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Biomedical subjects

G Adler

Publications and source records attributed to G Adler.

At least 163 records · Page 9Linked to original sources
PubMed1999

Caerulein-induced NF-kappaB/Rel activation requires both Ca2+ and protein kinase C as messengers.

The eukaryotic transcription factor NF-kappaB/Rel is activated by a large variety of stimuli. We have recently shown that NF-kappaB/Rel is induced during the course of caerulein pancreatitis. Here, we show that activation of NF-kappaB/Rel by caerulein, a CCK analog, requires increasing intracellular Ca2+ levels and protein kinase C activation. Caerulein induces a dose-dependent increase of nuclear NF-kappaB/Rel binding activity in pancreatic lobules, which is paralleled by degradation of IkappaBalpha. IkappaBbeta was only slightly affected by caerulein treatment. Consistent with an involvement of Ca2+, the endoplasmic reticulum-resident Ca2+-ATPase inhibitor thapsigargin activated NF-kappaB/Rel in pancreatic lobules. The intracellular Ca2+ chelator TMB-8 prevented IkappaBalpha degradation and subsequent nuclear translocation of NF-kappaB/Rel induced by caerulein. BAPTA-AM was less effective. Cyclosporin A, a Ca2+/calmodulin-dependent protein phosphatase (PP2B) inhibitor, decreased caerulein-induced NF-kappaB/Rel activation and IkappaBalpha degradation. The inhibitory effect of bisindolylmaleimide suggests that protein kinase C activity is also required for caerulein-induced NF-kappaB/Rel activation. These data suggest that Ca2+- as well as protein kinase C-dependent mechanisms are required for caerulein-induced NF-kappaB/Rel activation.

Animals↗
PubMed1999

Mild cognitive impairment in old-age depression is associated with increased EEG slow-wave power.

Reversible dementia in geriatric depression is known to be a risk factor for irreversible dementia. Whether just mild cognitive deficits in elderly depressed patients hold a similar risk is not known yet. It may be suggested that elderly depressed patients with mild cognitive deficits, who are prone to develop dementia, show EEG alterations similar to those observed in demented patients. We studied the relationships between cognitive performance, severity of depressive symptoms and quantitative EEG parameters in 31 unmedicated, nondemented, depressed patients aged 60 years or more. Twenty-one of the patients showed a cognitive performance characteristic of mild cognitive impairment. In these patients, the mean delta and theta power was significantly higher than in the patients without cognitive impairment. Total delta power was negatively correlated with cognitive performance. There was no relationship between cognitive performance or EEG parameters and the severity of depression.

Aged↗
PubMed1999

Mechanistic differences of various AT1-receptor blockers in isolated vessels of different origin.

The functional inhibitory characteristics of the angiotensin II type 1 receptor blockers (ARB) candesartan; irbesartan; and losartan and its active metabolite EXP 3174 (EXP) were studied in rabbit aortic strips and rat portal vein preparations in vitro. Moreover, plasma-protein binding was determined, and the binding was high (>98. 5%) for all ARBs. These values were needed to relate the concentrations of the ARBs used in vitro to the nonprotein bound concentrations in clinical use. In both vascular preparations, candesartan caused a marked decrease in the maximal contractile response of the angiotensin II (Ang II) concentration-response curve. Losartan, EXP, and irbesartan caused a rightward parallel shift without any major effects on the maximal response to Ang II. The inhibitory effect of candesartan developed slowly (maximal effect after >30 minutes) and lasted >2 hours despite repeated washing of the vessels. The effect of losartan, irbesartan, and EXP had a faster onset, and most of the inhibitory effect disappeared after washing. The duration of the inhibitory effects of the ARBs were not related to lipophilicity of the compounds. Cooling of the rat portal vein preparations to 4 degrees C before administration of candesartan prevented the persistent inhibition of Ang II response seen at 37 degrees C. For the other ARBs studied, the magnitude of inhibition and the speed of recovery of the Ang II response were independent of the incubation temperature before washing. In addition, when candesartan was given to conscious rats, the inhibitory effect on Ang II-induced blood pressure responses persisted during the 24-hour period despite nondetectable plasma concentrations of candesartan at 24 hours. It is concluded that functional inhibitory characteristics of candesartan differ from those of the other ARBs tested. At clinically relevant concentrations, candesartan is an insurmountable and long-lasting antagonist of the vascular contractile responses to Ang II.

