Original Article
Transforming Growth Factors β1 and α in Chronic Liver Disease Effects of Interferon Alfa Therapy
N Engl J Med 1991; 324:933-940April 4, 1991
- Abstract
- Abstract
Background.
Cirrhosis is a diffuse process of hepatic fibrosis and regenerative nodule formation of unknown pathogenesis. Transforming growth factor (TGF) β1 induces the production of extracellular matrix proteins by liver cells and has been implicated in the pathogenesis of hepatic fibrosis in laboratory animals. TGFα is a hepatocyte mitogen that participates in liver regeneration.
Methods.
Using Northern blot analysis, we studied the expression of TGFβ1 messenger RNA (mRNA) in liver specimens from 42 patients with chronic hepatitis and cirrhosis and 12 subjects with either normal or fatty livers. The results were correlated with measurements of procollagen Type I mRNA in liver tissue, procollagen Type III peptide in serum, and the degree of histologie injury. We also investigated whether TGFα mRNA would be detectable in biopsy specimens of livers with proliferative activity.
Results.
TGFβ1 mRNA expression correlated closely with the expression of procollagen Type I mRNA (r = 0.94) and serum procollagen Type III peptide (r = 0.89) and with the histologie activity index (r = 0.73). All patients with increased fibrogenic activity (serum procollagen Type III peptide level, >11.9 μg per liter) had increased levels of TGFβ1 mRNA (2 to 14 times the levels in the control group or in patients with normal fibrogenic activity), and both TGFα and H3 histone (a marker of DNA synthesis) mRNAs were detectable in patients with regenerative nodules. Six of eight patients with hepatitis C treated with interferon alfa for one year had sustained clinical responses with normalization of serum procollagen Type III peptide and aminotransferase activity. All these patients had normal levels of TGFβ1 mRNA in liver specimens obtained at the end of the year.
Conclusions.
TGFβ1 may have an important role in the pathogenesis of fibrosis in patients with chronic liver disease, and TGFα expression may be associated with liver regeneration in these patients. (N Engl J Med 1991; 324:933–40.)
Article Activity
- Article
FIBROSIS is an important component of advanced chronic inflammatory liver disease.1 2 3 4 5 In cirrhosis, fibrosis is accompanied by cell necrosis and nodular regeneration.2 , 3 Hepatic fibrosis is a complex process that involves changes in the amounts of extracellular matrix components, activation of cells capable of producing matrix materials, cytokine release, and tissue remodeling.1 , 4 5 6 7
In addition to being an inhibitor of DNA synthesis by hepatocytes,8 9 10 11 12 transforming growth factor (TGF) β1 is associated with hepatic fibrosis.13 14 15 TGFβ1 increases the production of extracellular matrix proteins and their receptors and inhibits the synthesis of matrix-degrading proteolytic enzymes.16 17 18 19 20 In the liver, TGFβ1 induces collagen synthesis in lipocytes.21 22 23 24 These cells, located in subendothelial spaces, are believed to become activated in hepatic fibrosis.1 , 4 , 6 , 23 24 25 26 27 Using an experimental model of schistosomiasis in mice, Czaja et al.13 found an increase in the content of TGFβ1 messenger RNA (mRNA) in the liver of infected animals, in parallel with an increase in Type I procollagen mRNA. Nakatsukasa et al.24 also found a positive correlation between TGFβ1 mRNA and procollagen I, III, and IV mRNAs in the livers of rats with carbon tetrachloride—induced hepatic fibrosis. In view of these observations, we wondered whether the expression of TGFβ1 mRNA would correlate with various indicators of liver fibrosis and injury in humans. We therefore measured the steady-state levels of TGFβ1 mRNA in liver biopsy specimens from patients with chronic hepatitis and cirrhosis and correlated its expression with that of procollagen Type I mRNA in the same biopsy specimen and with serum levels of procollagen Type III peptide. To determine the extent of proliferative activity in the livers of patients with chronic hepatic disease, we measured the expression of H3 histone mRNA, generally considered a good marker of DNA synthesis.28 29 30 Since TGFα is a potent hepatocyte mitogen produced in vivo and in vitro by hepatocytes stimulated to proliferate,9 , 31 we analyzed the correlation between the expression of H3 histone mRNA and TGFα mRNA in chronic liver disease. Finally, in a small group of patients with chronic hepatitis C, we determined whether treatment with interferon alfa reduced the fibrogenic and proliferative activity of the disease and the expression of TGFβ1 mRNA in the liver.
