Selective Alpha-Particle Mediated Depletion of Tumor Vasculature with Vascular Normalization

BACKGROUND: Abnormal regulation of angiogenesis in tumors results in the formation of vessels that are necessary for tumor growth, but compromised in structure and function. Abnormal tumor vasculature impairs oxygen and drug delivery and results in radiotherapy and chemotherapy resistance, respectively. Alpha particles are extraordinarily potent, short-ranged radiations with geometry uniquely suitable for selectively killing neovasculature. METHODOLOGY AND PRINCIPAL FINDINGS: Actinium-225 ((225)Ac)-E4G10, an alpha-emitting antibody construct reactive with the unengaged form of vascular endothelial cadherin, is capable of potent, selective killing of tumor neovascular endothelium and late endothelial progenitors in bone-marrow and blood. No specific normal-tissue uptake of E4G10 was seen by imaging or post-mortem biodistribution studies in mice. In a mouse-model of prostatic carcinoma, (225)Ac-E4G10 treatment resulted in inhibition of tumor growth, lower serum prostate specific antigen level and markedly prolonged survival, which was further enhanced by subsequent administration of paclitaxel. Immunohistochemistry revealed lower vessel density and enhanced tumor cell apoptosis in (225)Ac-E4G10 treated tumors. Additionally, the residual tumor vasculature appeared normalized as evident by enhanced pericyte coverage following (225)Ac-E4G10 therapy. However, no toxicity was observed in vascularized normal organs following (225)Ac-E4G10 therapy. CONCLUSIONS: The data suggest that alpha-particle immunotherapy to neovasculature, alone or in combination with sequential chemotherapy, is an effective approach to cancer therapy

213Bi-PAI2 conjugate selectively induces apoptosis in PC3 metastatic prostate cancer cell line and shows anti-cancer activity in a xenograft animal model

A novel α-particle emitting (213Bi) plasminogen activator inhibitor type 2 construct, which targets the membrane-bound urokinase plasminogen activator on prostate cancer cells, was prepared and evaluated in vitro and in a xenograft animal model. The PC3 prostate cancer cell line expresses urokinase plasminogen activator which binds to its receptor on the cell membrane; plasminogen activator inhibitor type 2 is bound to urokinase plasminogen activator/urokinase plasminogen activator receptor to form stable complexes. In vitro, the cytotoxicity of 213Bi-plasminogen activator inhibitor type 2 against prostate cancer cells was tested using the MTS assay and apoptosis was documented using terminal deoxynucleotidyl transferase-mediated deoxyuridinetriphosphate nick end-labelling (TUNEL) assay. In vivo, antiproliferative effects for tumours and prostate cancer lymph node metastasis were carried out in an athymic nude mouse model with a subcutaneous xenograft of PC3 cells. 213Bi-plasminogen activator inhibitor type 2 was specifically cytotoxic to PC3 cells in a concentration-dependent fashion, causing the cells to undergo apoptosis. A single local or i.p. injection of 213Bi-plasminogen activator inhibitor type 2 was able to completely regress the growth of tumours and lymph node metastases 2 days post subcutaneous inoculation, and obvious tumour regression was achieved in the therapy groups compared with control groups with 213Bi-plasminogen activator inhibitor type 2 when the tumours measured 30–40 mm3 and 85–100 mm3. All control animals and one of five (20%) mice treated with 3 mCi kg−1 213Bi-plasminogen activator inhibitor type 2 developed metastases in the lymph nodes while no lymphatic spread of cancer was found in the 6 mCi kg−1 treated groups at 2 days and 2 weeks post-cell inoculation. These results demonstrate that this novel 213Bi-plasminogen activator inhibitor type 2 conjugate selectively targets prostate cancer in vitro and in vivo, and could be considered for further development for the therapy of prostate cancer, especially for the control of micro-metastases or in minimal residual disease

Micro-computed tomography and histology to explore internal morphology in decapod larvae

