178 research outputs found
Editorial: Special Issue “Biomarkers in Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS)”
Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) is a disabling chronic disease of
still unknown origin and complex pathophysiology. The disease affects mainly female patients,
with a female to male ratio of about 9 to 1. Prevalence ranges from 52 to 500/100,000
in females and 8 to 41/100,000 in males. The diagnosis of IC/BPS is mainly hampered
by the lack of appropriate biomarkers and, therefore, extensive clinical examinations are
required to exclude “confusable” diseases [1]. In consequence, most patients experience
several years of ineffective treatments of various urinary tract symptoms often associated
with, but by themselves not characteristic of, IC/BPS. Unequivocal diagnosis of IC/BPS
is the prerequisite to find more effective therapeutic approaches. Therefore, more specific
biomarkers are needed to facilitate IC/BPS diagnosis and to stratify patients for treatment
at earlier stages of the disease. In this Special Issue, we gathered reviews and original work
elucidating the current developments in IC/BPS biomarker research
Identification of Key Biomarkers in Bladder Cancer: Evidence from a Bioinformatics Analysis
Bladder cancer (BCa) is one of the most common malignancies and has a relatively poor outcome worldwide. However, the molecular mechanisms and processes of BCa development and progression remain poorly understood. Therefore, the present study aimed to identify candidate genes in the carcinogenesis and progression of BCa. Five GEO datasets and TCGA-BLCA datasets were analyzed by statistical software R, FUNRICH, Cytoscape, and online instruments to identify differentially expressed genes (DEGs), to construct protein‒protein interaction networks (PPIs) and perform functional enrichment analysis and survival analyses. In total, we found 418 DEGs. We found 14 hub genes, and gene ontology (GO) analysis revealed DEG enrichment in networks and pathways related to cell cycle and proliferation, but also in cell movement, receptor signaling, and viral carcinogenesis. Compared with noncancerous tissues, TPM1, CRYAB, and CASQ2 were significantly downregulated in BCa, and the other hub genes were significant upregulated. Furthermore, MAD2L1 and CASQ2 potentially play a pivotal role in lymph nodal metastasis. CRYAB and CASQ2 were both significantly correlated with overall survival (OS) and disease-free survival (DFS). The present study highlights an up to now unrecognized possible role of CASQ2 in cancer (BCa). Furthermore, CRYAB has never been described in BCa, but our study suggests that it may also be a candidate biomarker in BCa
Biomarkers in the Light of the Etiopathology of IC/BPS
In this review, we focused on putatively interesting biomarkers of interstitial cystitis/bladder pain syndrome (IC/BPS) in relation to the etiopathology of this disease. Since its etiopathology is still under discussion, the development of novel biomarkers is critical for the correct classification of the patients in order to open personalized treatment options, on the one hand, and to separate true IC/BPS from the numerous confusable diseases with comparable symptom spectra on the other hand. There is growing evidence supporting the notion that the classical or Hunner-type IC (HIC) and the non-Hunner-type IC (NHIC) are different diseases with different etiopathologies and different pathophysiology at the full-blown state. While genetic alterations indicate close relationship to allergic and autoimmune diseases, at present, the genetic origin of IC/BPS could be identified. Disturbed angiogenesis and impairment of the microvessels could be linked to altered humoral signaling cascades leading to enhanced VEGF levels which in turn could enhance leucocyte and mast cell invasion. Recurrent or chronic urinary tract infection has been speculated to promote IC/BPS. New findings show that occult virus infections occurred in most IC/BPS patients and that the urinary microbiome was altered, supporting the hypothesis of infections as major players in IC/BPS. Environmental and nutritional factors may also influence IC/BPS, at least at a late state (e.g., cigarette smoking can enhance IC/BPS symptoms). The damage of the urothelial barrier could possibly be the result of many different causality chains and mark the final state of IC/BPS, the causes of this development having been introduced years ago. We conclude that the etiopathology of IC/BPS is complex, involving regulatory mechanisms at various levels. However, using novel molecular biologic techniques promise more sophisticated analysis of this pathophysiological network, resulting in a constantly improvement of our understanding of IC/BPS and related diseases
