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Z Halpern

Publications and source records attributed to Z Halpern.

At least 37 records · Page 2Linked to original sources
PubMed2000

Activation of c-K-ras mutations in human gastrointestinal tumors.

BACKGROUND & AIMS: Ras genes are the most frequently detected oncogenes in human malignancies. Data regarding the frequency of c-K-ras mutations in esophageal, gastric, and small bowel tumors are limited and controversial. METHODS: DNA was extracted from 262 formalin-fixed, paraffin-embedded sections of gastrointestinal samples and tumors, including Barrett's esophagus, esophageal squamous cell carcinomas and adenocarcinomas, and small and large bowel adenomas and adenocarcinomas. The presence of c-K-ras codon 12 mutations was determined using a nonradioactive polymerase chain reaction-based restriction fragment length polymorphism assay. RESULTS: c-K-ras mutations were detected in 1 of 39 (2%) patients with Barrett's esophagus, 1 of 21 (5%) adenocarcinomas, 0 of 27 squamous cell carcinomas of the esophagus, and 1 of 32 (3%) gastric adenocarcinomas. It was also present in 8 of 20 (40%) and 10 of 28 (36%) small bowel adenomas and adenocarcinomas, respectively. Similar numbers were observed in 10 of 25 (40%) large bowel adenomas and 11 of 30 adenocarcinomas (37%). Mutations were not associated with age, gender, histology, grade, stage, location, or mortality. CONCLUSIONS: The frequency of codon 12 c-K-ras mutations in small and large bowel tumors is approximately 10-fold higher than that of tumors in the upper gastrointestinal tract.

Adenocarcinoma↗
PubMed2000

The effects of hypothyroidism on liver status of cirrhotic patients.

We have shown, in animal models as well as in retrospective human study, that some degree of decreased thyroid function is beneficial for subjects with liver damage of various etiologies. Therefore, we herein present the results of a cohort population study. Between 1991 and 1994, 18 patients (12 women and 6 men; mean age, 59 +/- 24 years) with both biopsy-proven active cirrhosis (5 hepatitis C virus, 4 hepatitis B virus, 1 immunocompromised host, 2 primary biliary cirrhosis, 1 alcoholic, and 5 cryptogenic; Child's-Pugh criteria: A-8, B-8, C-2) and primary or induced (by either drug or surgery) thyroxine-treated hypothyroidism were prospectively followed. Each patient was examined at least twice yearly and served as their own control. The thyroid of the profiled patients ranged between euthyroidism and subclinical hypothyroidism. Liver function tests were evaluated and compared in states of normal versus increased thyroid-stimulating hormone (TSH) blood levels. A significant improvement in alanine aminotransferase (p < 0.001), alkaline phosphatase (p < 0.0001), albumin (p < 0.001), and bilirubin (p < 0.01) was found in the increased TSH group. Prothrombin time was also found to be significantly better (p < 0.001). We conclude that euthyroid patients with liver cirrhosis might benefit from a controlled hypothyroidism.

Aged↗
PubMed2000

Non-peptidic analogs of the cell adhesion motif RGD prevent experimental liver injury.

In chronic viral hepatitis, autoimmune hepatitis, and some chronic cholestatic liver diseases, T lymphocytes serve as effector cells of the immunostimulatory processes. Cellular interactions of immune cells with extracellular matrix components are regulated primarily via the beta 1 subfamily of integrin receptors. The target epitope of several such integrin receptors is the Arg-Gly-Asp sequence, a cell adhesion motif shared by several matrix-associated adhesive glycoproteins. We review the use of synthetic non-peptidic analogs of RGD in the prevention of immune-mediated, concanavalin A-induced liver damage in mice and in inhibiting the development of liver cirrhosis in rats. The Con A-induced elevation of serum transaminases and tumor necrosis factor-alpha and the infiltration of liver tissue by inflammatory cells were inhibited by pretreatment of the mice with the synthetic RGD mimetics. In rats, the progression of thioacetamide-induced liver cirrhosis was markedly inhibited by the co-administration of the RGD mimetic SF-6,5. The compounds described here may be examined therapeutically for pathological conditions in the liver, manifested as necro-inflammation and fibrosis.

