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Radioligand theranostics (RT) in oncology use cancer-type specific biomarkers and molecular imaging (MI), including positron emission tomography (PET), single-photon emission computed tomography (SPECT) and planar scintigraphy, for patient diagnosis, therapy, and personalized management. While the definition of theranostics was initially restricted to a single compound allowing visualization and therapy simultaneously, the concept has been widened with the development of theranostic pairs and the combination of nuclear medicine with different types of cancer therapies. Here, we review the clinical applications of different theranostic radiopharmaceuticals in managing different tumor types (differentiated thyroid, neuroendocrine prostate, and breast cancer) that support the combination of innovative oncological therapies such as gene and cell-based therapies with RT.

As France and Germany have become major targets of jihadist terrorism, the calls for stronger cooperation in counterterrorism at the European level have grown in earnest. However, a comparative ana...

Justice concerns figure prominently in local conflicts about the use of natural resources which pit local communities against corporations or state actors. Even where the addressees of local justice claims respond to those claims they may fail to satisfy them because they misperceive their nature. The chapter uses Nancy Fraser’s distinction of three dimensions of justice – procedural, distributive and recognition justice – to explore this argument with respect to a local mining conflict in Peru. It focuses on local protests against a mining company in the Moqeugua region. Local communities demanded compensation for the past environmental and health impact of mining activities. Addressees of these demands ignored the recognition-based aspects of these demands, i.e. the implication that compensation was offered to the victims of past harm. Instead of compensation, addressees offered social contributions in return for the willingness of the community to let the company continue with its operations, framing the conflict purely as a distributive conflict. Consequently, these attempts to resolve the conflict failed.

Cellular delivery of a replication-conditional herpes simplex virus type 1 (HSV-1) vector provides a means for gene therapy of invasive tumor cells. LacZ -bearing neural precursor cells, which can migrate and differentiate in the brain, were infected with a ribonucleotide reductase-deficient HSV-1 mutant virus (rRp450) that replicates only in dividing cells. Replication of rRp450 in neural precursor cells was blocked prior to implantation into the tumor by growth arrest in late G 1 phase through treatment with mimosine. Viral titers in the medium of mimosine-treated, rRp450-infected neural precursor cells were below detection levels 3 days after infection. In culture, after removal of mimosine and passaging, cells resumed growth and replication of rRp450 so that, 7 days later, virus was present in the medium and cell death was evident. Mimosine-treated neural precursor cells injected into established intracerebral CNS-1 gliomas in nude mice migrated extensively throughout the tumor and into the surrounding parenchyma beyond the tumor over 3 days. Mimosine-treated neural precursor cells, infected with rRp450 and injected into intracerebral CNS-1 tumors, also migrated within the tumor with the appearance of foci of HSV–thymidine kinase-positive (TK + ) cells, presumably including tumor cells, distributed throughout the tumor and in the surrounding parenchyma over a similar period. This migratory cell delivery method has the potential to expand the range of delivery of HSV-1 vectors to tumor cells in the brain.

Background This study investigates elements of herpes simplex virus type 1 (HSV-1) which influence transgene expression in tetracycline-regulated expression systems. Methods Different HSV-1 mutants were used to infect Vero cells that had been transfected with plasmids containing the luciferase gene under the control of tet-off or tet-on tetracycline-regulation systems. Results The baseline level of luciferase expression was elevated after infection with HSV-1 mutants lacking one or more immediate early genes encoding transactivating factors: ICP27, ICP4 and ICP0. With the tet-off system, not only was baseline expression elevated, but there was a complete loss of induction upon removal of tet when this regulatory system was brought into the cell by infection with helper virus-free amplicon vectors. Elevation of luciferase expression was also observed upon infection with the same HSV-1 mutants following transfection with a plasmid containing only a CMV minimal promoter driving luciferase (pUHC13-3). Only one HSV mutant (14HD3), which bears a disruption in the transactivation domain of VP16 and is deleted for both ICP4 genes, did not increase baseline luciferase expression after transfection of pUHC13-3. The disregulating effects were dependent on virus dose and were not influenced by treatment with interferon (IFN)-alpha, which suppresses viral gene expression. Additional assays involving cotransfection of pUHC13-3 with a plasmid encoding of the HSV-1 transactivating factor ICP4 revealed that ICP4 was the most potent inducer of gene expression from the tetO/CMV minimal promoter. Conclusion These results indicate that proteins encoded in the HSV-1 genome, especially the transactivating immediate early gene products (ICP4, ICP27 and ICP0) and the VP16 tegument protein can activate the tetO/ minimal CMV promoter and thereby interfere with the integrity of tetracycline-regulated transgene expression. Copyright # 2000 John Wiley & Sons, Ltd.

(1999). Germany's mediterranean challenge. Contemporary Security Policy: Vol. 20, No. 2, pp. 109-115.

