Katharina Leithner

Affective state of women following a prenatal diagnosis: predictors of a negative psychological outcome

The benefits of prenatal diagnostic procedures are well documented. However, the investigation of psychological consequences related to these procedures has remained a surprisingly neglected area of research. The main aim of the present study was to investigate the potential relationship between psychological outcome and associated (socio‐demographic, psychological and obstetric) variables in women attending a tertiary referral center for prenatal diagnosis and therapy for ultrasound scanning (due to the suspicion of a fetal malformation raised by the gynecologist in private practice), amniocentesis or chorionic villus sampling.

Immunohistochemical analysis of desmoid tumours.

Background/Aims: Although the standard treatment for desmoid tumours is complete surgical resection with wide margins, the optimal adjuvant treatment for recurrent or inoperable disease is unclear, often being based on sporadic immunohistochemical reports with a low number of cases. Therefore, a large immunohistochemical study was performed, to provide a theoretical basis for adjuvant treatment regimens. Methods: One hundred and sixteen tissue samples from 80 patients (49 female, 31 male; mean age, 34 years; range, 0–83) with desmoid tumours (46 extra-abdominal, 21 abdominal, 13 intra-abdominal) were tested for oestrogen receptors α and β, progesterone and androgen receptors, and somatostatin, in addition to HER2, cathepsin D, Ki-67, and c-KIT by immunohistochemistry. Results: All samples were negative for oestrogen receptor α, HER2, and the progesterone receptor. Positive staining for the androgen receptor was found in six extra-abdominal cases. Staining for oestrogen receptor β was positive in four extra-abdominal, two abdominal, and one intra-abdominal case. Staining for somatostatin was positive in six extra-abdominal, two abdominal, and one intra-abdominal case, and staining for cathepsin D was positive in all cases. Positive staining for Ki-67 was found in 14 extra-abdominal, three abdominal, and three intra-abdominal cases. C-KIT was detectable in one abdominal case only. Conclusions: The data from this immunohistochemical study show that the published effects of antioestrogens and imatinib mesylate in the treatment of aggressive fibromatoses may not be attributable to oestrogen receptor α or c-KIT expression.

Wikipedia and osteosarcoma: a trustworthy patients' information?

The English version of the online encyclopedia, Wikipedia, has been recently reported to be the prominent source of online health information. However, there is little information concerning the quality of information found in Wikipedia. Therefore, we created a questionnaire asking for scope, completeness, and accuracy of information found on osteosarcoma. Three independent observers tested the English version of Wikipedia, as well as the patient version and the health professional version of the US National Cancer Institute (NCI) website. Answers were verified with authoritative resources and international guidelines. The results of our study demonstrate that the quality of osteosarcoma-related information found in the English Wikipedia is good but inferior to the patient information provided by the NCI. Therefore, non-peer-reviewed commonly used websites offering health information, such as Wikipedia, should include links to more definitive sources, such as those maintained by the NCI and professional international organizations on healthcare treatments. Furthermore, frequent checks should make sure such external links are to the highest quality and to the best-maintained aggregate sites on a given healthcare topic.

Endothelin-1 Inhibits Background Two-Pore Domain Channel TASK-1 in Primary Human Pulmonary Artery Smooth Muscle Cells

Endothelin (ET)-1 causes long-lasting vasoconstriction and vascular remodeling by interacting with specific G-protein-coupled receptors in pulmonary artery smooth muscle cells (PASMCs), and thus plays an important role in the pathophysiology of pulmonary arterial hypertension. The two-pore domain K(+) channel, TASK-1, controls the resting membrane potential in human PASMCs (hPASMCs), and renders these cells sensitive to a variety of vasoactive factors, as previously shown. ET-1 may exert its vasoconstrictive effects in part by targeting TASK-1. To clarify this, we analyzed the ET-1 signaling pathway related to TASK-1 in primary hPASMCs. We employed the whole-cell patch-clamp technique combined with TASK-1 small interfering RNA (siRNA) in hPASMC and the isolated, perfused, and ventilated mouse lung model. We found that ET-1 depolarized primary hPASMCs by phosphorylating TASK-1 at clinically relevant concentrations. The ET sensitivity of TASK-1 required ET(A) receptors, phospholipase C, phosphatidylinositol 4,5-biphosphate, diacylglycerol, and protein kinase C in primary hPASMCs. The ET-1 effect on membrane potential and TASK-1 was abrogated using TASK-1 siRNA. This is the first time that the background K(+) channel, TASK-1, has been identified in the ET-1-mediated depolarization in native hPASMC, and might represent a novel pathologic mechanism related to pulmonary arterial hypertension.

