Detection of factor XIII-A is a valuable tool for distinguishing dendritic cells and tissue macrophages in granuloma annulare and necrobiosis lipoidica.

BACKGROUND: Factor XIII subunit A (FXIII-A) is used as a diagnostic marker in a wide range of dermatological diseases ranging from inflammatory lesions to malignancies, although neither the cell types responsible for its expression nor the mechanism(s) resulting in its local accumulation in pathological conditions have been characterized. OBJECTIVE: In this study, we aimed to gain information on the cells showing an immunohistochemical reaction for FXIII-A and answer the question whether macrophages and/or dendritic cells are labelled for FXIII-A. METHODS: We carried out our studies on samples of granuloma annulare (GA) and necrobiosis lipoidica (NL), the prime examples for granulomatous skin lesions with a non-infectious background in which extracellular matrix remodelling is a key feature without any sign of malignant transformation. We used markers for macrophages and dendritic cells in combination with the detection of FXIII-A in double labelling immunohistochemical reactions. RESULTS: We demonstrated that FXIII-A positivity clearly distinguishes macrophages (CD163+/FXIII-A+) from dendritic cells (CD11c+/FXIII-A-) not only in the normal dermis as previously described by Zaba et al. (J Clin Invest 2007; 117: 2517-2525) but also in the pathological conditions of GA and NL. Detecting the expression of DC-SIGN/CD209 and mannose receptor molecules on FXIII-A+ macrophages we confirmed that FXIII-A is expressed in the alternatively activated macrophages. However, while DC-SIGN/CD209 was invariably expressed on FXIII-A+ cells both in normal and pathological conditions of GA/NL (98.7% vs. 93.5/96%), mannose receptor was only partially coexpressed with FXIII-A (94.8% vs. 74.7/52.2%), suggesting that FXIII-A+ macrophages do not represent a homogenous population. CONCLUSIONS: FXIII-A selectively marks macrophages and distinguishes them from dendritic cells. The presence of FXIII-A is not a disease-specific marker but indicates a possible common mechanism of macrophage activation in various dermatological diseases.

Epidemiology of the metabolic syndrome in Hungary.

OBJECTIVES: Hungary has high cardiovascular mortality. Recent studies have revealed a high prevalence of several cardiovascular risk factors, including obesity, diabetes and hypertension. The objective of this study was to assess the prevalence of the metabolic syndrome in Hungary. STUDY DESIGN: Cross-sectional study. METHODS: Within the framework of the Hungarian General Practitioners' Morbidity Sentinel Stations Programme, a random sample of 2006 individuals aged 20-69 years was selected in 2006. Physical examinations, blood sampling and data collection were performed by general practitioners. Information on environmental factors was gathered using a questionnaire. The population prevalence was estimated based on the sample frequencies. RESULTS: The overall response rate was 91%. The age-adjusted prevalence of the metabolic syndrome using the 2009 Harmonized definition was 38% [95% confidence interval (CI) 35-42%] in males and 30% (95% CI 28-33%) in females aged 20-69 years. There were no significant regional differences in the frequency figures. CONCLUSIONS: The high prevalence of the metabolic syndrome is a serious public health problem in Hungary, and remains a major determinant of the high burden of cardiovascular disease.

Genome-wide analysis of extended pedigrees confirms IL2-IL21 linkage and shows additional regions of interest potentially influencing coeliac disease risk.

Coeliac disease is a chronic inflammatory condition of the small intestine, triggered by dietary exposure to gluten in genetically susceptible individuals. Risk alleles at HLA-DQA1 and HLA-DQB1 are necessary for disease development, but are alone not sufficient for disease onset. We aimed to identify novel loci underlying susceptibility to coeliac disease through the use of extended Finnish and Hungarian families with multiple affected individuals. An initial whole-genome linkage approach yielded several loci that were followed up further using the Immunochip custom array. Loci with a parametric logarithm of odds (LOD) score of >1.3 were identified at 4q, 6p [human leukocyte antigen (HLA) region], 6q, 7p, 17p, 17q and at 22p. The 4q and 6q loci have been identified previously in coeliac disease risk, whereas follow-up analyses indicate that the 17p and 22p loci may be novel risk loci for coeliac disease. These loci harbour previously described risk variants for other autoimmune diseases, but their segregation patterns do not explain the linkage to coeliac disease. We followed up the linkage to the 4q region, containing the previously described interleukin (IL)2 and IL21 genes. The risk variants at 4q in the studied pedigrees are most likely distinct from previously described risk variants, indicating that the observed linkage may be due to rare high-risk variants of still unknown nature. The importance of this locus to coeliac disease risk was further shown by the finding that serum levels of IL21 were elevated in both untreated and treated coeliac patients compared to controls.