Current gene therapy technology is limited by the paucity of methodology for determining the location and magnitude of therapeutic transgene expression in vivo . We describe and validate a paradigm for monitoring therapeutic transgene expression by noninvasive imaging of the herpes simplex virus type 1 thymidine kinase (HSV-1- tk ) marker gene expression. To test proportional coexpression of therapeutic and marker genes, a model fusion gene comprising green fluorescent protein (gfp) and HSV-1- tk genes was generated ( tkgfp gene) and assessed for the functional coexpression of the gene product, TKGFP fusion protein, in rat 9L gliosarcoma, RG2 glioma, and W256 carcinoma cells. Analysis of the TKGFP protein demonstrated that it can serve as a therapeutic gene by rendering tkgfp transduced cells sensitive to ganciclovir or as a screening marker useful for identifying transduced cells by fluorescence microscopy or fluorescence-activated cell sorting (FACS). TK and GFP activities in the TKGFP fusion protein were similar to corresponding wild-type proteins and accumulation of the HSV-1- tk -specific radiolabeled substrate, 2′-fluoro-2′-deoxy-1β-D-arabino-furanosyl-5-iodo-uracil (FIAU), in stability transduced clones correlated with gfp-fluorescence intensity over a wide range of expression levels. The tkgfp fusion gene itself may be useful in developing novel cancer gene therapy approaches. Valuable information about the efficiency of gene transfer and expression could be obtained by non-invasive imaging of tkgfp expression with FIAU and clinical imaging devices (gamma camera, positron-emission tomography [PET], single photon emission computed tomography [SPECT]), and/or direct visualization of gfp expression in situ by fluorescence microscopy or endoscopy.

Background The versatility of HSV-1 vectors includes large transgene capacity, selective replication of mutants in dividing cells, and availability of recombinant virus (RV) and plasmid-derived (amplicon) vectors, which can be propagated in a co-dependent, ‘piggyback’, manner. Methods A replication-defective piggyback vector system was generated in which the amplicon carries either of two genes essential for virus replication, IE2 (ICP27) or IE3 (ICP4), as well as lacZ; the RV is deleted in both these genes, and vector stocks are propagated in cells transfected with one of the complementary genes. In the replication-competent system, the amplicon carries the IE2 and lacZ; the RV had a large deletion in the IE2; and stocks are propagated in untransfected cells. Titers over successive passages, recombination between amplicon and RV, and the structural integrity of vector genomes were evaluated. The replication-competent system was tested for therapeutic efficacy in subcutaneous 9L gliosarcoma tumors in nude mice with activation of ganciclovir via the viral HSV-thymidine kinase gene. Results Both systems generated high titer amplicon vectors (about 107 tu/ml) and amplicon:RV ratios (0.6–3.0). No replication-competent RV was generated in either system. The replication-defective system showed low toxicity and increased packaging efficiency of amplicon vectors, as compared to single mutant RV helper virus. The replication-competent system allowed co-propagation of amplicon and RV; injection into tumors followed by ganciclovir treatment inhibited tumor growth without systemic toxicity. Conclusion New replication-defective and replication-competent piggyback HSV, vector systems allow gene delivery via amplicon vectors with reduced toxicity and co-propagation of both RV and amplicon vectors in target cells, with effective tumor therapy via focal virus replication and pro-drug activation. Copyright © 1999 John Wiley & Sons, Ltd.

The value of a project depends on its expected cash flows and the appropriate discount rate. Since discount rates are measured with historical data, their estimation is subject to measurement error. Measurement error can influence project decisions. This paper describes a method to gauge the variance of CAPM based cost of equity estimates and calculates it for a sample of 25 Swiss firms. The variances we obtain are fairly small. Nevertheless, even these small confidence intervals can lead to significant valuation differences.

BACKGROUND Glial fibrillary acidic protein (GFAP) is a biomarker candidate indicative of intracerebral hemorrhage (ICH) in patients with symptoms of acute stroke. GFAP is released rapidly in the presence of expanding intracerebral bleeding, whereas a more gradual release occurs in ischemic stroke. In this study the diagnostic accuracy of plasma GFAP was determined in a prospective multicenter approach. METHODS Within a 1-year recruitment period, patients suspected of having acute (symptom onset RESULTS The study included 205 patients (39 ICH, 163 ischemic stroke, 3 stroke mimic). GFAP concentrations were increased in patients with ICH compared with patients with ischemic stroke [median (interquartile range) 1.91 μg/L (0.41–17.66) vs 0.08 μg/L (0.02–0.14), P < 0.001]. Diagnostic accuracy of GFAP for differentiating ICH from ischemic stroke and stroke mimic was high [area under the curve 0.915 (95% CI 0.847–0.982), P < 0.001]. A GFAP cutoff of 0.29 μg/L provided diagnostic sensitivity of 84.2% and diagnostic specificity of 96.3% for differentiating ICH from ischemic stroke and stroke mimic. CONCLUSIONS Plasma GFAP analysis performed within 4.5 h of symptom onset can differentiate ICH and ischemic stroke. Studies are needed to evaluate a GFAP point-of-care system that may help optimize the prehospital triage and management of patients with symptoms of acute stroke.

