Cancer starts as a localised disease, which, if detected early, can often be treated successfully by removal of the primary tumour. A pernicious progression is the invasion of tumour cells into ...surrounding tissues, resulting in development of distant metastases. Because active migration of tumour cells is a prerequisite for tumour-cell invasion and metastasis, a pressing goal in tumour biology has been the elucidation of factors regulating the migratory activity of these cells. The most prominent regulatory factors are ligands to serpentine receptors—eg, chemokines and neurotransmitters. Many types of neurotransmitter receptors are expressed on tumour cells, supporting the theory that psychosocial factors are involved in the progression of cancer. Understanding how such receptors regulate migration and the availability of specific receptor antagonists could open up new avenues for chemoprevention of tumour-cell migration and metastatic development.
•We investigate the relationship of DNA methylation and miRNA expression.•Three bladder cancer cell lines are compared to primary urothelial cells.•Expression of miR-152 in 5637 is ...methylation-dependent.•Results suggest a causal connection for miR-200b in J82 and miR-10a in 5637.•Methylation of specific miRNA genes are biomarker candidates for bladder cancer.
Urinary miRNAs are discussed as potential biomarkers for bladder cancer. The majority of miRNAs, however, are downregulated, making it difficult to utilize reduced miRNA signals as reliable diagnostic tools. Because the downregulation of miRNAs is frequently associated with hypermethylation of the respective regulative sequences, we studied whether DNA hypermethylation might serve as an improved diagnostic tool compared to measuring downregulated miRNAs. miRNA expression arrays and individual qPCR were used to identify and confirm miRNAs that were downregulated in malignant urothelial cells (RT4, 5637 and J82) when compared to primary, non-malignant urothelial cells (HUEPC). DNA methylation was determined by customized PCR-arrays subsequent to methylation-sensitive DNA-restriction and by mass spectrometry. miRNA expression and DNA methylation were determined in untreated cells and in cultures treated with the demethylating agent 5-Aza-2′-deoxycytidine. miR-200b, miR-152 and miR-10a displayed differential expression and methylation among untreated cancer cell lines. In addition, reduced miRNA expression of miR-200b, miR-152, and miR-10a was associated with increased DNA methylation in malignant cells versus HUEPC. Finally, the demethylation approach revealed a causal relationship between both parameters for miR-152 in 5637 and also suggests a causal connection of both parameters for miR-200b in J82 and miR-10a in 5637. In conclusion, our studies in multiple bladder cancer cell lines and primary non-malignant urothelial cells suggest that hypermethylation of miR-152, miR-10a and miR-200b regulative DNA sequences might serve as epigenetic bladder cancer biomarkers.
The pathogenesis of hidradenitis suppurativa (HS), with its complex inflammatory network, is still elusive. Imbalances in DNA methylation can lead to genome destabilization and have been assumed to ...play a role in inflammatory diseases. Global DNA methylation and hydroxymethylation have not been studied in HS yet.
We conducted this study to investigate the global DNA methylation and hydroxymethylation status in lesional and perilesional HS skin compared to healthy controls.
Immunohistochemical analysis was performed for 5-methylcytosine (5-mC) and 5-hydroxymethylcytosine (5-hmC) in 30 lesional and 30 corresponding healthy-appearing perilesional HS tissue samples. We included 30 healthy subjects as an interindividual control group.
5-hmC levels were significantly lower in healthy-appearing perilesional (p < 0.0001) and lesional HS skin (p < 0.0001) when compared to healthy controls. There was no significant difference between lesional HS skin and perilesional HS skin regarding 5-hmC levels (p = 0.6654). In contrast to 5-hmC, 5-mC staining showed no significant changes between the 3 groups. Univariate analysis revealed no significant association between patients' characteristics, disease severity, and the levels of 5-mC and 5-hmC.
Our findings indicate that imbalances in DNA hydroxymethylation may play a role in the pathogenesis of HS rather than DNA methylation. Further studies are warranted to investigate the significance of DNA hydroxymethylation and the regulating enzymes in HS in order to advance our knowledge of the inflammatory network in this disease.
Purpose
The PIWI-interacting RNA machinery in malignant melanoma (MM) has not been sufficiently studied. We aimed to investigate the PIWIL3 expression profiles in primary melanomas and metastases of ...MM including a correlation with clinical data.
Methods
We studied 161 primary melanomas, 45 lymph node metastases, and 16 distant metastases of 183 patients with MM. We used immunohistochemistry to assess PIWIL3 protein expression in situ. The relationship between the immunoreactivity of PIWIL3 and clinical data was statistically evaluated.
