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Franke L.,Charité - Medical University of Berlin | Schmidtmann M.,Gastroenterology and Endocrinology | Schmidtmann M.,Charité - Medical University of Berlin | Riedl A.,Charité - Medical University of Berlin | And 4 more authors.
Journal of Gastroenterology | Year: 2010

Background: In the past decade, a strong argument has been built for the role of serotonin (5HT) and the serotonin transporter (SERT) in irritable bowel syndrome (IBS). However, it is still not clear how SERT contributes to this clinically heterogeneous disease. The present study addressed this issue by implementing platelet (plt) markers of SERT activity in the assessment protocol. Methods: Fasting blood samples of 149 (51 male/98 female) subjects with Rome II and III defined IBS subtypes, and 163 healthy control subjects (CSs; 75 male/88 female) were analyzed for platelet 5HT concentration and 5HT uptake activity [maximum uptake rate (Vmax) and affinity constant (Km)]. Results: Gender had a significant impact on platelet markers of SERT activity. Male IBS patients showed significantly lower median Vmax and K m values than the male CS (Vmax 1.706 vs. 2.148 nmol/109 plts × min, P < 0.001; Km 346 vs. 410 nmol, P = 0.008) without any significant reduction in platelet 5HT concentration (362 vs. 394 ng/109 plts). On the other hand, Vmax values were not different between female IBS patients and female CS (1.642 vs. 1.741 nmol/109 plts × min), but platelet 5HT concentration was significantly lower in females with diarrheapredominant IBS (363 vs. 435 ng/109 plts, P < 0.05). Conclusion: Although an absolute extrapolation from platelets to the gastrointestinal tissue does not appear to be justified, our findings demonstrated that the contribution of disturbed SERT activity to IBS is not uniform and is possibly gender-specific. The results suggest that an assessment of SERT function in platelets may help to elucidate the differences between IBS patients in response to drugs affecting the 5HT system. © Springer 2009.


Hoermann R.,Gastroenterology and Endocrinology | Eckl W.,Gastroenterology and Endocrinology | Hoermann C.,Gastroenterology and Endocrinology | Larisch R.,Klinikum Luedenscheid
European Journal of Endocrinology | Year: 2010

Objective: The present study re-evaluates the inverse log TSH-free thyroxine (fT4) relationship, which has generally been assumed to characterize the thyroid pituitary hypothalamic feedback regulation in thyroid function. Design and Methods: The correlation between fT4 and TSH was analyzed in two data sets from differing time periods involving 3223 and 6605 patients referred for thyroid testing, representing the whole range of thyroid functions from hypothyroidism to hyperthyroidism. Results: We found that the data do not support a linear log TSH-fT4 relationship; instead, the correlation's gradient varies with thyroid function. As a consequence, an alternate model, based on the error function, was introduced. When directly comparing the models by means of curve fitting, using F-test and Akaike criteria, the alternate model results in a significantly better fit. The model was verified in the independent second set of data. Subgroup analysis of untreated patients added further proof to the non-linear model. Conclusions: We propose a refined non-linear model to describe the relationship between TSH and fT4. It implies that TSH response to a deviating fT4 value may not be log-linear, but may be disproportionally related to the extent of the deviation from an optimum set point. A better understanding of the complex nature of the TSH-fT4 relationship may further the development of more precise clinical models and aid in better defining subclinical states of thyroid dysfunction. Also, it may encourage other biological interrelations to be reconsidered in the wake of advanced measurement techniques and more powerful computerized statistical procedures. © 2010 European Society of Endocrinology.


Kaemmerer D.,Zentralklinik Bad Berka | Specht E.,Jena University Hospital | Sanger J.,Laboratory of Pathology and Cytology | Wirtz R.M.,STRATIFYER Molecular Pathology GmbH | And 3 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2015

Context and Objectives: Gastroenteropancreatic neuroendocrine neoplasms are known for their overexpression of somatostatin receptors (SSTRs), which provide the molecular basis for diagnostic and therapeutic interventions. In contrast, few data on the SSTR expression profile exist for bronchopulmonary neuroendocrine neoplasms (BP-NEN). Design and Settings: A total of 240 formalin-fixed, paraffin-embedded specimens from 26 typical carcinoid (TC), 30 atypical carcinoid (AC), and 34 small cell lung cancer (SCLC) patients were examined retrospectively by immunohistochemistry (IHC) using specific rabbit monoclonal antibodies and evaluated by the immunoreactive score. Adjacent slides from 20 samples of each tumor type were subjected to additional RT-quantitative PCR mRNA analysis. Results: With different expression patterns, SSTRs were present in most of the tumor sections, at both the protein and mRNA levels. The RT-quantitative PCR data correlated with the IHC scores. SSTR1 was detected in approximately 65% of the TC and AC, but hardly in the SCLC, whereas both SSTR2A and SSTR5 were present in approximately 45% of each entity. Furthermore, the SSTR1 expression level was positively correlated with patient survival. Conclusions: Our results suggest that SSTRs can be used as novel diagnostic, prognostic, and therapeutic markers of BP-NEN. The differences in the SSTR expression profile between the three types of BP-NEN may help to set a diagnostic cutoff and predict patient prognosis. Similar to TC and AC, our results also revealed a previously unappreciated high level of SSTR2A expression in SCLC within a subgroup of patients. However, in most cases, pan-somatostatin analogs may represent an additional therapeutic option. Copyright © 2015 by the Endocrine Society.