Fine mapping of the CELIAC2 locus on chromosome 5q31-q33 in the Finnish and Hungarian populations.

Celiac disease is a chronic inflammation of the small intestine, arising in genetically predisposed individuals as a result of ingestion of dietary gluten. The only confirmed and functionally characterised genetic risk factors for celiac disease are the DQ2 or DQ8 heterodimers at the major histocompatibility complex (MHC) class II locus (CELIAC1). These genes are necessary but alone not sufficient for disease onset. Genome-wide linkage scans have suggested chromosome 5q31-q33 (CELIAC2) as an important risk locus for celiac disease. This region has also been associated to other inflammatory disorders, although as yet, no clear gene associations have been found. In the current study, 11 celiac disease candidate loci were screened for genetic linkage in the Hungarian population. As the CELIAC2 locus showed the strongest evidence for linkage, this locus was selected for follow-up. Seventeen candidate genes were selected from the CELIAC2 locus, and genotyped using 48 haplotype tagging single nucleotide polymorphisms (SNPs) in large Finnish and Hungarian family materials. A subset of these, 40 tagging SNPs in 15 genes, were genotyped in an independent set of Finnish and Hungarian cases and controls. We confirmed linkage of this region with celiac disease and report strong linkage in both the Finnish and Hungarian populations. The association analysis showed modest associations throughout the whole region. These association findings were not replicated in the case-control datasets. Our study strongly supports the role of the CELIAC2 locus in celiac disease, but it also highlights the need for a more powerful study design in the region, to locate the true disease risk variants.

Does socioeconomic status fully mediate the effect of ethnicity on the health of Roma people in Hungary?

BACKGROUND: Several models have been proposed to explain the association between ethnicity and health. It was investigated whether the association between Roma ethnicity and health is fully mediated by socioeconomic status in Hungary. METHODS: Comparative health interview surveys were performed in 2003-04 on representative samples of the Hungarian population and inhabitants of Roma settlements. Logistic regression models were applied to study whether the relationship between Roma ethnicity and health is fully mediated by socioeconomic status, and whether Roma ethnicity modifies the association between socioeconomic status and health. RESULTS: The health status of people living in Roma settlements was poorer than that of the general population (odds ratio of severe functional limitation after adjustment for age and gender 1.8 (95% confidence interval 1.4 to 2.3)). The difference in self-reported health and in functionality was fully explained by the socioeconomic status. The less healthy behaviours of people living in Roma settlements was also related very strongly to their socioeconomic status, but remained significantly different from the general population when differences in the socioeconomic status were taken into account, (eg odds ratio of daily smoking 1.6 (95% confidence interval 1.3 to 2.0) after adjustment for age, gender, education, income and employment). CONCLUSION: Socioeconomic status is a strong determinant of health of people living in Roma settlements in Hungary. It fully explains their worse health status but only partially determines their less healthy behaviours. Efforts to improve the health of Roma people should include a focus on socioeconomic status, but it is important to note that cultural differences must be taken into account in developing public health interventions.

Linkage and association study of FcgammaR polymorphisms in celiac disease.

The Fcgamma receptor cluster on chromosome 1q23 contains a number of genes that may affect susceptibility to celiac disease, but previous studies have yielded contradictory results. We studied the FcgammaRIIa*A519G (rs1801274) and FcgammaRIIIa*A559C (rs396991) single nucleotide polymorphisms in celiac disease families from Hungary and Finland and in celiac disease case-control materials from Hungary and Italy. Neither the Hungarian nor the Italian case-control material or a meta-analysis of the combined case-control material showed significant single-marker or haplotype association. In addition, neither linkage nor family-based association tests showed evidence for association in the Finnish or Hungarian family material. This study thus does not support a previous publication showing FcgammaR association with celiac disease.

The shared CTLA4-ICOS risk locus in celiac disease, IgA deficiency and common variable immunodeficiency.

