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Biomedical subjects

H Friess

Publications and source records attributed to H Friess.

At least 307 records · Page 17Linked to original sources
PubMed1994

Increased expression of acidic and basic fibroblast growth factors in chronic pancreatitis.

Acidic fibroblast growth factor (aFGF) and basic fibroblast growth factor (bFGF) belong to a family of mitogenic polypeptides that are involved in cellular proliferation and differentiation. In this study we investigated the potential role of aFGF and bFGF in chronic pancreatitis (CP), a fibrotic condition associated with acinar cell dedifferentiation and atrophy, and fibroblastic proliferation. By immunohistochemistry, aFGF and bFGF were abundant in pancreatic ductal and acinar cells in pancreatic tissues from CP patients. Immunoblotting with the same highly specific monoclonal antibodies demonstrated a marked increase in aFGF and bFGF in pancreatic homogenates from CP patients by comparison with the normal pancreas. Northern blot analysis indicated that, by comparison with normal controls, 16 of 21 CP tissues exhibited a 14-fold increase in aFGF mRNA levels, and 19 of 21 CP tissues exhibited a 15-fold increase in bFGF mRNA levels. In situ hybridization confirmed that this overexpression occurred in ductal and acinar cells, and indicated that both mRNA moieties colocalized with their respective proteins. These findings suggest that aFGF and bFGF may either be involved in the pathobiological mechanisms that occur in CP, or that their overexpression may be the consequence of other perturbations that occur in this disorder.

Adult↗
PubMed1994

[Molecular biology of pancreatic cancer: overexpression of fibroblast growth factors].

In the present study, the expression of a acidic fibroblast growth factor (aFGF), basic fibroblast growth factor (bFGF) and fibroblast growth factor receptor-1 were analyzed in 60 pancreatic cancer samples using Northern blot analysis, immunoblotting, in situ hybridization and immunohistochemical techniques. aFGF, bFGF and FGFR-1 were present in 63%, 55% and 52% of the tumor samples, respectively. Twenty-seven of the 60 pancreatic cancer tissue samples exhibited coexpression of aFGF and bFGF. In contrast, 14 of the tumor samples did not show immunoreactivity for aFGF or bFGF in the tumor cells. The expression of aFGF in the tumor cells had no influence on the postoperative survival period, whereas patients whose tumors were positive for bFGF and/or FGF-receptor-1 had significantly shorter postoperative survival periods. Our results suggest that bFGF and FGFR-1 may play a role in the growth behavior of pancreatic cancer and may contribute to tumor aggressiveness.

Adult↗
PubMed1994

Balance of expression of genes coding for extracellular matrix proteins and extracellular matrix degrading proteases in chronic pancreatitis.

Chronic pancreatitis is characterized by proliferation of the extracellular matrix and by increased deposition of interstitial extracellular matrix proteins (collagens type I and III, fibronectin). In this study we analyzed the balance of expression of mRNAs encoding extracellular matrix components (collagens I, III and IV, laminin, fibronectin), extracellular matrix degrading metalloproteinases (MMP-1, -2 and -3) and tissue inhibitors of metalloproteinases (TIMP-1 and -2) in chronic pancreatitis (n = 8) and control pancreas (n = 7) by northern blot analysis. Transcripts for MMP-1 (interstitial collagenase), MMP-3 (stromelysin) and TIMP-1 were not detectable in chronic pancreatitis and control tissues. Steady-state levels of transcripts encoding extracellular matrix proteins, MMP-2 (72 kDa collagenase IV) and TIMP-2 were enhanced in 7 out of 8 chronic pancreatitis tissue samples and showed a large degree of variation between individual patients. Transcript levels could not be correlated to the histologically detectable degree of inflammation and fibrosis or to the total amount of deposited collagen protein, which was high in all chronic pancreatitis tissue samples as determined by a standard colorimetric procedure. Increased steady state levels of transcripts encoding extracellular matrix proteins or extracellular matrix degrading proteases may thus reflect the activity of processes involved in the remodeling of the gland during chronic inflammation. The precise role of overexpression of MMP-2 and its inhibitor TIMP-2 will have to be elucidated in further studies.

