Biomedical subjects

A Zimmermann

Publications and source records attributed to A Zimmermann.

At least 91 records · Page 5Linked to original sources

PubMed2000

Nerve growth factor and Trk high affinity receptor (TrkA) gene expression in inflammatory bowel disease.

BACKGROUND: Nerve growth factor (NGF), a target derived factor for survival and maintenance of peripheral and central neurones, has been implicated in several chronic inflammatory processes. AIMS: To analyse the concomitant presence of NGF and its high affinity receptor TrkA in patients undergoing surgery for Crohn's disease (CD) and ulcerative colitis (UC). PATIENTS: CD tissues were obtained from 33 patients and UC tissue samples from 12 patients undergoing surgery. Normal intestinal tissue samples were obtained from 30 individuals through an organ donor programme. METHODS: Expression of NGF and TrkA was studied by northern blot analysis. Using in situ hybridisation and immunohistochemistry, the respective mRNA moieties and proteins were localised. Western blot analysis was used to confirm the specificity of NGF and TrkA antibodies. RESULTS: In CD, NGF mRNA was increased in 60% (2.4-fold; p<0.01) and TrkA mRNA in 54% (1.3-fold; p<0.05) of samples. In UC, NGF mRNA expression was enhanced in 58% (2.4-fold; p<0.01) and TrkA mRNA expression in 50% (1.5-fold; p<0.05) of samples. In situ hybridisation showed that NGF and TrkA mRNA were often concomitantly present in polymorphonuclear-like cells of the lamina propria, in mast cells, and in a few ganglia of Auerbach's plexus and Meissner's plexus. Immunohistochemistry revealed that lamina propria cells and inflammatory cells (mainly mast cells) were NGF and TrkA immunopositive. NGF was also present in Meissner's plexus (especially in CD) and TrkA in enteric glia surrounding intestinal ganglia. CONCLUSIONS: The concomitant enhanced expression of NGF and its receptor suggests activation of this pathway in chronic inflammation in CD and UC. The presence of NGF and TrkA in both neural and non-neural structures in CD and UC supports the hypothesis that neuroimmune interactions occur and are activated in both disorders.

Adolescent↗

PubMed2000

Metastatic angiosarcoma of the liver preoperatively presenting as giant hemangioma.

BACKGROUND: Hepatic angiosarcomas are rare tumors most often associated with exposure to vinyl chloride or other carcinogens. Only a few cases have been published without such a history. CASE REPORT: We report the case of a 73-year-old woman who was admitted to our medical department with unclear upper abdominal pain, thrombocytopenia and anemia. Both computed tomography and magnet resonance imaging revealed a giant hemangioma in the right liver with multiple small hemangiomas. To cure the problem of thrombocytopenia due to sequestration of blood cells in the hemangioma, we decided to resect the large tumor. Intraoperatively, however, the diagnosis of angiosarcoma with multiple metastases was made. The patient died 6 weeks after surgery. CONCLUSION: Problems in diagnosing angiosarcoma include the brief duration of antecedent symptoms, difficulties in radiological diagnosis, and patients without a history of professional exposure to carcinogens.

Diagnosis, Differential↗

PubMed2000

Divergent expression of cyclin-dependent kinase inhibitors (CKI) and p14ARF/p16 beta in non-Hodgkin's lymphomas and chronic lymphocytic leukemia.

