Image-Based Dosimetry in Dogs and Cross-Reactivity with Human Tissues of IGF2R-Targeting Human Antibody.

BACKGROUND: Osteosarcoma (OS) represents the most common primary bone tumor in humans and in companion dogs, being practically phenotypically identical. There is a need for effective treatments to extend the survival of patients with OS. Here, we examine the dosimetry in beagle dogs and cross-reactivity with human tissues of a novel human antibody, IF3, that targets the insulin growth factor receptor type 2 (IGF2R), which is overexpressed on OS cells, making it a candidate for radioimmunotherapy of OS. METHODS: [89Zr]Zr-DFO-IF3 was injected into three healthy beagle dogs. PET/CT was conducted at 4, 24, 48, and 72 h. RAPID analysis was used to determine the dosimetry of [177Lu]Lu-CHXA"-IF3 for a clinical trial in companion dogs with OS. IF3 antibody was biotinylated, and a multitude of human tissues were assessed with immunohistochemistry. RESULTS: PET/CT revealed that only the liver, bone marrow, and adrenal glands had high uptake. Clearance was initially through renal and hepatobiliary excretion in the first 72 h followed by primarily physical decay. RAPID analysis showed bone marrow to be the dose-limiting organ with a therapeutic range for 177Lu calculated to be 0.487-0.583 GBq. Immunohistochemistry demonstrated the absence of IGF2R expression on the surface of healthy human cells, thus suggesting that radioimmunotherapy with [177Lu]Lu-CHXA"-IF3 will be well tolerated. CONCLUSIONS: Image-based dosimetry has defined a safe therapeutic range for canine clinical trials, while immunohistochemistry has suggested that the antibody will not cross-react with healthy human tissues.

Podocalyxin enhances breast tumor growth and metastasis and is a target for monoclonal antibody therapy.

INTRODUCTION: Podocalyxin (gene name PODXL) is a CD34-related sialomucin implicated in the regulation of cell adhesion, migration and polarity. Upregulated expression of podocalyxin is linked to poor patient survival in epithelial cancers. However, it is not known if podocalyxin has a functional role in tumor progression. METHODS: We silenced podocalyxin expression in the aggressive basal-like human (MDA-MB-231) and mouse (4T1) breast cancer cell lines and also overexpressed podocalyxin in the more benign human breast cancer cell line, MCF7. We evaluated how podocalyxin affects tumorsphere formation in vitro and compared the ability of podocalyxin-deficient and podocalyxin-replete cell lines to form tumors and metastasize using xenogenic or syngeneic transplant models in mice. Finally, in an effort to develop therapeutic treatments for systemic cancers, we generated a series of antihuman podocalyxin antibodies and screened these for their ability to inhibit tumor progression in xenografted mice. RESULTS: Although deletion of podocalyxin does not alter gross cell morphology and growth under standard (adherent) culture conditions, expression of PODXL is required for efficient formation of tumorspheres in vitro. Correspondingly, silencing podocalyxin resulted in attenuated primary tumor growth and invasiveness in mice and severely impaired the formation of distant metastases. Likewise, in competitive tumor engraftment assays where we injected a 50:50 mixture of control and shPODXL (short-hairpin RNA targeting PODXL)-expressing cells, we found that podocalyxin-deficient cells exhibited a striking decrease in the ability to form clonal tumors in the lung, liver and bone marrow. Finally, to validate podocalyxin as a viable target for immunotherapy, we screened a series of novel antihuman podocalyxin antibodies for their ability to inhibit tumor progression in vivo. One of these antibodies, PODOC1, potently blocked tumor growth and metastasis. CONCLUSIONS: We show that podocalyxin plays a key role in the formation of primary tumors and distant tumor metastasis. In addition, we validate podocalyxin as potential target for monoclonal antibody therapy to inhibit primary tumor growth and systemic dissemination.

A three-thousand-year history of vegetation and human impact in Burgundy (France) reconstructed from pollen and non-pollen palynomophs analysis.

This article presents a 241 cm long sediment record documenting the vegetation history using pollen and non-pollen palynomorphs recovered from the Fénay marsh in Burgundy (Dijon area - France). The pollen and non-pollen palynomorphs (NPP) record largely reflects intensive human influence (clearing, cultivation and grazing) on the surrounding area from the Late Bronze Age and Hallstatt period. La Tène period is marked by drier conditions and a substantial increase in Alnus. During the Gallo-Roman period, high values of Alnus decrease to the benefit of Quercus. In the Early Middle Ages (5th-10th C), the swamp becomes a temporary pond and Cerealia type and Secale are cultivated in this very open landscape. During the Late Middle Ages (13th-15th C), the temporary pond is transformed into a larger and deeper pond, used by the Cistercians for hydraulic power and perhaps as a hemp-retting pit. By the end of the 16th C, the pond had dried out and was used for the cultivation of cereal.

Rheophysics of dense granular materials: discrete simulation of plane shear flows.

We study the plane shear flow of a dense assembly of dissipative disks using discrete simulation and prescribing the pressure and the shear rate. Those shear states are steady and uniform, and become intermittent in the quasistatic regime. In the limit of rigid grains, the shear state is determined by a single dimensionless number, called the inertial number I , which describes the ratio of inertial to pressure forces. Small values of I correspond to the quasistatic critical state of soil mechanics, while large values of I correspond to the fully collisional regime of kinetic theory. When I increases in the intermediate dense flow regime, we measure an approximately linear decrease of the solid fraction from the maximum packing value, and an approximately linear increase of the effective friction coefficient from the static internal friction value. From those dilatancy and friction laws, we deduce the constitutive law for dense granular flows, with a plastic Coulomb term and a viscous Bagnold term. The mechanical characteristics of the grains (restitution, friction, and elasticity) have a small influence in the dense flow regime. Finally, we show that the evolution of the relative velocity fluctuations and of the contact force anisotropy as a function of I provides a simple explanation of the friction law.