A recombinant, fully human, bispecific antibody neutralizes the biological activities mediated by both vascular endothelial growth factor receptors 2 and 3

Vascular endothelial growth factors (VEGF) and their receptors (VEGFR) have been implicated to play important roles in tumor-associated angiogenesis and lymphangiogenesis, and hence in tumor growth and metastasis. We previously produced a number of fully human antibodies directed against VEGF receptor 2 (VEGFR2) and VEGF receptor 3 (VEGFR3) and showed that these antibodies are capable of inhibiting growth factor (VEGF and VEGF-C)-induced receptor activation, migration, and proliferation of human endothelial cells. In this report, we constructed and produced a bispecific antibody, a diabody, using the variable domain genes of two neutralizing antibodies, IMC-1121 to VEGFR2 and hF4-3C5 to VEGFR3. The diabody binds to both VEGFR2 and VEGFR3 in a dose-dependent manner, and blocks interaction between VEGF/VEGFR2, VEGF-C/VEGFR2, and VEGF-C/VEGFR3. In cell-based assays, the diabody neutralized both VEGF and VEGF-C-stimulated activation of VEGFR2, VEGFR3, and p44/p42 mitogen-activated protein kinase in endothelial cells. Furthermore, the diabody was able to inhibit both VEGF and VEGF-C-induced migration of endothelial cells. Taken together, our results suggest that a dual blockade of both VEGFR2 and VEGFR3 simultaneously may represent a more potent approach to effective cancer therapy.     

Tolerance of nitrifying bacteria to copper and nickel

Evidence is mounting that soil microorganisms can become increasingly tolerant to metals on exposure. However, in situ investigations regarding the effects of metals, particularly Cu and Ni, on specific soil functions/communities are still limited in number. Here, we investigated whether preexposure of nitrifying bacteria to Cu or Ni can induce increased tolerance to these metals. We also investigated whether changes in the tolerance of populations exposed to Cu under field conditions (long term) or in a laboratory-spiked soil (short term) occur. The method used was specifically designed to avoid possible confounding factors because of aging of metals in soil. Sterilized soils were enriched with different concentrations of Ni or Cu and were inoculated with the same soil that was either uncontaminated or had been contaminated previously with metals. Nitrification was measured after 28 d. In the laboratory-spiked soil, the exposed nitrifier community showed an increased tolerance to Ni but not to Cu. However, we found an increased tolerance to Cu in the case of a nitrifying community exposed to Cu for nearly 80 years under field conditions. These results indicate that the capacity of nitrifying bacteria to adapt to at least some metals is a widespread phenomenon. However, acquisition of tolerance to Cu may be more difficult, or require more time, compared with tolerance to Ni.     

Does harvesting of iliac bone grafts with an acetabular reamer reduce complication rate?

Autogenous bone grafts are often used in orthopaedic surgery. One of the well-known techniques to obtain the grafts from either the anterior superior or posterior iliac spine uses a classic acetabular reamer. This retrospective study searches for the frequency of complications and discomfort in a population of 78 patients after this kind of bone graft harvesting. Data were collected by means of mail questionnaires. All possible major and minor complications such as haematomas, infections, pain and sensory alterations were investigated. We had no major complications. We only found minor sensory and pain complications. We were able to procure large amounts of cancellous bone graft through this method. This method of cancellous grafting reduces the rate of major complications, but there is no difference in the occurrence of postoperative pain as compared with standard techniques. The minor sensory complications are comparable with other methods of iliac spine harvesting. When performing iliac spine bone harvesting procedures,good knowledge of the nerve anatomy is of prominent importance.     

Selectively enhanced radiation sensitivity in prostate cancer cells associated with proteasome inhibition

The purpose of this study is to evaluate the utility of MG-132, a broad spectrum proteasome inhibitor, to selectively enhance radiation sensitivity in prostate cancer without affecting normal surrounding urothelial tissue. PC3 prostate cancer cells and normal URO-tsa bladder epithelial cells were treated with or without MG-132 and exposed to 0, 2, 4, or 6 Gy radiation. Cell viability and clonogenic survival assays were performed, and nuclear factor kappa-B (NF-kappaB) activity was evaluated with electrophoretic mobility shift assay (EMSA). MG-132 was associated with decreased cell viability (between 24% and 33%) and clonogenic survival (between 71% and 88%) alone and in combination with radiation in PC3 cells. MG-132 had no effect on cell viability or clonogenic survival following radiation in URO-tsa cells. Constitutive and radiation-induced NF-kappaB binding activity was higher in PC3 cells compared with URO-tsa cells. Furthermore, MG-132 at concentrations associated with reductions in cell viability and clongenic survival inhibited NF-kappaB binding activity in PC3 cells with no effect in URO-tsa cells. These results provide strong evidence that proteasome inhibition and concomitant NF-kappaB inhibition can be used to selectively enhance tumor radiation sensitivity in prostate cancer without affecting normal surrounding bladder tissue.     

Selective inhibition of ADAM metalloproteases blocks HER-2 extracellular domain (ECD) cleavage and potentiates the anti-tumor effects of trastuzumab

The HER-2 receptor tyrosine kinase is an important regulator of cell proliferation and survival, and it is a clinically validated target of therapeutic intervention for HER-2 positive breast cancer patients. Its extracellular domain (ECD) is frequently cleaved by protease(s) in HER-2 overexpressing breast cancer patients, rendering the remaining membrane-bound portion (p95) a constitutively activated kinase. The presence of both serum ECD and cellular p95 protein has been linked to poor clinical outcome as well as reduced effectiveness of some therapeutic treatments. We have identified a series of potent, selective small molecule inhibitors of ADAM proteases, exemplified here by INCB003619, and demonstrate that these inhibitors effectively block HER-2 cleavage in HER-2 overexpressing human breast cancer cell lines. Intriguingly, when used in combination, INCB003619 dramatically enhances the antiproliferative activity of suboptimal doses of the anti-HER-2 antibody, trastuzumab, in HER-2 overexpressing/shedding breast cancer cell lines, accompanied by reduced ERK and AKT phosphorylation. Furthermore, INCB003619, in combination with trastuzumab, augments the pro-apoptotic and antiproliferative effects of the chemotherapeutic agent paclitaxel. Consistent with these in vitro data, INCB003619 reduces serum ECD levels and enhances the antitumor effect of trastuzumab in a xenograft tumor model derived from the HER-2 overexpressing BT-474 breast cancer cell line. Collectively, these findings suggest that blocking HER-2 cleavage with selective ADAM inhibitors may represent a novel therapeutic approach for treating HER-2 overexpressing breast cancer patients.     

A business case for patient care ergonomic interventions

This article provides a framework for a business case for patient ergonomic programs that accentuates the financial gains to be realized from such programs as compared to meeting safety requirements. An introduction is made to such commonly used measures as payback period, net present value analysis and internal rate of return. Financial measures on a successful patient handling project in the Veterans Health Administration are outlined and policy implications discussed.