Animals↗
PubMed2000

Additive deleterious effect of smoking on gastroduodenal pathology and clinical course in Helicobacter pylori-positive dyspeptic patients.

BACKGROUND: Cigarette smoking has long been regarded as an important factor in the pathogenesis of peptic ulcer disease. OBJECTIVE: To investigate whether cigarette smoking has an additive effect on the clinical presentation and course of disease in Helicobacter pylori-positive dyspeptic patients. PATIENTS AND METHODS: The study group comprised 596 consecutive H. pylori-positive dyspeptic patients (334 males and 262 females, mean age 50.6, range 12-81 years). Following upper gastrointestinal endoscopy, patients were subdivided by diagnosis as follows: Non-ulcer patient group (n = 312: gastritis 193, duodenitis 119), gastric ulcer (n = 19), and duodenal ulcer (n = 265). H. pylori infection was confirmed by histology and/or rapid urease test. In addition, 244 patients had a positive 14C-urea breath test prior to antimicrobial treatment. The patients' medical history and smoking habits were obtained using a detailed questionnaire completed by the patients and their referring physicians. RESULTS: There were 337 non-smoking patients, 148 current smokers and 111 past smokers. Gastric and duodenal ulcers were significantly less prevalent in non-smokers than in current or past smokers (gastric 1.8%, 4.1%, 6.3%; duodenal 39.8%, 50%, 51.4%, respectively) (P < 0.05). The incidence of gastrointestinal bleeding was significantly lower in non-smokers than in current or past smokers (7.1%, 8.1% and 20.7%, respectively) (P < 0.05). Bacterial density, as assessed by the UBT value in 244 patients, was higher in non-smokers (mean 352.3 +/- 273 units) than in past smokers (mean 320.8 +/- 199) or current-smokers (mean 229.9 +/- 162) (P < 0.05). Logistic regression analysis revealed that male gender, current smoking, and immigration from developing countries were all significant independent risks for developing duodenal ulcer, while only past smoking was associated with a higher rate of upper gastrointestinal bleeding in the past. CONCLUSIONS: In H. pylori-positive dyspeptic patients, current smoking as well as male gender and immigration from developing countries are associated with an increased risk for duodenal ulcer. This effect does not seem to be related to the bacterial density or increased urease activity of H. pylori organisms.

Adolescent↗
PubMed1999

[Photodynamic therapy for dysphagia due to esophageal carcinoma].

Surgery is the mainstay in the treatment of esophageal carcinoma and is effective for palliation of dysphagia. Patients unfit for surgery are difficult therapeutic problems. We evaluated photodynamic therapy for palliation of dysphagia in this condition. Patients were given 5-aminolevulinic acid, 60 mg/kg, orally and 24 hour later gastroscopy was performed during which red light illumination (100 j/cm2 for 600 seconds) was administered. This was repeated 48 hours later. The degree of dysphagia was recorded before and 14 days after treatment. 8 patients with an advanced non-resectable tumor, or who were unfit for surgery, were thus treated. 4 had squamous cell carcinoma of the mid-esophagus and 4 had adenocarcinoma of the lower esophagus. There was mild, self-limited photosensitivity in all. Liver and renal function tests and blood count were not affected by the treatment. Dysphagia was improved in all except 1 patient. A patient with early stage disease continued to eat a normal diet. We believe that photodynamic therapy with systemic aminolevulinic acid as a photosensitizer and a non-laser light source is feasible and safe in advanced esophageal cancer. It is an effective modality for relief of dysphagia in that condition.

Adenocarcinoma↗
PubMed1999

Amphiregulin and hepatocyte-derived extracellular matrix regulate proliferation and autocrine growth factor expression in colon cancer cell lines of varying liver-colonizing capability.