Angiotensin II↗
PubMed1999

[Pathological bone density in chronic inflammatory bowel diseases--prevalence and risk factors].

INTRODUCTION: Osteopenia and osteoporosis are frequent but often underestimated complications in inflammatory bowel disease. In patients with IBD, several factors could contribute to osteopenia, but the pathogenetic mechanisms are still not completely understood. We carried out a prospective study to evaluate the prevalence and possible etiologic factors for osteopenia and subsequent osteoporosis in IBD-patients. METHODS: 140 patients with inflammatory bowel disease (Crohn's disease n = 125, ulcerative colitis n = 15) underwent clinical and spine radiological assessments. Lumbar bone mineral densities were measured by dual energy X-ray absorptiometry (DXA). Markers of bone formation and resorption and vitamin D were assessed in n = 95 patients. Patients were asked about medication, previous or actual intestinal stenosis, smoking and intestinal resection. A lactose-H2-breath test was undertaken if lactose intolerance was clinically suspected. RESULTS: Compared to age- and sex-matched healthy controls (Z-score), the prevalence of osteopenia (Z < -1) was 62%, while osteoporosis (Z < -2) occurred in 38%. The mean bone density of IBD-patients was osteopenic with no significant differences between Crohn's disease (Z = -1.24) and ulcerative colitis (Z = -1.25). Osteoporotic fractures were seen in three patients (2.1%). Crohn's disease patients with osteoporosis showed a significant lower body mass index (BMI) than patients with normal bone density. 52.9% of patients with manifest osteoporosis underwent systemic steroid treatment in the preceding year, but only 34% of those with normal bone density. Except hemoglobin, none of the biochemical markers showed a significant difference between osteoporosis, osteopenia and patients with normal bone density. CONCLUSION: The results show a high prevalence of osteopenia and osteoporosis in IBD. Since osteoporosis is often associated with low body mass index, multiple intestinal resections and previous systemic steroid treatment, we suggest a bone densitometry in these patients. Since etiology of osteoporosis in IBD is multifactorious and not completely understood, there is still no standard treatment. The effect of osteoanabolic and antiresorptive agents must be evaluated in further studies.

Adolescent↗
PubMed1999

Anti-TNF antibody in Crohn's disease--status of information, comments and recommendations of an international working group.

The chimeric anti-TNF antibody Remicade (Infliximab) has recently been approved for human use by the FDA and is now available on the market. Since there is considerable interest in this kind of treatment among patients with Crohn's disease, an international working group has summarized the presently available information about efficacy, side effects and possible problems of this treatment. Studies show that Remicade is effective in the treatment of active Crohn's disease, maintaining remission and fistulae. The working group does not see Infliximab as a first-line treatment for Crohn's disease. It may be used in active phase recurrent disease, chronic active disease and fistulae if standard treatment was not successful. For the surveillance special attention has to be given to the unknown malignancy rate of Infliximab. Infusion should be performed in an institution, routinely performing intravenous infusions and a two-hour surveillance of the patients should be guaranteed to recognize anaphylactic reactions or acute side effects. There is presently no information indication that the combination with immunosuppressants might increase risks or side effects of this treatment. Due to the limited information available the working group would prefer to use Remicade in studies only and recommends central collection and documentation of all data on efficacy and side effects for the next year.

Antibodies, Monoclonal↗
PubMed1999

Invasion and metastasis in pancreatic cancer.

Understanding the molecular mechanisms of invasion and metastasis is crucial for the development of novel therapeutic strategies to treat metastases. Considerable studies revealed that the establishment of metastasis is the final outcome of a series of processes such as tumor growth, angiogenesis, tumor cell detachment and invasion of extracellular matrix. Each step of this multistep process is essential for tumor cell survival and establishment of secondary lesions and is regulated by interactions of tumor cells with host microenvironment. This review is focused on the molecular mechanisms involved in the regulation of this processes. The central role of adhesion molecules and ECM degrading proteinases in disruption of cell-cell and cell-ECM associations as well as degradation of extracellular matrix and basement membranes is emphasized.

Cell Adhesion↗
PubMed1999

Novel technology for detection of genomic and transcriptional alterations in pancreatic cancer.