Kaemmerer D.,Zentralklinik Bad Berka | Reimann C.,Jena University Hospital | Specht E.,Jena University Hospital | Wirtz R.M.,Stratifyer Molecular Pathology GmbH | And 4 more authors.
Oncotarget | Year: 2015

Introduction: For many tumors, the overexpression of the chemokine receptor CXCR4 is associated with increased malignancy and poor patient outcomes. However, comprehensive data for neuroendocrine neoplasms of the lung are still lacking. Methods: CXCR4 expression was evaluated in a panel of bronchopulmonary neuroendocrine neoplasms (BP-NEN) comprising typical carcinoids (n = 26), atypical carcinoids (n = 30), and small cell lung cancers (SCLC, n = 34). Samples were analyzed by immunohistochemistry using the novel monoclonal rabbit anti-human CXCR4 antibody UMB-2 and by qRT-PCR. The expression was correlated with clinical data and overall patient survival. Results: CXCR4 was predominantly localized at the plasma membrane of the tumor cells. CXCR4 was expressed with a high intensity in almost all of the 30 SCLC samples. In contrast, it was detected infrequently and with low intensity in the typical carcinoid and atypical carcinoid samples. There was a significant correlation between the immunohistochemistry and qRT-PCR data. Additionally, there was a significant negative relationship between CXCR4 expression and overall survival. Conclusions: With increasing malignancy, BP-NEN clearly differ in the extent of CXCR4 expression. As in other tumor entities, CXCR4 overexpression significantly correlates with negative patient outcome. Due to its particular high expression rate in SCLC, CXCR4 may serve as a promising new target for diagnostic and pharmacological intervention as well as for peptide receptor-based radionuclide therapy.


PubMed | Gastroenterology and Endocrinology
Type: Journal Article | Journal: Neuroendocrinology | Year: 2011

Pancreatic neuroendocrine tumors (pancreatic NET) are relatively rare, slowly growing tumors, although their incidence is increasing, and patients may survive for several years with metastatic disease. Apart from symptomatic relief, there have been few treatment options for these tumors in the past. More recently, investigators have explored the potential of molecularly targeted agents in treating pancreatic NET, with some success. In this review, we consider the data supporting exploitation of different targets in pancreatic NET, including peptide receptors, receptor tyrosine kinases (involved in tumor angiogenesis and more directly supporting tumor growth), and intracellular targets, such as the mammalian target of rapamycin (mTOR), which has a central role in regulating cell growth, metabolism, and apoptosis. Probably due to the paucity of pancreatic NET, many clinical trials to date have included heterogeneous NET populations, and there are few randomized studies of this specific patient population. Very recently, promising results have been achieved in placebo-controlled, phase III trials with the multitargeted tyrosine kinase inhibitor, sunitinib, and the mTOR inhibitor, everolimus. These agents have been approved or are currently being reviewed by authorities for use in patients with pancreatic NET. Here we review potential molecular targets in pancreatic NET and summarize the available data for targeted agents from phase II and III trials open to patients with this tumor.


PubMed | Center for PET CT, Zentralklinik Bad Berka, Stratifyer Molecular Pathology GmbH, Jena University Hospital and Gastroenterology and Endocrinology
Type: Journal Article | Journal: Oncotarget | Year: 2015

For many tumors, the overexpression of the chemokine receptor CXCR4 is associated with increased malignancy and poor patient outcomes. However, comprehensive data for neuroendocrine neoplasms of the lung are still lacking.CXCR4 expression was evaluated in a panel of bronchopulmonary neuroendocrine neoplasms (BP-NEN) comprising typical carcinoids (n = 26), atypical carcinoids (n = 30), and small cell lung cancers (SCLC, n = 34). Samples were analyzed by immunohistochemistry using the novel monoclonal rabbit anti-human CXCR4 antibody UMB-2 and by qRT-PCR. The expression was correlated with clinical data and overall patient survival.CXCR4 was predominantly localized at the plasma membrane of the tumor cells. CXCR4 was expressed with a high intensity in almost all of the 30 SCLC samples. In contrast, it was detected infrequently and with low intensity in the typical carcinoid and atypical carcinoid samples. There was a significant correlation between the immunohistochemistry and qRT-PCR data. Additionally, there was a significant negative relationship between CXCR4 expression and overall survival.With increasing malignancy, BP-NEN clearly differ in the extent of CXCR4 expression. As in other tumor entities, CXCR4 overexpression significantly correlates with negative patient outcome. Due to its particular high expression rate in SCLC, CXCR4 may serve as a promising new target for diagnostic and pharmacological intervention as well as for peptide receptor-based radionuclide therapy.

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