Mentalizing in female inpatients with major depressive disorder.

Abstract Depression is associated with profound impairments in social and interpersonal functioning. However, little research has addressed deficits in mentalizing capacity that may underlie these impairments. The aim of this study was, therefore, to investigate the capacity for mentalization in female inpatients with depression in comparison with healthy controls. We assessed 46 inpatients with major depressive disorder with regard to psychiatric diagnoses, severity of depression, cognitive impairment, and verbal intelligence. In addition, 20 healthy controls matched for sex, age, and education were included. Mentalization was scored on the Adult Attachment Interview using the Reflective Functioning Scale. The female inpatients with depression showed a significantly lower capacity for mentalization compared with the healthy controls. Mentalization deficits were not restricted to depression-specific topics. Moreover, deficits in mentalizing capacity were related to illness duration, number of admissions, and cognitive impairment. The results indicate severe impairment in the ability of the female inpatients with depression to identify and interpret mental states of the self and others. Correlations with illness duration and number of admissions suggest that a chronic course of depression results in further mentalizing impairments. The investigation of mentalization may be of particular importance for the development of targeted psychotherapeutic interventions for depression.

PCK2 activation mediates an adaptive response to glucose depletion in lung cancer

Cancer cells are reprogrammed to utilize glycolysis at high rates, which provides metabolic precursors for cell growth. Consequently, glucose levels may decrease substantially in underperfused tumor areas. Gluconeogenesis results in the generation of glucose from smaller carbon substrates such as lactate and amino acids. The key gluconeogenic enzyme, phosphoenolpyruvate carboxykinase (PEPCK), has been shown to provide metabolites for cell growth. Still, the role of gluconeogenesis in cancer is unknown. Here we show that the mitochondrial isoform of PEPCK (PCK2) is expressed and active in three lung cancer cell lines and in non-small cell lung cancer samples. PCK2 expression and activity were enhanced under low-glucose conditions. PEPCK activity was elevated threefold in lung cancer samples over normal lungs. To track the conversion of metabolites along the gluconeogenesis pathway, lung cancer cell lines were incubated with 13C3-lactate and label enrichment in the phosphoenolpyruvate (PEP) pool was measured. Under low glucose, all three carbons from 13C3-lactate appeared in the PEP pool, further supporting a conversion of lactate to pyruvate, via pyruvate carboxylase to oxaloacetate, and via PCK2 to phosphoenolpyruvate. PCK2 small interfering RNA and the pharmacological PEPCK inhibitor 3-mercaptopicolinate significantly enhanced glucose depletion-induced apoptosis in A549 and H23 cells, but not in H1299 cells. The growth of H23 multicellular spheroids was significantly reduced by 3-mercaptopicolinate. The results of this study suggest that lung cancer cells may utilize at least some steps of gluconeogenesis to overcome the detrimental metabolic situation during glucose deprivation and that in human lung cancers this pathway is activated in vivo.

Hypoxia-induced cisplatin resistance is reversible and growth rate independent in lung cancer cells

Hypoxia frequently occurs in solid tumors and is known to contribute to chemotherapy resistance. However, the mechanisms leading to chemotherapy resistance are not entirely known. We investigated hypoxia-induced resistance to cisplatin in NSCLC cell lines. We show that chronic moderate hypoxia induced resistance to cisplatin in NSCLC cells without involvement of selection pressure. Our data suggest that stabilization of the hypoxia-inducible factor 1 alpha and down-regulation of the pro-apoptotic protein BAX play a role in this process. Furthermore, we provide evidence that hypoxia-induced resistance to cisplatin is not due to the reduced growth rate of cancer cells under hypoxic conditions.

Nuclear and cytoplasmic death receptor 5 as prognostic factors in patients with non-small cell lung cancer treated with chemotherapy.