Chronic B-cell lymphocytic leukaemia (CLL) and low-grade B-cell Non Hodgkin's lymphomas (Lg-NHL) are characterized by slow accumulation of neoplastic cells arrested in the G0/G1 phase of the cell cycle. In contrast, proliferation rates are high in aggressive B-cell lymphomas (Hg-NHL). Divergent expression of cyclin-dependent kinase inhibitors (CKI) in the cell cycle may contribute to these differences. We analysed CLL as well as low and high grade B-cell NHL for expression of G1-specific and universal CKI by competitive RT-PCR and immunostaining. p16(INK4A) expression was low in all types of neoplasms. Highest p14(ARF) /p16 beta expression levels were found in normal lymphocytes. Expression of this CKI was significantly lower in CLL, but still higher in CLL than in the lymphomas (median 27 vs. 3 mRNA transcripts x 10(3), p = 0.0001). p14(ARF) /p16 beta immunostaining correlated with mRNA expression. Highest p21 mRNA levels were found in CLL, but three of four CLL with abundant p21 mRNA production were negative on immunostaining. High grade lymphomas showed markedly decreased p21 expression (3.9 in Hg-NHL vs. 12 in Lg-NHL and 29 in CLL; values expressed as mRNA transcripts x 10(3), p < 0.009). mRNA and protein expression of p27 was considerably higher in CLL than in the lymphomas. Differential CKI expression in various B-cell neoplasias may provide important biological markers, if not the molecular underpinning of their different cell cycle kinetics. Targeted interference with such genes governing cell cycle control in lymphoid neoplasia may pave the way towards new treatment strategies.

Adult↗

PubMed2000

Neurotensin receptor-1 mRNA analysis in normal pancreas and pancreatic disease.

By autoradiography, neurotensin (NT) binding is specifically detectable in pancreatic cancer, but not in the normal pancreas, chronic pancreatitis (CP), or other pancreatic disorders. In the present study, we investigated whether this is due to NT receptor-1 (NTR-1) mRNA up-regulation and whether NTR-1 mRNA could also be used as a specific diagnostic marker and treatment target in pancreatic cancer. Fifteen normal pancreas tissue samples, 20 CP samples, and 30 pancreatic cancer samples were studied. Expression and localization of NTR-1 mRNA was investigated by Northern blot analysis and in situ hybridization. Furthermore, consecutive tissue sections were analyzed for NTR-1 mRNA expression and NT binding. By Northern blot analysis, NTR-1 mRNA expression was 4.4-fold (P < 0.01) and 3.0-fold (P < 0.01) higher in pancreatic cancer and CP tissue samples, respectively, compared with normal controls. There was no difference in NTR-1 mRNA levels between CP and cancer samples (P > 0.05). In pancreatic cancer, the NTR-1 mRNA levels were higher in advanced tumor stage (stages III and IV) than early tumor stage (stages I and II; P < 0.05), but no difference was found between well/moderately differentiated (grades 1 and 2) and poorly differentiated/undifferentiated cancers (grades 3 and 4; P > 0.05). By in situ hybridization, NTR-1 mRNA signals were weakly present in the cytoplasm of acinar and ductal cells of the normal pancreas. Moderate to intense NTR-1 mRNA signals were present in the cytoplasm of acinar cells dedifferentiating into tubular complexes and degenerating acinar cells of CP samples. In the cancer samples, NTR-1 mRNA was moderately to intensely expressed in the cytoplasm of cancer cells. When on consecutive tissue sections NTR-1 mRNA expression was compared with the presence of NTR-1, measured by receptor autoradiography, a correlation was found in carcinomas but not in CP samples, in which no receptors were detectable by autoradiography. The enhanced expression of NTR-1 mRNA in pancreatic cancer cells further suggests that neuroendocrine hormones might modulate pancreas cancer cell behavior. However, its relatively high levels in CP excludes NTR-1 mRNA as a specific parameter for pancreatic cancer and for the differentiation of pancreatic cancer from CP.

Adult↗

PubMed1999

Rapid detection of the HIV type 1 reverse transcriptase codon T215Y by reverse transcription-polymerase chain reaction with fluorogenic probes.