Methods
Study Groups
Liver biopsy specimens were obtained from 46 patients with elevated serum alanine aminotransferase (ALT) activity who had either clinical features suggesting chronic liver disease or a previous diagnosis of such disease. Specimens were also taken from eight patients with normal results of liver-function tests who had undergone cholecystectomy for cholelithiasis, with no clinical complications. The protocol for this study was approved by the ethics committee of the University of Navarra (Pamplona, Spain), and informed consent was given by all patients. The specimens (minimal size, 16 mm long) were obtained with a TruCut biopsy needle. Approximately half of each specimen was immediately frozen in liquid nitrogen and stored at –80°C until it was used for RNA extraction; the rest of the specimen was processed for histologie study according to standard procedures.
The specimens of 4 of the 46 patients showed fatty liver but no fibrosis or necrosis. These 4 patients together with the 8 with normal liver function constituted the control group (7 women and 5 men, ranging in age from 29 to 51 years; mean age, 46). The 42 patients with hepatic fibrosis or necrosis (20 with chronic hepatitis and 22 with cirrhosis) included 16 women and 26 men, ranging in age from 21 to 62 years (mean, 42). This group of 42 patients was divided into three subgroups as follows.
Chronic Hepatitis B Infection
Eleven patients (three women and eight men, ranging in age from 21 to 61 years; mean age, 34) had positive tests for at least six months for serum hepatitis B surface antigen and anti—core antibody and negative tests for antibody against hepatitis B surface antigen. In three of these patients, markers for viral replication (hepatitis B virus e antigen, viral DNA, and viral DNA-polymerase activity) were present in serum; in the other eight, these markers were absent and anti-e antibody was present. All patients were negative for anti-delta antibody.
Chronic Hepatitis C Infection
Twenty-nine patients (12 women and 17 men, ranging in age from 21 to 62 years; mean age, 45) had elevated serum levels of ALT activity for at least six months and a diagnosis of chronic hepatitis (14 patients) or cirrhosis (15 patients) based on liver biopsy. All had a history of parenteral exposure to hepatitis C virus and a positive serum test for anti—hepatitis C antibodies. None of the patients had detectable serum hepatitis B surface antigen or antinuclear, anti-smooth muscle, or mitochondrial antibodies, and all had normal serum levels of copper, iron, transferrin, ceruloplasmin, and α1-antitrypsin. Likewise, none had drug- or alcohol-induced liver disease.
Nonviral Chronic Liver Disease
Two patients had nonviral chronic liver disease. They were a 50-year-old woman with primary biliary cirrhosis (antimitochondrial antibody titer, 1/320; histologie stage IV) and a 21-year-old man with active cirrhosis associated with ulcerative colitis (viral markers and autoantibodies were absent).
None of the patients in the three groups had serum antibodies to human immunodeficiency virus Type 1 (HIV-1).
Interferon Treatment
Eight patients (four with chronic hepatitis and four with cirrhosis; two women and six men, ranging in age from 21 to 59 years; mean age, 37) from the subgroup with hepatitis C were studied after one year of treatment with interferon alfa-nl (lymphoblastoid interferon; Wellferon, Galloso—Wellcome, Madrid). These patients were treated in a randomized trial that included a total of 36 patients.32 Although liver specimens were obtained from the eight patients before and after treatment, RNA could be measured only in the final biopsy specimen since no samples had been obtained for RNA extraction at the time of the original biopsy. Interferon was given according to the following schedule.
Induction Phase
Daily doses of 3 million units were given until serum ALT levels decreased to less than 50 U per liter (upper limit of normal range, 40) and remained stable for two weeks. If this failed to occur within two months after the start of treatment, the daily dose was increased to 4.5 million units. This dose was given until the serum ALT levels decreased to less than 50 U per liter and remained at this concentration for a two-week period, or for two months if the serum ALT level did not fall to less than 50 U per liter. At the end of the induction phase, seven of the eight patients had serum ALT levels in the normal range.
Maintenance Phase
All eight patients (including the patient who had not responded to treatment during the induction phase) were treated with 3 million units of interferon three times a week for 3 months, followed by doses of 1.5 million units three times a week, for a total of 12 months of treatment (induction and maintenance phases).
During the one-year treatment period, six of the eight patients had normal serum ALT levels. One patient had a transient response (normal serum ALT levels for several months, followed by reactivation of liver disease and abnormal ALT levels). The patient who did not have a response to interferon during the induction phase also had no response (no change in serum ALT level) during the rest of the treatment period.