Chronic Disease↗
PubMed1993

Overexpression of acidic and basic fibroblast growth factors in human pancreatic cancer correlates with advanced tumor stage.

Acidic fibroblast growth factor (aFGF) and basic FGF (bFGF) are mitogenic polypeptides that may contribute to cancer cell proliferation. In the present study we examined aFGF and bFGF expression in human pancreatic cancer. Northern blot analysis of total RNA isolated from 12 pancreatic cancers revealed elevated aFGF and bFGF mRNA levels in 12 and 10 samples, respectively, by comparison with the normal human pancreas. Immunostaining demonstrated the presence of aFGF and bFGF in many cancer cells and in the atrophic acini and ducts adjacent to the cancer cells, but to a much lesser extent in the surrounding fibroblasts. By in situ hybridization, both mRNA moieties colocalized with their respective proteins and were abundant in many cancer cells. Immunoblotting confirmed that cancer tissues with increased aFGF and bFGF immunoreactivity contained elevated levels of both proteins. To determine the significance of aFGF and bFGF expression in the pancreatic cancer cells, immunohistochemical analysis of 78 human pancreatic carcinomas was performed. aFGF and bFGF immunoreactivity was present in the cancer cells in 47 (60%) and 44 (56%) of the tumors, respectively. There was a significant correlation between the presence of either aFGF or bFGF in the cancer cells and advanced tumor stage, and the presence of bFGF and shorter patient survival. These data suggest that aFGF and bFGF are overexpressed in a significant proportion of human pancreatic carcinoma cells and that this overexpression may contribute to disease progression.

Adult↗
PubMed1993

Aberrant expression of type I fibroblast growth factor receptor in human pancreatic adenocarcinomas.

Acidic and basic fibroblast growth factors are mitogenic polypeptides that are overexpressed in pancreatic cancer. To determine whether fibroblast growth factors may exert direct effects on pancreatic cancer cells in vivo, we compared the expression of the high-affinity type I fibroblast growth factor receptor (FGFR-1) in human pancreatic tissues. In the normal pancreas, FGFR-1 immunostaining was seen mainly in acinar cells. In pancreatic cancers, FGFR-1 was abundant in ductal-like cancer cells which also exhibited many FGFR-1 mRNA in situ hybridization grains. Analysis by the polymerase chain reaction and RNase protection revealed that the 2-immunoglobulin-like and the 3-immunoglobulin-like forms of FGFR-1 were expressed in all tissue samples, and that the 2-immunoglobulin-like form was overexpressed in the cancer tissues by comparison with the normal tissues. These findings suggest that the 2-immunoglobulin-like form of FGFR-1 may contribute to aberrant autocrine and paracrine pathways in pancreatic cancer.

Adenocarcinoma↗
PubMed1993

Enhanced expression of the type II transforming growth factor beta receptor in human pancreatic cancer cells without alteration of type III receptor expression.

We have recently found that human pancreatic adenocarcinomas exhibit strong immunostaining for the three mammalian transforming growth factor beta (TGF-beta) isoforms. These important growth-regulating polypeptides bind to a number of proteins, including the type I TGF-beta receptor (T beta R-I), type II TGF-beta receptor (T beta R-II), and the type III TGF-beta receptor (T beta R-III). In the present study we sought to determine whether T beta R-II and T beta R-III expression is altered in pancreatic cancer. Northern blot analysis indicated that, by comparison with the normal pancreas, pancreatic adenocarcinomas exhibited a 4.6-fold increase (P < 0.01) in mRNA levels encoding T beta R-II. In contrast, mRNA levels encoding T beta R-III were not increased. In situ hybridization showed that T beta R-II mRNA was expressed in the majority of cancer cells, whereas mRNA grains encoding T beta R-III were detectable in only a few cancer cells and were present mainly in the surrounding stroma. These findings suggest that enhanced levels of T beta R-II may have a role in regulating human pancreatic cancer cell growth, while T beta R-III may function in the extracellular matrix.