AIM: The present review summarizes our strategies aimed at identifying and characterizing genetic alterations occurring at the transcriptional and chromosomal level in pancreatic cancer. METHODS: To study transcriptional alterations we have used a number of techniques including modified versions of differential hybridizations and cDNA-RDA (representational difference analysis). Comparative genomic hybridization (CGH) was used to study chromosomal aberrations occurring in pancreatic cancer tissues. RESULTS: The study of transcriptional alterations led to the identification of more than 500 genes with differential expression in pancreatic cancer. The sum of these alterations represented the first expression profile characteristic for pancreatic tumors. The CGH analysis allowed the identification of a number of chromosomal regions containing putative tumor suppressor genes or oncogenes. These regions are presently being characterized at the molecular level. In a first approach the myb-oncogene was identified as the relevant oncogene of an amplification on 6q occurring in up to 10% of pancreatic cancer patients. CONCLUSIONS: Genes isolated in both approaches represent potential new disease genes for pancreatic cancer and are at present being characterized by individual or serial analysis.

Chromosome Aberrations↗
PubMed1999

A phase II study of weekly 24-h infusion of high-dose 5-fluorouracil in advanced pancreatic cancer.

No single agent or combination chemotherapy protocol, with the exception of gemcitabine, has so far proven superior to standard bolus 5-fluorouracil regimes for the treatment of advanced pancreatic cancer. The present phase II trial was designed to study whether the effectivity of 5-fluorouracil can be improved with a weekly high-dose 5-fluorouracil schedule. 26 patients with cytologically or histologically verified, metastasized (n = 21) or locally advanced (n = 5) previously untreated adenocarcinoma of the pancreas were included in this study. Treatment consisted of weekly applications of 2,600 mg/m2 5-fluorouracil as 24-h infusion on days 1, 8, 15, 22, 29, 36. Treatment was repeated at day 50 and was continued until disease progression. Primary endpoints of the study were response rates and toxicity, secondary endpoints were survival and clinical benefit in terms of performance status, body weight and analgesia consumption. Toxicity of the regimen was mild with only four instances of grade-3 toxicity. Response rates were 8% (95% CI = 1.2-13.7) with two partial remissions. Improvement of at least one parameter of clinical benefit for > or = four weeks was observed for 11.5% of the study patients. The most prominent effect was a transient stabilization of objective tumor measurements (48% [95% CI = 27.8-68.7]) and individual parameters of clinical benefit (50-75%). Median survival was 248 days (95% CI = 164-459) for all patients included in the study. The present study indicates that the high-dose 5-fluorouracil regimen shows weak activity in advanced pancreatic cancer which seems comparable to gemcitabine.

Adenocarcinoma↗
PubMed1998

The splice-pattern of CD44 is altered in chronic pancreatitis exhibiting dysplastic changes.

Recent studies have shown that several splice variants of CD44, might be involved in tumor progression. Since chronic pancreatitis is suggested to be a risk factor for pancreatic cancer we investigated the splice pattern of CD44 in chronic pancreatitis to elucidate the role of CD44 in pancreas tumorigenesis. The expression of CD44-isoforms was examined in 40 specimens of chronic pancreatitis and 12 specimens of normal pancreas by immunohistochemistry, Westernblotting and exon specific RT-PCR. Pancreatic cancer tissue from two patients who developed pancreatic cancer 2 and 3 years following surgery for chronic pancreatitis were analyzed. Strong expression of CD44s was found in all cells, whereas the expression of CD44v6 was restricted to ductal cells. Westernblotting revealed an overexpression of CD44v6 in chronic pancreatitis as compared to normal pancreas. Exon specific analysis revealed an altered splice pattern of CD44, similar to that in pancreatic cancer, in 12.5% of the chronic pancreatitis specimens. Both patients who developed pancreatic cancer after chronic pancreatitis exhibited this altered splice pattern in both, chronic pancreatitis and pancreatic cancer. These results suggest that variant forms of CD44-mRNA might be expressed in early dysplastic alterations in chronic pancreatitis.

Blotting, Western↗
PubMed1998

Src stimulates insulin-like growth factor I (IGF-I)-dependent cell proliferation by increasing IGF-I receptor number in human pancreatic carcinoma cells.