We studied the effect of two members of the epidermal growth factor (EGF) family--amphiregulin and heparin-binding EGF-like growth factor (HB-EGF)-on cell proliferation, growth factor and growth factor receptor expression, and cell differentiation in two human colon cell lines of varying liver-colonizing potential. The effect of amphiregulin and HB-EGF was assessed both in cells grown on plastic, as well as on cells grown on hepatocyte-derived extracellular matrix (ECM). We found that both colon cell lines were sensitive to HB-EGF stimulation of cell proliferation. Amphiregulin inhibited cell proliferation in KM12 cells and stimulated the strongly metastatic cell line KM12SM to a slight extent. When the cells were cultured on hepatocyte-derived ECM, amphiregulin inhibited the weakly metastatic KM12 and stimulated the growth of KM12SM. HB-EGF synergistically acted with hepatocyte-derived ECM to enhance cell proliferation in both colon cell lines. Expression of ligands of the EGF family, such as transforming growth factor-alpha (TGF-alpha) and amphiregulin, was decreased in both cell lines when cultured on ECM. Hepatocyte-derived ECM decreased expression of cripto in KM12 and increased it in KM12SM cells. Neither cripto nor TGF-alpha mRNA levels was affected by growing the cells in the presence of amphiregulin. However, amphiregulin increased expression of its own mRNA in the weakly metastatic KM12 and decreased it in the strongly metastatic KM12SM when the cells were cultured on plastic. Amphiregulin and HB-EGF stimulated expression of erb-B2 in both cell lines cultured on plastic. Surprisingly, when the cells were grown on hepatocyte-derived ECM, amphiregulin inhibited erb-B2 expression in both cell lines. We observed no effect of amphiregulin on cell differentiation as assessed by alkaline phosphatase expression. Our studies demonstrate one mechanism that could play a role in site-specific metastasis. We found an inhibitory response to an autocrine growth factor in the context of hepatocyte-derived ECM in a weakly metastatic cell and a stimulatory effect of the same growth factor when strongly metastatic cells were cultured on the same ECM.

Amphiregulin↗
PubMed1999

Evaluation of a new immunochromatographic test for Helicobacter pylori IgG antibodies in elderly symptomatic patients.

AIM: To determine the diagnostic value of a new serum and whole blood serological IgG antibody test, FlexPack HP, for the diagnosis of Helicobacter pylori in elderly symptomatic patients. METHODS: 94 consecutive symptomatic patients who underwent upper endoscopy were studied (mean age, 62.6 years). On endoscopy, the presence of H. pylori infection was examined by biopsies from gastric antrum and body for rapid urease test and histologic examination. Blood was drawn prior to endoscopy and both blood and serum were immediately analyzed for human IgG antibodies to H. pylori by a new commercially available qualitative immunochromatographic method, FlexPack HP. This test incorporates high-molecular weight cell-associated proteins (HM-CAP), which are highly specific for H. pylori IgG antibodies. RESULTS: Overall agreement for FlexPack HP whole blood vs FlexPack HP serum was 100%, and agreement with biopsy results was 71%. The gold standard (detection of H. pylori by histology or urease test) identified H. pylori in 61 patients (65%). Complete agreement was observed between the gold standard test and the serology kit in 72% (68/94) of sera (51 positive and 17 negative). Disagreement was found in sera of 26 patients; 16 sera were negative by the gold standard and positive by FlexPack HP and 10 patients were found negative by serology. The sensitivity of FlexPack HP was 84% and the specificity 52% when compared with the gold standard. CONCLUSIONS: FlexPack HP serum and whole blood test is a simple and reliable method for the detection of H. pylori antibodies, with 100% agreement between the serum and blood results. In the elderly symptomatic patients the sensitivity of FlexPack HP was similar to that of other serologic tests, but the specificity was relatively low, limiting its use in this population.

Aged↗
PubMed1999

The hydroxyl radical scavengers dimethylsulfoxide and dimethylthiourea protect rats against thioacetamide-induced fulminant hepatic failure.

