92 kDa type IV collagenase (MMP-9) is expressed in neutrophils and macrophages but not in malignant epithelial cells in human colon cancer

Degradation of the extracellular matrix during cancer invasion is accomplished by the concerted action of several proteolytic enzymes, including matrix metalloproteinases (MMPs). We have studied the immunohistochemical localization of one of these enzymes, 92-kDa type IV collagenase (MMP-9), in short-term fixed specimens of 19 colon adenocarcinomas and 2 biopsies of adjacent normal colon. Staining was confined to neutrophils and macrophages, as identified by double staining. All neutrophils were positive in all cases. Some positively stained tumor-infiltrating macrophages were seen in 6 (32%) of the tumors, located adjacent to invasive tumor glands. No cancer cells were stained in any of the cases. In normal colon tissue, staining was only seen of scattered neutrophils in vessels and of macrophages in Peyer's patches. Routinely processed specimens from 7 of the 19 carcinomas were analyzed by in situ hybridization. In agreement with previous results, a MMP-9 mRNA signal was in all cases seen in a subpopulation of tissue macrophages surrounding invasive tumor glands, while no MMP-9 mRNA was detected in any other cell types, including neutrophils and cancer cells. Our results indicate that in this type of cancer all neutrophils contain MMP-9, which has been produced before they infiltrate the tumors; that a subpopulation of the tumor-infiltrating macrophages most likely in all cases produces MMP-9 but that the content of this protein is low due to a rapid turnover and that malignant epithelial cells do not produce or contain detectable amounts of MMP-9. These findings extend previous results indicating that stromal cells are actively involved in the generation and regulation of extracellular proteolysis during cancer invasion. © 1996 Wiley-Liss, Inc.     

Colorectal cancer extracellular acidosis decreases immune cell killing and is partially ameliorated by pH-modulating agents that modify tumor cell cytokine profiles

Tumor cells upregulate myriad proteins that are important for pH regulation, resulting in the acidification of the extracellular tumor microenvironment (TME). Abnormal pH is known to dampen immune function, resulting in a worsened anti-tumor immune response. Understanding how extrinsic alterations in pH modulate the interactions between immune cells and tumors cells will help elucidate opportunities for new therapeutic approaches. We observed that pH impacts the function of immune cells, both natural killer (NK) and T cells, which is relevant in the context of a highly acidic TME. Decreased NK and T cell activity was correlated with decreasing pH in a co-culture immune cell-mediated tumor cell-killing assay. The addition of pH-modulating drugs cariporide, lansoprazole, and acetazolamide to the co-culture assay was able to partially mitigate this dampened immune cell function. Treatment of colorectal cancer (CRC) cells with NHE1 inhibitor cariporide increased CRC cell-secreted cytokines involved in immune cell recruitment and activation and decreased cytokines involved in epithelial-mesenchymal transition (EMT). Cariporide treatment also decreased CRC cell shed TRAIL-R2, TRAIL-R3, and PD-L1 which is relevant in the context of immunotherapy. These experiments can help inform future investigations into how the pH of the tumor microenvironment may be extrinsically modulated to improve anti-tumor immune response in solid tumors such as colorectal cancer.     

Hyaluronic acid skin fillers: Adverse reactions and skin testing

BACKGROUND: Hyaluronic acid (HA) fillers have been proposed as alternatives to other temporary skin fillers, such as bovine collagen, for treating facial skin lines and for providing lip augmentation. Several types of commercial HA fillers are now available in many countries. They include Restylane, which is produced by microbiologic engineering techniques, and Hylaform, which is HA extract derived from rooster combs. They have been approved for use in several countries, but not currently in the United States. There are no recommendations to perform pretreatment skin testing by the manufacturers. OBJECTIVE: Our purpose is to describe and comment on our experiences with Hylaform and Restylane fillers. Observation of any side effects and skin testing results were documented. METHODS: Between September 1996 and September 2000, 709 patients were treated with Hylaform and Restylane and were followed up clinically for at least 1 year. Three of these patients (0.42%) developed delayed skin reactions. Three other patients were referred for evaluation of their skin reactions from other practitioners. Five of these 6 patients agreed to skin testing of their forearms. RESULTS: In the 5 patients tested, challenge intradermal skin testing was positive in 4 patients; the reactions started approximately 8 weeks after injection. CONCLUSIONS: There was a slight incidence of delayed inflammatory skin reactions to two HA fillers. Both of these reactions occurred after the first and repeat injections. Challenge skin testing was positive in 4 of 5 tested patients.     

Morphologically unusual feline spinocervical tract neurons

Intracellular horseradish peroxidase studies of spinocervical tract neurons in the cat have demonstrated that they have dendritic arbors primarily confined to laminae III through V. In the present intracellular staining study of this class of neuron we retrieved one cell with its soma in lamina I which arborized in laminae I through III and another cell with a soma in lamina III and a dendritic arbor which extended from lamina I through V. These data indicate therefore that a small proportion of neurons forming the spinocervical tract do not have dendritic arbors that are confined to laminae III through V. These two cells were capable of receiving monosynaptic input from primary afferent fibers innervating mechanical nociceptors and C-fibers.     

The epidemiology of multiple sclerosis in Queensland, Australia

An epidemiological survey of multiple sclerosis (MS) in the State of Queensland was undertaken with its prevalence day being the national census day on June 30th, 1981, 20 years after a regional survey within the State. The relationship between increasing prevalence of MS and increasing south latitude within the State of Queensland which was suggested by the 1961 study was confirmed in the present study. The prevalence rate had increased significantly over the 20-year period between the studies but the State remained a medium frequency zone for MS (prevalence rate between 5 and 29 per 100 000 of population). Although a real increase in disease frequency could not be excluded as a contributing factor to the rise in prevalence, it was most likely due predominantly to an increase in life expectancy amongst the MS population and also in differential migration of a population at a greater risk of developing MS than the indigenous population. The proportions of Australian-born patients who had migrated to Queensland from the higher risk southern regions of Australia or travelled overseas to countries known to be high-risk for MS prior to disease onset, had fallen between the two surveys thus exerting, if anything, a negative influence on the change in prevalence. Analysis of MS prevalence rates amongst migrant populations in Queensland as compared to the more southerly city of Perth in Western Australia, suggested that the risk of acquisition of MS may extend over a wider age range than is generally accepted. Finally, there was an absence of MS cases amongst the Aboriginal population in Queensland but it can only cautiously be concluded from this study that the disease is rare in these peoples.