A phase I and pharmacodynamic study of AT9283, a small-molecule inhibitor of aurora kinases in patients with relapsed/refractory leukemia or myelofibrosis.

Background: This study sought to identify the maximum tolerated dose (MTD) of AT9283, an inhibitor of Aurora kinases A and B, in patients with relapsed or refractory leukemias. Other endpoints included pharmacokinetics, safety and tolerability, pharmacodynamics, and preliminary evidence of efficacy.

Patients And Methods: AT9283 was administered as a continuous 72-hour infusion every 21 days.

A preclinical assessment of the safety and biodistribution of an adenoviral vector containing the herpes simplex virus thymidine kinase gene (Cerepro) after intracerebral administration.

Background: Cerepro (sitimagene ceradenovec) is an adenoviral vector containing herpes simplex virus thymidine kinase gene (HSV-tk), which is being developed for the treatment of high-grade glioma with oral ganciclovir (GCV). The nonclinical safety and biodistribution of Cerepro were assessed following intravenous (i.v.

Transgenic pigs expressing human CD59, in combination with human membrane cofactor protein and human decay-accelerating factor.

Background: The expression of human complement regulators has been proved as an effective strategy to overcome hyperacute rejection in discordant xenogeneic organ transplantation. In this study, we tested the hypotheses that expression of triple transgenes for human complement regulators and provide more effective protection to the transplanted pig tissues.

Methods: Pigs transgenic for human complement regulatory proteins, human CD59 (hCD59) and human membrane cofactor protein (hMCP), have been generated using large genomic constructs.

AdvHSV-tk gene therapy with intravenous ganciclovir improves survival in human malignant glioma: a randomised, controlled study.

Malignant glioma is a devastating brain tumor with no effective treatment. This randomised, controlled study involved 36 patients with operable primary or recurrent malignant glioma. Seventeen patients were randomized to receive AdvHSV-tk gene therapy (3 x 10(10) pfu) by local injection into the wound bed after tumor resection, followed by intravenous ganciclovir (GCV), 5 mg/kg twice daily for 14 days.

Reduced sensitivity to human serum inactivation of enveloped viruses produced by pig cells transgenic for human CD55 or deficient for the galactosyl-alpha(1-3) galactosyl epitope.

Complement activation mediated by the major xenogeneic epitope in the pig, galactosyl-alpha(1-3) galactosyl sugar structure (alpha-Gal), and human natural antibodies could cause hyperacute rejection (HAR) in pig-to-human xenotransplantation. The same reaction on viruses bearing alpha-Gal may serve as a barrier to zoonotic infection. Expressing human complement regulatory proteins or knocking out alpha-Gal epitopes in pig in order to overcome HAR may therefore pose an increased risk in xenotransplantation with regard to zoonosis.

Activation of primary porcine endothelial cells induces release of porcine endogenous retroviruses.

Background: Endothelial cells form the interface between the porcine graft and the recipient and frequently become activated after xenotransplantation. To evaluate the safety of xenotransplantation further, we assessed the effect of cellular activation on the expression and release of porcine endogenous retroviruses from primary endothelial cells isolated from transgenic and nontransgenic pigs.

Methods: Primary porcine endothelial cells, cultured from pigs transgenic for human decay accelerating factor, were treated with human tumor necrosis factor-alpha, porcine interferon-gamma, or lipopolysaccharide.

Production and characterization of a pig line transgenic for human membrane cofactor protein.

A pig line transgenic for human membrane cofactor protein (hMCP) has been established. Offspring from the founder were produced by crossing the founder with pigs heterozygous for the human decay accelerating factor (hDAF) transgene. As a result, pigs transgenic for both hMCP and hDAF have been produced.

Posttransplant lymphoproliferative disorder associated with primate gamma-herpesvirus in cynomolgus monkeys used in pig-to-primate renal xenotransplantation and primate renal allotransplantation.

Background: A series of immunosuppressed cynomolgus monkeys were used in porcine-to-primate and primate-to-primate renal transplantation. In a number of animals nodal and extranodal lymphomas as well as areas of lymphoid hyperplasia in multiple organs (posttransplant lymphoproliferative disorder, PTLD) were recorded.

Methods: PTLD was characterized with respect to manifestation sites, histopathology, immunophenotype, and association with primate Epstein Barr-like Virus by in situ hybridization and quantitative polymerase chain reaction.