Adenocarcinoma↗
PubMed1993

p53 mutations are common in pancreatic cancer and are absent in chronic pancreatitis.

Pancreatic expression of the p53 tumor suppressor gene was studied in pancreatic adenocarcinomas and chronic pancreatitis. By immunohistochemistry, 16 of 34 (47%) cancers and none of the 24 chronic pancreatitis samples revealed nuclear staining. Sequence analysis indicated that 8 of 24 (33%) cancers were mutated for the p53 gene. Point substitutions occurred at codons 35, 105, 133, 213, 213, 258, and 299. A three base-pair in-frame insertion was identified between codons 261 and 262. None of 8 chronic pancreatitis samples exhibited p53 gene mutations. These data support a role for p53 gene alterations in human pancreatic cancer, and suggest that loss of its regulatory functions may constitute one of the differences between pancreatic cancer and chronic pancreatitis.

Adenocarcinoma↗
PubMed1993

CA 494--a new tumor marker for the diagnosis of pancreatic cancer.

In 59 patients with ductal pancreatic cancer the monoclonal antibody (MAb) BW 494, which detects the CA 494 glycoprotein antigen, was analyzed in comparison with the reference tumor markers CA 19-9 and CEA. Eighty-one patients with non-pancreatic malignancies of the gastrointestinal (GI) tract, 95 with chronic pancreatitis, 124 with benign non-pancreatic GI diseases, 30 with diabetes mellitus (type I or type II) and 114 healthy blood donors served as controls. The sensitivity of pancreatic cancer was 90%, 44% and 90% for CA 19-9, CEA and CA 494, respectively. In chronic pancreatitis, as the most important control population for pancreatic cancer, the specificity was 85%, 72% and 94% for CA 19-9, CEA and CA 494, respectively.

Adolescent↗
PubMed1993

Gallbladder dynamics in chronic pancreatitis. Relationship to exocrine pancreatic function, CCK, and PP release.

Gallbladder dynamics, cholecystokinin (CCK), and pancreatic polypeptide (PP) release were studied in 14 patients with chronic pancreatitis (CP) (2 females, 12 males; age range 24-56 years) and 12 control subjects (4 females, 8 males, 21-50 years). On day 1, gallbladder contractility was investigated after ceruletide intravenous infusion (2.5 ng/kg/min for 10 min). On day 2, a mixed standard test meal (1450 kJ) was administered orally. Gallbladder volume was assessed at three time intervals before (-30, -15, 0 min) and at 5, 10, 20, 30, 40, 50, 60, 80, 100 and 120 min after stimulation by means of ultrasonography. CCK and PP plasma levels were determined at each time interval. Exocrine pancreatic function was assessed using the pancreolauryl serum test (PLT). Six patients with CP had severe exocrine pancreatic insufficiency (EPI) (PLT < 1.8 micrograms/ml) with steatorrhea, eight patients had mild-moderate EPI. Fasting gallbladder volume was increased in CP (32.3 +/- 3.1 cm3) as compared to controls (20.5 +/- 1.2 cm3) (P < 0.01). Peak gallbladder contraction (percent of initial volume) in CP ranged from 5 to 55% (controls: 8-46%) following ceruletide and from 17 to 86% (controls: 27-80%) following the test meal (NS). There was no correlation between the degree of EPI according to PLT and peak gallbladder contraction. Gallbladder emptying in CP patients was not different from controls, although the postprandial CCK response was significantly impaired (P < 0.01). Postprandial PP response in CP was correlated with the PLT result (r = 0.78; P < 0.01) but not with gallbladder emptying or refilling time.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Enhanced expression of transforming growth factor beta isoforms in pancreatic cancer correlates with decreased survival.