We examined the potential function of Src in human pancreatic carcinoma. Overexpression of kinase-activated SrcY527F resulted in a significant increase of insulin-like growth factor I (IGF-I)-dependent cell proliferation in the cell line PANC-1. Western blotting and competition binding studies demonstrated 2.3 +/- 0.2-fold increase in IGF-I receptor expression and 2.8 +/- 0.4-fold increase in IGF-I-specific binding sites/cell. SrcY527F transfection alone did not change receptor affinity or basal receptor tyrosine phosphorylation, whereas IGF-I-stimulated receptor phosphorylation was increased by 2.1 +/- 0.5-fold. IGF-I mRNA expression and protein secretion did not change to exclude autocrine activation. We conclude that Src stimulates IGF-I-dependent proliferation of PANC-1 cells by increasing the number of IGF-I receptors/cell.

Cell Division↗
PubMed1998

[Diagnosis of a "hereditary pancreatitis" by the detection of a mutation in the cationic trypsinogen gene].

HISTORY AND CLINICAL FINDINGS: A 71-year-old woman was admitted with the suspected diagnosis of pancreatic carcinoma. As a child she had had repeated attacks of abdominal pain of undetermined cause. When aged 48 years she had developed diabetes mellitus. Her now 42-year-old daughter had from the age of 9 years suffered from repeated attacks of acute pancreatitis that had finally led to chronic pancreatitis. The patient's 15-year-old grandchild was having recurrent bouts of abdominal pain. INVESTIGATIONS: Imaging procedures revealed calcifications in the pancreas and an infiltrating space-occupying lesion, about 3 cm in diameter, in the head of the pancreas with lymph node and liver metastases. Cytological analysis of material aspirated from the space-occupying mass showed typical findings of ductal pancreatic carcinoma. FURTHER TESTS, TREATMENT AND COURSE: At first the patient's course was not typical for a genetically-determined disease, but the family history raised the suspicion of hereditary pancreatitis. A genetic test (Afl-III-RFLP test) demonstrated the mutation Arg 117 His in the cationic trypsinogen gene in all diseased or symptomatic family members. The patient died of the complications of the pancreatic cancer. CONCLUSION: Genetic tests are valuable in the diagnosis of hereditary pancreatitis, because the increased cancer risk can be met by frequent examinations in affected family members.

Abdominal Pain↗
PubMed1998

Postoperative plasma interleukin-6 in patients with renal cancer correlates with C-reactive protein but not with total fibrinogen or with high molecular weight fibrinogen fraction.

The concentration of fibrinogen (Fb) and its fractions, the levels of interleukin-6 (I1-6), C-reactive protein (CRP), and immunoglobulin G (IgG) were determined in 38 patients operated on because of renal cancer. The increased Fb and I1-6 concentrations were found in approximately one-half of the patients with malignancy. The relations among the high molecular weight (HMW) and two low molecular weight (LMW and LMW') fibrinogen fractions in these patients before surgery did not differ from the corresponding relations in normal subjects. The levels of all (except IgG) compounds studied increased after surgery and the peak of I1-6 was observed on the first postoperative day but that of CRP on the third day. The concentrations of total Fb and of its HMW fraction were the highest also on the third postoperative day and this was in contrast with the decline of low molecular weight fractions at the same time. These variations of estimated variables can be regarded as being relevant to the acute phase response. We have noted a correlation between the maximal concentrations of I1-6 and CRP, but not between the corresponding concentrations of Il-6 and total Fb or HMW Fb; this may suggest that the concentration of Fb is also under the control of a factor other than I1-6.

Adult↗
PubMed1998

Sulfasalazine: a potent and specific inhibitor of nuclear factor kappa B.