IgA deficiency (IgAD) and common variable immunodeficiency (CVID) often co-occur in families, associating with chronic inflammatory diseases such as celiac disease (CD). ICOS (inducible co-stimulator) and CTLA4 (cytotoxic T-lymphocyte-associated protein-4) may be important in both disorders, as ICOS is necessary for Ig class-switching and CTLA4 negatively regulates T-cell activation. Linkage and association of CD with CTLA4-ICOS is well documented, we thus aimed to further pinpoint CD susceptibility by haplotype-tagging analysis. We genotyped 663 CD families from Finland and Hungary, 575 additional CD patients from Finland, Hungary and Italy; 275 Swedish and Finnish IgAD individuals and 87 CVID individuals for 14-18 genetic markers in CTLA4-ICOS. Association was found between CTLA4-ICOS and both IgAD (P=0.0015) and CVID (P=0.0064). We confirmed linkage of CTLA4-ICOS with CD (LOD 2.38, P=0.0005) and found association of CTLA4-ICOS with CD (P=0.0009). Meta-analysis of the IgAD, CVID and CD materials revealed intergenic association (P=0.0005). Disease-associated markers were associated with lower ICOS and higher CTLA4 expression, indicating that the risk haplotypes contain functional variants. In summary, we identified a novel shared risk locus for IgAD, CVID and CD, the first report of association between CTLA4-ICOS and IgAD. Association between CD and CTLA4-ICOS was also confirmed in a large European data set.

Myosin IXB gene region and gluten intolerance: linkage to coeliac disease and a putative dermatitis herpetiformis association.

BACKGROUND: Coeliac disease is caused by dietary gluten, which triggers chronic inflammation of the small intestine in genetically predisposed individuals. In one quarter of the patients the disease manifests in the skin as dermatitis herpetiformis. Recently, a novel candidate gene, myosin IXB on chromosome 19p13, was shown to be associated with coeliac disease in the Dutch and Spanish populations. The same gene has previously been associated with inflammatory bowel disease, systemic lupus erythematosus and rheumatoid arthritis risk, making myosin IXB a potential shared risk factor in these inflammatory disorders. METHODS: In this study, previously reported myosin IXB variants were tested for genetic linkage and association with coeliac disease in 495 Hungarian and Finnish families and in an additional 270 patients and controls. RESULTS AND CONCLUSION: The results show significant linkage (logarithm of odds (LOD) 3.76, p = 0.00002) to 19p13 which supports the presence of a genuine risk factor for coeliac disease in this locus. Myosin IXB variants were not associated with coeliac disease in this study; however, weak evidence of association with dermatitis herpetiformis was found. The association could not explain the strong linkage seen in both phenotypes, indicating that the role of other neighbouring genes in the region cannot be excluded. Therefore, more detailed genetic and functional studies are required to characterise the role of the myosin IXB gene in both coeliac disease and dermatitis herpetiformis.

Genetic epidemiology literature in Europe: an overview.

BACKGROUND: Genetic epidemiology deals with the aetiology, distribution and control of disease in groups of relatives, and with inherited causes of disease in populations. The main goal of this overview, part of the collaborative study SPHERE (Strengthening Public Health Research in Europe) was to have an up-to-date, detailed summary of the available information for epidemiologists and researchers on the present status of genetic epidemiology in Europe. METHODS: The PubMed literature search engine was used to recruit papers published in Europe (EU15, EU + 10 and non-EU countries) in this field restricted to the time period of 1 January 1987 and 31 December 2004. RESULTS: The number of publications increased significantly in Europe in the period analysed, however, the publication activity was restricted mainly to EU15 countries, with only sporadic papers from EU + 10 countries. Research areas studied are slightly different in Europe and in the USA with a larger emphasis on cancer, mental disease and behavioural disease genetic epidemiology in Europe. CONCLUSION: The aim must be to develop research to support policy in this important field as is already seen in the United States.

Identification of factor XIII-A as a marker of alternative macrophage activation.