RNA Extraction and Northern Blot Analysis
RNA was isolated from frozen liver tissue according to a modification of the Chirgwin procedure.8 , 31 , 33 The liver specimens were homogenized in 4 M guanidinium thiocyanate solution. After lowspeed centrifugation to remove cellular debris, the samples were layered on a 3.5-ml cushion of 5.7 M cesium chloride in 25 mM sodium acetate (pH 5). They were then centrifuged for 20 hours at 20,000 rpm in a Beckman SW40 Ti rotor. The RNA was dissolved in water and recovered by ethanol precipitation. RNA content was measured by spectrophotometry (absorbance at 260 am}.
RNA samples (10 μg per lane) were fractioned by electrophoresis in 6.2 percent formaldehyde—1.1 percent agarose gels and transferred to nitrocellulose filters in 20× SSC (I× SSC is 0.15 M sodium chloride—0.015 M trisodium citrate). To ensure that similar amounts of RNA were loaded into the various gel lanes, the quantity of 18S and 28S RNA was determined by ethidium bromide fluorescence staining before RNA transfer. The blots were then hybridized at 42°C for 72 hours with 32P-labeled complementary DNA probes for human TGFβ1,8 human TGFα (925-bp EcoRI fragment of human prepro-TGFα, provided by Dr. G.I. Bell), human α1(I) procollagen34 (clone Hf677, provided by Dr. K. Zaret), murine H3 histone gene (SalI—BamHI 204-bp fragment from histone 3.2, provided by Dr. L. Biempica), and rat glyceraldehyde-3-phosphate dehydrogenase35 , 36 (provided by Dr. R. Wu). All probes were labeled by nick translation.8 After washing at 50°C, the filters were exposed to Kodak XAR-2 film at – 70°C with intensifying screens. The autoradiographs were quantitated by scanning densitometry with a Gilford spectrophotometer. The expression of α1(I) procollagen mRNA was determined in only 34 patients because of technical problems with the hybridization procedure in one of the filters.
The expression of glyceraldehyde-3-phosphate dehydrogenase mRNA was used as the internal control for each specimen. The content of TGFβ1 mRNA (densitometry absorbance after 96 hours of autoradiographic exposure), TGFα mRNA (192 hours of exposure), procollagen I mRNA (24 hours of exposure), and H3 histone mRNA (192 hours of exposure) was normalized to that of glyceraldehyde-3-phosphate dehydrogenase mRNA (2 hours of exposure) in the same biopsy sample.
Amino-Terminal Peptide of Procollagen Type III
Serum procollagen III amino-terminal peptide was measured with a commercial radioimmunoassay kit (RIA-gnost P-III-P; Behringwerke AG, Marburg, Germany). Normal values (mean ±SD, 9.9± 1.0 μg per liter) were established from serum measurements in 12 normal subjects (4 women and 8 men, ranging in age from 29 to 49 years; mean age, 39).
Viral Markers
Commercially available radioimmunoassay kits were used to detect hepatitis B surface and e antigens; antibodies to the surface, e, and core antigens; and anti—hepatitis delta antibodies (AUSRIA II, AUSAB, CORAB, HBe kit, and anti-Delta kit; Abbott Laboratories, North Chicago). Serum levels of hepatitis B virus DNA and DNA-polymerase activity were measured by dot hybridization and enzymatic reaction as previously reported.37 , 38 Antibodies against hepatitis C and HIV-1 were determined by enzyme-linked immunosorbent assay (Ortho, Raritan, N.J., and Abbott Laboratories, respectively).
Liver Biopsies
Biopsy specimens were graded for their degree of periportal, portal, and lobular inflammation and fibrosis according to the scoring system of Knodell et al.39 Coded specimens were examined by a pathologist who had no knowledge of their source.
Statistical Analysis
The results are presented as means ±SD. The results were evaluated by analysis of variance, polynomial regression, the Mann—Whitney test, the Wilcoxon signed-rank test, and Fisher's exact test.
