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Biomedical subjects

Christoph Röcken

Publications and source records attributed to Christoph Röcken.

At least 19 recordsLinked to original sources
PubMed2007

Gene polymorphisms of folate metabolizing enzymes and the risk of gastric cancer.

Multiple studies have reported an association between disturbances of folate metabolism and increased risk of gastric cancer, including low intake of folate, low levels of folate in blood or genetic factors affecting folate metabolism. Among the genetic factors, in particular a common polymorphism in the gene encoding for 5,10-methylenetetrahydrofolate reductase (MTHFR C677T) has been linked to gastric cancer. Other polymorphisms in folate-metabolising genes have been less frequently investigated. Therefore, we analyzed this polymorphism, the glutamate carboxypeptidase (GCP) II C1561T and the reduced folate carrier (RFC) G80A in a case-control study involving 106 patients with histologically confirmed and characterized gastric cancer with adjustment for other established risk factors for gastric cancer in comparison to 106 age- and sex-matched controls. Neither the MTHFR nor the GCP gene polymorphisms showed an association to cancer diagnosis, to tumor stage, grade of differentiation or Lauren type. However, non-cardia cancers were more likely to exhibit the 80GA and 80AA RFC genotypes, compared to cancers of the gastric cardia (adjusted OR 0.28; 95% CI=0.11-0.71). Thus, gene polymorphisms of the RFC gene might contribute to an increased risk of developing distal gastric cancer.

Aged↗
PubMed2007

The expression of low density lipoprotein receptor-related protein in colorectal carcinoma.

Low density lipoprotein receptor-related protein (LRP) is a multifunctional cell surface receptor binding many different ligands including proteinases and their inhibitors, some of which are known to be involved in tumor biology. We studied the expression of LRP and its putative role in colorectal carcinoma. Tissue samples were obtained from 50 patients with colorectal carcinoma and fixed in formalin and embedded in paraffin. Immunohistochemical staining was performed using antibodies directed against LRP, cathepsin B and urokinase-type plasminogen activator (u-PA). The expression of LRP was further studied by polymerase chain reaction. The TNM stage was determined according to UICC guide lines and was based upon histological analysis. LRP was primarily expressed in stroma cells [36 patients (72%)] and less frequently in tumor cells [6 patients (12%)]. In 22% of all cases LRP was prominent at the invasion front. Cathepsin B was found both in the tumor stroma [50 (100%)] and in the tumor cells [46 (92%)]. u-PA was present in the tumor stroma [44 (88%)] and in the tumor cells [44 (88%)]. In stromal cells the expression of LRP correlated significantly with the expression of u-PA (p=0.043). Furthermore, the expression of LRP and of u-PA in tumor cells correlated with the tumor stage according to UICC (p=0.038 and 0.018, respectively). We provide evidence that LRP is expressed in colorectal cancer. As LRP forms complexes with u-PA and its inhibitor, we suspect that LRP can influence the known effects of u-PA on tumor biology.

Adult↗
PubMed2006

Immunohistochemical detection of bombesin receptor subtypes GRP-R and BRS-3 in human tumors using novel antipeptide antibodies.

Bombesin (BN)-like peptides can stimulate cancer cell growth through binding to their specific G protein-coupled receptors. It is well established that BN receptors are being overexpressed in a subset of human tumors; however, little is known about the cellular and subcellular localization of individual BN receptor subtypes in these tissues. In this study, we developed and characterized novel antipeptide antibodies to the carboxy terminal regions of the gastrin-releasing peptide-preferring bombesin receptor (GRP-R) and the bombesin receptor subtype-3 (BRS-3). Specificity of the antisera was demonstrated by (1) detection of broad bands migrating at Mr 50,000-70,000 in Western blots of membranes from receptor-expressing tissues; (2) cell surface staining of transfected cells; (3) translocation of GRP-R receptor immunostaining after BN exposure; and (4) abolition of tissue immunostaining by preadsorbtion of the antibodies with their immunizing peptides. The distribution of BN receptors was investigated in 74 formalin-fixed, paraffin-embedded human tumors. GRP-R receptors were most frequently detected in breast and prostate carcinomas. BRS-3 receptors were often detected in prostate and pancreatic carcinomas and in pituitary adenomas. Immunoreactive GRP-R and BRS-3 receptors were in many cases predominantly confined to the plasma membrane and uniformly present on nearly all tumor cells. The development of these novel antipeptide antibodies will facilitate the identification of those tumors, which may be targets for diagnostic or radiotherapeutic application of subtype-selective BN analogs.

