heart. The p38 kinase pathway also has a controversial role in cardiac hypertrophy. MAPK-activated protein kinase-2 (MK2) is a well-established p38 downstream kinase, yet its contribution to p38-mediated pathological response in heart has not been investigated. We examined the specific contribution of MK2 to the pathological remodeling induced by p38. We used a cardiomyocyte specific and inducible transgenic approach to determine the functional and molecular impact of acute activation of the p38 pathway in heart in either a MK2 wild-type or a MK2-null background. p38 activation in wild-type mice led to a rapid onset of lethal cardiomyopathy associated with cardiomyocyte hypertrophy, interstitial fibrosis, and contractile dysfunction. Inactivation of MK2 partially but significantly reduced cardiomyocyte hypertrophy, improved contractile performance, and prevented early lethality. MK2 inactivation had no effect on the mRNA levels of hypertrophic marker genes or the proinflammatory gene cyclooxygenase (COX)-2. However, MK2 had a major role in COX-2 protein synthesis without affecting the mRNA level or protein stability. p38 activity in adult myocytes can contribute to pathological hypertrophy and remodeling in adult heart and that MK2 is an important downstream molecule responsible for specific features of p38-induced cardiac pathology.
    Circulation Research 03/2010; 106(8):1434-43. · 11.86 Impact Factor
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    ABSTRACT: Cyclooxygenase-2 (COX-2) is an important mediator of inflammation in stress and disease states. Recent attention has focused on the role of COX-2 in human heart failure and diseases owing to the finding that highly specific COX-2 inhibitors (i.e., Vioxx) increased the risk of myocardial infarction and stroke in chronic users. However, the specific impact of COX-2 expression in the intact heart remains to be determined. We report here the development of a transgenic mouse model, using a loxP-Cre approach, which displays robust COX-2 overexpression and subsequent prostaglandin synthesis specifically in ventricular myocytes. Histological, functional, and molecular analyses showed that ventricular myocyte specific COX-2 overexpression led to cardiac hypertrophy and fetal gene marker activation, but with preserved cardiac function. Therefore, specific induction of COX-2 and prostaglandin in vivo is sufficient to induce compensated hypertrophy and molecular remodeling.
    Journal of Molecular and Cellular Cardiology 02/2010; 49(1):88-94. · 5.15 Impact Factor
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    ABSTRACT: Bioluminescence imaging has been extensively applied to in vivo small animal imaging. Quantitative three-dimensional bioluminescent source information obtained by using bioluminescence tomography can directly and much more accurately reflect biological changes as opposed to planar bioluminescence imaging. Preliminary simulated and experimental reconstruction results demonstrate the feasibility and promise of bioluminescence tomography. However, the use of multiple approximations, particularly the diffusion approximation theory, affects the quality of in vivo small animal-based image reconstructions. In the development of new reconstruction algorithms, high-order approximation models of the radiative transfer equation and spectrally resolved data introduce new challenges to the reconstruction algorithm and speed. In this paper, an SP(3)-based (the third-order simplified spherical harmonics approximation) spectrally resolved reconstruction algorithm is proposed. The simple linear relationship between the unknown source distribution and the spectrally resolved data is established in this algorithm. A parallel version of this algorithm is realized, making BLT reconstruction feasible for the whole body of small animals especially for fine spatial domain discretization. In simulation validations, the proposed algorithm shows improved reconstruction quality compared with diffusion approximation-based methods when high absorption, superficial sources and detection modes are considered. In addition, comparisons between fine and coarse mesh-based BLT reconstructions show the effects of numerical errors in reconstruction image quality. Finally, BLT reconstructions using in vivo mouse experiments further demonstrate the potential and effectiveness of the SP(3)-based reconstruction algorithm.
    Physics in Medicine and Biology 10/2009; 54(21):6477-93. · 2.70 Impact Factor
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    ABSTRACT: Bioluminescence imaging is a very sensitive imaging modality, used in preclinical molecular imaging. However, in its planar projection form, it is non-quantitative and has poor spatial resolution. In contrast, bioluminescence tomography (BLT) promises to provide three dimensional quantitative source information. Currently, nearly all BLT reconstruction algorithms in use employ the diffusion approximation theory to determine light propagation in tissues. In this process, several approximations and assumptions that are made severely affect the reconstruction quality of BLT. It is therefore necessary to develop novel reconstruction methods using high-order approximation models to the radiative transfer equation (RTE) as well as more complex geometries for the whole-body of small animals. However, these methodologies introduce significant challenges not only in terms of reconstruction speed but also for the overall reconstruction strategy. In this paper, a novel fully-parallel reconstruction framework is proposed which uses a simplified spherical harmonics approximation (SPN). Using this framework, a simple linear relationship between the unknown source distribution and the surface measured photon density can be established. The distributed storage and parallel operations of the finite element-based matrix make SPN-based spectrally resolved reconstruction feasible at the small animal whole body level. Performance optimization of the major steps of the framework remarkably improves reconstruction speed. Experimental reconstructions with mouse-shaped phantoms and real mice show the effectiveness and potential of this framework. This work constitutes an important advance towards developing more precise BLT reconstruction algorithms that utilize high-order approximations, particularly second-order self-adjoint forms to the RTE for in vivo small animal experiments.
    Optics Express 09/2009; 17(19):16681-95. · 3.55 Impact Factor
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    ABSTRACT: Reporter genes can provide a way of noninvasively assessing gene activity in vivo. However, current reporter gene strategies may be limited by the immunogenicity of foreign reporter proteins, endogenous expression, or unwanted biological activity. We have developed a reporter gene based on carcinoembryonic antigen (CEA), a human protein with limited normal tissue expression. To construct a CEA reporter gene for PET, a CEA minigene (N-A3) was fused to the extracellular and transmembrane domains of the human Fc gamma RIIb receptor. The NA3-Fc gamma RIIb recombinant gene, driven by a CMV promoter, was transfected in Jurkat (human T cell leukemia) cells. Expression was analyzed by flow cytometry, immunohistochemistry (IHC), and microPET imaging. Flow cytometry identified Jurkat clones stably expressing NA3-Fc gamma RIIb at low, medium, and high levels. High and medium NA3-Fc gamma RIIb expression could also be detected by Western blot. Reporter gene positive and negative Jurkat cells were used to establish xenografts in athymic mice. IHC showed staining of the tumor with high reporter gene expression; medium and low N-A3 expression was not detected. MicroPET imaging, using an anti-CEA (124)I-labeled single-chain Fv-Fc antibody fragment, demonstrated that only high N-A3 expression could be detected. Specific accumulation of activity was visualized at the N-A3 positive tumor as early as 4 h. MicroPET image quantitation showed tumor activity of 1.8 +/- 0.2, 15.2 +/- 1.3, and 4.6 +/- 1.2 percent injected dose per gram (%ID/g) at 4, 20, and 48 h, respectively. Biodistribution at 48 h demonstrated tumor uptake of 4.8 +/- 0.8%ID/g. The CEA N-A3 minigene has the potential to be used as a reporter gene for imaging cells in vivo.
    European Journal of Nuclear Medicine 09/2008; 36(1):104-14. · 4.53 Impact Factor