Prognostic value of indoleamine 2,3 dioxygenase in patients with higher‐risk myelodysplastic syndromes treated with azacytidine

Hypomethylating agents (HMAs) are widely used in patients with higher‐risk myelodysplastic syndromes (MDS) not eligible for stem cell transplantation; however, the response rate is <50%. Reliable predictors of response are still missing, and it is a major challenge to develop new treatment strategies. One current approach is the combination of azacytidine (AZA) with checkpoint inhibitors; however, the potential benefit of targeting the immunomodulator indoleamine‐2,3‐dioxygenase (IDO‐1) has not yet been evaluated. We observed moderate to strong IDO‐1 expression in 37% of patients with high‐risk MDS. IDO‐1 positivity was predictive of treatment failure and shorter overall survival. Moreover, IDO‐1 positivity correlated inversely with the number of infiltrating CD8+ T cells, and IDO‐1+ patients failed to show an increase in CD8+ T cells under AZA treatment. In vitro experiments confirmed tryptophan catabolism and depletion of CD8+ T cells in IDO‐1+ MDS, suggesting that IDO‐1 expression induces an immunosuppressive microenvironment in MDS, thereby leading to treatment failure under AZA treatment. In conclusion, IDO‐1 is expressed in more than one‐third of patients with higher‐risk MDS, and is predictive of treatment failure and shorter overall survival. Therefore, IDO‐1 is emerging as a promising predictor and therapeutic target, especially for combination therapies with HMAs or checkpoint inhibitors

Assessment and Diagnostic Classification Using DC:0-5 in Early Childhood Mental Health Clinics: The Protocol for the Developmental Psychiatry Diagnostic Challenges Study (DePsy)

Mental health problems in early childhood are common, but there is a lack of psychiatric research on this age group. DC:0-5 is a multiaxial classification system for mental disorders in early childhood, providing a framework for standardizing clinical practice and research. However, research on the validity of DC:0-5 is scarce. The Developmental Psychiatry Diagnostic Challenges Study (DePsy) is a multi-site, prospective clinical study including six German early childhood mental health (ECMH) clinics. The main objective of the study is to contribute to the validation of Axis I and Axis II of DC:0-5. A second aim of the study is to describe the population of the participating clinics regarding diagnoses, family context, and treatment outcomes. Additionally, the impact of environmental risk factors, including parental Adverse Childhood Experiences (ACEs) and media use, on child psychopathology and caregiver–child relationships will be examined. Over two years, patients aged 0.0–5.9 years old will be enrolled in the study. Assessments include ICD-10 and DC:0- 5 diagnoses, developmental tests, video-based observations of caregiver—child interactions, and questionnaires on child psychopathology, media use, parental stress, and treatment satisfaction. Study results will promote the standardization of assessment and treatment in ECMH clinics aiming to improve the development of patients and their families

Conversations under a Tung Tree

<p>Secreted frizzled related protein 3 (SFRP3) contains a cysteine-rich domain (CRD) that shares homology with Frizzled CRD and regulates WNT signaling. Independent studies showed epigenetic silencing of <i>SFRP3</i> in melanoma and hepatocellular carcinoma. Moreover, a tumor suppressive function of SFRP3 was shown in androgen-independent prostate and gastric cancer cells. The current study is the first to investigate <i>SFRP3</i> expression and its potential clinical impact on non-small cell lung carcinoma (NSCLC). WNT signaling components present on NSCLC subtypes were preliminary elucidated by expression data of The Cancer Genome Atlas (TCGA). We identified a distinct expression signature of relevant WNT signaling components that differ between adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC). Of interest, canonical WNT signaling is predominant in LUAD samples and non-canonical WNT signaling is predominant in LUSC. In line, high SFRP3 expression resulted in beneficial clinical outcome for LUAD but not for LUSC patients. Furthermore, <i>SFRP3</i> mRNA expression was significantly decreased in NSCLC tissue compared to normal lung samples. TCGA data verified the reduction of <i>SFRP3</i> in LUAD and LUSC patients. Moreover, DNA hypermethylation of <i>SFRP3</i> was evaluated in the TCGA methylation dataset resulting in epigenetic inactivation of <i>SFRP3</i> expression in LUAD, but not in LUSC, and was validated by pyrosequencing of our NSCLC tissue cohort and <i>in vitro</i> demethylation experiments. Immunohistochemistry confirmed SFRP3 protein downregulation in primary NSCLC and indicated abundant expression in normal lung tissue. Two adenocarcinoma gain-of-function models were used to analyze the functional impact of SFRP3 on cell proliferation and regulation of <i>CyclinD1</i> expression <i>in vitro</i>. Our results indicate that <i>SFRP3</i> acts as a novel putative tumor suppressor gene in adenocarcinoma of the lung possibly regulating canonical WNT signaling.</p