Traditionally, the internal morphology of crustacean larvae has been studied using destructive techniques such as dissection and microscopy. The present study combines advances in microcomputed tomography (micro-CT) and histology to study the internal morphology of decapod larvae, using the common spider crab (Maja brachydactyla Balss, 1922) as a model and resolving the individual limitations of these techniques. The synergy of micro-CT and histology allows the organs to be easily identified, revealing simultaneously the gross morphology (shape, size, and location) and histological organization (tissue arrangement and cell identification). Micro-CT shows mainly the exoskeleton, musculature, digestive and nervous systems, and secondarily the circulatory and respiratory systems, while histology distinguishes several cell types and confirms the organ identity. Micro-CT resolves a discrepancy in the literature regarding the nervous system of crab larvae. The major changes occur in the metamorphosis to the megalopa stage, specifically the formation of the gastric mill, the shortening of the abdominal nerve cord, the curving of the abdomen beneath the cephalothorax, and the development of functional pereiopods, pleopods, and lamellate gills. The combination of micro-CT and histology provides better results than either one alone.Financial support was provided by the Spanish Ministry of Economy and Competitiveness through the INIA project (grant number RTA2011-00004-00-00) to G.G. and a pre-doctoral fellowship to D.C. (FPI-INIA)

Kinematic variability, fractal dynamics and local dynamic stability of treadmill walking

<p>Abstract</p> <p>Background</p> <p>Motorized treadmills are widely used in research or in clinical therapy. Small kinematics, kinetics and energetics changes induced by Treadmill Walking (TW) as compared to Overground Walking (OW) have been reported in literature. The purpose of the present study was to characterize the differences between OW and TW in terms of stride-to-stride variability. Classical (Standard Deviation, SD) and non-linear (fractal dynamics, local dynamic stability) methods were used. In addition, the correlations between the different variability indexes were analyzed.</p> <p>Methods</p> <p>Twenty healthy subjects performed 10 min TW and OW in a random sequence. A triaxial accelerometer recorded trunk accelerations. Kinematic variability was computed as the average SD (MeanSD) of acceleration patterns among standardized strides. Fractal dynamics (scaling exponent α) was assessed by Detrended Fluctuation Analysis (DFA) of stride intervals. Short-term and long-term dynamic stability were estimated by computing the maximal Lyapunov exponents of acceleration signals.</p> <p>Results</p> <p>TW did not modify kinematic gait variability as compared to OW (multivariate T², p = 0.87). Conversely, TW significantly modified fractal dynamics (t-test, p = 0.01), and both short and long term local dynamic stability (T²p = 0.0002). No relationship was observed between variability indexes with the exception of significant negative correlation between MeanSD and dynamic stability in TW (3 × 6 canonical correlation, r = 0.94).</p> <p>Conclusions</p> <p>Treadmill induced a less correlated pattern in the stride intervals and increased gait stability, but did not modify kinematic variability in healthy subjects. This could be due to changes in perceptual information induced by treadmill walking that would affect locomotor control of the gait and hence specifically alter non-linear dependencies among consecutive strides. Consequently, the type of walking (i.e. treadmill or overground) is important to consider in each protocol design.</p

Specific binding of TES-23 antibody to tumour vascular endothelium in mice, rats and human cancer tissue: a novel drug carrier for cancer targeting therapy

The tissue distribution of anti-tumour vascular endothelium monoclonal antibody (TES-23) produced by immunizing with plasma membrane vesicles from isolated rat tumour-derived endothelial cells (TECs) was assessed in various tumour-bearing animals. Radiolabelled TES-23 dramatically accumulated in KMT-17 fibrosarcoma, the source of isolated TECs after intravenous injection. In Meth-A fibrosarcoma, Colon-26 adenocarcinoma in BALB/c mice and HT-1080 human tumour tissue in nude mice, radioactivities of 125I-labelled TES-23 were also up to 50 times higher than those of control antibody with little distribution to normal tissues. The selective recognition of TES-23 to TECs was competitively blocked by preadministration of unlabelled TES-23 in vivo. Furthermore, immunostaining of human tissue sections showed specific binding of TES-23 on endothelium in oesophagus cancers. These results indicate that tumour vascular endothelial cells express common antigen in different tumour types of various animal species. In order to clarify the efficacy of TES-23 as a drug carrier, an immunoconjugate, composed of TES-23 and neocarzinostatin, was tested for its anti-tumour effect in rats bearing KMT-17 fibrosarcomas. The immunoconjugate (TES-23-NCS) caused marked regression of the tumour, accompanied by haemorrhagic necrosis. Thus, from a clinical view, TES-23 would be a novel drug carrier because of its high specificity to tumour vascular endothelium and its application to many types of cancer. © 1999 Cancer Research Campaig

Mouse models of neurodegenerative disease: preclinical imaging and neurovascular component.