Early detection of viral mutations, particularly those mutations associated with cross-resistance to antiretroviral drugs, is critical both for understanding the mechanism of drug resistance and for the clinical management of patients infected with HIV-1. One of the frequently observed mutations in the HIV-1 reverse transcriptase (RT)-coding region is ACC --> TAC at codon 215, resulting in a change of wild-type threonine (T) to tyrosine (Y); this mutation has been associated with decreased phenotypic susceptibility to zidovudine (ZDV). We describe a technique for the detection of the T215Y mutation using reverse transcription-polymerase chain reaction (RT-PCR) amplification of viral sequences and a 5' nuclease assay requiring fluorogenic probes. In addition to detecting the presence of the ACC --> TAC mutation at codon 215, this assay provides an increased ability to detect low levels of mutant species in a mixed population, relative to conventional sequencing. Further advantages of this technique include the rapid and high-throughput nature of the assay, the accuracy of the assay relative to conventional DNA sequencing, and the convenience of combining RT-PCR virus amplification with the allelic discrimination assay, without the need for purification of PCR products.

Anti-HIV Agents↗

PubMed1999

ErbB-4 mRNA expression is decreased in non-metastatic pancreatic cancer.

The erbB-4 gene encodes a detected receptor protein that possesses intrinsic tyrosine kinase activity and belongs to the family of the epidermal growth factor receptor (EGFR); erbB-4 is stimulated by the heregulins and betacellulin, which enables this receptor to form heterodimers with erbB-2, a prerequisite for erbB-2 activation. Because the expression of erbB-4 mRNA is generally low in the pancreas, quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) was used to determine the erbB-4 levels in human normal and cancerous pancreatic tissue. Our results show that the mRNA expression of this receptor is 6-fold decreased in the non-metastatic stages of pancreatic cancer when compared to tumors with lymph node or distant metastases or to the normal pancreas. In addition, immunohistochemistry demonstrated that in the normal pancreas, the erbB-4 antigen was predominantly present in the cell membrane and cytoplasm of the ductal and acinar cells and at a much lower level, in islet cells. In pancreatic cancer, 61 of 75 samples exhibited weak to moderate immunoreactivity for erbB-4 in the tumor cells. Moreover, in the peri-tumorous region with chronic pancreatitis-like morphological changes, there was weak-to-moderate erbB-4 immunostaining in small ductules and degenerating acinar cells. Uni- and multivariate survival analyses using as variables age, sex, stage of cancer, histo-pathological grading, and erbB-4 immunoreactivity, revealed a significant effect for stage of cancer (p < 0.01) whereby the risk of dying was 2.3 times higher in patients with metastases than in patients without. However, the level of erbB-4 immunoreactivity in pancreatic cancer cells had no influence on patient survival.

Adult↗

PubMed1999

Concomitant analysis of the epidermal growth factor receptor family in esophageal cancer: overexpression of epidermal growth factor receptor mRNA but not of c-erbB-2 and c-erbB-3.

The epidermal growth factor receptor family consists of four closely related transmembrane receptors: epidermal growth factor receptor (EGF-R), c-erbB-2, c-erbB-3, and c-erbB-4. Overexpression of each receptor may lead to cell transformation and contributes to tumor progression in various malignancies. Although these factors have been analyzed in many cancers separately, little is known about their concomitant expression in esophageal cancer. Based on the finding that EGF-R and c-erbB-2 form highly active transmembranous heterodimers that enhance cell growth and proliferation, we used Northern blot analysis and immunohistochemistry to analyze the concomitant expression of EGF-R, c-erbB-2, and c-erbB-3 in tissue samples obtained from 39 patients undergoing esophagectomy for esophageal cancer. Northern blot analysis revealed a fourfold increase (p < 0.01) in EGF-R mRNA levels in the esophageal cancer samples in comparison with normal tissue samples. The c-erbB-2 receptor was only 1.25-fold elevated in the esophageal cancers, which failed to be statistically significant (p = 0.31). In contrast, c-erbB-3 mRNA levels were 3.5-fold lower (p < 0.01) in the esophageal cancers than in the normal tissues. Immunohistochemical analysis showed weak EGF-R, c-erbB-2, and c-erbB-3 immunostaining in the normal esophageal tissue. In esophageal cancer samples, immunoreactivity for EGF-R, c-erbB-2, and c-erbB-3 was mainly located in the cancer cells. Strong EGF-R, c-erbB-2, and c-erbB-3 immunoreactivity was present in 59%, 64%, and 64% of the esophageal cancer samples, respectively. In consecutive tissue sections, identical cancer cell clusters often exhibited these three closely related receptors simultaneously. However, correlation of the immunohistochemical findings with the clinicopathologic patient parameters revealed that the presence of EGF-R, c-erbB-2, or c-erbB-3 had no influence on patient survival (p > 0.05). In addition, the simultaneous presence of these receptors did not influence survival. Our findings indicate that in esophageal cancer the presence of EGF-R, c-erbB-2, and c-erbB-3 alone or in combination seems to have no major influence on patient prognosis and does not alter tumor growth behavior significantly.