Factor XIII subunit A of blood coagulation (FXIII-A) is known to be synthesized but not secreted by the monocyte/macrophage cell line. On the basis of its intracellular localization and substrate profile, FXIII-A is thought to be involved in certain intracellular processes. Our present study was designed to monitor the changes in FXIII-A gene expression and protein production in long-term culture of human monocytes during their differentiation into macrophages in the presence of activating agents (interleukin-4, interferon-gamma, Mycobacterium bovis BCG) inducing classical and alternative activation pathways. By using quantitative RT-PCR and fluorescent image analysis at the single-cell level we demonstrated that the expression of FXIII-A both at the mRNA as well as at the protein level is inversely regulated during the two activation programmes. Here we conclude that FXIII-A expression is an intracellular marker for alternatively activated macrophages, while its absence in monocyte-derived macrophages indicates their classically activated state.

Factor XIII subunit A as an intracellular transglutaminase.

Over the last 2 decades there has been increasing evidence that the role of factor XIII (FXIII) is not restricted to the area of hemostasis and that its subunit A functions as an intracellular enzyme in platelets and monocytes/macrophages. FXIII is already expressed during compartmentalisation of the precursors of megakaryocyte/platelet and monocyte/macrophage cell lines in the bone marrow. FXIII-A, produced by megakaryocytes, is packaged into budding platelets and is present in huge quantity in circulating ones. It seems very likely that it plays an important role in the cytoskeletal remodelling associated with the activation stages of platelets. FXIII-A can also be detected in blood monocytes and in all subsets of monocyte-derived macrophages throughout the body. FXIII-A is mainly localised in the cytoplasm, in association with cytoskeletal filaments, but at a relatively early stage of macrophage differentiation it also appears transiently in the nucleus. Cytoplasmic expression has a very close relationship with phagocytic activities. Further research is needed to understand the biological significance of its nuclear presentation.

Phorbol ester treatment inhibits proliferation and differentiation of cultured human skeletal muscle satellite cells by differentially acting on protein kinase C isoforms.

We have previously shown that cultured human skeletal muscle cells express five protein kinase C (PKC) isoforms (PKCalpha, -gamma, -eta, -theta, and -zeta) and that expression levels of various PKC isozymes differentially change during differentiation. In this study we investigated the effects of the PKC activator phorbol 12-myristate 13-acetate (PMA) on differentiation and on PKC isozymes of human skeletal muscle satellite cells. PMA inhibited the growth and fusion of cultured human myoblasts in a dose-dependent manner. In addition, prolonged treatment of cells with PMA suppressed the expression of the myogenic differentiation marker desmin showing similar dose-response characteristics. Furthermore, PMA also induced the intracellular translocation of PKCgamma, -eta, and -theta, whereas cellular localization of PKCalpha and -zeta were not altered. These changes in subcellular localization patterns were of great importance since only those PKC isoforms were translocated that possessed alterations in their expression levels during differentiation. Our findings, therefore, suggest that the PMA-induced inhibition of differentiation of human skeletal muscle cells is mediated by certain PKC isoforms. Moreover, these data strongly argue for differential and isozyme-specific roles of various PKC isoforms in these processes.

Chromosomal imbalances in primary and metastatic melanomas revealed by comparative genomic hybridization.

Characteristic genetic changes underlying the metastatic progression of malignant melanoma is incompletely understood. The goal of our study was to explore specific chromosomal alterations associated with the aggressive behavior of this neoplasm. Comparative genomic hybridization was performed to screen and compare genomic imbalances present in primary and metastatic melanomas. Sixteen primary and 12 metastatic specimens were analyzed. We found that the pattern of chromosomal aberrations is similar in the two subgroups; however, alterations present only in primary and/or metastatic tumors were also discovered. The mean number of genetic changes was 6.3 (range 1-14) in primary and 7.8 (range 1-16) in metastatic lesions. Frequent losses involved 9p and 10q, whereas gains most often occurred at 1q, 6p, 7q, and 8q. Distinct, high-level amplifications were mapped to 1p12-p21 and 1p22-p31 in both tumor types. Amplification of 4q12-q13.1, 7q21.3-qter and 8q23-qter were detected only in primary tumors. The 20q13-qter amplicon was present in a metastatic tumor. The number of genetic alterations were significantly higher in primary tumors which developed metastases within one year after the surgery compared to tumors without metastasis during this time period. Fluorescence in situ hybridization with centromeric and locus-specific probes was applied to validate CGH results on a subset of tumors. Comparison of FISH and CGH data gave good correlation. The aggressive behavior of melanoma is associated with accumulation of multiple genetic alterations. Chromosome regions, which differ in the primary and metastatic lesions, may represent potential targets to identify metastases-related chromosomal alterations.