BACKGROUND/AIMS: Reactive oxygen species, proinflammatory cytokines, glutathione depletion and nitric oxide have all been implicated in the pathogenesis of fulminant hepatic failure. The aim of the present study was to examine the respective roles of these factors in the pathogenesis of thioacetamide-induced fulminant hepatic failure in rats. METHODS: Fulminant hepatic failure was induced by 3 consecutive intraperitoneal injections of thioacetamide (400 mg/kg) at 24-h intervals. Rats were pretreated with one of the following agents: the free radical scavengers dimethylsulfoxide (4 g/kg every 6 h) or dimethylthiourea (200 mg/kg every 12 h), the glutathione donor, N-acetylcysteine (130 or 200 mg/kg every 6 h), or the anti-tumor necrosis factor-alpha agents pentoxifylline (100 and 200 mg/kg) and soluble tumor necrosis factor receptor (100 or 1000 microg/rat). The nitric oxide synthase inhibitor N-mono-methyl arginine ester (L-NAME, 0.1 mg/ml) was administered in the drinking water, starting 7 days prior to thioacetamide administration. RESULTS: Serum levels of liver enzymes, blood ammonia and prothrombin time and the stage of hepatic encephalopathy were significantly improved in rats treated with dimethylsulfoxide or dimethylthiourea compared to the other treatment groups (p<0.001). Liver histology and the survival rate in these rats were not adversely affected by thioacetamide administration (p<0.001), while in all the other treatment groups those parameters were similar to control rats with fulminant hepatic failure. Furthermore, dimethylsulfoxide ameliorated liver damage and improved survival even when its administration was initiated 8 and 16 h after the first thioacetamide injection. The hepatic concentration of methanesulfinic acid, which is produced after direct interaction of dimethylsulfoxide with hydroxyl radicals, was increased five-fold in rats treated with thioacetamide+dimethylsulfoxide (p<0.001), suggesting a role for hydroxyl radical scavenging in the protection from fulminant hepatic failure in this model. In the group of thioacetamide-treated rats that were pretreated with L-NAME, liver enzymes, blood ammonia levels and the mortality rate were higher than in the control group, treated with thioacetamide only. CONCLUSIONS: In thioacetamide-induced fulminant hepatic failure, the hydroxyl radical scavengers dimethylsulfoxide and dimethylthiourea prevent liver injury. Neither N-acetylcysteine nor antagonists of tumor necrosis factor-alpha are protective in this rat model. Inhibition of nitric oxide formation aggravates liver damage and reduces the survival of rats with thioacetamide-induced liver damage.

Alanine Transaminase↗
PubMed1999

Treatment of concanavalin A-induced hepatitis in mice with low molecular weight heparin.

BACKGROUND/AIMS: Heparin has been noted to inhibit inflammation independent of its known anti-coagulant activity. In the present study, we examined the ability of heparin and low molecular weight heparin to prevent immune-mediated, concanavalin A-induced liver damage. METHODS: Mice were pretreated with either heparin or low molecular weight heparin (Fragmin) prior to their inoculation with concanavalin A (10 mg/kg). Liver enzymes, liver histology, and the serum levels of tumor necrosis factor-a, interleukin-6, and interleukin-10 were examined in the control and treated mice. RESULTS: The histopathologic damage in the liver, and the concanavalin A-induced release of aminotransferases, tumor necrosis factor-a, and interleukin-6 were significantly inhibited in mice pretreated with low molecular weight heparin, whereas the serum levels of the anti-inflammatory cytokine interleukin-10 were increased (p<0.01). Interestingly, maximal inhibition was obtained with low low molecular weight heparin doses (5 and 1 microg/mouse, p<0.001), while higher doses were less effective. Concanavalin A-induced liver injury was not prevented by pretreatment of the mice with heparan sulphate (p<0.001), which although it is structurally similar to heparin possesses neither anti-inflammatory nor anti-coagulant properties. CONCLUSIONS: This study demonstrates the efficacy of low molecular weight heparin in preventing immune-mediated liver damage in mice.

Alanine Transaminase↗
PubMed1999

Hypothyroidism protects rat liver from acetaminophen hepatotoxicity.