Adenocarcinoma↗

PubMed1999

Transforming growth factor betas and their signaling receptors in human hepatocellular carcinoma.

BACKGROUND: Transforming growth factor betas (TGF-betas) are multifunctional polypeptides that have been suggested to influence tumor growth. They mediate their functions via specific cell surface receptors (type I ALK5 and type II TGF-beta receptors). The aim of this study was to analyze the roles of the three TGF-betas and their signaling receptors in human hepatocellular carcinoma (HCC). METHODS: HCC tissue samples were obtained from 18 patients undergoing partial liver resection. Normal liver tissues from 7 females and 3 males served as controls. The tissues for histological analysis were fixed in Bouin's solution and paraffin embedded. For RNA analysis, freshly obtained tissue samples were snap frozen in liquid nitrogen and stored at -80 degrees C until used. Northern blot analysis was used in normal liver and HCC to examine the expression of TGF-beta1, -beta2, -beta3 and their receptors: type I ALK5 (TbetaR-I ALK5), type II (TbetaR-II), and type III (TbetaR-III). Immunohistochemistry was performed to localize the corresponding proteins. RESULTS: All three TGF-betas demonstrated a marked mRNA overexpression in HCC in comparison with normal controls, whereas the levels of all three TGF-beta receptors showed no significant changes. Intense TGF-beta1, TGF-beta2, and TGF-beta3 immunostaining was found in hepatocellular carcinoma cells and in the perineoplastic stroma with immunohistochemistry, whereas no or mild immunostaining was present in the normal liver. For TbetaR-I ALK5 and TbetaR-II, the immunostaining in both HCC and normal liver was mild to moderate, with a slightly higher intensity in the normal tissues. CONCLUSION: The upregulation of TGF-betas in HCC suggests an important role for these isoforms in hepatic carcinogenesis and tumor progression. Moreover, the localization of the immunoreactivity in both malignant hepatocytes and stromal cells suggests that TGF-betas act via autocrine and paracrine pathways in this neoplasm.

Activin Receptors, Type I↗

PubMed1999

Microvesicular steatosis, hemosiderosis and rapid development of liver cirrhosis in a patient with Pearson's syndrome.

BACKGROUND/AIMS: Pearson's marrow-pancreas syndrome consists of refractory sideroblastic anemia with vacuolization of marrow precursors and exocrine pancreas dysfunction. Patients with this disease usually have large deletions of the mitochondrial genome. We report a patient with Pearson's syndrome who had predominantly hepatic manifestations such as microvesicular steatosis, hemosiderosis and rapidly developing cirrhosis. METHODS: Analysis of the mitochondrial and nuclear genomes, determination of enzyme activities and of the hepatic iron content were performed using standard techniques of molecular biology and biochemistry. RESULTS: The patient had typical ringed sideroblasts in a bone marrow smear and a 7436-bp deletion of the mitochondrial genome in all tissues investigated, compatible with Pearson's syndrome. He died within 3 months after birth due to liver failure. Histopathological analysis of the liver revealed complete cirrhosis with signs of chronic cholestasis, microvesicular steatosis and massive hemosiderosis. In addition, the patient was heterozygous for the C282Y and H63D mutations of the hemochromatosis gene. CONCLUSIONS: Pearson's syndrome should be added to the list of neonatal diseases which can cause microvesicular steatosis, hepatic accumulation of iron and liver cirrhosis.

