Preclinical characterisation of the GM-CSF receptor as a therapeutic target in rheumatoid arthritis.

OBJECTIVE: Previous work has suggested that the granulocyte macrophage colony stimulating factor (GM-CSF)-GM-CSF receptor α axis (GM-CSFRα) may provide a new therapeutic target for the treatment of rheumatoid arthritis (RA). Therefore, we investigated the cellular expression of GM-CSFRα in RA synovial tissue and investigated the effects of anti-GM-CSFRα antibody treatment in vitro and in vivo in a preclinical model of RA. METHODS: We compared GM-CSFRα expression on macrophages positive for CD68 or CD163 on synovial biopsy samples from patients with RA or psoriatic arthritis (PsA) to disease controls. In addition, we studied the effects of CAM-3003, an anti-GM-CSFR antibody in a collagen induced arthritis model of RA in DBA/1 mice. The pharmacokinetic profile of CAM-3003 was studied in naïve CD1(ICR) mice (see online supplement) and used to interpret the results of the pharmacodynamic studies in BALB/c mice. RESULTS: GM-CSFRα was expressed by CD68 positive and CD163 positive macrophages in the synovium, and there was a significant increase in GM-CSFRα positive cells in patients in patients with RA as well as patients with PsA compared with patients with osteoarthritis and healthy controls. In the collagen induced arthritis model there was a dose dependent reduction of clinical arthritis scores and the number of F4/80 positive macrophages in the inflamed synovium after CAM-3003 treatment. In BALB/c mice CAM-3003 inhibited recombinant GM-CSF mediated margination of peripheral blood monocytes and neutrophils. CONCLUSIONS: The findings support the ongoing development of therapies aimed at interfering with GM-CSF or its receptor in various forms of arthritis, such as RA and PsA.

Long-term changes in dietary and food intake behaviour in the Diabetes Prevention Program Outcomes Study.

AIMS: To compare change in dietary intake, with an emphasis on food groups and food intake behaviour, over time across treatment arms in a diabetes prevention trial and to assess the differences in dietary intake among demographic groups within treatment arms. METHODS: Data are from the Diabetes Prevention Program and Diabetes Prevention Program Outcomes Study. Participants were randomized to a lifestyle intervention (n = 1079), metformin (n = 1073) or placebo (n = 1082) for an average of 3 years, after which the initial results regarding the benefits of the lifestyle intervention were released and all participants were offered a modified lifestyle intervention. Dietary intake was assessed using a food frequency questionnaire at baseline and at 1, 5, 6 and 9 years after randomization. RESULTS: Compared with the metformin and placebo arms, participants in the lifestyle arm maintained a lower total fat and saturated fat and a higher fibre intake up to 9 years after randomization and lower intakes of red meat and sweets were maintained for up to 5 years. Younger participants had higher intakes of poultry and lower intakes of fruits compared with their older counterparts, particularly in the lifestyle arm. Black participants tended to have lower dairy and higher poultry intakes compared with white and Hispanic participants. In the lifestyle arm, men tended to have higher grain, fruit and fish intakes than women. CONCLUSIONS: Changes in nutrient intake among participants in the lifestyle intervention were maintained for up to 9 years. Younger participants reported more unhealthy diets over time and thus may benefit from additional support to achieve and maintain dietary goals.

Cloning and expression of a novel cysteine-rich secreted protein family member expressed in thyroid and pancreatic mesoderm within the chicken embryo.

We have isolated a new chicken gene that is a member of the cysteine-rich secreted protein family (CRISP). The CRISP family is composed of over 70 members that are found in many phyla of organisms, including: vertebrates, plants, fungi, yeast, and insects. Here we describe the cloning of a novel member of this family, SugarCrisp, and its expression pattern throughout chicken embryogenesis. We also describe its utility as a marker of thyroid and pancreatic mesoderm in the developing chicken embryo and its expression within the human and mouse in glandular tissue.

A multicenter review of the treatment of major truncal necrotizing infections with and without hyperbaric oxygen therapy.

To examine the effectiveness of hyperbaric oxygen (HBO) therapy in the treatment of major truncal necrotizing infections, a retrospective (1980 to 1992) analysis of the medical records of 30 patients treated with HBO therapy and 24 patients treated without HBO therapy was undertaken. The two groups were similar; however, there was a selection bias towards more frequent clostridial infections in a younger population in the HBO group. There was no difference in length of hospital stay, intensive care unit (ICU) stay, or duration of antibiotic therapy between groups. The mortality rates were 9/30 (30%) in the HBO group versus 10/24 (42%) (nonsignificant difference) in the non-HBO group. The total number of operations was greater in the HBO-treated group. This study failed to show that the use of HBO in the treatment of major truncal necrotizing infections statistically reduced mortality or the number of débridements. We believe, however, that the apparent selection bias and the trend towards increased survival in the HBO-treated group (12%) justifies the continued use of and research with HBO therapy.

Photodynamic therapy of squamous cell carcinoma. An evaluation of a new photosensitizing agent, benzoporphyrin derivative and new photoimmunoconjugate.