Amino Acid Sequence↗
PubMed2006

Aristaless-like homeobox-4 gene methylation is a potential marker for colorectal adenocarcinomas.

BACKGROUND & AIMS: The identification of novel genetic and epigenetic markers indicative of changes in the pathogenesis of colon cancer, along with easier-to-use, more sensitive assay methods, may improve the detection, treatment, and overall prognosis of this malignancy. METHODS: Using methylation-specific arbitrarily primed polymerase chain reaction, a fragment of the Aristaless-like homeobox-4 (ALX4) gene that was highly methylated in colon adenomas and cancer was identified. Methylation of ALX4 was analyzed in colorectal adenomas and cancers, in the liver metastases of patients with colorectal cancer, and in 61 other neoplasias, including gastric, esophageal, and hepatocellular cancer and cholangiocarcinoma. ALX4 methylation was also analyzed in the serum of 30 patients with colon cancer. RESULTS: ALX4 gene methylation was confirmed in colon adenomas (11/13) and more frequently present in primary colorectal cancers (30/47) compared with the normal colon mucosa (0/21) (P < .0001). In addition, ALX4 methylation was frequently observed in adenocarcinomas of the esophagus (12/14), stomach (11/15), and bile ducts (4/5) compared with all other cancers (P < .001). ALX4 gene methylation was also more frequently found in sera of patients with colon cancer compared with noncancer controls (P < .0001). Using a cutoff of 41.4 pg/mL, sensitivity and specificity were 83.3% and 70%, respectively. CONCLUSIONS: Apart from colon adenomas and primary and metastatic colorectal cancers, ALX4 is frequently methylated in adenocarcinomas of the gastrointestinal tract. ALX4 gene methylation in sera of patients with cancer may thus serve as a methylation-specific test for colon and other gastrointestinal cancers.

Adenocarcinoma↗
PubMed2006

Immunocytochemical localisation of plasma membrane GHRH receptors in human tumours using a novel anti-peptide antibody.

Antagonists of growth hormone releasing hormone (GHRH) directly inhibit the growth of a variety of human neoplasms. However, the plasma membrane receptor mediating these effects has not been immunocytochemically visualised in primary tumour cells. Given that previous attempts using an antibody to the amino-terminal region did not result in the visualisation of plasma membrane receptors, we have developed and characterised an anti-peptide antibody to the carboxy-terminal region 403-422 of the human pituitary GHRH receptor. This sequence is identical to residues 339-358 of splice variant 1 (SV1) of tumoural GHRH receptors. Specificity of the antibody was demonstrated by (1) immunocytochemical staining of GHRH receptor-transfected cells, (2) detection of a broad glycosylated protein band migrating at Mr 50,000-60,000 in Western blots of membranes from human pituitary, and (3) abolition of tissue immunostaining by preadsorbtion of the antibody with its immunising peptide. The distribution of GHRH receptors was investigated in 69 formalin-fixed, paraffin-embedded human tumours showing that GHRH receptors were frequently expressed in breast, ovarian and prostate carcinomas. Immunoreactive GHRH receptors were clearly confined to the plasma membrane and uniformly present on nearly all tumour cells. In Western blots of membranes prepared from human tumours, the anti-GHRH receptor antibody detected a non-glycosylated protein band migrating at Mr 40,000, which corresponds to the expected molecular weight of splice variant 1 of tumoural GHRH receptors. Together, our findings provide direct evidence for the presence of GHRH receptor protein on the plasma membrane of primary human tumour cells. The GHRH receptor visualisation could be of value for a rapid immunohistochemical identification of those tumours which could be a target for diagnostic or therapeutic intervention using GHRH analogues.

