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A Tannapfel

Publications and source records attributed to A Tannapfel.

At least 19 recordsLinked to original sources
PubMed2007

[Role of epigenetics in the carcinogenesis of head and neck carcinomas - possible new targeted therapy?].

In search of new targeted therapies for squamous cell carcinoma of the head neck (HNSCC), a better understanding of the carcinogenesis is of outmost importance. Recent studies show that not only genetic but also epigenetic alterations initiate the multistep process of tumordevelopment. Epigenetic changes lead to altered gene expression without alterations of the DNA sequence. The best characterized epigenetic change is the methylation of the promoter region of genes, especially of tumorsuppressor genes. The methylation of the promoter region blocks the promoter and therefore represses transcription. The loss of the gene products of tumorsuppressor genes leads to increased proliferation and decreased apoptosis. Methylation of tumorsuppressor genes was shown in precancerous lesions of HNSCC, which emphasizes the importance of methylation as an early biomarker. Several studies of tumor cell cultures show reactivated expression of proteins and as a result reduction of proliferation and induction of apoptosis after treatment with demethylating agentens. This presents a very promising new option for a targeted therapy.

Antimetabolites, Antineoplastic↗
PubMed2007

Sirolimus improves early microcirculation, but impairs regeneration after pancreatic ischemia-reperfusion injury.

Ischemia and reperfusion injury remains a relevant problem in clinical pancreas transplantation. We investigated the effect of sirolimus (SRL) in a rodent model of 90-min warm pancreatic ischemia. Four groups were studied: (1) sham surgery and vehicle; (2) sham surgery and SRL; (3) warm ischemia and vehicle; (4) warm ischemia and SRL. SRL (1.5 mg/kg/day) and vehicle were administered intraperitoneally for 3 days prior to surgery until the animals were killed. Microcirculation was assessed immediately after reperfusion by means of intravital fluorescence microscopy. Histopathological injury, apoptosis, proliferation and biochemical parameters were analyzed at 2 h, 1 day and 5 days after surgery. Ninety minutes after ischemia, intravital microscopy revealed an improved functional capillary density (p < 0.05) and reduction of adherent leucocytes (p < 0.01) and platelets (p < 0.05) in the SRL-treated group compared to the vehicle-treated controls. In contrast, on day 5 after ischemia, the pancreatic tissue of SRL-treated animals showed a higher grade of histological injury (p < 0.05) and higher rate of apoptotic cells (p < 0.05) than the vehicle controls. In summary, our data indicate that administration of SRL improves microcirculation at a very early stage, but results in an impairment of the recovery phase after pancreatic ischemia-reperfusion injury.

Animals↗
PubMed2006

Basement membrane component laminin-5 is a target of the tumor suppressor Smad4.

The tumor suppressor Smad4 is involved in carcinogenesis mainly of the pancreas and colon. Functional inactivation of Smad4 is a genetically late event that occurs upon transition from premalignant stages to invasive and metastatic growth. Smad4 encodes an intracellular messenger common to all signalling cascades induced by members of the transforming growth factor-beta (TGF-beta) superfamily of cytokines. Despite extensive knowledge about the mechanisms of TGF-beta/Smad signal transduction, little is known about Smad4 targets involved in the transition to malignancy. The hallmark of invasive growth is a breakdown of the basement membrane (BM), a specialized sheet of extracellular matrix produced through cooperation of epithelial and stromal cells. Laminin-5, a heterotrimeric epithelial-derived BM component, is commonly lost in carcinomas but not in premalignant tumors. Herein, we report that in human colon and pancreatic tumor cells, Smad4 functions as a positive transcriptional regulator of all three genes encoding laminin-5. Coordinate re-expression of the three laminin-5 chains induced by reconstitution of Smad4 leads to secretion and deposition of the heterotrimeric molecule in BM-like structures. These data define the expression control of an essential BM component as a novel function for the tumor suppressor Smad4.

Adenocarcinoma↗
PubMed2006

Biocompatibility of bacterial contaminated prosthetic meshes and porcine dermal collagen used to repair abdominal wall defects.