Analysis of genetic alterations in salivary gland tumors by comparative genomic hybridization.

In order to define and map chromosomal copy number alterations in salivary gland tumors (SGTs), a comparative genomic hybridization (CGH) technique was applied to two pleomorphic adenomas (PAs), one adenoid cystic carcinoma (ACC), and one basal cell adenocarcinoma (BCAC). The PAs exhibited regional copy number losses at 5q12.4-q14.1, 9q12-q21.13, and 16q11.2, as well as a gain at 20p12.1; among these, the losses at the 9q12-q21.11 and 16q11.2 regions were common to both PAs. The ACC showed overrepresentations of the entire regions of chromosomes 16 and 20, a regional gain at 22q12.3-q13.1, and no losses. In the BCAC, regional gains at 9p21.1-pter, 18q21.1-q22.3, and 22q11.23-q13.31 as well as losses at 2q24.2 and 4q25-q27 were seen; the gain at 22q12.3-q13.1 was common in both the ACC and the BCAC. These CGH data indicate that different genetic alterations are present in the different types of SGTs, and that the alterations involve several chromosomes. The discovery of common alterations in the same and/or different types of tumors might be important in the understanding of the development and progression of the SGTs.

Multiplex PCR assay for screening deletions in the low density lipoprotein receptor gene.

BACKGROUND: In different populations of the world, more than 150 genetic alterations of the LDL receptor gene have been identified; each of which can result in hypercholesterolaemia, but no hot spots in the gene were detected so far. Because of the existence of very variable genetic alterations in different ethnic communities, none of the assays developed for screening mutations/deletions in a population defined can be adapted to study the possible genetic defects. The present study was designed to develop a new, multiplex PCR-based, molecular biological method to screen the whole coding region of the LDL receptor gene. METHODS: Using primer pairs completely flanking the promoter and the entire exonal region, in the PCR reactions 83-386-bp long, DNA sequences were synthesised in seven different reaction mixtures. The reaction conditions of the multiplex PCR system were optimised in order to synthesise all exons and the promoter region of the gene using only two annealing temperatures. The products could be visualised separately by agarose gel electrophoresis/ethidium bromide staining. RESULTS: A rapid, effective test enabling the screening of DNA alterations in the entire LDL receptor gene was developed. Using this simple multiplex PCR assay, deletions affecting more than 10 bp in any part of the gene can be easily detected by a single agarose gel electrophoresis. CONCLUSIONS: The simplicity, specificity and versatility of the assay make it suitable system for routine screening of LDL receptor gene mutations in large population samples. This PCR assay can be recommended for screening of LDL-RG deletions in populations or groups at high risk for cardiovascular diseases.

Factor XIII of blood coagulation as a nuclear crosslinking enzyme.

Intracellular localization and distribution of Factor XIII subunit A (FXIIIA) was investigated in association with monocyte-macrophage differentiation in a long term culture of human monocytes by light- and electron microscopical as well as biochemical and immunobiochemical techniques. To allow the detection of FXIIIA in cells with well-preserved ultrustructure, immunosera against glutaraldehyde-derivatized recombinant FXIIIA were developed in rabbits, then characterized and used in this study. In the early phase of macrophage differentiation intranuclear accumulation of FXIIIA was detected as a transient phenomenon in cells of the 2nd day culture by optical sectioning with 0,7 microm steps in laser scanning confocal microscopy and immunoblotting technique. FXIIIA could be detected by immunoelectron microscopic postembedding staining over electrodense DNA-containing areas. Fluoresceinated monodansylcadaverine incorporation assay was used to demonstrate that FXIIIA is not only present in the nuclei, but also expresses its transglutaminase activity. Our finding of the nuclear accumulation of FXIIIA in differentiating human macrophages is also unique in that a blood clotting factor has, for the first time, been localized in nuclei and has been shown to be an intracellular crosslinking enzyme. The possible role of nuclear FXIIIA in association with cellular processes involving chromatin structure remodeling, such as cell death, cell differentiation or cellular proliferation requires further in-depth investigation.

[Fluorescence in situ hybridization in the diagnosis and follow-up of chronic myelogenous leukemia]. / Fluoreszcencia in situ hibridizációval szerzett tapasztalataink a krónikus myeloid leukaemia diagnosztikájában és követésében.