BACKGROUND: Transforming growth factor beta s (TGF-beta s) constitute a family of bifunctional polypeptide growth factors that either inhibit or stimulate cell proliferation. Perturbations in TGF-beta expression and function may lead to loss of negative constraints on cell growth. In this study, we examined TGF-beta expression in human pancreatic cancer. METHODS: The distribution of TGF-beta isoforms in 60 human pancreatic cancers was examined using immunohistochemical, Northern blot, and in situ hybridization techniques. RESULTS: Immunohistochemical analysis showed the presence of TGF-beta 1 (47% of tumors), TGF-beta 2 (42% of tumors), and TGF-beta 3 (40% of tumors) in the cancer cells. The presence of TGF-beta 2 was associated with advanced tumor stage (P < 0.05). Furthermore, there was a significant correlation between the absence of TGF-beta s in the tumors and longer postoperative survival. Northern blot analysis indicated that, by comparison with the normal pancreas, pancreatic adenocarcinomas showed 11- (P < 0.001), 7- (P < 0.05), and 9-fold (P < 0.001) increases in the messenger RNA (mRNA) levels encoding TGF-beta 1, TGF-beta 2, and TGF-beta 3, respectively. By in situ hybridization, these mRNA moieties colocalized with their respective proteins in the cancer cells. CONCLUSIONS: These findings show that human pancreatic cancers show increased levels of TGF-beta isoforms and enhanced TGF-beta mRNA expression and suggest that the presence of TGF-beta s in pancreatic cancer cells may contribute to disease progression.

Adenocarcinoma↗
PubMed1993

Overexpression of HER2/neu oncogene in human pancreatic carcinoma.

The HER2/neu oncogene encodes a transmembrane protein that possesses intrinsic tyrosine kinase activity. Its overexpression has been associated with the malignant phenotype. In this study we examined HER2/neu expression in the normal and cancerous human pancreas. In the normal pancreas HER2/neu immunostaining was observed in acinar and ductal cells. HER2/neu immunoreactivity was expressed in 34 of 76 (45%) pancreatic carcinomas. There was a significant correlation between tumors with well-differentiated histology and HER2/neu expression. Northern blot analysis demonstrated HER2/neu mRNA expression in the normal pancreas and in situ hybridization confirmed its distribution in both acinar and ductal cells. In cancer tissues Northern blot analysis indicated that HER2/neu mRNA levels were elevated in 13 of 25 (52%) of the tumors in comparison with the normal tissues. In addition, in situ hybridization demonstrated a strong but heterogenous distribution of mRNA grains in these tumors. Southern blot analysis did not demonstrate HER2/neu gene amplification in any of the tumors. These data indicate that the HER2/neu protein is synthesized in the normal exocrine pancreas and is frequently overexpressed in well-differentiated adenocarcinomas of the pancreas as a result of increased HER2/neu mRNA levels.

Adult↗
PubMed1993

Low-dose octreotide treatment is not effective in patients with advanced pancreatic cancer.

Octreotide (SMS 201-995), a long-acting somatostatin analogue, has been shown to decelerate growth of human pancreatic cancer in vitro and in vivo. We analyzed the efficacy of octreotide treatment in 22 patients (14 men, 8 women) with histologically verified ductal pancreatic cancer. All patients had advanced tumor stages (stage III: 13 patients; stage IV: 9 patients). Octreotide was given by self-administered subcutaneous injection (3 x 100 micrograms/day). When there was evidence of tumor progression, the dose of octreotide was increased to 3 x 200 micrograms/day. A monthly follow-up, including clinical status, CT scan or ultrasonography, and tumor marker carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19-9 determination was carried out. There were no severe side effects apart from slight burning sensation at the injection site. No partial or complete remission was seen. Eighteen patients showed tumor progression with a median survival time of 17 weeks (range 3-42 weeks). In three patients a "no change" evaluation with a median survival time of 46 weeks (range 40-68 weeks) was registered. In these three patients the serum tumor markers CA 19-9 and CEA did not show an increase to more than twice the baseline value during this time. One patient discontinued the octreotide treatment because of tumor progression. The results of the analysis indicate that low-dose octreotide treatment is not effective in patient suffering from advanced tumor stages of pancreatic cancer.