Recent data from animal studies suggest that induced hypothyroidism inhibits the development of liver injury in several animal models, including liver cirrhosis and fulminant hepatic failure in rats, and immune-mediated acute liver injury in mice. The aim of the present study was to determine whether hypothyroidism would likewise prevent acetaminophen-induced hepatic damage in rats. Liver damage was induced by acetaminophen (2 g/kg) administered by gavage to fasting rats as a single dose. Hypothyroidism was induced by methimazole, propylthiouracil, or surgical thyroidectomy and confirmed by elevated serum levels of TSH. Hypothyroidism significantly inhibited acetaminophen-induced liver damage as manifested by the decreased serum levels of liver enzymes, malondialdehyde and blood ammonia, as well as by the higher hepatic glutathione content, in all three groups of hypothyroid rats compared to euthyroid controls (P < 0.01). Histopathologic analysis showed significantly less liver necrosis and inflammation in the acetaminophen-treated hypothyroid rats. Oxygen extraction, measured in isolated perfused rat liver preparation, was also reduced in the hypothyroid livers to 42+/-8% compared to 81+/-14% of controls (P < 0.01). However, the expression of CYP2E1 in the livers of hypothyroid rats, as measured by western blot analysis, was not decreased compared to control rats. These results suggest that induced hypothyroidism, regardless of the mode of induction, protects rat liver from acetaminophen hepatotoxicity. This effect may be related to hypometabolism of liver cells, but the exact mechanism needs further clarification.

Acetaminophen↗
PubMed1999

Inhibition of concanavalin A-induced acute T cell dependent hepatic damage in mice by hypothyroidism.

AIMS/BACKGROUND: Concanavalin A (Con A) activates T lymphocytes and causes acute T-cell-mediated hepatic injury in mice. Decreased thyroid hormonal production is associated with a variety of immunological manifestations, including inactivation of macrophages with reduced TNF production and reduced soluble IL-2 receptors in the serum. We have recently shown that hypothyroidism prevents the development of cirrhosis and also minimizes hepatic damage in rats with fulminant hepatic failure. In the present study we examined the effects of hypothyroidism on a mouse model of Con A induced T cell-mediated acute hepatitis. METHODS: Hypothyroidism was induced both medically (MMI, PTU) and surgically. Eight groups of 10 mice each were studied: euthyroid controls (2 groups: water, Con A) and hypothyroid (6 groups: MMI, PTU, Surgical, MMI-Con A, PTU-Con A, Surgical-Con A). RESULTS: Hepatic inflammation was significantly decreased in each of the Con A treated hypothyroid groups of mice. The serum transaminases, TNF-alpha and IL-6 levels were significantly elevated in the Con A treated group while near normal levels were found in the hypothyroid Con A treated groups (mean+/-SE AST: 1499+/-18 vs 78+/-10 IU/l, p<0.001; TNF: 2500+/-250 vs 135+/-15 pg/ml, p<0.001, IL-6: 12,200+/-300 vs 1260+/-140 pg/ml, p<0.001, respectively). CONCLUSIONS: Hypothyroidism, independent of the mode of induction, can effectively inhibit the development of acute T cell-mediated liver damage in mice. These results suggest that some decrease in thyroid function might have a role in the prevention of immune mediated liver diseases.

Alanine Transaminase↗
PubMed1999

Altered thyroid status modulates portal pressure in normal rats.

BACKGROUND & AIMS: Disturbances in thyroid function in humans and experimental animal models have been associated with alterations in liver function and portal circulation. We have previously shown that hypothyroidism can significantly reduce portal pressure in portal vein ligated rats as well as inhibit the development of cirrhosis and fulminant hepatic failure following toxic liver injury. The aim of this study was to determine the effects of increased and decreased thyroid function on portal pressure in rats with normal liver histology and portal circulation. METHODS: Three groups of 12 Wistar rats each were studied over a 30 day period: euthyroid (Group 1), hyperthyroid (Group 2) and hypothyroid (Group 3). Hyperthyroidism was induced by subcutaneous injection of triiodothyronine (400 microg/100g body weight) every ten days during the study period. Hypothyroidism was induced by methimazole (0.04% in drinking water) from 2 weeks prior to and throughout the 30 day study. Serum triiodothyronine (T3) and thyroid stimulating hormone (TSH) levels were determined to confirm the induction of hyper- and hypothyroidism. Portal pressure was assessed by direct catheterization of the portal vein prior to sacrifice. Indirect confirmation of changes in portal circulation was obtained by determining splenic weight at the time of sacrificing the animals. Animals were sacrificed at 10 day intervals throughout the 30 day study. RESULTS: Triiodothyronine treated rats were hyperthyroid compared to controls, with an elevation in serum T3 levels (3.8+/-0.9 mmol/L vs 1.3+/-0.4 mmol/L, p<0.05). In rats treated with methimazole, hypothyroidism was confirmed by a 7-fold increase in serum TSH compared to controls (1.8+/-0.4 vs 0.24+/-0.04 mmol/L, p<0.01). Portal pressure was significantly higher in the triiodothyronine treated rats compared to controls (12.8+/-1.7 and 9.6+/-0.75 cm H2O, p<0.001). Splenic weights in hyperthyroid rats were significantly higher than in controls (579+/-44 vs 478+/-46 mg, p<0.01). Portal pressure was significantly lower in the methimazole treated group compared to the control group (8.13+/-0.68 vs 9.6+/-0.75 cm H2O, p<0.01) as were splenic weights (400+/-33 vs 478+/-46 mg, p<0.01). CONCLUSION: These studies demonstrate that disturbed thyroid function exerts significant hemodynamic effects on the portal circulation in normal rats and complements results from previous similar studies in cirrhotic animals.