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The LIPO-HSV-1-tk gene transfer system was developed for a 3-day pump application in a first prospective Phase I?II clinical study. Eight patients suffering from recurrent glioblastoma multiforme were treated intratumorally on the basis of convection-enhanced delivery using the nonviral vector system. It was possible to identify the target tissue together with assessment of vector distribution and gene product expression, as well as the metabolic effect of ganciclovir treatment, noninvasively, by the combination of magnetic resonance imaging and positron emission tomography as a multimodal molecular imaging system. The therapy was well tolerated without major side effects. In two of eight patients, we observed a greater than 50% reduction of tumor volume and in six of eight patients focal treatment effects. The noninvasive visualization of therapeutic effects on tumor metabolism and documentation of gene expression will be important for the further successful development and implementation of patient individual gene therapy.

Gliomas account for about 60% of all primary CNS tumors; two-thirds of all gliomas comprise the most malignant form, glioblastoma multiforme, or glioma grade IV. Although much progress has been achieved in the treatment of other solid tumors over the last few decades, the median survival of patients with glioblastoma remains at around 12 mo after standard treatment, which includes bulk resection and irradiation, as well as chemotherapy in some cases (1). Essentially, no patient can expect to survive 5 yr. New treatment modalities like immunotherapy have been applied so far with only limited success (2). With the improvement of methods for in vivo and ex vivo gene delivery, gene therapy became a new, promising approach to glioma therapy. Gliomas appear to be a particularly good target for a gene therapy approach using locally applied vectors, as the growth of gliomas is restricted to the brain. Clinical trials are under way using retrovirus and adenovirus vectors which carry the herpes simplex virus type-1 (HSV-1) thymidine kinase gene (HSV-tk). This gene encodes a prodrug-activating enzyme, which in infected cells converts the nontoxic prodrug, ganciclovir (GCV), to its cytotoxic phosphorylated form (3-5). There is an ever-increasing list of other prodrug-activation systems that showed efficacy in culture and in preclinical studies using rodent glioma models. These include, for example, cytosine deaminase converting 5-fluorocytosine to 5-fluoro-uracil (6), cytochrome P450-2B1 converting cyclophosphamide to phosphoramide mustard (7), deoxycytidine kinase phosphorylating cytosine arabinoside (8), and the Escherichia coli guanine phosphoribosyl transferase (gpt) metabolizing 6-thioxanthine and 6-thioguanine to toxic nucleoside analogs (9). Moreover, gene therapy approaches to brain tumors include the viral transfer of immune-enhancing cytokines, particularly granulocyte/macrophage colony-stimulating factor (10), or antisense to TGF-β to glioma cells (11) used for vaccination purposes. Other approaches use the transfer of genes that modulate angiogenesis (12,13) or are involved in apoptosis like p53 (14). All aforementioned gene-transfer methods use nonreplicative viral vectors.

This was a radiologists' preference study to compare a digital chest radiography system that utilizes a large-area silicon flat-panel detector with conventional radiography for visualizing anatomic regions of the chest. Conventional and digital posteroanterior (PA) and lateral chest radiographs were obtained in 115 patients. The PA and lateral image pairs were compared independently by three radiologists rating the overall appearance, 11 anatomic regions in the PA, and 9 in the lateral views. Statistical analysis was performed with the Wilcoxon signed-rank test with Bonferroni-Holm adjustment (p=0.05). For the PA view, the digital system performed significantly better for the overall appearance and for all anatomic regions except for the peripheral pulmonary vasculature and hilum, where no significant difference was found. For the lateral digital images, the regions trachea, costodiaphragmatic recess, and hilum were rated significantly worse. The regions retrosternal and retrocardiac lung were rated significantly better. The other regions and the overall appearance showed no significant differences. The described digital chest radiography system showed statistically superior visualization of anatomic regions for PA and an ambiguous performance for lateral images as compared with conventional radiography. After changing some image processing parameters for the lateral view, this system may be suitable for digitalization of chest radiography.

Publisher Summary There is a rich array of possible intervention points and times in stimulation of central nervous system (CNS) repair using genetic engineering techniques. These can be broken down into three cell categories: neurons, pathways, and innervation targets—and three time intervals—immediately after injury, during neurite regrowth, upon target recognition, and upon reinnervation. At the time of injury it should be possible to inject vectors and cells directly into the damaged site. The most nontoxic, yet efficient direct gene delivery vectors in the current formulations would be adenovirus and adenoassociated virus (AAV), gutless adenovirus, helper virus-free herpes simplex virus (HSV) amplicons, and lentivirus. Genes that might be helpful for neurons in the injury period include those coding for anti-apoptotic proteins or protective proteins for free radicals. Grafted cells could be preprogrammed genetically with a pro-drug-activation suicide gene, so that systemic application of the pro-drug would lead to cell death. An ideal system would be activation of a cell death geneunder the control of a tetracycline inducible promoter.

On November 17, 1988, the board of directors of Nestle AG decided to allow foreign investors to hold Nestle registered stock, reversing a longstanding practice. This decision had a tremendous impact on the prices of the firm's three classes of common stock, as well as on the prices of several other corporations traded on the Zurich stock exchange. These price changes can be explained by the hypothesis that demand curves slope down.