BACKGROUND AND AIMS: A contaminated or infected surgical site is considered a contraindication for the use of the nonabsorbable alloplastic materials employed to repair abdominal wall defects. Therefore, the biocompatibility of new prosthetic materials was investigated. MATERIALS AND METHODS: Meshes measuring 1.5x1.5 cm made of conventional and titanium-coated polypropylene, polyglycol, or porcine dermal collagen were implanted under the abdominal wall of 96 rats (eight groups of 12 animals each) employing the inlay technique. Implantation of all four materials was performed both under semisterile conditions and bacterial contamination of the mesh. The meshes were explanted after 28 days. RESULTS: All the materials implanted under semisterile conditions were incorporated into the abdominal wall with only few intraabdominal adhesions (mean adhesion scores: 1.0, 1.2, 1.0, 0.8 points, respectively, not significant). With the porcine dermal collagen, proliferation rate and the proportion of inflammatory cells were statistically lower (p<0.01). In the bacterial contamination group, all meshes were associated with a suppurating infection and strong adhesions between the bowel and mesh, which were most prominent in the case of dermal collagen (mean adhesion scores: 1.6, 1.7, 1.7, and 1.9 points, respectively, not significant). In this group, two animals died of peritonitis. In comparison with the other materials, the proliferation rate was significantly elevated (p=0.03). No significant differences were seen between the other materials employed. CONCLUSION: Irrespective of the material employed, implantation of alloplastic meshes in an abdominal wall contaminated with bacteria, is associated with suppurating infections, in particular in the case of the membrane-like porcine dermal collagen. Nonabsorbable alloplastic meshes and dermal skin grafts should therefore not be used to repair infected abdominal wall defects.

Abdominal Wall↗
PubMed2006

Evaluation of potential mechanisms underlying genotype-phenotype correlations in multiple endocrine neoplasia type 2.

Distinct dominant activating mutations in the RET proto-oncogene are responsible for the development of multiple endocrine neoplasia type 2 (MEN 2). Concise examination of the mutated codons led to the detection of a striking genotype-phenotype correlation between the mutated codon and the MEN 2 phenotype in terms of onset and aggressiveness of the disease, suggesting that manifestation and clinical progression is conditioned by the type of mutation. To gain insight into the molecular basis for this genotype-phenotype correlation, we analysed the impact of common and rare mutations identified in MEN 2A (C609Y, C634R), MEN 2B (A883F, M918T) and familial medullary thyroid carcinoma (Y791F) patients on several aspects of cell transformation, including proliferation, apoptosis, anchorage-independent growth and signaling. We found that tumor cells arising from distinct extracellular or intracellular MEN 2 mutations clearly differ in their proliferation properties owing to the activation of different molecular pathways, but importantly, also in resistance to apoptosis. Whereas MEN 2A mutants resulted in accelerated cell proliferation, MEN 2B-RET mutants significantly enhanced suppression of apoptosis, which may account, at least partially, for some of the clinical differences in MEN 2 patients.

Animals↗
PubMed2006

A lightweight polypropylene mesh (TiMesh) for laparoscopic intraperitoneal repair of abdominal wall hernias: comparison of biocompatibility with the DualMesh in an experimental study using the porcine model.

BACKGROUND: Despite numerous experimental studies, conducted most often with the open small-animal model, the ideal structure for a mesh with maximum biocompatibility in the intraabdominal region has yet to be found. To date, few experimental models have been concerned with the laparoscopic intraabdominal implantation of meshes. Numerous experimental and clinical studies appear to have identified expanded polytetrafluoroethylene (ePTFE), in the form of DualMesh, as the gold standard. Since publications have reported fistula formation and marked adhesions to be associated with the use of polypropylene meshes, only few studies have investigated meshes made of this material. It is known, however, that a reduction in the amount of material and an increase in pore size results in better mesh biocompatibility. METHODS: Six pigs each underwent laparoscopic intraabdominal placement of either a TiMesh or a DualMesh, both of which were prepared for implantation in standardized fashion. After 87 +/- 2 days, the pigs were killed, and postmortem laparoscopy was performed, followed by the removal of the tissue embedding the mesh for assessment of adhesions and shrinkage, and for histologic workup. The specimens were processed both histologically and immunohistochemically. RESULTS: In all but one case, the greater omentum adhered, usually over discrete areas, to the mesh. In every case the omentum was separable from the mesh surface only by sharp dissection. With the titanium-coated polypropylene meshes, the average total adhesion area was only 0.085, as compared with 0.25 for the GoreTex meshes (p = 0.055). The GoreTex meshes showed an average shrinkage to almost half of the original surface area (median, 0.435). The average shrinkage of the TiMesh, was to 0.18 of the original area (p = 0.006), which thus was significantly smaller. Determination of the partial volume of the inflammatory cells showed significantly lower median figures for the TiMesh (p = 0.009). Measurements of the proliferation marker Ki67 showed significantly higher values for ePTFE than for TiMesh (p = 0.011). The apoptosis index was significantly higher for the ePTFE membranes (p = 0.002). CONCLUSIONS: Titanium-coated polypropylene mesh (TiMesh) is clearly superior to the DualMesh in terms of biocompatibility, and is thus suitable for the laparoscopic intraperitoneal repair of abdominal wall and incisional hernias.