Antibodies↗
PubMed2006

Immunolocalization of full-length NK1 tachykinin receptors in human tumors.

Biological effects of substance P (SP) are mediated by the neurokinin-1 (NK1) receptor that exists as a full-length and as a carboxy-terminally truncated isoform in humans. Although NK1 receptor mRNA and binding sites have been detected in certain malignancies, little is known about the cellular and subcellular localization of NK1 receptor protein in human neoplastic tissues. We developed and characterized a novel anti-peptide antibody to the carboxy-terminal region of the human full-length NK1 receptor. Specificity of the antiserum was demonstrated by (1) detection of a broad band migrating at molecular mass 70,000-90,000 Da in Western blots of membranes from NK1-expressing tissues; (2) cell-surface staining of NK1-transfected cells; (3) translocation of NK1 receptor immunostaining after SP exposure; and (4) abolition of tissue immunostaining by preadsorption of the antibody with its immunizing peptide. Distribution of NK1 receptors was investigated in 72 formalin-fixed, paraffin-embedded human tumors showing that NK1 receptors were frequently expressed in glioblastomas and breast and pancreatic carcinomas. Immunoreactive NK1 receptors were clearly confined to the plasma membrane and uniformly present on nearly all tumor cells. Development of this novel NK1 receptor antibody allows the efficient localization of NK1 receptor protein in human formalin-fixed, paraffin-embedded tissues. NK1 receptor visualization with this simple and rapid immunohistochemical method will facilitate identification of tumors with a sufficient receptor overexpression for diagnostic or therapeutic intervention using SP analogs.

Antibodies↗
PubMed2006

Budesonide induces complete remission in autoimmune hepatitis.

AIM: Prednisone and azathioprine represent the standard treatment for autoimmune hepatitis (AIH). However, only 65% of the patients enter complete histological remission. Recently, budesonide (BUD) was reported to be a promising alternative. In this study we assessed the efficacy and safety of BUD in AIH. METHODS: Eighteen patients (12 women, 6 men; mean age 45.4+/-21 years)with AIH were treated with BUD (Budenofalk) 3 mg thrice daily and followed up for at least 24 wk. Seven patients also had features of primary biliary cirrhosis (n=5) or primary sclerosing cholangitis (n=2). Advanced liver fibrosis or cirrhosis was present in 6 patients. RESULTS: Fifteen (83%) patients had a complete clinical and biochemical remission. Ten patients, including five with acute hepatitis,were given BUD as first-line therapy, of which seven enter remission. Three patients, two with liver cirrhosis, did not improve.All patients with second-line therapy experienced long-term remission. A histological remission was also seen in three patients. Clinically relevant BUD-induced side effects were recorded only in patients with liver cirrhosis (n=4). CONCLUSION: BUD is effective in remission induction in the majority of our patients with AIH. Side effects and treatment failure was mainly observed in patients with liver cirrhosis.

Adult↗
PubMed2006

The tyrosine kinase inhibitor imatinib fails to inhibit pancreatic cancer progression.