Results
TGFβ1 mRNA Expression and Fibrogenesis We first determined whether the various indicators of fibrogenesis correlated with each other in the 42 patients with chronic hepatitis or cirrhosis. The expression of procollagen Type I mRNA in liver specimens on Northern blot analysis correlated directly with the serum levels of procollagen Type III aminoterminal peptide (r = 0.91, P<0.001) (Fig. 1Figure 1
Serum Concentrations of Procollagen Type III Peptide in Relation to Hepatic Procollagen α1(1) mRNA Expression (A) and Serum ALT Activity (B) in Patients with Chronic Liver Disease (○) and Control Patients (•).A). Furthermore, the serum levels of procollagen Type III peptide correlated significantly with the serum levels of ALT (r = 0.84, P<0.001) (Fig. 1B). We then measured the expression of TGFβ1 mRNA and procollagen Type I mRNA in each specimen from the patients with chronic hepatic disease and the control group (Fig. 2Figure 2
Representative Northern Blot Analysis of TGFβ1, Procollagen α1(I), and Glyceraldehyde-3-Phosphate Dehydrogenase (GAP) mRNAs in Liver Specimens from Control Patients, Patients with Chronic Hepatitis, and Patients with Cirrhosis.). To eliminate variations that might be caused by technical procedures, the levels of TGFβ1 mRNA and procollagen Type I mRNA in each patient were calculated in relation to the level of glyceraldehyde-3-phosphate dehydrogenase in the same sample (Fig. 2). An analysis of the results in all patients revealed that the expression of TGFβ1 in the biopsy specimens correlated strongly with that of liver procollagen Type I mRNA (r = 0.94, P<0.001; n = 32) and with the serum levels of procollagen Type III peptide (r = 0.89, P<0.001) (Fig. 3Figure 3
Hepatic TGFβ1 mRNA Expression in Relation to the Serum Concentration of Procollagen Type III Peptide in 42 Patients with Chronic Liver Disease (○) and 12 Control Patients (•).). Liver concentrations of TGFβ1 mRNA and serum concentrations of procollagen Type III peptide were low in the control patients (mean procollagen Type III peptide concentration, 10.0±0.3 μg per liter) but varied widely in the patients with chronic liver disease (Fig. 3).To analyze in more detail the relation between TGFβ1 mRNA expression and fibrogenesis, the patients were divided into two groups according to the serum level of procollagen Type III peptide: those with high fibrogenic activity (serum procollagen Type III peptide >11.9 μg per liter, corresponding to 2 SD above the mean in the normal subjects) and those with normal fibrogenic activity. The patients with high fibrogenic activity had increased levels of TGFβ1 mRNA, ranging from 2 to 14 times above the amounts found in the control group, whereas the patients with normal fibrogenic activity had TGFβ1 mRNA levels that did not differ from the level in the control group (Fig. 4Figure 4
Hepatic TGFβ1 mRNA Expression in Control Patients and Patients with Chronic Liver Disease Untreated or Treated with Interferon.). Although there was considerable variation, the highest levels of hepatic TGFβ1 mRNA were detected in patients with cirrhosis who had high fibrogenic activity.TGFβ1 mRNA Expression and Tissue Injury
The histologie activity index described by Knodell et al.39 can be used as a semiquantitative method to assess the degree of histologie injury in chronic liver disease. For each patient, the scores for the total index and some subindexes were compared with the levels of TGFβ1 mRNA in the same biopsy sample. TGFβ1 mRNA expression correlated directly with the total index (r = 0.73, P<0.001) and some subindexes (piecemeal necrosis: r = 0.67, P<0.001; fibrosis: r = 0.69, P<0.001; lobular injury: r = 0.54, P<0.005; and portal inflammation: r = 0.53, P<0.01).
Expression of H3 Histone and TGFα mRNAs in Chronic Liver Disease
To assess the level of proliferative activity in the livers of the 42 patients and the control group, we examined the expression of H3 histone gene mRNA in liver specimens. H3 mRNA was detectable by Northern blot analysis of specimens (Fig. 5Figure 5
Representative Northern Blot Analysis of TGFβ1, TGFα, and H3 Histone mRNAs in Liver Specimens.) in all 22 patients with cirrhosis, but in only 11 of 20 patients (55 percent) with chronic hepatitis (P<0.01 by Fisher's exact test). H3 mRNA was also detected in 8 of the 12 control patients, although in very low amounts (Fig. 5).The pattern of expression of TGFα mRNA was similar to that of H3 histone (Fig. 5). TGFα mRNA was detectable in all patients with cirrhosis and in 60 percent of those with chronic hepatitis (P<0.01 by Fisher's exact test) and was present in very low amounts in 4 of the 12 control patients. However, the intensity of the TGFα bands in the Northern blots was lower than that of the H3 histone mRNA (Fig. 5) and close to the limit of sensitivity of the method. Thus, although the determinations of H3 histone mRNA in all patients could be used for quantitative analysis, quantitation of TGFα mRNA was possible in only 16 patients. In these samples the expression of H3 histone mRNA correlated with that of TGFα mRNA (r = 0.70, P<0.01; data not shown).
