Three-dimensional histologic validation of high-resolution SPECT of antibody distributions within xenografts

Longitudinal imaging of intratumoral distributions of antibodies in vivo in mouse cancer models is of great importance for developing cancer therapies. In this study, multipinhole SPECT with sub-half-millimeter resolution was tested for exploring intratumoral distributions of radiolabeled antibodies directed toward the epidermal growth factor receptor (EGFr) and compared with full 3-dimensional target expression assessed by immunohistochemistry. (111)In-labeled zalutumumab, a human monoclonal human EGFr-targeting antibody, was administered at a nonsaturating dose to 3 mice with xenografted A431 tumors exhibiting high EGFr expression. Total-body and focused in vivo tumor SPECT was performed at 0 and 48 h after injection and compared both visually and quantitatively with full 3-dimensional immunohistochemical staining for EGFr target expression. SPECT at 48 h after injection showed that activity was predominantly concentrated in the tumor (10.5% ± 1.3% of the total-body activity; average concentration, 30.1% ± 4.6% of the injected dose per cubic centimeter). (111)In-labeled EGFr-targeting antibodies were distributed heterogeneously throughout the tumor. Some hot spots were observed near the tumor rim. Immunohistochemistry indicated that the antibody distributions obtained by SPECT were morphologically similar to those obtained for ex vivo EGFr target expression. Regions showing low SPECT activity were necrotic or virtually negative for EGFr target expression. A good correlation (r = 0.86, P <0.0001) was found between the percentage of regions showing low activity on SPECT and the percentage of necrotic tissue on immunohistochemistry. Multipinhole SPECT enables high-resolution visualization and quantification of the heterogeneity of (111)In-zalutumumab concentrations in viv

The Emergence of the Corporate Form

The Dutch East India Company (VOC) is generally viewed as the first modern corporation, yet its 1602 charter did not introduce all features of legal personality. A detailed historical analysis reveals how its statute proved inadequate to sustain the massive military investment needed to secure a strong trade position in Asia. In response, legal innovations were introduced in the subsequent twenty years. In 1612, state intervention overruled shareholder rights and created capital lock-in. The associated loss of control by shareholders was ultimately compensated by long-term profits, as the escalated commitment to Asia allowed the VOC to outperform its competitors. Once capital became permanent, VOC directors needed and gained the final corporate feature of general limited liability in 1623. We argue that this transition could be achieved while preserving private interests because the Dutch Republic’s limited form of government protected long term private capital, while autocratic colonial powers maintained a royal monopoly on colonial trade. The English East India Company adopted the much-admired Dutch model only half a century later, as the crown became subject to parliamentary control. By then the Dutch grip on South-East Asia had become entrenched, leading its competitors to focus elsewhere