Abdominal Wall↗
PubMed2006

[Mycosis fungoides and B-cell chronic lymphocytic leukemia: an extremely rare coincidence].

The simultaneous appearance of mycosis fungoides (MF) and B-cell chronic lymphocytic leukemia (B-CLL) in the same patient is extremely rare. Only seven cases have been described in literature. A 72-year-old patient was diagnosed with coincident MF, stage Ib, and B-CLL, Binet stage A. Hypotheses on simultaneous occurrence of B- and T-cell malignancies as well as a new therapeutic option are discussed.

Aged↗
PubMed2006

[Methylation and other new concepts for the origin of hepatocellular carcinoma].

Methylation takes place when a methyl group, comprised of a carbon and three hydrogen atoms (CH3), attaches to the individual DNA bases. This modification of the DNA leads to a change in gene expression. Changes in the methylation status of the DNA belong to the most common gene changes leading to malignant tumours. Recent studies have shown that three different mechanisms play a role in the effect of methylation: global hypomethylation, hypermethylation of individual gene segments and the deregulated expression of DNA methyltransferases. Such DNA methylation is also one of the most homogenous and consistent molecular changes in hepatocellular carcinoma (HCC). Moreover, the hypermethylation of specific genes has been shown to precede the development of malignant tumours. Thus, DNA methylation is a possible biomarker for the early discovery of HCC. The reversibility of methylation also offers a possible future treatment option.

Carcinoma, Hepatocellular↗
PubMed2006

Cytology and mRNA expression analysis of fine needle aspirates of thyroid nodules in an East German region with borderline iodine deficiency.

Fine needle aspiration cytology (FNAC) is widely recommended as an important tool for pre-operative identification of malignancy in patients with nodular thyroid disease. To assess the diagnostic contribution of FNAC and the potential of quantitative mRNA analysis in fine needle aspirates in daily practice, we conducted a prospective study in thyroid clinics (n=2) and endocrine practices (n=3), respectively in an East German region with borderline iodine deficiency. Two-hundred and forty-four consecutive FNACs were obtained over a period of 2 years (2002-2004) from euthyroid patients presenting for first evaluation of a solitary thyroid nodule. The mean nodule size for FNAC was 27 mm (range: 10-79 mm). In 55% of patients FNAC was performed after scintiscan detection of a cold or normal functioning thyroid nodule (CTN), while in the remainder FNAC was performed as a primary investigation. FNAC outcomes were: 57.8% benign, 22.1% indeterminate, 2.5% suspicious for malignancy, 17.6% non-diagnostic. Messenger RNA levels for a house keeping gene (beta-actin) and a thyroid specific marker (thyroglobulin, Tg) were studied as basic molecular markers using real-time PCR. Both in the IN VIVO and EX VIVO FNA series, beta-actin and Tg mRNA levels were positively correlated with the thyrocyte cell yield/respective FNA smear. However, subgroup analysis showed that FNAC with histologically confirmed follicular thyroid cancer and/or microfollicular adenoma exhibited significantly lower Tg mRNA expression despite high beta-actin levels. Sufficient mRNA quantities were obtained in >90% of FNA specimen to allow quantitative mRNA analysis of at least 5 further genes. In conclusion, quantitative mRNA analysis is feasible in FNA on a routine basis and provides a perspective for a molecular distinction of thyroid nodules, once specific marker genes have been defined for benign and malignant thyroid tumours respectively.

Actins↗
PubMed2005

Alpha1-and beta2-adrenoceptors in the human liver with mass-forming intrahepatic cholangiocarcinoma: density and coupling to adenylate cyclase and phospholipase C.

Besides the regulation of hepatic metabolic pathways in which adrenoceptors are mainly involved, their effect on the second messenger cAMP is thought to be related to the growth and differentiation of neoplastic cells. However, few studies have been done on the status of these structures in the human liver affected by cholangiocarcinoma (CC). Thus, in this study, changes in densities of alpha1- and beta2-adrenoceptors (alpha1-and beta2-ARs) were investigated in membranes of human liver with cholangiocarcinoma, and for comparison, in membranes of non-adjacent non-tumour liver using the potent antagonists [3H]-prazosin and [1I]-iodocyanopindolol (ICYP) respectively. In addition, the activity of membrane-bound phospholipase C (PLC) and adenylate cyclase (AC) was also studied. In CC liver, the density of alpha1-and beta2-ARs was significantly reduced, compared with non-tumour liver tissues (alpha1-ARs: 23.38+/-4.69 vs 80.35+/-10.52, P=0.0002 beta2-ARs: 14.27+/-2.93 vs 33.22+/-4.32 fmol/mg protein, P=0.03), whereas the ligand affinities (KD) remained unchanged. The beta2-selective antagonist ICI 118,551 was about 100 times more potent in inhibiting ICYP binding than the beta1-selective antagonist CGP 20712A; thus, more than 98% of the beta-ARs were of the beta2-subtypes. The AC activity upon stimulants acting on beta-AR (isoprenaline), G-protein (GTP, NaF) and AC (forskolin) was decreased in CC liver. Similarly, noradrenaline-stimulated PLC activity was significantly reduced in tumour tissues. In conclusion, in CC liver the alpha1- and beta2-ARs density was down-regulated and the neoplastic invasion blunted AC and PLC activity. These quantitative changes may help to elucidate not fully understood pathogenetic mechanisms of disturbed hepatic metabolic processes, such as hypoglycemia during cancer in human liver.