Effect of Interferon Treatment
TGFβ1 mRNA Expression
Eight patients with chronic hepatitis C virus infection (cirrhosis or chronic hepatitis) and high fibrogenic activity were treated for one year with interferon as described in Methods. Six of these patients (Fig. 4) had a sustained clinical response to treatment, with normalization of serum procollagen Type III peptide levels (concentration before vs. after therapy, 16.4±4.0 vs. 9.3±1.3 μg per liter; P<0.05 by Wilcoxon's signed-rank test) and serum ALT activity. In all six of these patients, hepatic TGFβ1 mRNA expression was in the normal range at the end of the treatment period and did not differ from expression in untreated patients with normal fibrogenic activity or the control patients. TGFβ1 mRNA expression was normal in one patient who had only a transient response to interferon (indicated by the asterisk in Fig. 4), but it remained high in the patient who did not respond to the treatment (indicated by the square in Fig. 4; the serum level of Type III peptide in this patient was 16.0 p.g per liter after therapy). Representative Northern blot analyses of TGFβ1 mRNA in liver specimens of interferon-treated and untreated patients are shown in Figure 6Figure 6
Representative Northern Blot Analysis of TGFβ1 mRNA in Liver Specimens from Patients with Chronic Liver Disease Untreated or Treated with Interferon.. The expression of the mRNA was much lower in the treated and the control patients than in the untreated patients, with the exception of one patient with chronic hepatitis and normal fibrogenic activity, who had low levels of TGFβ1 mRNA (third lane from left, Fig. 6).H3 Histone mRNA Expression and Tissue Injury
The expression of H3 histone mRNA in the patients treated with interferon was similar to that in the control patients (Fig. 7Figure 7
Effect of Interferon Therapy on Hepatic H3 Histone mRNA Expression in Patients with Chronic Hepatitis C Virus Infection.). This was true not only of the six patients who responded to interferon but also of the two who had a transient response or no response to treatment (indicated by the asterisk and square in Fig. 7). Portal and lobular inflammation and the degree of histologie damage decreased (Table 1Table 1
Changes in the Histologie Activity Index and Subindexes in Patients with Chronic Hepatitis C Virus Infection Who Responded to Therapy with Interferon.*) in the seven patients who had some response to treatment (six patients with a sustained response and one with a transient response).Discussion
Although the changes in liver architecture that occur in cirrhosis have been described in detail, the pathogenesis of fibrosis in this process is largely unknown. Collagens Type I and III, present in approximately equal amounts, constitute about 80 percent of the total collagen content of the normal human liver.1 , 4 5 6 7 In fibrosis, the amounts of collagen increase, but the increases in Type I collagen are generally greater than those in Type III, increasing the ratio of Type I to Type III twofold to fourfold.1 , 4 , 5 It is not known whether these changes are due to increased collagen synthesis, decreased collagen degradation, or both.
The expression of procollagen Type I mRNA in the liver is a good indicator of fibrogenic activity.7 , 40 The serum level of procollagen Type III peptide also serves as a marker for liver fibrogenesis, although some peptide may be derived from collagen degradation.1 , 4 , 7 , 41 We found that the expression of TGFβ1 mRNA in the liver correlated directly with both the hepatic level of procollagen Type I mRNA and the serum level of collagen Type III peptide. In patients with increased fibrogenic activity (indicated by high serum levels of procollagen Type III peptide), the expression of hepatic TGFβ] mRNA was 2 to 14 times higher than that in the control patients. These results indicate that collagen synthesis is an important component of fibrogenesis in chronic liver disease, and are in agreement with the work of Annoni et al.42 Furthermore, the results suggest that TGFβ1 may play a part in the pathogenesis of fibrosis in chronic hepatitis and cirrhosis.
