Keratinocyte growth factor protects mice from chemotherapy and radiation-induced gastrointestinal injury and mortality.

Keratinocyte growth factor (KGF) stimulates the proliferation and differentiation of epithelial cells including those of the gastrointestinal tract. Although chemotherapeutics and radiation exposure kill rapidly proliferating tumor cells, rapidly dividing normal cells of the host's gastrointestinal tract are also frequently damaged, leading to the clinical condition broadly termed "mucositis." In this report, recombinant human KGF used as a pretreatment in several mouse models of chemotherapy and/or radiation-induced gastrointestinal injury significantly improved mouse survival. Using multiple-dose 5-fluorouracil, methotrexate, and radiation in combination and total body radiation alone models, KGF increased survival by 55% or greater. In the models that used chemotherapy with or without radiation, KGF significantly ameliorated weight loss after injury and accelerated weight gain during recovery. The basis of these systemic benefits appears to be due in part to the trophic effects of the growth factor on the intestinal epithelium because KGF pretreatment caused an increase in measures of mucosal thickness (villus height and crypt depth) that persisted during the course of 5-fluorouracil chemotherapy. Treatment with KGF also afforded a 3.5-fold improvement in crypt survival in the small intestine, suggesting that KGF also has a direct effect on the crypt stem cells. These data indicate that KGF may be therapeutically useful to lessen the intestinal side effects of current cancer therapy regimens.

Combined treatment of acute EAE in Lewis rats with TNF-binding protein and interleukin-1 receptor antagonist.

Experimental autoimmune encephalomyelitis (EAE) is a term given to describe a collection of animal models representing the human disease multiple sclerosis (MS). Although not fully understood, the involvement of cytokines and the immune system in either EAE or human MS is well established. Past efforts have shown that inhibition of proinflammatory cytokines tumor necrosis factor (TNF-alpha) or interleukin-1 (IL-1) result in amelioration of acute EAE in Lewis rats. The present study examined this model for the effect of concomitant inhibition of both TNF-alpha and IL-1, which resulted in a modest but significant therapeutic effect that was superior to inhibition of either single agent alone with respect to four of the five variables used to follow the progression of disease in this model, i.e., clinical severity, frequency of disease, loss of body weight, and day of onset. These results are in accordance with the idea that combination treatments are likely to prove superior to single agent therapy in the treatment of autoimmune inflammatory disease.

Keratinocyte growth factor is an important endogenous mediator of hair follicle growth, development, and differentiation. Normalization of the nu/nu follicular differentiation defect and amelioration of chemotherapy-induced alopecia.

The growth and development of hair follicles is influenced by a number of different growth factors and cytokines, particularly members of the fibroblast growth factor (FGF) family. Keratinocyte growth factor (KGF or FGF-7) is a recently identified 28-kd member of the FGF family that induces proliferation of a wide variety of epithelial cells, including keratinocytes within the epidermis and dermal adnexa. Because KGF induces marked proliferation of keratinocytes, and both KGF and KGF receptor (KGFR) mRNA are expressed at high levels in skin, we sought to localize KGF and KGFR in skin by in situ hybridization. KGFR mRNA was relatively strongly expressed by keratinocytes in the basilar epidermis as well as throughout developing hair follicles of rat embryos and neonates. KGF mRNA was expressed at lower levels than was KGFR but could be localized to follicular dermal papillae in rat embryos and neonates. These results prompted us to investigate the effects of KGF on hair follicles in two distinct murine models of alopecia. In the first model, recombinant KGF (rKGF) induced dose-dependent hair growth over most of the body in nu/nu athymic nude mice when administered intraperitoneally or subcutaneously over 17 to 18 days. When administered subcutaneously, rKGF induced the most extensive hair growth at the sites of injection. Histologically, rKGF induced marked follicular and sebaceous gland hypertrophy, a normalization of the nu/nu follicular keratinization defect, and an increase in follicular keratinocyte proliferation as assessed by bromodeoxyuridine labeling. In the second model, a neonatal rat model of cytosine arabinoside chemotherapy-induced alopecia in which interleukin-1, epidermal growth factor, and acidic FGF have all demonstrated some degree of alopecia cytoprotection, rKGF induced a dose-dependent cytoprotective effect, abrogating as much as 50% of the alopecia in this model when administered beginning 1 day before the onset of chemotherapy. Taken together, these data suggest that KGF is an important endogenous mediator of normal hair follicle growth, development, and differentiation.

Coley's toxins, tumor necrosis factor and cancer research: a historical perspective.

As far back as the 1700s, it was recorded that certain infectious disease processes could exert a beneficial therapeutic effect upon malignancy. Most prominent among the numerous deliberate efforts made to take advantage of these observations was that of a pioneering New York surgeon, William B. Coley, active career 1891-1936. Using a bacterial vaccine to treat primarily inoperable sarcoma. Coley accomplished a cure rate of better than 10%. This review examines the history of these efforts and presents a discussion of their corresponding relevance to present day immunotherapy.

