AbstractAimZebrafish larvae with their simplified pronephros are an ideal model to study glomerular physiology. Although several groups use zebrafish larvae to assess glomerular barrier function, temporary or slight changes are still difficult to measure. The aim of this study was to investigate the potential of in vivo two‐photon microscopy (2‐PM) for long‐term imaging of glomerular barrier function in zebrafish larvae.MethodsAs a proof of principle, we adapted the nitroreductase/metronidazole model of targeted podocyte ablation for 2‐PM. Combination with a strain, which expresses eGFP‐vitamin D‐binding protein in the blood plasma, led to a strain that allowed induction of podocyte injury with parallel assessment of glomerular barrier function. We used four‐dimensional (4D) 2‐PM to assess eGFP fluorescence over 26 h in the vasculature and in tubules of multiple zebrafish larvae (5 days post‐fertilization) simultaneously.ResultsBy 4D 2‐PM, we observed that, under physiological conditions, eGFP fluorescence was retained in the vasculature and rarely detected in proximal tubule cells. Application of metronidazole induced podocyte injury and cell death as shown by TUNEL staining. Induction of podocyte injury resulted in a dramatic decrease of eGFP fluorescence in the vasculature over time (about 50% and 90% after 2 and 12 h respectively). Loss of vascular eGFP fluorescence was paralleled by an endocytosis‐mediated accumulation of eGFP fluorescence in proximal tubule cells, indicating proteinuria.ConclusionWe established a microscopy‐based method to monitor the dynamics of glomerular barrier function during induction of podocyte injury in multiple zebrafish larvae simultaneously over 26 h.

01 Sep 2010·Cancer Prevention ResearchQ3 · MEDICINE

Vascular Endothelial Growth Factor Receptor 2–Targeted Chemoprevention of Murine Lung Tumors

Q3 · MEDICINE

Article

Author: Dempsey, Edward C. ; Le, Mysan ; Miller, York E. ; Merrick, Daniel ; Karoor, Vijaya

AbstractNo clinically effective chemoprevention for lung cancer has been found. Angiogenesis is an early feature of both adenocarcinoma and squamous cell lung cancer. We investigated the effects of vascular endothelial growth factor (VEGF) receptor-2 (VEGFR-2) inhibition on lung carcinogenesis in a murine model of adenocarcinoma. The VEGFR-2 tyrosine kinase inhibitor, vandetanib, was given to FVB/N mice in chow for 7 days at varying doses to show pharmacologic activity by inhibition of VEGF-mediated VEFGR-2 and ERK phosphorylation. Plasma levels corroborated adequate dosage. For chemoprevention experiments, mice were injected i.p. with 1 mg/g of urethane, a carcinogen found in tobacco smoke. Chow containing vandetanib, 75 mg/kg/d, or control chow was given to mice, starting 7 days after urethane administration. Sixteen weeks after urethane injection, mice were sacrificed, tumors enumerated and measured. Vandetanib resulted in reductions in tumor multiplicity (6.5 ± 0.86 versus 1.0 ± 0.30, P = 0.001) and average tumor volume (0.85 ± 0.10 versus 0.15 ± 0.09 mm3, P = 0.001), but not incidence (71% versus 100%, P = ns), compared with control. As vandetanib has other activities besides VEGFR-2 tyrosine kinase inhibition, we gave the anti–VEGFR-2 monoclonal antibody, DC101, for weeks 11 to 15 of a urethane carcinogenesis protocol with an arrest in tumor volume increase, but no change in multiplicity or incidence. Further investigation of the chemopreventive effect of vandetanib and other VEGF signaling inhibitors is needed. Cancer Prev Res; 3(9); 1141–7. ©2010 AACR.

01 Nov 2007·The Journal of ImmunologyQ2 · MEDICINE

TLR4/MD-2 Monoclonal Antibody Therapy Affords Protection in Experimental Models of Septic Shock

Q2 · MEDICINE

Article

Author: Spiller, Stephan ; Herren, Suzanne ; Elson, Greg ; Ferlin, Walter ; Wagner, Hermann ; Hugues, Stephanie ; Ulevitch, Richard ; Mathison, John ; Kirschning, Carsten J. ; Daubeuf, Bruno ; Kosco-Vilbois, Marie

AbstractOveractivation of the immune system upon acute bacterial infection leads to septic shock. Specific bacterial products potently stimulate immune cells via toll-like receptors (TLRs). Gram-negative bacteria induce a predominantly TLR4-driven signal through LPS release. To neutralize LPS signaling in experimental models of sepsis, we generated mAbs toward the TLR4/myeloid differentiation protein-2 (MD-2) complex. The binding properties of an array of selected rat mAbs differed in respect to their specificity for TLR4/MD-2 complex. The specificity of one such mAb, 5E3, to murine TLR4 was confirmed by its recognition of an epitope within the second quarter of the ectodomain. 5E3 inhibited LPS-dependent cell activation in vitro and prevented proinflammatory cytokine production in vivo following LPS challenge in a dose-dependent manner. Furthermore, 5E3 protected mice from lethal shock-like syndrome when applied using both preventative and therapeutic protocols. Most notably, in the colon ascendens stent peritonitis model of polymicrobial abdominal sepsis, administration of a single dose of 5E3 (50 μg) protected mice against mortality. These results demonstrate that neutralizing TLR4/MD-2 is highly efficacious in protecting against bacterial infection-induced toxemia and offers TLR4/MD-2 mAb treatment as a potential therapy for numerous clinical indications.

100 Deals associated with PAT-PM-2

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Discovery	JP	Takeda Pharmaceutical Co., Ltd.	-
Neoplasms	Discovery	DE	OncoMab GmbH	-
Neoplasms	Discovery	US	Acceptys, Inc.	-
Neoplasms	Discovery	US	Acceptys, Inc.	-
Neoplasms	Discovery	AU	Patrys Ltd.	-
Neoplasms	Discovery	JP	Takeda Pharmaceutical Co., Ltd.	-
Neoplasms	Discovery	DE	OncoMab GmbH	-
Neoplasms	Discovery	AU	Patrys Ltd.	-

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