Transcription factors of the NF-kappaB/Rel family are critical for inducible expression of multiple genes involved in inflammatory responses. Sulfasalazine and its salicylate moiety 5-aminosalicylic acid are among the most effective agents for treating inflammatory bowel disease and rheumatoid arthritis. However, the mode of action of these drugs remains unclear. Here we provide evidence that the transcription factor NF-kappaB is a target of sulfasalazine-mediated immunosuppression. Treatment of SW620 colon cells with sulfasalazine inhibited TNFalpha-, LPS-, or phorbol ester- induced NF-kappaB activation. NF-kappaB-dependent transcription was inhibited by sulfasalazine at micro- to millimolar concentrations. In contrast, 5-aminosalicylic acid or sulfapyridine did not block NF-kappaB activation at all doses tested. TNFalpha-induced nuclear translocation of NF-kappaB was prevented by sulfasalazine through inhibition of IkappaBalpha degradation. When blocking proteasome-mediated degradation of IkappaBalpha, we could demonstrate that sulfasalazine interfered with IkappaBalpha phosphorylation, suggesting a direct effect on an IkappaBalpha kinase or on an upstream signal. Inhibition of NF-kappaB activation seems to be specific since other DNA-binding activities such as AP1 were not affected. These results demonstrate that sulfasalazine is a potent and specific inhibitor of NF-kappaB activation, and thus may explain some of the known biological properties of sulfasalazine.

Anti-Infective Agents↗
PubMed1998

Identification of a new tumour-associated antigen TM4SF5 and its expression in human cancer.

In a previous large-scale screening for differentially expressed genes in pancreatic cancer, a gene was identified that was highly overexpressed in pancreatic cancer encoding a novel putative tetraspan transmembrane protein highly homologous to the tumour-associated antigen L6. Using a radiation hybrid panel the identified human gene named TM4SF5 (transmembrane 4 superfamily member 5) was localized to chromosome 17 in the region 17p13.3. The cloned TM4SF5 cDNA has a 32bp 5'-untranslated region (UTR), a 591bp open reading frame (ORF) and a 85bp 3'UTR. The predicted TM4SF5 protein with 197 amino acids contains three NH2-terminal hydrophobic transmembrane regions, followed by an extracellular hydrophilic domain containing two potential N-linked glycosylation sites and a COOH-terminal hydrophobic transmembrane region. These structural features are shared by the L6 antigen and a number of related cell surface proteins associated with cell growth. TM4SF5 was overexpressed in pancreatic cancer tissues as compared to both normal pancreas and chronic pancreatitis tissues, and was detected at high levels in other tumour tissues. Although the precise function of TM4SF5 remains to be elucidated it may be useful in a clinical setting for tumour diagnosis and/or therapy. This hypothesis is supported by the strong homology to the L6 antigen, which has proved promising in immunological, therapeutic and diagnostic approaches.

Amino Acid Sequence↗
PubMed1998

Overexpression and activation of the tyrosine kinase Src in human pancreatic carcinoma.

Src family tyrosine kinases participate in the regulation of cell adhesion, cell growth and differentiation. Here, we examine for the first time the potential role of Src for growth regulation of human pancreatic carcinoma cells. By immunohistochemical analysis, Src was overexpressed in 13/13 pancreatic carcinoma tissue but not in 6 normal pancreatic tissue specimen. In Western blots of total cellular extracts, Src protein expression was elevated in 14/17 carcinoma cell lines as compared to normal pancreas or cultured human pancreatic duct cells. Kinase activity was only detectable in cancer cells and did not correlate with the amount of kinase protein or with the expression of the regulatory kinase Csk, indicating that Src is not regulated through protein expression or through expression of Csk. The Src-specific tyrosine kinase inhibitor herbimycin A decreased cell growth in a dose-dependent manner. We suggest that Src family kinases participate in growth regulation of pancreatic cancer cells.

Aged↗
PubMed1998

Cloning of a new Kunitz-type protease inhibitor with a putative transmembrane domain overexpressed in pancreatic cancer.

In a previous large scale screen for differentially expressed genes in pancreatic cancer, we identified a gene highly overexpressed in cancer encoding a novel putative transmembrane protein with two Kunitz-type serine protease inhibitor domains. The identified gene named kop (Kunitz domain containing protein overexpressed in pancreatic cancer) was assigned to chromosome 19 in the region 19q13.1. Kop was detected at high levels in pancreatic cancer cell lines and was overexpressed in pancreatic cancer tissues as compared to both, normal pancreas and chronic pancreatitis tissues. Being a member of the Kunitz-type serine protease inhibitor family, this new gene may participate in tumour cell invasion and metastasis and in the development of the marked desmoplastic reaction typical for human pancreatic cancer tissues. In this context, the fact that kop has a putative transmembrane domain may have functional implications of particular interest.

Adenocarcinoma↗