Barbarians at the British Museum: Anglo-Saxon Art, Race and Religion

A critical historiographical overview of art historical approaches to early medieval material culture, with a focus on the British Museum collections and their connections to religion

Funktionelle Charakterisierung des putativen Tumorsuppressorgens SFRP3 im humanen nicht-kleinzelligen Lungenkarzinom

Lung cancer remains the leading cancer related death among men and the second most common among women in Germany, while it is diagnosed mostly accidentally or in advanced stages due to missing adequate early detection. Fundamental research tend to analyze in detail the moleculare processes and crucial abberant pathways leading to lung cancer progression. In the last decade distinct moleculare investigations were established to analyze genetical alterations of the tumor relevant EGFR pathway (Kosaka et al. 2004; Shigematsu et al. 2005; Wu et al. 2008). However, genetical abberations of the canonical WNT signaling pathway are equally crucial to tumor progression of various cancer subtypes, e.g. lung cancer. Increased expression of extra cellular WNT ligands or the loss of WNT antagonists as well as members of the ß-Catenin destruction complex are linked to promote a constitutive active canonical WNT signaling. To date no investigation systematically compared the expression profile of important WNT molecules in the individual non-small cell lung cancer subtypes: adenocarcinoma and squamous cell carcinoma. The present studie analyzed for the first time the expression pattern of extra cellular WNT ligands and antagonists within the NSCLC subtypes resulting in a potential subtype specific activation of the WNT signaling pathway. In this context Box Plot analysis of the expression profile of pivotal WNT target genes validated an increased expression of these genes in adenocarcinoma of the lung. Furthermore, the expression patterns of WNT antagonists of the secreted frizzled related protein (SFRP) members were also liable to a subtype specific expression. SFRP1 and SFRP2 are the most investigated WNT antagonists. Downregulation of SFRP1 and SFRP2 was linked to tumor progression of various cancer subtypes and epigenetic silencing of both molecules was already analyzed in non-small cell lung cancer. The pontential regulation of SFRP3 as well as its influence on progression of NSCLC is unknown. Continuative investigations of a cryopreserved tissue collective and the independent TCGA dataset resulted in a loss of SFRP3 expression in primary NSCLC tissues. Furthermore, a progression line of adenocarcinoma patients indicated a downregulation of SFRP3 expression due to progressive tumor stage linked to a poor clinical outcome. Immunhistochemical analysis of primary NSCLC and normal lung tissue visualized for the first time the SFRP3 protein localization in type I and type II pneumocytes as well as in ciliated epithelium of bronchioles and validated SFRP3 protein reduction in primary NSCLC tissues. Qualitative and quantitative methylation examinations clarified a significant increase of SFRP3 exon I methylation, while the association between SFRP3 hypermethylation and mRNA reduction could be verified in6LUAD samples of the TCGA dataset. The present studie supposed to investigate the potential influence of SFRP3 loss to development and progression of the human non-small cell lung cancer. In this context the establishment of gain-of-function models constituted the background of futher functional investigations. The LUAD cell line A549 visualized initially an increased cell motility behavior as well as a mesenchymal cell formation with accompany of actin cytoskeleton strengthening due to high SFRP3 expression. However, the transfected LUAD cell line A549 exhibited low constitutaional WNT1 mRNA expression, for which reason the canonical WNT signaling pathway was assumed to be insufficient active. Proliferation analysis of SFRP3/WNT1 double transfected A549 cells showed a significant decrease of cell growth. In line, expression analysis of the canonical WNT target gene CyclinD1 resulted in a highly significant decrease of CyclinD1 mRNA expression in double transfected A549 cells. These results leading to the hypothezise of a potentially WNT antagonistic function of SFRP3 in a WNT1 dependent manner. Kaplan-Meier survival analysis verified the clinical importance of the WNT1 and SFRP3 association implicating a beneficial clinical outcome for LUAD patients with high SFRP3 as well as WNT1 expression.In summary, the present studie identified a subtype specific activity of the WNT signaling pathway in NSCLC for the first time. Furthermore, the potential tumor suppressor function of SFRP3 was confirmed in association to a WNT1 induced and active canonical WNT signaling pathway in adenocarcinoma of the lung. Additionally, a WNT indepent and potentially tumor promoting function of SFRP3 may persist

Metabolic recovery of the Antarctic liverwort Cephaloziella varians during spring snowmelt