In cultured cells, TGFβ1 stimulates the synthesis of collagens and other extracellular matrix components and retards their degradation. 16 17 18 19 20 In addition, TGFβ1 is capable of activating lipocytes, cells that are probably a major site of synthesis of matrix proteins in chronic liver disease.1 , 4 , 6 , 7 , 21 22 23 24 , 43 44 45 46 48 49 A parallel increase in hepatic TGFβ1 and procollagen mRNAs has been found in experimental models of liver fibrosis.21 , 24 In particular, Nakatsukasa et al.24 found increased levels of TGFβ1 mRNA in lipocytes, myofibroblasts, and fibroblasts in rats with carbon tetrachloride-induced liver fibrosis. In the early stages of fibrosis, TGFβ1 mRNA was also detected in inflammatory cells infiltrating the liver. Similar studies are necessary to determine which cells may be the sources of TGFב1 mRNA in the livers of patients with chronic hepatitis or cirrhosis. Nevertheless, it is reasonable to speculate that in the development of cirrhosis, TGβ1 produced by lipocytes and perhaps other nonparenchymal cells induces collagen synthesis in these same cells.
A substantial proportion of patients with chronic hepatitis C have improved during treatment with interferon alfa.50 51 52 53 Although the response to treatment was sometimes transient, the lobular and periportal inflammation of the liver regressed in many patients. As part of a larger study of the effects of this form of interferon in patients with chronic hepatitis C,32 we determined the amount of TGFβ1 mRNA and procollagen Type I mRNA in liver specimens from patients treated with interferon for one year. Patients who responded to treatment had normalization of the biochemical indicators of fibrogenesis (serum level of procollagen Type III peptide and expression of Type I procollagen mRNA in the liver) and normal amounts of liver TGFβ1 mRNA at the end of treatment. Although the number of patients studied was small, the results suggest that treatment with interferon decreases fibrogenesis. In this and other studies,50 , 52 , 53 the histopathological score for liver fibrosis changed little during treatment although the scores for portal inflammation, piecemeal necrosis, and lobular injury decreased. Perhaps the degradation and resorption of fibrous tissue requires more than 12 months, as it does in patients with cirrhosis treated with colchicine.54 We do not know whether the effect of interferon on Type I procollagen mRNA is a consequence of its action on TGFβ31 expression or whether the effect depends on the inhibition of viral replication. In experimental models of liver fibrosis that did not involve viral infection, interferon gamma decreased the expression of procollagen I and III mRNAs in liver cells in a dose-dependent manner, both in vivo and in vitro.55
TGFa mRNA was detected in the livers of all patients with regenerative nodules, but only in some patients with chronic hepatitis but no cirrhosis. In addition, the expression of TGFα mRNA closely correlated with that of H3 histone mRNA, a good indicator of cell proliferation.28 29 30 These findings suggest that in patients with cirrhosis, TGFα is associated with hepatic-cell proliferation as in liver regeneration in rats after partial hepatectomy.31 Hepatocellular necrosis is an important initiating event in both extracellular matrix deposition and cell proliferation (regeneration) in cirrhosis.2 , 4 ' 9 , 27 In patients with chronic hepatitis C who had a sustained response to interferon treatment, serum ALT activity and H3 histone mRNA expression were normal.
In summary, TGFβ1 may have an important role in fibrogenesis in chronic hepatitis and cirrhosis, and interferon therapy in patients with chronic hepatitis C can decrease the expression of TGFβ1 mRNA and procollagen Type I mRNA in the liver. Furthermore, we suggest that TGFα may be associated with cell proliferation in patients with chronic liver disease.
We are indebted to Ms. Deborah A. Martin, Ms. Elizabeth Ko, and Ms. Carol White (Brown University, Providence, R.I.) for technical support; to Dr. Miguel A. Muñoz and Dr. Joan Camps (Clínica Universitaria, Pamplona, Spain) and Dr. Miguel A. Simon (Social Security Hospital, Logroño, Spain) for collaboration in clinical work; and to Drs. G.I. Bell, K. Zaret, L. Biempica, J. Tso, X.-H. Sun, and R. Wu for the gift of various probes.
Source Information
From the Center for Biomedical Research, Department of Internal Medicine, Clinica Universitaria, University of Navarra, Pamplona, Spain (A.C., J.P.), and the Department of Pathology and Laboratory Medicine, Division of Biology and Medicine, Brown University, Providence, R.I. (A.C., N.F.). Address reprint requests to Dr. Fausto at the Department of Pathology, Box G-B518, Brown University, Providence, RI 02912. Supported by Beca Sandoz 1988 from the Spanish Society of Internal Medicine and Beca PF90 16247035 from the Ministerio de Educación y Ciencia of Spain (to Dr. Castilla), a grant from the Fundación Ramon Areces (to Dr. Prieto), and grants (CA-23226 and CA-35249) from the National Cancer Institute (to Dr. Fausto).
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