BACKGROUND Death receptor 4 (DR4) and death receptor 5 (DR5) are tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) receptors that activate apoptosis via the extrinsic apoptosis pathway. DcR1 and DcR2 are decoy receptors for TRAIL that act antagonistically. Intracellular trafficking of TRAIL receptors has been described, but the role of the subcellular localization of TRAIL receptors in non-small cell lung cancer (NSCLC) progression is unclear. METHODS Expression and intracellular localization of pro-apoptotic and decoy TRAIL receptors were analyzed by immunohistochemistry in 50 samples of advanced or recurrent NSCLC. Using confocal microscopy, localization of TRAIL receptors was studied in NSCLC cell lines. RESULTS Cytoplasmic staining for all four TRAIL receptors was observed in the majority of samples. Nuclear staining was infrequent in the case of DR4 (12%) and DcR2 (8%), while DR5 and DcR1 were localized in the nucleus in 27% and 60% of samples. When overall survival was analyzed, cytoplasmic staining for DR5 in tumor cells (P=0.025) and nuclear staining for DR5 in tumor cells (P=0.007) were significant prognostic factors in univariate, as well as in multivariate analysis including clinicopathologic factors (P=0.026 and 0.021, respectively). In A549, NCI-H358, and A427 NSCLC cells all four TRAIL receptors were found to be mainly located perinuclearly, but also in the nucleus. CONCLUSION The study for the first time shows that TRAIL receptors are found in different intracellular compartments including the nucleus in NSCLC cells and that both nuclear and cytoplasmic DR5 might predict improved survival in patients with advanced NSCLC.

Panobinostat reduces hypoxia-induced cisplatin resistance of non-small cell lung carcinoma cells via HIF-1α destabilization

BackgroundLung cancer is one of the most frequent cancer types and the leading cause of cancer death worldwide. Cisplatin is a widely used chemotherapeutic for non-small cell lung carcinoma (NSCLC), however, its positive effects are diminished under hypoxia. We wanted to determine if co-treatment with cisplatin and histone deacetalyse (HDAC) inhibitor panobinostat can reduce hypoxia-induced cisplatin resistance in NSCLC cells, and to elucidate mechanism involved.MethodsExpression status of different HDACS was determined in two cell lines and in tumor tissue from 20 patients. Cells were treated with cisplatin, panobinostat, or with combination of both under normoxic and hypoxic (1% O2) conditions. Cell cycle, viability, acetylation of histones, and activation of apoptosis were determined. HIF-1α stability and its interaction with HDAC4 were analyzed.ResultsMost class I and II HDACs were expressed in NSCLC cells and tumor samples. Co-treatment of tumor cells with cisplatin and panobinostat decreased cell viability and increased apoptosis more efficiently than in primary, non-malignant bronchial epithelial cells. Co-treatment induced apoptosis by causing chromatin fragmentation, activation of caspases-3 and 7 and PARP cleavage. Toxic effects were more pronounced under hypoxic conditions. Co-treatment resulted in destabilization and degradation of HIF-1α and HDAC4, a protein responsible for acetylation and de/stabilization of HIF-1α. Direct interaction between HDAC4 and HIF-1α proteins in H23 cells was detected.ConclusionsHere we show that hypoxia-induced cisplatin resistance can be overcome by combining cisplatin with panobinostat, a potent HDAC inhibitor. These findings may contribute to the development of a new therapeutic strategy for NSCLC.

Expression of Insulin-Like Growth Factor-I (IGF-I) in Aneurysmal Bone Cyst

The effects of insulin-like growth factor-I on bone tissue and its role in bone development have been extensively investigated, but there is little information on its role in the pathogenesis of aneurysmal bone cyst. Therefore, using the techniques of immunohistochemistry and in situ hybridization, the authors studied the expression of insulin-like growth factor-I in 19 specimens of aneurysmal bone cyst. Insulin-like growth factor-I or specific mRNA sequences encoding for insulin-like growth factor-I were detectable in all specimens tested and were mainly localized in multinucleate giant cells. In contrast, only insignificant levels of insulin-like growth factor-I expression were detectable in normal human bone tissue. Taken together with the previously reported role of insulin-like growth factor-I in the pathogenesis of giant cell tumor, the findings of this study suggest that insulin-like growth factor-I may play a role in the pathogenesis of aneurysmal bone cyst.