Imatinib targets KIT and platelet-derived growth factor receptors (PDGFR) and is highly effective in the treatment of CML and GIST patients. Pancreatic cancers express KIT and PDGFRs. Therefore, 26 patients with unresectable pancreatic cancer were randomized to either gemcitabine (1000 mg/m2 weekly) or imatinib (2x400 mg po) treatment daily. Pancreatic adenocarcinoma was confirmed histologically and expression of KIT and PDGFRbeta was determined immunohistochemically in the biopsy specimens. Quality of life was assessed with two standard questionnaires. No objective responses were seen in either group. Median time to progression was 77 and 29 days (P=0.411) and median survival time was 140 and 60 days (P=0.517) for gemcitabine and imatinib, respectively. Survival and treatment responses were independent of KIT and PDGFRbeta expression in patients treated with imatinib. Grade 3/4 toxicities of imatinib treatment were anemia, elevated liver enzymes, vomiting, and dyspnea. Patients treated with imatinib reported diarrhoea and/or altered bowel function more frequently, which were treatable symptomatically. Quality of life was similar in both groups. In this small series of pancreatic cancer patients, treatment with imatinib was not associated with a significant control of cancer progression.

Adenocarcinoma↗
PubMed2006

Troglitazone inhibits tumor growth in hepatocellular carcinoma in vitro and in vivo.

Peroxisome proliferator-activated receptor gamma (PPARgamma) has been implicated in the differentiation and growth inhibition of cancer cells. We examined the effects of PPARgamma activation by troglitazone on hepatocellular carcinoma (HCC) cell growth, proliferation, and apoptosis in vitro and in vivo. We also studied relationships between PPARgamma activation and cyclooxygenase-2 (COX-2) expression. Human HCC cell lines Huh7 and Hep3B were cultured in the presence or absence of troglitazone. Cell growth was determined via WST-1 assay, proliferation by cell cycle analysis and proliferating cell nuclear antigen (PCNA) Western blotting, and apoptosis by flow cytometry and TUNEL. Tumor growth after subcutaneous implantation of Huh7 cells in nude mice was monitored, and the effects of treatment with troglitazone were determined. In resected HCCs, PPARgamma expression was less compared with the histologically normal surrounding liver. In cultures of Hep3B and Huh7 cells, basal expression of PPARgamma was relatively low, but troglitazone caused dose-dependent induction of PPARgamma expression. Cell cycle analysis revealed a decreased proportion of cells in S phase, with arrest at G0/G1. Concomitant downregulation of PCNA and an increase in TUNEL staining, cells were consistent with decreased proliferation and induction of apoptosis by troglitazaone. Troglitazone-mediated PPARgamma activation also suppressed COX-2 expression and induced p27 in HCC cells. Administration of troglitazone to Huh7 tumor-bearing mice significantly reduced tumor growth and caused tumor regression. In conclusion, collectively, these results indicate that PPARgamma could be a regulator of cell survival and growth in HCC. PPARgamma therefore represents a putative molecular target for chemopreventive therapy or inhibition of liver cancer growth.

Animals↗
PubMed2006

ALys amyloidosis caused by compound heterozygosity in exon 2 (Thr70Asn) and exon 4 (Trp112Arg) of the lysozyme gene.

Hereditary amyloidoses are caused by germline mutations, which increase the propensity of a protein to form cross-beta aggregates and deposit as amyloid. Hereditary amyloidoses are particularly interesting as they help to understand how changes in the primary structure of an otherwise non-amyloidogenic protein contribute to amyloidogenesis. Here we report on a novel form of systemic ALys amyloidosis, caused by compound heterozygosity in exon 2 (p.T70N) and exon 4 (p.W112R) of the lysozyme gene (LYZ), with both mutations being present on the same allele. This type of hereditary ALys amyloidosis is characterized by extended amyloid deposits in the upper gastrointestinal tract, entire colon, and kidney, leading to gastrointestinal bleeding. Both mutations are probably effective in disease manifestation. The novel mutation at position 112 in the mature protein is located within the alpha-helical domain of the protein and therefore outside the cluster of residues that has so far been implicated in ALys amyloidosis. Taken together with the p.T70N mutation, this results in a lysozyme species where the correct folding of various protein domains is probably impaired and increases the propensity of amyloid fibril formation. Interestingly, this form of ALys amyloidosis is also characterized by the occurrence of proteolytic fragments of lysozyme in the amyloid deposits.

Adult↗
PubMed2006

Advances, challenges, and limitations in serum-proteome-based cancer diagnosis.