We measured the responses of pigments and chlorophyll a fluorescence parameters of the Antarctic leafy liverwort Cephaloziella varians to snowmelt during austral spring 2005 at Rothera Point on the western Antarctic Peninsula. Although no changes to the concentrations of UV-B photoprotective pigments were detected during snowmelt, chlorophyll and carotenoid concentrations and maximum photosystem (PS)II yield (F v /F m) were respectively 88, 60 and 144% higher in the tissues of the liverwort that had recently emerged from snow than in those under a 10 cm depth of snow. A laboratory experiment similarly showed that effective PSII yield increased rapidly within the first 45 min after plants sampled from under snow were removed to an illuminated growth cabinet. The pigmentation and PSII yields of plants during snowmelt were also compared with those of plants in January, during the middle of the growing season at Rothera Point. During snowmelt, plants had lower F v /F m values, chlorophyll a/b ratios and concentrations of UV-B photoprotective pigments and carotenoids than during mid-season, suggesting that although there is some recovery of PSII activity and increases in concentrations of photosynthetic pigments during snowmelt, the metabolism of C. varians is restricted during this period

BDNF Is Associated with SFRP1 Expression in Luminal and Basal-Like Breast Cancer Cell Lines and Primary Breast Cancer Tissues : a Novel Role in Tumor Suppression?

Secreted frizzled related protein 1 (SFRP1) functions as an important inhibitor of the Wnt pathway and is a known tumor suppressor gene, which is epigenetically silenced in a variety of tumors e.g. in breast cancer. However, it is still unclear how SFRP1 exactly affects the Wnt pathway. Our aim was to decipher SFRP1 involvement in biochemical signaling in dependency of different breast cancer subtypes and to identify novel SFRP1-regulated genes. We generated SFRP1 over-expressing in vitro breast cancer models, reflecting the two major subtypes by using basal-like BT20 and luminal-like HER2-positive SKBR3 cells. DNA microarray expression profiling of these models revealed that SFRP1 expression potentially modulates Bone morphogenetic protein- and Smoothened signaling (p<0.01), in addition to the known impact on Wnt signaling. Importantly, further statistical analysis revealed that in dependency of the cancer subtype model SFRP1 may affect the canonical and non-canonical Wnt pathway (p<0.01), respectively. While SFRP1 re-expression generally mediated distinct patterns of transcriptionally induced or repressed genes in BT20 and SKBR3 cells, brain derived neurotrophic factor (BDNF) was identified as a SFRP1 induced gene in both cell lines. Although BDNF has been postulated as a putative oncogene, the co-regulation with SFRP1 indicates a potential suppressive function in breast cancer. Indeed, a positive correlation between SFRP1 and BDNF protein expression could be shown (p<0.001) in primary breast cancer samples. Moreover, TCGA dataset based analysis clearly underscores that BDNF mRNA is down-regulated in primary breast cancer samples predicting a poor prognosis of these patients. In line, we functionally provide evidence that stable BDNF re-expression in basal-like BT20 breast cancer cells blocks tumor cell proliferation. Hence, our results suggest that BDNF might rather mediate suppressive than promoting function in human breast cancer whose mode of action should be addressed in future studies

BDNF Is Associated with SFRP1 Expression in Luminal and Basal-Like Breast Cancer Cell Lines and Primary Breast Cancer Tissues : a Novel Role in Tumor Suppression?

<div><p>Secreted frizzled related protein 1 (SFRP1) functions as an important inhibitor of the Wnt pathway and is a known tumor suppressor gene, which is epigenetically silenced in a variety of tumors e.g. in breast cancer. However, it is still unclear how SFRP1 exactly affects the Wnt pathway. Our aim was to decipher SFRP1 involvement in biochemical signaling in dependency of different breast cancer subtypes and to identify novel SFRP1-regulated genes. We generated SFRP1 over-expressing <i>in vitro</i> breast cancer models, reflecting the two major subtypes by using basal-like BT20 and luminal-like HER2-positive SKBR3 cells. DNA microarray expression profiling of these models revealed that SFRP1 expression potentially modulates Bone morphogenetic protein- and Smoothened signaling (p<0.01), in addition to the known impact on Wnt signaling. Importantly, further statistical analysis revealed that in dependency of the cancer subtype model SFRP1 may affect the canonical and non-canonical Wnt pathway (p<0.01), respectively. While SFRP1 re-expression generally mediated distinct patterns of transcriptionally induced or repressed genes in BT20 and SKBR3 cells, brain derived neurotrophic factor (<i>BDNF</i>) was identified as a SFRP1 induced gene in both cell lines. Although BDNF has been postulated as a putative oncogene, the co-regulation with SFRP1 indicates a potential suppressive function in breast cancer. Indeed, a positive correlation between SFRP1 and BDNF protein expression could be shown (p<0.001) in primary breast cancer samples. Moreover, TCGA dataset based analysis clearly underscores that <i>BDNF</i> mRNA is down-regulated in primary breast cancer samples predicting a poor prognosis of these patients. In line, we functionally provide evidence that stable BDNF re-expression in basal-like BT20 breast cancer cells blocks tumor cell proliferation. Hence, our results suggest that BDNF might rather mediate suppressive than promoting function in human breast cancer whose mode of action should be addressed in future studies.</p></div