Photodynamic therapy for cancer depends on the relatively selective distribution of photosensitizing agents to malignant as compared with normal tissues, rendering the malignant cells more susceptible to light-mediated damage. Photodynamic therapy has been used with only moderate success to date. The purpose of this study was to compare a new photosensitizing agent, benzoporphyrin derivative (BPD), to the standard agent presently in use, photofrin II, in a hamster cheek pouch model of squamous cell carcinoma. As well we have investigated the potential of using a tumour-specific monoclonal antibody-BPD conjugate to improve the tumour localizing properties of BPD. Treatment consisted of photodynamic therapy with either photofrin II, BPD, or a tumour-specific anti-epidermal growth factor receptor-BPD conjugate. Control groups of light alone, anti-EGFr, tumour non-specific MoAb, and tumour non-specific MoAb-BPD conjugate were included with the contralateral cheek pouch of each animal acting as a dark control. An assessment of differential delivery of BPD to tumour and to normal mucosa was undertaken using a spectrophotometric assay. Parametric statistical analysis included Student's t-tests and linear regression while non-parametric analysis was undertaken using Fisher's exact test. Animals receiving BPD alone demonstrated tumour-to-tissue levels of approximately 2:1 while animals receiving the tumour-specific anti-EGFr-BPD conjugate had significantly better tumour:tissue ratios of 26:1 (P < 0.005). Animals treated with photofrin II had a 1 month cancer-free survival of 27% while animals treated with BPD had an improved survival of 67% (P = 0.03). The group treated with the tumour-specific anti-EGFr-BPD conjugate at a twentieth the total dose of BPD had an 80% 1 month cancer-free survival which was not statistically different from the group treated with BPD alone. Benzoporphyrin appears to be a more effective photosensitizing agent than Photofrin II and its tumour selectivity can be improved using a tumour specific monoclonal antibody conjugate.

Efficacy of 131I ablation following thyroidectomy in patients with invasive follicular thyroid cancer.

The role of thyroid ablation following thyroidectomy for invasive follicular cancer remains controversial. The use of iodine 131 (131I) ablation as adjuvant therapy may facilitate follow-up of patients in whom serum thyroglobulin levels and 131I total body scans are used to detect metastatic disease. It is uncertain if 131I ablation improves survival of patients with follicular thyroid cancer. Thus, the purpose of this study was to determine if survival is enhanced following ablation, with particular reference to those patients with minimally invasive cancer. Between the years 1955 to 1988, 142 patients with invasive thyroid follicular cancer were treated at the British Columbia Cancer Agency, of whom 71 had minimal invasion and no extrathyroidal extension of tumor. In this group of patients, 46 underwent hormone suppression only, 17 had ablation, and 8 had neither. The average follow-up was 9 years and extended beyond 15 years in many patients. Data were entered in a mainframe computer, and Kaplan-Meier survival analysis was used, comparing crude survival, disease-specific survival, and disease-free survival. There was no significant difference between groups. In patients with follicular thyroid cancer and capsular invasion only, 131I ablation does not improve survival compared with patients treated with thyroid hormone suppression only.

Nutritional requirements of Plasmodium falciparum in culture. I. Exogenously supplied dialyzable components necessary for continuous growth.

Continuous cultivation of Plasmodium falciparum presently requires the nutritionally complex medium, RPMI 1640. A basal medium of KCl, NaCl, Na2HPO4, Ca(NO3)2, MgSO4, glucose, reduced glutathione, HEPES buffer, hypoxanthine, phenol red (in RPMI 1640 concentrations), and 10% (v/v) exhaustively dialyzed pooled human serum was used to determine which vitamins and amino acids had to be exogenously supplied for continuous cultivation. Supplementation of basal medium with calcium pantothenate, cystine, glutamate, glutamine, isoleucine, methionine, proline, and tyrosine was necessary for continuous growth. This semi-defined minimal medium supported continuous growth of four isolates of P. falciparum at rates slightly less than those obtained with RPMI 1640. Adding any other vitamin or amino acid did not improve growth. Incorporation of several non-essential amino acids, particularly phenylalanine and leucine, into proteins was markedly enhanced in the minimal medium compared to RPMI 1640.

Do polyunsaturated fats predispose to malignant melonoma?

The consumption of polyunsaturated fats of patients with malignant melanoma and of a control group of patients with benign naevi has been compared in order to determine whether polyunsaturated fats predispose to the development of malignant melanoma. Patients with malignant melanoma had not consumed excessive quantities of polyunsaturated fats. Thus, there was no evidence to indicate that ingestion of polyunsaturated fats is associated with an increase in incidence of melanoma.

Byssotoxin A, a secondary metabolite of Byssochlamys fulva.

Byssochlamys fulva, isolated from corn, was grown on nutrient-amended shredded wheat medium for 14 days at 25 C. Crude solvent extract from these cultures was toxic to brine shrimp, chicken embryos, and rats. The extract was slightly inhibitory to the germination of of pea seeds, but was nontoxic to ten species of bacteria and one of yeast. One metabolite was isolated, given the trivial name byssotoxin A, and partially characterized chemically and physically.