Adenylyl Cyclases↗
PubMed2005

TAp73/Delta Np73 influences apoptotic response, chemosensitivity and prognosis in hepatocellular carcinoma.

We investigated the mechanisms by which TAp73 beta and dominant-negative p73 (Delta Np73) regulate apoptosis. TAp73 beta transactivated the CD95 gene via the p53-binding site in the first intron. In addition, TAp73 beta induced expression of proapoptotic Bcl-2 family members and led to apoptosis via the mitochondrial pathway. Endogenous TAp73 was upregulated in response to DNA damage by chemotherapeutic drugs. On the contrary, DeltaNp73 conferred resistance to chemotherapy. Inhibition of CD95 gene transactivation was one mechanism by which DeltaNp73 functionally inactivated the tumor suppressor action of p53 and TAp73 beta. Concomitantly, DeltaNp73 inhibited apoptosis emanating from mitochondria. Thus, DeltaNp73 expression in tumors selects against both the death receptor and the mitochondrial apoptosis activity of TAp73 beta. The importance of these data is evidenced by our finding that upregulation of DeltaNp73 in hepatocellular carcinoma patients correlates with reduced survival. Our data indicate that Delta Np73 is an important gene in hepatocarcinogenesis and a relevant prognostic factor.

Apoptosis↗
PubMed2005

Predictive value of heparanase expression in the palliative therapy of pancreatic cancer.

BACKGROUND/AIMS: Patients with pancreatic ductal adenocarcinoma (PDA) have a median survival of less than six months from diagnosis. Palliative chemotherapy with the current standard gemcitabine does only marginally improve median survival. There may be subgroups of patients receiving palliative therapy that have a better prognosis. Factors predicting response to palliative therapy are ill-defined, though. Heparanase, an endoglycosidase degrading components of the extracellular matrix, promotes cell invasion, is involved in angiogenesis and plays a role in tumor metastases. It is expressed in PDA and its expression is associated with shorter postoperative survival after pancreatic resections. METHODS: 58 patients with inoperable PDA were treated with gemcitabine therapy. Tissue sections from primary or metastatic tumor were used for immunohistochemical analysis. Heparanase expression was determined and correlated to tumor response, time to progression and survival. RESULTS: Heparanase expression was detectable by immunohistochemistry in 36 out of 58 (62%) patients analyzed. Overall survival was 7.4 vs. 13.3 months (p = 0.006) in heparanase-positive and -negative tumors, respectively. Progression-free survival was 1.3 vs. 3.4 months, respectively (p = 0.47). CONCLUSION: Heparanase expression may be a useful marker to predict response to palliative therapy with gemcitabine in PDA.

Adenocarcinoma↗
PubMed2005

Identification of functional genes during Fas-mediated apoptosis using a randomly fragmented cDNA library.

We describe a general strategy for the identification of functional genes that, when downregulated, result in a selectable phenotype. This strategy is based on expression selection of cDNA fragments that counteract their cognate genes. A cDNA library containing random fragments expressed in human HepG2, A375 and CLS-354 cells was used to identify functional genes whose inhibition conferred resistance to Fas-induced apoptosis. Thirty-five clones were isolated, 28 of which were derived from unknown genes, that tagged 19 individual genes and 7 of which referred to known genes that tagged the apoptosis-related protein (APR)-1, -2 and indoleamine-pyrrole 2,3,-dioxygenase (IDO). The ability of APR-1-, -2- and IDO-derived antisense RNAs to induce resistance to Fas in HepG2, A375 and CLS-354 cells suggested that APR-1, -2 and IDO genes are involved in the machinery of Fas-mediated apoptosis. Our gene discovery strategy provides a generally applicable procedure to identify functional genes that interfere with apoptosis, and may therefore be clinically relevant for tumor therapy.