Administration, Oral↗
PubMed1999

The efficacy of omeprazole-based short-term triple therapy in Helicobacter pylori-positive older patients with dyspepsia.

OBJECTIVE: To evaluate the efficacy of 1-week triple therapy with omeprazole, clarithromycin,and tinidazole (OCT) in Helicobacter pylori-positive older patients with dyspepsia. DESIGN: A prospective, nonrandomized therapeutic study. SETTING: The primary care and referral center of a gastroenterological outpatient clinic at a central university hospital serving an urban population (>1 million) in Israel. PARTICIPANTS: The study group consisted of 134 patients (71 men, and 63 women) more than 60 years old who were referred for evaluation of symptoms of dyspepsia and were endoscopically diagnosed as H. pylori positive. The patients were divided into two groups: those who received their first course of anti-H. Pylori therapy during this study (Group 1) and those who had previously received standard metronidazole and bismuth combination therapies that failed to eradicate the H. pylori (Group 2). MEASUREMENTS: All the patients underwent upper gastrointestinal endoscopy, and H. pylori infection was confirmed by a rapid urease test (CUTest) and/or histological staining. Therapeutic efficacy was assessed by a 13C-urea breath test 4 weeks after completion of treatment. RESULTS: The mean age of the study population was 68.8 years (range 60-87). There were 112 patients in Group 1 and 22 patients in Group 2. Endoscopic findings were: gastritis (in 46), gastric ulcer (8), duodenal ulcer (52), and duodenitis (28). The H. pylori eradication rate was significantly higher in Group 1 patients (104/112, 92.9%) than in patients of Group 2 (15/22, 68.2%). There was no difference in the eradication rate in relation to gender, endoscopic diagnosis, more advanced age, place of birth, or smoking habits. The compliance in both groups was equally good, and no major side effects were recorded. CONCLUSIONS: A 1-week OCT triple therapy is well tolerated and effective as first line therapy for H. pylori among older people. It is less effective in patients previously treated.

Aged↗
PubMed1998

Hepatocyte extracellular matrix modulates expression of growth factors and growth factor receptors in human colon cancer cells.

We investigated the role of hepatocyte extracellular matrix (ECM) on the growth of human colon cancer cell lines. We cultured four cell lines with different liver-colonizing potential on ECM derived from primary rat hepatocyte cultures. We investigated the effect of ECM on cell proliferation, clonal growth, and expression of growth factors and growth factor receptors. The highly metastatic cells showed better clonal growth and produced larger colonies on ECM. The proliferation of all colon cancer cell lines was enhanced on hepatocyte ECM, yet inhibited on fibroblast ECM. Screening of autocrine growth factors and receptors showed that the cells expressed growth factors and receptors of the EGF family: EGF receptor, erb-B2, amphiregulin, and cripto. The expression of cripto mRNA, but not of amphiregulin, was induced in KM12SM cells grown on ECM. All colon cancer cell lines grown on ECM showed increased expression of erb-B2. The effect of ECM on erb-B2 expression was mediated by the heparin chains of heparin proteoglycan. ECM from hepatocytes grown in the presence of nitrophenyl-beta-D-xylopyrannoside or sodium chlorate, which prevent formation of heparin proteoglycan, as well as ECM treated with heparinase, had no effect on erb-B2 expression. Our studies suggest a role for liver ECM as a determinant of colon cancer metastasis. Liver ECM acts, in part, via induction of members of the EGF family of growth factors and their receptors.