The effect of the platelet-derived glycosaminoglycan serglycin on in vitro proplatelet-like process formation.

The formation of proplatelet-like processes on megakaryocytes cultured in vitro has been shown to be inhibited by prothrombin, found residually in human serum, which is converted in culture to thrombin. This study reports that another factor found in human serum will counter this inhibition and permit proplatelet-like process formation to occur in vitro even in the presence of inhibitory concentrations of thrombin. The factor was purified from human platelet lysates and identified by amino acid sequence analysis as the proteoglycan serglycin. A similar, if not identical, factor was found at elevated levels in the plasma of thrombocytopenic rabbits. Serglycin probably functions as a proplatelet potentiator by virtue of a tendency to complex with thrombin. Thrombin in complex with serglycin retains its enzymatic properties, but is apparently sterically hindered from interacting with the megakaryocyte cell surface. In preliminary studies, the in vivo administration of serglycin in mice resulted in an increased number of circulating platelets when given in combination with interleukin-6 (IL-6).

Megakaryocyte proplatelet-like process formation in vitro is inhibited by serum prothrombin, a process which is blocked by matrix-bound glycosaminoglycans.

The process of platelet shedding from megakaryocytes is incompletely understood, due in part to the impossibility of studying this dynamic process in vivo. Megakaryocytes in situ and in in vitro cultures display extended cytoplasmic processes constricted at platelet-sized intervals which presumably are the structural intermediates between megakaryocytes and platelets. This study describes the establishment of a serum-free culture system of purified guinea pig megakaryocytes in which extensive cytoplasmic process formation can be observed on 21 to 29% of the cells. The addition of as little as 0.05% pooled human serum to the cultures will completely but reversibly block process development. The serum inhibitor was identified as residual prothrombin, which upon contact with megakaryocytes is converted to the serine esterase thrombin. Thrombin directly prevents the formation of new processes and also induces retraction of existing processes. When megakaryocytes are cultured on Matrigel, process formation occurs even in an excess of thrombin. This potentiation of process development in the presence of inhibitory factors is mediated by the glycosaminoglycan content of Matrigel. The physiological implications of these observations are discussed.

Platelet factor 4 mRNA expression in human erythroleukemic cells: regulation by phorbol esters and certain cytokines.

Developing megakaryocytes are distinguished from progenitor cells by the appearance of platelet proteins such as platelet factor 4 (PF 4). The human erythroleukemic cell line HEL can also be induced to produce PF 4 by incubation in phorbol esters. HEL cells were used here as a model system in which to study the phenomenon of inducible PF 4 production at both the mRNA and protein levels. The cytokines interleukin 1 beta (IL-1 beta), interleukin 3 (IL-3), interleukin 6 (IL-6), granulocyte-macrophage colony-stimulating factor (GM-CSF), erythropoietin (EPO), and transforming growth factor-beta (TGF-beta) were also evaluated for their effects on PF 4 mRNA induction in HEL cells.

[Bilateral primary giant cell tumor (osteoclastoma) of the ribs]. / Bilateraler primärer Riesenzelltumor (Osteoklastom) der Rippen.

The primary giant-cell tumour is a semimalignant bone tumour which occurs primarily on the epiphysis of the long tubular bones and the methaphysis. The present case report describes the bilateral occurrence of this tumour in the region of the osseous thorax. The paper also deals with diagnostic, therapeutical and prognostic problems.

[The origin of bronchial carcinoma in siderofibrosis]. / Entstehung eines Bronchialkarzinoms auf der Basis einer Sidero-Fibrose.

Investigations of diseases due to professional exposure, especially the development of malignant tumors, are of increasing interest. In the present case the development of a bronchogenic carcinoma on the base of sidero-fibrosis in a 46-year-old man (E-welder) is described. Several aspects of the problem are discussed.

[Pulmonary echinococcosis--primary site of Echinococcus cysticus]. / Der Lungenechinokokkus--primäre Lokalisation des Echinococcus cysticus.

The liver is the preferred organ of echinococcus cysticus, however in 20% of the cases cysts are found in the lung. Case report on a 54-year-old woman who was admitted to the hospital with an echinococcus cysticus in the left upper lobe. Differential-diagnostic problems, therapeutic possibility and prognostic aspects of echinococcus of lung are discussed.

[Primary site of hemangiopericytoma in the lung]. / Primäre Lokalisation eines Haemangioperizytoms in der Lunge.

Hemangiopericytoma is a uncommon tumor of vascular origin, whose biological reaction is very interesting. The following case report describe a primary hemangiopericytoma of the left lower lobe in a 34-year-old woman. Diagnostics, therapy and prognosis of this tumor are discussed.

[Pulmonary alveolar proteinosis--an occupational disease?]. / Die pulmonale alveoläre Proteinose--eine berufsbedingte Erkrankung?

Pulmonary alveolar proteinosis is characterized by an uniform pathomorphologic picture. Actual knowledge regarding causal relationships is discussed reporting a case history.