Phase I trial of inhaled natural interleukin 2 for treatment of pulmonary malignancy: toxicity, pharmacokinetics, and biological effects

Safety, local and systemic immunomodulation, and tumor response to treatment with aerosolized natural interleukin 2 (nIL-2) applied five times a day were studied in a Phase I trial in 16 patients with pulmonary malignancies refractory to conventional therapy. The toxicity of inhaled nIL-2 was different from that observed after systemic administration. Reversible airway irritation causing a nonproductive cough represented the dose-limiting toxicity. Mild to moderate reduction of the vital capacity and forced expiratory volume (FEV1) with minor effects on relative FEV1, peak expiratory flow, airway resistance, and PaO2 was experienced by individual patients. In 14 patients suffering from pulmonary metastases due to renal cell cancer, one durable complete response, one partial response, and one mixed response were observed. Inhalation of nIL-2 aerosol resulted in a dose-dependent expansion of pulmonary immunocompetent cells in bronchoalveolar lavage fluid. Posttreatment bronchoalveolar lavage showed an activated lymphocyte phenotype with increased HLA-DR expression. The only systemic biological effect detectable in peripheral blood was a marked increase of soluble interleukin 2 receptor serum levels. We conclude that treatment with aerosolized nIL-2 is an effective means for site-specific immunomodulation and deserves further investigation for the treatment of malignant and inflammatory lung disease.     

Plasminogen activator inhibitor-1 secretion of endothelial cells increases fibrinolytic resistance of an in vitro fibrin clot: evidence for a key role of endothelial cells in thrombolytic resistance

Time-dependent thrombolytic resistance is a critical problem in thrombolytic therapy for acute myocardial infarction. Platelets have been regarded as the main source of plasminogen activator inhibitor-1 (PAI-1) found in occlusive platelet-rich clots. However, endothelial cells are also known to influence the fibrinolytic capacity of blood vessels, but their ability to actively mediate time-dependent thrombolytic resistance has not been fully established. We will show that, in vitro, tumor necrosis factor-alpha-stimulated endothelial cells secrete large amounts of PAI-1 over a period of hours, which then binds to fibrin and protects the clot from tissue plasminogen activator-induced fibrinolysis. In vivo, endothelial cells covering atherosclerotic plaques are influenced by cytokines synthesized by plaque cells. Therefore, we propose that continuous activation of endothelial cells in atherosclerotic blood vessels, followed by elevated PAI-1 secretion and storage of active PAI-1 in the fibrin matrix, leads to clot stabilization. This scenario makes endothelial cells a major factor in time-dependent thrombolytic resistance.     

Synthesis and evaluation of hexafluorodimethylcarbinol functionalized polymers as microsensor coatings

Polystyrenes, polyacrylates, and poly(3,4-isoprenes) incorporating the hexafluorodimethylcarbinol functionality have been synthesized, characterized, and tested as microsensor coatings on a surface acoustic wave (SAW) device for dimethyl methylphosphonate (DMMP) vapor absorption sensitivity. The syntheses involved monomer functionalization and polymerization or hexafluoroacetone reaction with preformed polymer. All fluoroalcohol functionalized polymer coatings displayed sub parts per million level sensitivity with the slope of the absorption isotherm steepest at low DMMP concentrations. The order of sensitivity for the isomeric polystyrene fluoroalcohols (meta > para ? ortho) paralleled that of the relative free hydroxyl to hydrogen-bonded hydroxyl content. Strong hydrogen bonding between the fluoroalcohol polymers and DMMP vapor was observed by IR spectroscopy. Acylation of the fluoroalcohol group markedly reduced the DMMP sensitivity.     

Internal excitation of intermediate mass fragments from collisions of 36Ar+Ag nuclei at 35 MeV/nucleon

An extruding wire knife was used to give adult male CFHB rats a minimally traumatic unilateral mechanical lesion of the medial forebrain bundle. In addition, some rats received bilateral intrastriatal injections of one of three fluorescent retrograde tracers either eight days before or eight days after the lesion. Injections made after the lesion revealed that about half of the animals had complete lesions of the nigrostriatal tract, while the other half were incompletely lesioned, the mean proportion of non-axotomized neurons being 23%. Over the 10 weeks following the lesions, the number of tyrosine hydroxylase-immunoreactive cells in the lesioned substantia nigra fell linearly, reaching a mean of 29% of that of the control substantia nigra. In the animals which were completely lesioned, neuronal survival at 10 weeks varied between 6 and 12%. That the disappearance of tyrosine hydroxylase-immunoreactive neurons was due to cell death rather than the loss of tyrosine hydroxylase itself was confirmed by labelling the cells with Fluoro Gold before axotomy; the tracer was seen in survival neurons, microglia and in a few involuted neurons which continued to be tyrosine hydroxylase-immunoreactive. This percentage of neurons surviving axotomy corresponds to the proportion of substantia nigra neurons which project to the contralateral striatum, and these neurons were in the region of the substantia nigra from which the contralateral projection originated. It is concluded that following mechanical transection of the nigrostriatal tract, all truly axotomized substantia nigra neurons die over a period of about 10 weeks.