Chronic myelogenous leukaemia is a clonal myeloproliferative stem cell disease. Its cytogenetical hallmark is the Philadelphia chromosome (Ph) or the BCR/ABL fusion gene. Their identification is important both in the diagnosis and the follow-up of the disease. In our department we have investigated the BCR/ABL gene arrangement in 21 patients with fluorescence in situ hybridization. The aim of the analysis in freshly suspected patients without any previous therapy was to confirm diagnosis and mapping the ratio of Philadelphia positive cells. In contrast to the 95-100% Ph-positivity of mononuclear cells by classical cytogenetical examinations we found BCR/ABL gene arrangement only in various but always lower proportions. Therefore the latter examination gives a better representation of residual normal hemopoesis. Out of 9 patients who had received interferon treatment for at least 6 months, 4 gave a major, 4 a minor cytogenetical answer and in 1 case there was no cytogenetical response. Seven patients reached a complete and 2 a partial hematological remission. Among 5 other patients receiving interferon treatment, in 2 cases with double Ph-positivity we found a rapid progression. The data of 3 patients had to be excluded from the evaluation due to the so far short following time.

Mutation of the RB1 gene caused unilateral retinoblastoma in early Age.

Fluorescence in situ hybridization (FISH) was applied for the detection of the retinoblastoma tumor-suppressor gene deletion on retinoblastoma tumor cells obtained from the unilateral tumor of a 3-month-old boy. Both retinoblastoma tumor cells and peripheral lymphocytes of the patient showed one hybridization signal per cell at the retinoblastoma-1 locus, indicating that one copy of the gene was deleted. Peripheral blood lymphocytes obtained from the patient's parents had two copies per cell for the gene. Retinoblastoma nuclear phosphoprotein expression could not be detected in the tumor tissue. No copy number alterations were detected with ten different centromeric DNA probes in the tumor cells. The deletion at the RB1 locus detected by FISH suggested that this gene alteration was heritable. The parental peripheral blood lymphocytes did not show the loss of the gene; thus the first deletion may have taken place in either of the parental germ cells. The second somatic mutation of the RB1 gene was probably under the detection limit of FISH. The second allelic alterations were detected by using the polymerase chain reaction for all exons of the retinoblastoma gene.

[Trends of premature mortality from cardiovascular diseases in Hungary and the European Union, 1970-1997]. / A keringési rendszer betegségei okozta korai halálozás trendjei Magyarországon és az Európai Unióban, 1970-1997.

It is a well known fact that in Hungary--as in the European Countries, in general--the trends of premature mortality are mainly determined by the trends of mortality caused by cardiovascular diseases. The timeliness of our present study on changes in trends of early cardiovascular mortality in the period of 1970-1997 in Hungary in comparison with trends of EU countries is underlined by the upcoming access of Hungary to the European Union. The evaluation is based on WHO data, the relative risk of premature mortality due to different forms of cardiovascular diseases for different sex and age groups of the Hungarian population is expressed as a ratio between standardized mortality rates of Hungarian groups and that of EU-average and of countries specified. Detailed data demonstrate that the risk of early death caused by cardiovascular--especially ischaemic heart and cerebrovascular--diseases, in contrast with EU countries, is significantly increased in Hungary, most significantly in age groups of 35-44 and 45-64 years for both sexes. The authors' results draw the attention to the possible shortcomings of health care systems and the lack of comprehensive health promotion (including prevention) programs in Hungary.

Effect of tumor-conditioned medium on intercellular communication and proliferation of Balb/c 3T3 cells.

The possible role of tumor cell-derived factors in the regulation of gap junctional intercellular communication and proliferation of fibroblasts was studied in a model system of Balb/c 3T3 cells growing in tumor conditioned medium by Lucifer Yellow CH dye-transfer and BrdU incorporation assays. Six to 24 h incubation of Balb/c 3T3 cells in a medium conditioned by WiDr adenocarcinoma cells enhanced the gap junctional communication between the cells by 25-40% as revealed by intercellular transfer of a fluorescent dye Lucifer Yellow CH. Simultaneously the cell proliferation rates were examined and found to be reduced by 23% at 24 h treatment. Since adenocarcinoma cells are known to secrete different growth factor-like polypeptides into their conditioned medium, we suppose that tumors that produce these molecules might alter their host environment through the enhancement of cell-cell communication thereby facilitating the exchange of modulatory factors.