Antibodies↗
PubMed2005

[Ten fractures in 21 years].

A 78 year old woman had suffered ten spontaneous bone fractures, the first occurring when she was 57 years old. She is now wheel-chair bound. After 21 years, the underlying osteomalacia due to oligosymptomatic celiac disease with malabsorption was diagnosed. The treatment consists of a gluten free diet and substitution of calcium and vitamin D until there is a normalisation of calcium, vitamin D and alkaline phosphatase. Any spontaneous fracture deserves a careful search for metabolic bone disease. An elevation of alkaline phosphatase indicates osteomalacia rather than osteoporosis.

Aged↗
PubMed2005

Impact of mycophenolate mofetil versus azathioprine on early recurrence of hepatitis C after liver transplantation.

The aim of this study was to evaluate the impact of mycophenolate mofetil (MMF) on incidence, delay, severity and clinical course of early recurrent hepatitis C after liver transplantation (LT). A total of 21 hepatitis C virus (HCV)-positive patients after LT were prospectively enrolled in this study. All of them received a quadruple induction cyclosporine A (CsA)-based immunosuppression, augmented by MMF (n=12) or by azathioprine (n=9, AZA). MMF tended to delay recurrent disease (50+/-35 versus 35+/-35 weeks, P=0.5) with significantly lower levels of aminotransferases (P<0.05). Furthermore, patients under MMF revealed less severe allograft fibrosis at disease recurrence (stage of fibrosis: 1.5+/-0.5 versus 2.2+/-1.2; P=0.07). But stage of fibrosis significantly increased in the MMF-group (P<0.05) during 6 months of antiviral treatment. Three patients in the MMF-group and none of the controls suffered from severe fibrosing cholestatic recurrent hepatitis C. Initial post-LT administration of MMF tended to delay recurrent hepatitis C and to limit initial HCV-related biochemical and morphological graft dysfunction. But during clinical follow-up, its immunosuppressive capabilities exceeded possible antiviral properties, finally leading to significant progression of graft fibrosis. Thus, concomitant dose reduction of other basic immunosuppressants might be useful in this clinical setting.

Adult↗
PubMed2005

Evaluation of peroxisome proliferator-activated receptor-gamma expression in benign and malignant thyroid pathologies.

Impairment of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) function through a dominant negative PAX-8/PPAR-gamma fusion gene or other events resulting in wild-type PPAR-gamma downregulation has been implicated in malignant thyroid cell transformation. The aim of our study was to perform a systematic evaluation of PPAR-gamma mRNA and protein expression in normal thyroid tissue as opposed to benign thyroid pathologies of different functional status and thyroid malignancy, to gain further insights into a putative physiological role of PPAR-gamma in the thyroid and to define whether PPAR-gamma could serve as a marker of thyroid cell differentiation. Ten cold benign (CTN) and 10 toxic (TTN) thyroid nodules and corresponding normal thyroid tissues, 10 follicular thyroid cancers (FTC), 10 papillary thyroid cancers (PTC) and 8 Graves' disease (GD) thyroids were studied by real-time polymerase chain reaction (PCR), immunohistochemistry and reverse transcriptase (RT)-PCR (PAX-8/PPAR-gamma fusion gene). PPAR-gamma mRNA expression was demonstrated in all samples. When comparing benign nodular and normal thyroid tissue of the same patient no significant difference in PPAR-gamma mRNA expression was observed. PPAR-gamma mRNA levels were similar in CTN and FTC. In contrast, PPAR-gamma mRNA expression was downregulated in 9 of 10 PTC and all GD samples, whereby at least 4 fold downregulation (compared with normal and benign nodular thyroid tissues) was observed in the latter. Immunohistochemistry showed an increased, patchy PPAR-gamma nuclear staining in CTNs and TTNs and only faint staining in the corresponding normal thyroid tissues. A diffuse and weak PPAR-gamma staining pattern was observed in all GD samples. No PAX-8/PPAR-gamma rearrangements were detected in any of the 68 thyroid tissue samples. In conclusion PPAR-gamma mRNA and protein expression levels are not concordant in benign thyroid nodular disease. Furthermore there is no clear-cut association of PPAR-gamma mRNA expression with follicular thyroid tumorigenesis. Absence of a PAX-8/PPAR-gamma fusion gene in the series of 68 thyroid samples is in agreement with the suggestion of PAX-8/PPAR-gamma rearrangement being restricted to a subset of follicular thyroid cancers. The marked downregulation of PPAR-gamma in GD warrants further investigation and could be linked, for example, with changes in apoptosis.

Adenoma↗