Bioinformatics Analysis Identifying Key Biomarkers in Bladder Cancer
Our goal was to find new diagnostic and prognostic biomarkers in bladder cancer (BCa), and to predict molecular mechanisms and processes involved in BCa development and progression. Notably, the data collection is an inevitable step and time-consuming work. Furthermore, identification of the complementary results and considerable literature retrieval were requested. Here, we provide detailed information of the used datasets, the study design, and on data mining. We analyzed differentially expressed genes (DEGs) in the different datasets and the most important hub genes were retrieved. We report on the meta-data information of the population, such as gender, race, tumor stage, and the expression levels of the hub genes. We include comprehensive information about the gene ontology (GO) enrichment analyses and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. We also retrieved information about the up- and down-regulation of genes. All in all, the presented datasets can be used to evaluate potential biomarkers and to predict the performance of different preclinical biomarkers in BCa
A Comprehensive Bioinformatics Analysis of Notch Pathways in Bladder Cancer
Background: A hallmark of Notch signaling is its variable role in tumor biology, ranging from tumor-suppressive to oncogenic effects. Until now, the mechanisms and functions of Notch pathways in bladder cancer (BCa) are still unclear. Methods: We used publicly available data from the GTEx and TCGA-BLCA databases to explore the role of the canonical Notch pathways in BCa on the basis of the RNA expression levels of Notch receptors, ligands, and downstream genes. For statistical analyses of cancer and non-cancerous samples, we used R software packages and public databases/webservers. Results: We found differential expression between control and BCa samples for all Notch receptors (NOTCH1, 2, 3, 4), the delta-like Notch ligands (DLL1, 3, 4), and the typical downstream gene hairy and enhancer of split 1 (HES1). NOTCH2/3 and DLL4 can significantly differentiate non-cancerous samples from cancers and were broadly altered in subgroups. High expression levels of NOTCH2/3 receptors correlated with worse overall survival (OS) and shorter disease-free survival (DFS). However, at long-term (>8 years) follow-up, NOTCH2 expression was associated with a better OS and DFS. Furthermore, the cases with the high levels of DLL4 were associated with worse OS but improved DFS. Pathway network analysis revealed that NOTCH2/3 in particular correlated with cell cycle, epithelial–mesenchymal transition (EMT), numbers of lymphocyte subtypes, and modulation of the immune system. Conclusions: NOTCH2/3 and DLL4 are potential drivers of Notch signaling in BCa, indicating that Notch and associated pathways play an essential role in the progression and prognosis of BCa through directly modulating immune cells or through interaction with cell cycle and EMT
Immunocytochemical Analysis of Endogenous Frizzled-(Co-)Receptor Interactions and Rapid Wnt Pathway Activation in Mammalian Cells
The differential activation of Wnt pathways (canonical: Wnt/-catenin; non-canonical:
planar cell polarity (PCP), Wnt/Ca2+) depends on the cell-specific availability and regulation of Wnt
receptors, called Frizzled (FZD). FZDs selectively recruit co-receptors to activate various downstream
effectors. We established a proximity ligation assay (PLA) for the detection of endogenous FZD–coreceptor
interactions and analyzed time-dependent Wnt pathway activation in cultured cells. Prostate
cancer cells (PC-3) stimulated by Wnt ligands (Wnt5A, Wnt10B) were analyzed by Cy3-PLA for the
co-localization of FZD6 and co-receptors (canonical: LRP6, non-canonical: ROR1) at the single-cell
level. Downstream effector activation was assayed by immunocytochemistry. PLA allowed the
specific (siRNA-verified) detection of FZD6–LRP6 and FZD6–ROR1 complexes as highly fluorescent