Adenocarcinoma↗
PubMed1993

Prevention of postoperative complications following pancreatic surgery.

Major pancreatic resection is still accompanied by considerable morbidity and even mortality. Complications which occur after pancreatic surgery are chiefly associated with exocrine pancreatic secretion, hence, the inhibition of exocrine pancreatic secretion perioperatively is a promising concept in the prevention of complications. The hormone somatostatin and its synthetic analogue octreotide have been shown to profoundly inhibit exocrine pancreatic secretion, particularly the secretion of proteases. In a randomized, placebo-controlled, multicenter double-blind trial we analyzed the potential role of octreotide in the prevention of postoperative complications after major pancreatic surgery. A significant reduction in complications such as fistula, abscess, fluid collection, sepsis, pulmonary insufficiency, and postoperative acute pancreatitis could be demonstrated in patients who received octreotide at 3 x 100 micrograms/day subcutaneously. Octreotide was particularly effective in patients undergoing Whipple resection for cancer.

Double-Blind Method↗
PubMed1993

Enzyme treatment after gastrointestinal surgery.

After gastrointestinal surgery, patients often suffer from maldigestion. The extent of this maldigestion syndrome depends on the type of surgical procedure performed. After total pancreatectomy, subtotal left resection, resection for chronic pancreatitis. Whipple operation with ductal occlusion, and total gastrectomy, patients need obligatory enzyme treatment. After partial pancreatectomy without duct occlusion or partial gastrectomy, enzyme treatment should be initiated when exocrine pancreatic insufficiency occurs.

Chronic Disease↗
PubMed1993

Synthesis and expression of transforming growth factor beta-1, beta-2, and beta-3 in the endocrine and exocrine pancreas.

The actions of transforming growth factor-beta isoforms as potent regulators of growth and differentiation have led to the examination of their presence in the human pancreas. The cellular localization of TGF-beta 1, TGF-beta 2, and TGF-beta 3 was assessed in the normal human pancreas by using immunohistochemical and in situ hybridization techniques. Although cytoplasmic immunoreactivity for TGF-beta 1, TGF-beta 2, and TGF-beta 3 was found in islet cells, acinar cells, and ductal cells, a differential immunostaining pattern for TGF-beta isoforms was observed. In the endocrine pancreas, the islet cells demonstrated diffuse cytoplasmic immunostaining for TGF-beta 1, TGF-beta 2, and TGF-beta 3. However, only TGF-beta 2 and TGF-beta 3 exhibited an intense pattern of immunostaining in a few endocrine cells. Most of the positive islet cells coexpressed insulin. In contrast, in the exocrine pancreas, a greater number of acinar cells showed immunoreactivity for TGF-beta 1 than for TGF-beta 2 and TGF-beta 3. In the ductal cells, all three TGF-beta isoforms showed a similar intensity and pattern of immunostaining and were observed more frequently in the smaller distal ductules than in the larger pancreatic ducts. TGF-beta 1 and TGF-beta 3, but not TGF-beta 2, immunostaining was detected strongly in the smooth muscle cells and weakly in the endothelial cells of the blood vessels, whereas the fibroblasts of the interstitium were completely negative. In situ hybridization revealed that mRNA encoding all three TGF-beta isoforms colocalized with their respective proteins in islets, acinar cells, and ductal cells. In contrast, mRNA expression was absent in the smooth muscle cells and endothelium of the vessels. These results suggest that TGF-beta isoforms may act by both autocrine and paracrine mechanisms in the pancreas. The differential pattern of expression observed for each TGF-beta isoform implies unique roles for these proteins in the regulation of the endocrine and exocrine pancreas.

DNA Probes↗