Disease Progression↗

PubMed1999

Myofibroblasts in the cirrhotic rat liver reflect hepatic remodeling and correlate with fibrosis and sinusoidal capillarization.

BACKGROUND/AIMS: Myofibroblasts are essential in fibrogenesis during development of cirrhosis. In the present study we stereologically quantitated MFB's and correlated them with fibrosis and sinusoidal capillarization. METHODS: Male SD rats were rendered cirrhotic by chronic exposure to phenobarbital/CCl4, (CIR; n = 16); untreated littermates served as controls (CTR; n = 10). Sinusoidal capillarization was assessed by a multiple indicator dilution technique as previously described. The volume fractions of myofibroblasts and other liver components were estimated by morphometry. RESULTS: Myofibroblasts averaged 15.7 +/- SD 0.7% in CIR as compared to 6.7% +/- SD 0.4% in CTR (p < 0.01). An extra-littoral compartment of myofibroblasts was found in portal tracts and within fibrous septa. In CIR, hepatocytes showed a bimodal distribution of volume fractions, and hepatocyte volume distribution disclosed a mirror image of that of myofibroblasts. Connective tissue was markedly increased in CIR, averaging 13.2 +/- 1.2% in CIR vs. 1.2 +/- 0.3% in CTR (p < 0.0001). Extravascular albumin space--a measure of sinusoidal capillarization--was reduced by 44% in CIR (0.028 +/- 0.017 vs. 0.050 +/- 0.010 ml/g; p < 0.001). The volume fraction of myofibroblasts correlated best with extravascular albumin space (r = -0.84, p < 0.001). Multiple regression analysis selected only extravascular albumin space and connective tissue to be determined by the volume fraction of myofibroblasts (r = 0.923; p < 0.001). CONCLUSION: We conclude that increased myofibroblasts reflect the degree of hepatic remodeling rather than cirrhosis inasmuch as myofibroblast volume fraction inversely reflects that of hepatocyte bimodality. Myofibroblasts form an extra-littoral compartment in this model of CIR and correlate with hepatic fibrosis and sinusoidal capillarization.

Actins↗

PubMed1999

Overexpression of Smad2 and colocalization with TGF-beta1 in human pancreatic cancer.

Smad2 belongs to a family of cytoplasmic molecules that are critical components in the transforming growth factor beta (TGF-beta) signaling pathway. Upon ligand binding, the type II TGF-beta receptor (TbetaRII) heterodimerizes with and activates TGF-beta receptor type I (TbetaRI). Activated TbetaRI phosphorylates Smad2, which then heterodimerizes with Smad4, translocates into the nucleus, and subsequently effects gene transcription. Previously we have shown that pancreatic cancers overexpress TGF-betas and TbetaRII. Here, we show by northern blot analysis that Smad2 mRNA levels are significantly increased in pancreatic cancer samples in comparison with normal pancreatic tissues. By immunohistochemistry, Smad2 is present in the cancer cells of 67% of the pancreatic cancer samples. Analysis of serial sections reveals coexpression of Smad2 and TGF-beta1 in the cancer cells. Furthermore, TGF-beta1 increases steady-state levels of Smad2 mRNA in the TGF-beta1-sensitive pancreatic cancer cell line COLO-357. It is suggested that pancreatic cancer cells have the capacity to up-regulate Smad2 expression, which may lead to excessive activation of specific components of the TGF-beta-signaling pathway.

Aged↗

PubMed1999

Molecular aspects of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a highly malignant tumor with a poor prognosis. The success of its established treatment modalities is frequently limited by the advanced stage of the tumor at the time of diagnosis. Therefore, it is important to understand the mechanisms that control its growth behavior. In the present study, we review some aspects of molecular and cellular processes involved in growth control and metastatic potential of HCC. These include some growth factors and their receptors, oncogenes and tumor suppressor genes, and factors that control angiogenesis and extracellular matrix formation. These factors may be important targets for novel therapeutic approaches in the future.