Recent advances in medicine have dramatically reduced the incidence and mortality of many cardiovascular, infectious, and certain neoplastic diseases; the overall mortality for most malignant solid tumors remains high. The poor prognosis in these cancers is due, in part, to the absence of adequate early screening tests, leading to delays in diagnosis. Three strategies have been applied to fight cancer: analysis of the molecular mechanisms involved in its pathogenesis and progression, improvement of early diagnosis, and the development of novel treatment strategies. There have been major advances in our understanding of cancer biology and pathogenesis and in the development of new (targeted) treatment modalities. However, insufficient progress has been made with respect to improving the methods for the early diagnosis and screening of many cancers. Therefore, cancer is often diagnosed at advanced stages, delaying timely treatment and leading to poor prognosis. Proteome analysis has recently been used for the identification of biomarkers or biomarker patterns that may allow for the early diagnosis of cancer. This tool is of special interest, since it allows for the identification of tumor-derived secretory products in serum or other body fluids. In addition, it may be used to detect reduced levels or loss of proteins in the serum of cancer patients that are present in noncancer individuals. These changes in the serum proteome may result from cancer-specific metabolic or immunological alterations, which are, at least partly, independent of tumor size or mass, thereby facilitating early discovery.

Biomarkers, Tumor↗
PubMed2006

Identification and confirmation of increased fibrinopeptide a serum protein levels in gastric cancer sera by magnet bead assisted MALDI-TOF mass spectrometry.

Gastric cancer is the second most common malignancy and prognosis remains dismal. The reasons for the poor prognosis are the lack of sensitive serum markers for early detection and screening of high-risk individuals as well as the limited treatment options in advanced cancer stages. Using MALDI-TOF mass spectrometry after prefractionation of sera with magnet hydrophobic C8 coated beads sera from 14 patients with gastric cancer and 14 healthy controls mass spectra were generated. A peptide fragment was found to be highly elevated in cancer sera and was identified as fibrinopeptide A. To confirm proteome analysis of gastric cancer sera, we then screened a larger series of patients with gastric cancer (n = 99), high-risk individuals (n = 13) and normal controls (n = 111) for fibrinopeptide A serum levels. Interestingly, the mean logarithmic concentrations of serum fibrinopeptide A levels were significantly higher in cancer patients (mean 3.636 +/- 0.3738; p < 0.0001) and high-risk individuals (mean 3.569 +/- 0.4722; p < 0.05) compared to normal controls (mean 3.303 +/- 0.4012). In contrast, we observed no association of fibrinopeptide A levels with tumor stage, tumor location, presence of regional or distant metastasis, and Lauren type of gastric cancer. In conclusion, MALDI-TOF mass spectrometry of prefractionated gastric cancer sera allows the identification of potential biomarkers that may lead to the development of serum based tests for screening of high-risk individuals.

Aged↗
PubMed2006

Constitutive activation of NF-kappaB in human hepatocellular carcinoma: evidence of a cytoprotective role.

Activation of nuclear factor-kappaB (NF-kappaB) can promote or inhibit apoptosis. Oxidative stress is an important mechanism by which certain anticancer drugs kill cancer cells, and is also one of the mechanisms that activate NF-kappaB. We therefore examined hepatic expression of the NF-kappaB monomer p65 in human hepatocellular carcinoma (HCC) tissue samples from eight patients and compared it with their respective samples of surrounding liver tissues. We also studied the effect of NF-kappaB inhibition in human HCC cells exposed to oxidative stress, by infecting HuH7 cells with a recombinant adenovirus carrying mutant IkappaBalpha (mIkappaBalpha). Cultured HuH7 cells were infected with mIkappaBalpha or beta-galactosidase (beta-Gal) for 24 hr followed by treatment with increasing concentrations of H2O2. Cytotoxicity, NF-kappaB translocation, NF-kappaB DNA binding, cell proliferation, and apoptosis were determined. The monomer p65 was overexpressed in six of eight human HCC tissues. In HuH7 cells, introduction of mIkappaBalpha potently inhibited the translocation, activation, and DNA binding of NF- kappaB. In control (beta-Gal-infected) HuH7 cells, exposure to H2O2 produced a dose-dependent increase in apoptosis, regardless of NF-kappaB status. mIkappaBalpha-mediated inhibition of NF-kappaB activation sensitized HuH7 cells to H2O2-induced inhibition of cell growth, and further promoted cell death. Addition of H2O2 (200-500 microM) to control or mIkappaBalpha-infected HuH7 cells enhanced caspase-3 activity and cleavage. Adenovirus-mediated transfer of mIkappaBalpha potently inhibits NF-kappaB activity in HuH7 cells, and this enhances oxidative stress-induced cell killing.