Neurodegenerative diseases represent great challenges for basic science and clinical medicine because of their prevalence, pathologies, lack of mechanism-based treatments, and impacts on individuals. Translational research might contribute to the study of neurodegenerative diseases. The mouse has become a key model for studying disease mechanisms that might recapitulate in part some aspects of the corresponding human diseases. Neurode- generative disorders are very complicated and multifacto- rial. This has to be taken in account when testing drugs. Most of the drugs screening in mice are very di cult to be interpretated and often useless. Mouse models could be condiderated a ‘pathway models’, rather than as models for the whole complicated construct that makes a human disease. Non-invasive in vivo imaging in mice has gained increasing interest in preclinical research in the last years thanks to the availability of high-resolution single-photon emission computed tomography (SPECT), positron emission tomography (PET), high eld Magnetic resonance, Optical Imaging scanners and of highly speci c contrast agents. Behavioral test are useful tool to characterize di erent ani- mal models of neurodegenerative pathology. Furthermore, many authors have observed vascular pathological features associated to the di erent neurodegenerative disorders. Aim of this review is to focus on the di erent existing animal models of neurodegenerative disorders, describe behavioral tests and preclinical imaging techniques used for diagnose and describe the vascular pathological features associated to these diseases

Role of Cancer Microenvironment in Metastasis: Focus on Colon Cancer

One person on three will receive a diagnostic of cancer during his life. About one third of them will die of the disease. In most cases, death will result from the formation of distal secondary sites called metastases. Several events that lead to cancer are under genetic control. In particular, cancer initiation is tightly associated with specific mutations that affect proto-oncogenes and tumour suppressor genes. These mutations lead to unrestrained growth of the primary neoplasm and a propensity to detach and to progress through the subsequent steps of metastatic dissemination. This process depends tightly on the surrounding microenvironment. In fact, several studies support the point that tumour development relies on a continuous cross-talk between cancer cells and their cellular and extracellular microenvironments. This signaling cross-talk is mediated by transmembrane receptors expressed on cancer cells and stromal cells. The aim of this manuscript is to review how the cancer microenvironment influences the journey of a metastatic cell taking liver invasion by colorectal cancer cells as a model

The Ionizing Radiation-Induced Bystander Effect: Evidence, Mechanism, and Significance

It has long been considered that the important biological effects of ionizing radiation are a direct consequence of unrepaired or misrepaired DNA damage occurring in the irradiated cells. It was presumed that no effect would occur in cells in the population that receive no direct radiation exposure. However, in vitro evidence generated over the past two decades has indicated that non-targeted cells in irradiated cell cultures also experience significant biochemical and phenotypic changes that are often similar to those observed in the targeted cells. Further, nontargeted tissues in partial body-irradiated rodents also experienced stressful effects, including oxidative and oncogenic effects. This phenomenon, termed the “bystander response,” has been postulated to impact both the estimation of health risks of exposure to low doses/low fluences of ionizing radiation and the induction of second primary cancers following radiotherapy. Several mechanisms involving secreted soluble factors, oxidative metabolism, gap-junction intercellular communication, and DNA repair, have been proposed to regulate radiation-induced bystander effects. The latter mechanisms are major mediators of the system responses to ionizing radiation exposure, and our knowledge of the biochemical and molecular events involved in these processes is reviewed in this chapter

Subsidiary roles as determinants of subsidiary technology sourcing: empirical evidence from China

Emerging economies have become new destinations for knowledge sourcing, forcing Multinational Enterprises (MNEs) to reconfigure their global innovation strategies and structure. While foreign subsidiaries located in emerging economies were conventionally viewed as having market or efficiency seeking roles, they have started to evolve towards knowledge-seeking roles. We argue that the conventional wisdom shall be reassessed considering this recent shift. We empirically investigate 129 manufacturing MNE subsidiaries of Fortune 500 companies in China, in terms of their roles and sources of technology. Our results indicate that market and knowledge seeking subsidiaries located in China tend to have a positive impact on the generation of new knowledge, either through locally established MNE R&D laboratories or through collaborations with local firms and scientific institutions