Animals↗

PubMed1999

[Surgical treatment of echinococcosis of the liver].

UNLABELLED: Echinococcosis is a parasitic disease which is most frequently located in the liver. The treatment of choice is surgery. METHODS: A total of 23 patients were hospitalised for liver echinococcosis during the period from January 1993 to September 1998. RESULTS: The diagnosis was in 20 cases (87%) cystic echinococcosis and in 3 patients (13%) alveolar echinococcosis. The regular intervention of cyst desinfection with cystectomy was carried out in 85% of the cases with cystic echinococcosis, whereas atypical or segmental liver resections were performed in 15%. Two patients with alveolar echinococcosis were operated upon by radical/extended liver resections, one was found intraoperatively inoperable. The mean hospital stay was 15.4 days with a mortality of 0% and a postoperative morbidity of 57%, including bile leaks in 30%. A perioperative antiparasitic chemotherapy with albendazole was prescribed in 91%. The apparent rate of recurrence was 7% for uncomplicated cystic echinococcosis. CONCLUSIONS: Cyst desinfection with cystectomy has been proved to be effective as the standard operative intervention for cystic echinococcosis. For alveolar echinococcosis, radical resections are required. Due to the risk of recurrence (especially in alveolar echinococcosis), the effectiveness of surgery should be improved by a perioperative chemotherapy with albendazole.

Adolescent↗

PubMed1999

Transforming growth factor-betas and their signaling receptors are coexpressed in Crohn's disease.

OBJECTIVE: To evaluate mechanisms that contribute to tissue repair and tissue remodeling in Crohn's disease (CD). SUMMARY BACKGROUND DATA: Transforming growth factor-betas (TGF-betas) are involved in different chronic inflammatory disorders. They function by binding to two receptors, type I (TbetaR-I) subtype ALK5 and type II (TbetaR-II), which are concomitantly required for signal transduction. METHODS: Tissues were obtained from 18 patients with CD (10 female patients, 8 male patients, median age 38.7 years [range 16 to 58 years]) undergoing surgery because of CD-related complications. Tissue samples of 18 healthy organ donors (10 female subjects, 8 male subjects, median age 50.3 years [range 15 to 65 years]) served as controls. The expression and localization of TGF-beta1, TGF-beta2, TGF-beta3, TbetaR-IALK5, TbetaR-II, and TbetaR-III were studied by Northern blot analysis, in situ hybridization, and immunohistochemistry. RESULTS: On Northern blot analysis, 94% of the CD samples exhibited enhanced TGF-beta1, TGF-beta3, and TbetaR-II mRNA expression compared with controls. TGF-beta2 was increased in 72%, TbetaR-IALK5 in 72%, and TbetaR-III in 82% of the patients with CD. On in situ hybridization and immunohistochemical analysis, TGF-beta1, TbetaR-IALK5, and TbetaR-II were seen to be colocalized in the lamina propria cells and in the lymphocytes closest to the luminal surface, but also in the remaining epithelial cells, and in fibroblasts of CD tissue samples. CONCLUSIONS: The concomitant overexpression of TGF-betas and their signaling receptors in CD points to a potential role of these regulatory molecules in the pathophysiology of CD. Activation of TGF-beta-mediated pathways might promote the repair of mucosal injury by enhancing the process of reepithelization, but might also contribute to extracellular matrix generation and subsequently to intramural fibrosis and intestinal obstruction.

Adolescent↗

PubMed1999

Connective tissue growth factor is a regulator for fibrosis in human chronic pancreatitis.