Adenoviridae↗
PubMed2006

Immunohistochemical classification of amyloid in surgical pathology revisited.

We aimed to reassess the suitability of immunohistochemical classification of amyloid in surgical pathology. One hundred sixty-nine biopsies from 121 patients diagnosed with amyloid during the period from 1994 to 2004 were included. Amyloid was classified immunohistochemically, using antibodies directed against amyloid P-component, AA amyloid, apolipoprotein AI, fibrinogen, keratoepithelin, lactoferrin, lysozyme, beta2-microglobulin (beta2M), immunoglobulin-derived lambda-light and kappa-light chains, and transthyretin. Amyloid was most commonly present in biopsies from the hepatogastrointestinal tract. The deposits were classified immunohistochemically in 156 (92%) biopsies. In 13 biopsies of 12 patients, amyloid remained unclassified. AL amyloidosis was diagnosed in 76 (45%) biopsies and was further categorized into AL amyloid of kappa-light chain origin [32 (42%) biopsies] or lambda-light chain origin [20 (26%)]. In 24 (32%) biopsies, the amyloid deposits did not show unequivocal staining for lambda-light or kappa-light chain. However, these cases were categorized as "probably AL amyloid, not otherwise specified", because no other antibody showed unequivocal staining of the amyloid deposits. AA amyloidosis was diagnosed in 32, ATTR amyloidosis in 21, and AApoAI amyloidosis in 3 biopsies. Other types of amyloid included AKer and ALac amyloids each in 1, and ALys and ACal amyloids each in 2 biopsies. Abeta2M amyloid was not diagnosed in any case. Immunohistochemical classification of amyloid still poses problems. Although classification of AA, AApoAI, ALys, ALac, and ATTR amyloids is relatively straightforward, classification of AL amyloid and rare hereditary amyloidoses is a serious obstacle and sometimes even impossible when conclusive clinical information or additional protein biochemical or molecular biologic studies are not available.

Adult↗
PubMed2006

Molecular screening of gastric cancer by proteome analysis.

Gastric cancer affects annually more than 800,000 individuals worldwide and remains a challenge for clinicians and oncologists. Most patients with gastric cancer are diagnosed in advanced stages, when a curative resection is impossible, which leads to an overall poor prognosis. Finding new diagnostic and treatment procedures is of paramount importance to improve patient prognosis, which will be improved most dramatically by techniques that allow the detection of gastric cancer in its early stages. So far the value of conventional tumour markers such as Ca72-4 or carcinoembryonic antigen is limited, and even markers developed from molecular biological studies on the carcinogenesis of gastric cancer, such as E-cadherin and others, have not proved to be of adequate sensitivity and specificity to allow the early detection of gastric cancer. With the development of innovative diagnostic tools, such as proteome analysis, new biomarkers may be identified that may allow early diagnosis and thus screening for gastric cancer, particularly in at-risk patient populations. Recent studies have indicated that these biomarkers may be derived from the tumour itself or reflect a specific metabolic or immunological response to cancer that can be used to find gastric cancer patients at an early and putatively curative stage of the disease.

Biomarkers, Tumor↗