spots. Incubation with Wnt10B led to increased FZD6–LRP6 interactions after 2 to 4 min and resulted
in nuclear accumulation of -catenin within 5 min. Wnt5A stimulation resulted in a higher number
of FZD6–ROR1 complexes after 2 min. Elevated levels of phosphorylated myosin phosphatase
target 1 suggested subsequent Wnt/PCP activation in PC-3. This is the first study demonstrating
time-dependent interactions of endogenous Wnt (co-)receptors followed by rapid Wnt/-catenin
and Wnt/PCP activation in PC-3. In conclusion, the PLA could uncover novel signatures of Wnt
receptor activation in mammalian cells and may provide new insights into involved signaling route
Cytokine Effects on Gap Junction Communication and Connexin Expression in Human Bladder Smooth Muscle Cells and Suburothelial Myofibroblasts
BACKGROUND: The last decade identified cytokines as one group of major local cell signaling molecules related to bladder dysfunction like interstitial cystitis (IC) and overactive bladder syndrome (OAB). Gap junctional intercellular communication (GJIC) is essential for the coordination of normal bladder function and has been found to be altered in bladder dysfunction. Connexin (Cx) 43 and Cx45 are the most important gap junction proteins in bladder smooth muscle cells (hBSMC) and suburothelial myofibroblasts (hsMF). Modulation of connexin expression by cytokines has been demonstrated in various tissues. Therefore, we investigate the effect of interleukin (IL) 4, IL6, IL10, tumor necrosis factor-alpha (TNFα) and transforming growth factor-beta1 (TGFβ1) on GJIC, and Cx43 and Cx45 expression in cultured human bladder smooth muscle cells (hBSMC) and human suburothelial myofibroblasts (hsMF). METHODOLOGY/PRINCIPAL FINDINGS: HBSMC and hsMF cultures were set up from bladder tissue of patients undergoing cystectomy. In cytokine stimulated cultured hBSMC and hsMF GJIC was analyzed via Fluorescence Recovery after Photo-bleaching (FRAP). Cx43 and Cx45 expression was assessed by quantitative PCR and confocal immunofluorescence. Membrane protein fraction of Cx43 and Cx45 was quantified by Dot Blot. Upregulation of cell-cell-communication was found after IL6 stimulation in both cell types. In hBSMC IL4 and TGFβ1 decreased both, GJIC and Cx43 protein expression, while TNFα did not alter communication in FRAP-experiments but increased Cx43 expression. GJ plaques size correlated with coupling efficacy measured, while Cx45 expression did not correlate with modulation of GJIC. CONCLUSIONS/SIGNIFICANCE: Our finding of specific cytokine effects on GJIC support the notion that cytokines play a pivotal role for pathophysiology of OAB and IC. Interestingly, the effects were independent from the classical definition of pro- and antiinflammatory cytokines. We conclude, that connexin regulation involves genomic and/or post-translational events, and that GJIC in hBSMC and hsMF depend of Cx43 rather than on Cx45
A neural network z-vertex trigger for Belle II
We present the concept of a track trigger for the Belle II experiment, based
on a neural network approach, that is able to reconstruct the z (longitudinal)
position of the event vertex within the latency of the first level trigger. The
trigger will thus be able to suppress a large fraction of the dominating
background from events outside of the interaction region. The trigger uses the
drift time information of the hits from the Central Drift Chamber (CDC) of
Belle II within narrow cones in polar and azimuthal angle as well as in
transverse momentum (sectors), and estimates the z-vertex without explicit
track reconstruction. The preprocessing for the track trigger is based on the
track information provided by the standard CDC trigger. It takes input from the
2D () track finder, adds information from the stereo wires of the
CDC, and finds the appropriate sectors in the CDC for each track in a given
event. Within each sector, the z-vertex of the associated track is estimated by
a specialized neural network, with a continuous output corresponding to the
scaled z-vertex. The input values for the neural network are calculated from
the wire hits of the CDC.Comment: Proceedings of the 16th International workshop on Advanced Computing
and Analysis Techniques in physics research (ACAT), Preprint, reviewed
version (only minor corrections
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