OBJECTIVE: To evaluate the parameters that mediate fibrogenesis in chronic pancreatitis (CP). BACKGROUND: Connective tissue growth factor (CTGF), which is regulated by transforming growth factor beta (TGF-beta), has recently been implicated in skin fibrosis and atherosclerosis. In the present study, the authors analyzed the concomitant presence of TGF-beta1 and its signaling receptors-TGF-beta receptor I, subtype ALK5 (TbetaR-I(ALK5)), and TGF-beta receptor II (TbetaR-II)-as well as CTGF and collagen type I in the pancreatic tissue of patients undergoing surgery for chronic pancreatitis. PATIENTS AND METHODS: CP tissue samples were obtained from 40 patients (8 women, 32 men) undergoing pancreatic resection. Tissue samples of 25 previously healthy organ donors (12 women, 13 men) served as controls. The expression of TGF-beta1, TbetaR-I(ALK5), TbetaR-II, CTGF, and collagen type I was studied by Northern blot analysis. By in situ hybridization and immunohistochemistry, the respective mRNA moieties and proteins were localized in the tissue samples. RESULTS: Northern blot analysis showed that CP tissue samples exhibited concomitant enhanced mRNA expression of TGF-beta1 (38-fold), TbetaR-II (5-fold), CTGF (25-fold), and collagen type I (24-fold) compared with normal controls. In addition, TbetaR-I(ALK5) mRNA was increased in 50% of CP tissue samples (1.8-fold). By in situ hybridization, TGF-beta1, TbetaR-I(ALK5), and TbetaR-II mRNA were often seen to be colocalized, especially in the ductal cells and in metaplastic areas where atrophic acinar cells appeared to dedifferentiate into ductal structures. In contrast, CTGF was located in degenerating acinar cells and principally in fibroblasts surrounding these areas. Moreover, CTGF mRNA expression levels correlated positively with the degree of fibrosis in CP tissues. CONCLUSION: The concomitant overexpression of CTGF, collagen type I, TGF-beta1, and its signaling receptors in CP suggests that these proteins contribute to enhanced extracellular matrix synthesis and accumulation, resulting finally in the fibrogenesis observed in CP.

Adult↗

PubMed1999

Nerve growth factor and its high-affinity receptor in chronic pancreatitis.

OBJECTIVE: To study the mechanisms that are involved in nerve growth and contribute to pain generation in chronic pancreatitis (CP). SUMMARY BACKGROUND DATA: Chronic pancreatitis is a painful disease associated with characteristic nerve changes, including an increase in nerve number and diameter. The mechanisms that influence nerve growth are not known. Nerve growth factor (NGF) and its high-affinity tyrosine kinase receptor A (TrkA) are involved in neural development and survival and growth of central and peripheral nerves. METHODS: Nerve growth factor and TrkA were investigated by Northern blot analysis, in situ hybridization, and immunohistochemical staining in the pancreases of 24 patients with CP, and the findings were correlated with clinical parameters. RESULTS: By Northern blot analysis, NGF and TrkA mRNA expression were increased in 42% (13.1-fold) and 54% (5.5-fold) of the CP samples (p < 0.01), respectively. In situ hybridization revealed that in CP, enhanced NGF mRNA expression was present in metaplastic ductal cells, in degenerating acinar cells, and in acinar cells dedifferentiating into tubular structures. TrkA mRNA was intensely present in the perineurium. Further, enhanced NGF and TrkA mRNA signals were also present in intrapancreatic ganglia cells in CP samples. Immunohistochemistry confirmed the in situ hybridization findings. Analysis of the molecular findings with clinical parameters revealed a significant relation (p < 0.05) between NGF mRNA levels and pancreatic fibrosis (r = 0.64) and acinar cell damage (r = 0.74) and between TrkA mRNA and pain intensity (r = 0.84). CONCLUSION: Activation of the NGF/TrkA pathway occurs in CP. It might influence neural morphologic changes and the pain syndrome in this disorder.

Adult↗

PubMed1999

Growth factor receptors are differentially expressed in cancers of the papilla of vater and pancreas.

