Ex vivo generation of functional dendritic cells from mobilized CD34+ hematopoietic stem cells

Gene engineering to enhance tumour immunogenicity and elicit curative responses against established tumours and tumour recurrences has become an attractive prospect. Gene engineering enables new genes to be selectively inserted into the genome of a tumour cell, or the construction of new fusion plasmids coding tumour antigens and immunomodulatory molecules. The rationale behind current research is to enhance the immune recognition of tumour antigens through their association with the molecules on which immune recognition depends. The immunotherapy data obtained in many experimental tumour systems provide a realistic assessment of the potential and limits of this technological approach. Experimental vaccination of rodents has been shown to induce a significant immune memory, even against poorly immunogenic tumours, that can prevent tumour growth and cure initial metastases, but is poorly effective against established tumours. Its use in tumour prevention is a fresh dawning perspective.     

Pyrazoline bisphosphonate esters as novel antiinflammatory and antiarthritic agents

Vinylidenebisphosphonic acid tetraethyl ester (1) and diazo ketones 7a-1 in ether at 22 degrees C yield pyrazoline bisphosphonate tetraethyl esters 8a-1 in moderate to good yield. These compounds were evaluated in animal models of arthritis: rat adjuvant-induced polyarthritis (AIP) and murine antigen-induced arthritis (AIA) and a murine model of chronic inflammation, the delayed type hypersensitivity granuloma reaction (DTH-GRA). (5-Benzoyl-2,4-dihydro-3H-pyrazol-3-ylidene)-bisphosphonic acid tetraethyl ester (8a), and [5-(3-fluorobenzoyl)-2,4-dihydro-3H-pyraxol-3-ylidene]- bisphosphonic acid tetraethyl ester (8d) significantly inhibited the arthritis models, AIP (15 mg/kg) and AIA (25 mg/kg), as well as the DTH-GRA (25 mg/kg). Conversion of 8a to the corresponding bisphosphonic acid, 10a, resulted in loss of activity. Compounds with alkyl substituents on the pyrazoline nitrogen, 9a-d, were inactive in the DTH-GRA. These results show that 8a and 8d have novel antiinflammatory activity and are capable of inhibiting chronic arthritis and inflammation in animals. Such compounds might be useful in man for treating chronic tissue injury associated with arthropathies such as inflammatory joint disease as well as other chronic inflammatory diseases.     

The modulation of cellular responses to poly(2-hydroxyethyl methacrylate) hydrogel surfaces: phosphorylation decreases macrophage collagenase production in vitro

We examined the regulation of collagenase production by the monocyte/macrophage THP-1 cell line when these cells were exposed to poly(2-hydroxyethyl methacrylate) (PHEMA) hydrogel surfaces with different chemistries and morphologies. Tissue culture modified polystyrene (TCP), used as a control surface, induced the maximum collagenase response. Copolymer hydrogels containing 2-ethoxyethyl methacrylate (EMA) or methyl methacrylate (MMA) also induced a high response, while PHEMA hydrogels induced a low level response and the phosphorylated hydrogel induced no response. This pattern was altered when the morphology of the hydrogels was changed to that of a sponge. The overall enzyme response to the sponge hydrogels was lower than that to the homogeneous hydrogels. Sponges containing EMA and MMA produced low level response relative to the TCP control. PHEMA and phosphorylated sponges produced little and no response respectively. The dramatically reduced enzyme response to phosphorylated surfaces was not a consequence of cell death, and may be a phenomenon related to changes in cell surface charge.     

Reversal of pretreatment hypotension and control of hemorrhage in trauma patients by a simple device

The injection of a suspension of Walker 256 carcinoma cells into the carotid artery of rats produced a model of hematogenously spread cerebral metastases. Most animals died from massive extracerebral tumors of the head and jaw; brain tumors were present in only one-quarter. External carotid artery ligation prior to tumor inoculation did not increase the incidence of fatal brain tumor. When cyclophosphamide, 15 mg/kg, was injected as a single dose on the fourteenth day after tumor inoculation, most of the extracerebral tumor disappeared. Fifty percent of the animals so treated were cured of tumor, but 90% of the remainder died of large intracerebral tumors. Severe cytopathic changes resulting from cyclophosphamide were present in extracerebral or choroid plexus tumors but were mild or nonexistent in intracerebral tumors. These selective effects of cyclophosphamide suggest that water-soluble agents are less effective against tumor in the brain than against extracerebral tumors despite the fact that metastatic tumor breaks down the blood-brain barrier.