Animals↗
PubMed1998

Extracellular matrix modulates expression of growth factors and growth-factor receptors in liver-colonizing colon-cancer cell lines.

Site-specific metastasis is determined by the extracellular matrix (ECM) of the colonized organ. We have shown that hepatocyte-derived ECM stimulated proliferation of colon-cancer cells via induction of autocrine growth factors and their receptors. The ECM component responsible was heparin proteoglycan. We therefore investigated the effect of exogenously added heparin on colon cell lines of varying liver-colonizing potential. The cells were grown on typical liver matrix components, such as fibronectin and collagens type I and IV. We assessed the effect of these matrix components on clonal growth, proliferation and expression of autocrine growth factors and their receptors. The clonal growth of the KM12 cells was not affected by heparin, while the other cell lines were inhibited by heparin. Cell proliferation in weakly metastatic KM12, but not in strongly metastatic KM12SM, was inhibited by heparin on plastic. Weakly metastatic LS174T, but not strongly metastatic LiM6, was inhibited by heparin on fibronectin. Expression of erb-B2 was also differently modulated by heparin in weakly metastatic vs. highly metastatic cells. In weakly metastatic cells, heparin reduced erb-B2 levels when cells were on plastic and fibronectin, while in strongly metastatic cells, erb-B2 was induced by heparin. In all 4 cell lines, mRNA for cripto was induced by heparin when the cells were grown on fibronectin. In KM12SM cells, amphiregulin was induced by heparin in cells on fibronectin and collagen IV. We show that soluble heparin, similar in its carbohydrate chemistry to liver heparin proteoglycan, regulates the growth of colon-cancer cells. This effect depends on other matrix components found in the liver and is mediated in part by EGF family members.

Amphiregulin↗
PubMed1998

Hypothyroidism minimizes liver damage and improves survival in rats with thioacetamide induced fulminant hepatic failure.

Recent data from animal studies suggest that induced hypothyroidism prevents the hyperdynamic circulation in portal vein ligated rats, liver cirrhosis in rats chronically treated with thioacetamide (TAA), and immune-mediated acute liver injury induced in mice by concanavalin A. Therefore, the aim of this present study is to determine whether hypothyroidism would likewise prevent fulminant hepatic failure (FHF) in rats. FHF was induced by 3 consecutive ip injections of TAA (400 mg/kg) at 24-hour intervals. Hypothyroidism was induced in rats by either methimazole (MMI) or propylthiouracil (PTU) and surgical thyroidectomy and was confirmed by elevated serum thyroid stimulating hormone levels. Serum levels of liver enzymes, blood ammonia, and prothrombin time were significantly lower in all 3 groups of hypothyroid rats. The stage of hepatic encephalopathy (HE) and the survival rates were significantly improved in the hypothyroid rats (P < .01); the histologic examination of their livers showed less necrosis and inflammation (P < .01). In the hypothyroid rats, the serum levels of malondialdehyde 48 hours after thioacetamide (TAA) administration were lower than in control rats (P < .01). Exogenous supplementation of hypothyroid rats with L-thyroxine started 48 hours before TAA administration abrogated the protective effects of hypothyroidism. The serum levels of tumor necrosis factor alfa (TNF-alpha), interleukin (IL) 2 and IL-6 after 24 hours were slightly lower in the hypothyroid rats, but the administration of soluble receptor of TNF (10-1,000 microg/rat) did not prevent the induction of fulminant liver failure by TAA. Oxygen extraction, studied in isolated perfused liver preparation, was significantly lower in livers of hypothyroid rats (P < .01). These results suggest that induced hypothyroidism decreases the development of liver injury in a rat model of FHF. The mechanism may involve diminished oxidative cell injury caused by decreased oxygen utilization and hypometabolism associated with hypothyroidism.

Ammonia↗