OBJECTIVE: To compare growth factor receptor expression in papilla of Vater cancer and pancreatic cancer. SUMMARY BACKGROUND DATA: Cancer of the papilla of Vater has a much better prognosis than pancreatic cancer. Earlier symptoms may result in earlier diagnosis, but different biologic growth behaviors and genetic alterations might also be explanations. PATIENTS AND METHODS: Surgical specimens from papilla of Vater cancers (24 patients) and pancreatic cancers (80 patients), normal papilla of Vater tissues (20 patients), and normal pancreatic tissues (24 patients) were frozen and fixed. The authors compared the expression of the epidermal growth factor receptor (EGFR) and c-erbB2 and c-erbB3 by Northern blot, in situ hybridization, and immunohistochemistry. RESULTS: In papilla of Vater cancer, Northern blots showed comparable EGFR and c-erbB2 mRNA expression but significantly lower c-erbB3 mRNA levels than in normal papilla. In pancreatic cancer, mRNA expression was enhanced compared with normal controls for EGFR (4-fold), c-erbB2 (2.5-fold), and c-erbB3 (5.2-fold). In situ hybridization confirmed this and showed mRNA expression only in cancer cells. EGFR immunohistochemical staining scores were comparable in papilla of Vater cancer (1.17 +/- 0.22) and normal papilla (1.42 +/- 0.25). Staining scores for c-erbB2 (2.72 +/- 0.40 vs. 3.89 +/- 0.37) and c-erbB3 (2.78 +/- 0.35 vs. 3.89 +/- 0.53) were slightly lower than controls in papilla of Vater cancer. In pancreatic cancer, immunostaining scores for EGFR, c-erbB2, and c-erbB3 were significantly higher than controls. CONCLUSION: Members of the EGFR family show similar or lower expression in papilla of Vater cancer than in normal controls. In pancreatic cancer, these receptors are upregulated. This supports the hypothesis that papilla of Vater cancer and pancreatic cancer have biologic differences that may contribute to the different growth of these tumors.

Adult↗

PubMed1999

Group II and IV phospholipase A(2) are produced in human pancreatic cancer cells and influence prognosis.

BACKGROUND: Phospholipase A(2) (PLA(2)) is involved in regulating biosynthesis of arachidonic acid and its metabolites. There are three major structurally different forms of PLA(2): group I, also called pancreatic PLA(2) (PLA(2)-I); group II, referred to as secretory non-pancreatic or synovial or platelet PLA(2) (PLA(2)-II); group IV, referred to as cytosolic PLA(2) (PLA(2)-IV). AIMS: To examine PLA(2)-I, PLA(2)-II, and PLA(2)-IV in normal and pancreatic cancer tissues. Patients-PLA(2) was studied in 58 pancreatic adenocarcinomas, obtained from 25 women and 33 men undergoing pancreatic resection. Normal organ donor pancreas served as control. METHODS: The enzymes were analysed by northern blot, in situ hybridisation, and immunohistochemistry. The molecular findings were correlated with clinical variables of the patients. RESULTS: Northern blot analysis of total RNA showed enhanced PLA(2) group II and IV mRNA expression in 52% and 55% of the pancreatic cancer samples respectively compared with the normal controls (p = 0.0013 and p = 0.0025). On immunohistochemical analysis, intense PLA(2)-I immunoreactivity was seen in acinar cells, but not in ductal cells, in the normal pancreas. In pancreatic cancer cells, PLA(2)-I immunostaining was absent. PLA(2)-II immunostaining was visible only in some acinar and ductal cells in the normal pancreas, whereas in pancreatic cancer increased PLA(2)-II immunoreactivity was present in 65% of the cancer samples. On in situ hybridisation, weak PLA(2)-IV mRNA signals were detected in acinar and ductal cells of normal samples; these signals were present to a much greater extent in pancreatic cancer cells. The presence of PLA(2)-II in pancreatic cancer was associated with a higher degree of fibrosis (p<0.01). Furthermore, there was a significant correlation between the enhanced expression of PLA(2)-II and longer survival after surgery (p<0.03), but not of PLA(2)-IV and longer postoperative survival. CONCLUSION: These data suggest that PLA(2)-II and PLA(2)-IV are upregulated in human pancreatic cancer, and that upregulation of PLA(2)-II in pancreatic cancer covariates negatively with cancer cell growth.

Adenocarcinoma↗