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Molecular-genetic imaging is advancing from a valuable preclinical tool to a guide for patient management. The strategy involves pairing an imaging reporter gene with a complementary imaging agent in a system that can be used to measure gene expression or protein interaction or track gene-tagged cells in vivo. Tissue-specific promoters can be used to delineate gene expression in certain tissues, particularly when coupled with an appropriate amplification mechanism. Here we show that the progression elevated gene-3 (PEG-3) promoter, derived from a rodent gene mediating tumor progression and metastatic phenotypes, can be used to drive imaging reporters selectively to enable detection of micrometastatic disease in mouse models of human melanoma and breast cancer using bioluminescence and radionuclide-based molecular imaging techniques. Because of its strong promoter activity, tumor specificity and capacity for clinical translation, PEG-3 promoter-driven gene expression may represent a practical, new system for facilitating cancer imaging and therapy., Targeted imaging of cancer remains a major but elusive goal. Such imaging could provide early diagnosis, aid in treatment planning and benefit therapeutic monitoring. By leveraging the expanding list of [...]

The heart initially compensates for hypertension-mediated pressure overload by enhancing its contractile force and developing hypertrophy without dilation. [G.sub.q] protein--coupled receptor pathways become activated and can depress function, leading to cardiac failure. Initial adaptation mechanisms to reduce cardiac damage during such stimulation remain largely unknown. Here we have shown that this initial adaptation requires regulator of G protein signaling 2 (RGS2). Mice lacking RGS2 had a normal basal cardiac phenotype, yet responded rapidly to pressure overload, with increased myocardial [G.sub.q] signaling, marked cardiac hypertrophy and failure, and early mortality. Swimming exercise, which is not accompanied by [G.sub.q] activation, induced a normal cardiac response, while Rgs2 deletion in [G.sub.[alpha]q]-overexpressing hearts exacerbated hypertrophy and dilation. In vascular smooth muscle, RGS2 is activated by cGMP-dependent protein kinase (PKG), suppressing [G.sub.q]-stimulated vascular contraction. In normal mice, but not Rgs2-/- mice, PKG activation by the chronic inhibition of cGMP-selective phosphodiesterase 5 (PDE5) suppressed maladaptive cardiac hypertrophy, inhibiting [G.sub.q]-coupled stimuli. Importantly, PKG was similarly activated by PDE5 inhibition in myocardium from both genotypes, but PKG plasma membrane translocation was more transient in Rgs2-/- myocytes than in controls and was unaffected by PDE5 inhibition. Thus, RGS2 is required for early myocardial compensation to pressure overload and mediates the initial antihypertrophic and cardioprotective effects of PDE5 inhibitors., Introduction The adult heart responds to sustained pressure overload by developing ventricular hypertrophy. The signaling events mediating this process are substantially driven by activation of GPCRs, which in turn stimulate [...]

Sustained cardiac pressure overload induces hypertrophy and pathological remodeling, frequently leading to heart failure. Genetically engineered hyperstimulation of guanosine 3',5'-cyclic monophosphate (cGMP) synthesis counters this response. Here, we show that blocking the intrinsic catabolism of cGMP with an oral phosphodiesterase-5A (PDE5A) inhibitor (sildenafil) suppresses chamber and myocyte hypertrophy, and improves in vivo heart function in mice exposed to chronic pressure overload induced by transverse aortic constriction. Sildenafil also reverses pre-established hypertrophy induced by pressure load while restoring chamber function to normal. cGMP catabolism by PDE5A increases in pressure-loaded hearts, leading to activation of cGMP-dependent protein kinase with inhibition of PDE5A. PDE5A inhibition deactivates multiple hypertrophy signaling pathways triggered by pressure load (the calcineurin/NFAT, phosphoinositide-3 kinase (PI3K)/Akt, and ERK1/2 signaling pathways). But it does not suppress hypertrophy induced by overexpression of calcineurin in vitro or Akt in vivo, suggesting upstream targeting of these pathways. PDE5A inhibition may provide a new treatment strategy for cardiac hypertrophy and remodeling., Author(s): Eiki Takimoto [1, 5]; Hunter C Champion [1, 5]; Manxiang Li [1, 5]; Diego Belardi [1]; Shuxun Ren [2]; E Rene Rodriguez [3]; Djahida Bedja [4]; Kathleen L Gabrielson [...]

Inflammation has been recognized increasingly as a critical pathologic component of a number of heart diseases. A mouse model of autoimmune myocarditis was developed to study the role of immune mediators in the development of cardiac dysfunction. We have found previously that IFN-[gamma] deficiency promotes inflammation in murine myocarditis, it has been unclear, however, how IFN-[gamma] deficiency in myocarditis affects cardiac function and what underlying immune mechanisms are responsible for these effects. In this work, we show that IFN-[gamma] knockout (KO) mice have more pronounced systolic and diastolic dysfunction and greater frequency of progression to dilated cardiomyopathy and heart failure compared with WT mice. Cardiac dysfunction in the KO mice is associated with the expansion of activated (CD[44.sup.high]) CD[3.sup.+] T cells due to reduced apoptosis of CD[4.sup.+], but not CD[8.sup.+], T cells. CD[4.sup.+] T cells in the KO mice show impaired up-regulation of CD25 upon activation, resulting in the expansion of CD[4.sup.+]CD[44.sup.+]CD[25.sup.-] T cells and their infiltration into the heart. CD[4.sup.+]CD[25.sup.-] T cells are less apoptosis-prone compared with the CD[25.sup.+] population, and their infiltration into the heart is associated with greater severity of myocarditis. We conclude that IFN-[gamma] deficiency in autoimmune myocarditis is associated with preferential expansion of CD[4.sup.+]CD[44.sup.+]CD[25.sup.-] T cells resulting in increased cardiac inflammation. An exaggerated inflammatory response in IFN-[gamma] KO mice causes cardiac dysfunction, leading to dilated cardiomyopathy and heart failure. activation-induced cell death | autoimmunity | pressure-volume relations

Partial and/or heterogeneous irradiation of established (i.e., large, vascularized) tumors by α‐particles that exhibit only a 4–5 cell‐diameter range in tissue, limits the therapeutic effect, since regions not being hit by the high energy α‐particles are likely not to be killed. This study aims to mechanistically understand a delivery strategy to uniformly distribute α‐particles within established solid tumors by simultaneously delivering the same α‐particle emitter by two diverse carriers, each killing a different region of the tumor: (1) the cancer‐agnostic, but also tumor‐responsive, liposomes engineered to best irradiate tumor regions far from the vasculature, and (2) a separately administered, antibody, targeting any cancer‐cell's surface marker, to best irradiate the tumor perivascular regions. We demonstrate that on a prostate specific membrane antigen (PSMA)‐expressing prostate cancer xenograft mouse model, for the same total injected radioactivity of the α‐particle emitter Actinium‐225, any radioactivity split ratio between the two carriers resulted in better tumor growth inhibition compared to the tumor inhibition when the total radioactivity was delivered by any of the two carriers alone. This finding was due to more uniform tumor irradiation for the same total injected radioactivity. The killing efficacy was improved even though the tumor‐absorbed dose delivered by the combined carriers was lower than the tumor‐absorbed dose delivered by the antibody alone. Studies on spheroids with different receptor‐expression, used as surrogates of the tumors' avascular regions, demonstrated that our delivery strategy is valid even for as low as 1+ (ImmunoHistoChemistry score) PSMA‐levels. The findings presented herein may hold clinical promise for those established tumors not being effectively eradicated by current α‐particle radiotherapies. [ABSTRACT FROM AUTHOR]