Results
We observed a significantly (
P
= 0.000059) higher median immunoreactivity score in primary melanomas (4.9; range, 0.1–6), lymph node metastases (5.1; range, 3.3–6), and distant metastases (5.6; range, 4.5–6). PIWIL3 was expressed significantly higher (
P
= 0.0002) in primary nodular melanomas and acral melanomas (5.2; range, 3.4–6) when compared to other melanoma subtypes (4.7; range, 0.1–6). On univariate analysis, a significant positive correlation was observed between primary melanoma PIWIL3 expression and tumor thickness (
r
= 0.2;
P
= 0.014). On univariate and multivariate analysis, PIWIL3 did not prove to be an independent predictor for melanoma relapse or death.
Conclusions
Our data indicate that PIWIL3 protein expression is elevated in more aggressive primary MM and metastatic disease. As also observed in other malignancies, PIWIL3 seems to play a role in MM progression.
Background: Monogenetic forms of amyotrophic lateral sclerosis (ALS) offer an opportunity for unraveling the molecular mechanisms underlying this devastating neurodegenerative disorder. In order to ...identify a link between ALS-related metabolic changes and neurodegeneration, we investigated whether ALS-causing mutations interfere with the peripheral and brain-specific expression and signaling of the metabolic master regulator PGC (PPAR gamma coactivator)-1α (PGC-1α).Methods: We analyzed the expression of PGC-1α isoforms and target genes in two mouse models of familial ALS and validated the stimulated PGC-1α signaling in primary adipocytes and neurons of these animal models and in iPS derived motoneurons of two ALS patients harboring two different frame-shift FUS/TLS mutations.Results: Mutations in SOD1 and FUS/TLS decrease Ppargc1a levels in the CNS whereas in muscle and brown adipose tissue Ppargc1a mRNA levels were increased. Probing the underlying mechanism in neurons, we identified the monocarboxylate lactate as a previously unrecognized potent and selective inducer of the CNS-specific PGC-1α isoforms. Lactate also induced genes like brain-derived neurotrophic factor, transcription factor EB and superoxide dismutase 3 that are down-regulated in PGC-1α deficient neurons. The lactate-induced CNS-specific PGC-1α signaling system is completely silenced in motoneurons derived from induced pluripotent stem cells obtained from two ALS patients harboring two different frame-shift FUS/TLS mutations.Conclusion: ALS mutations increase the canonical PGC-1α system in the periphery while inhibiting the CNS-specific isoforms. We identify lactate as an inducer of the neuronal PGC-1α system directly linking brain metabolism and neuroprotection. Changes in the PGC-1α system might be involved in the ALS accompanied metabolic changes and in neurodegeneration.
Inhibitors for metastasis development Lang, Kerstin; Drell, 4th, Theodore L; Zaenker, Kurt S ...
Recent patents on anti-cancer drug discovery
1, Številka:
1
Journal Article
Recenzirano
A leading cause of death, cancer remains the bane of modern society and one of the most challenging research fields. Cancer is initially a localized disease that can be often treated well at a very ...early stage. However the vast majority of cancer deaths result from a pernicious progression of the disease, the development of distant metastases. It must therefore be a pressing research goal to focus on the pharmacological prevention of metastasis development. This review summarizes the current understanding of the cellular and molecular mechanisms of metastasis development, and suggests possible approaches for its inhibition.
Information on biomarkers of urothelial carcinomas (UC) for clinical decision-making is limited. Here, we newly identified and verified CXCL16 as a promising novel biomarker in urine for high grade ...and muscle invasive UC in a cross-sectional cohort of 308 UC patients, 126 urological hospital controls, and 50 population controls using antibody arrays and ELISA. Median CXCL16 levels in urine was significantly higher in UC patients (273.2 pg/mg creatinine) compared to hospital (148.1 pg/mg) and population controls (85.1 pg/mg) with a particular preference for high grade (460.8 pg/mg), muscle invasive (535.7 pg/mg) and primary UC (327.8 pg/mg) (all p<0.0001). Group differences were confirmed after adjusting or stratifying for potential clinical and individual characteristics, such as leukocyte counts, haematuria, age, gender, and smoking status. In contrast, CXCL16 showed less discriminating power in low grade (244.3 pg/mg), non-muscle invasive (≤pT1, 251.2 pg/mg) and recurrent UC (203.9 pg/mg). In agreement with its function in immune defence, expression of CXCL16 in tissue samples of primary UC patients (n=53) showed only a weak or no immunoreactivity compared to urological hospital controls (n=32). Expression of CXCR6, the G-protein-coupled receptor of CXCL16, remained unchanged. Our findings suggest that evading the immune defence by shedding cell-surface CXCL16 and its increased elimination in urine is a molecular feature of high grade and muscle invasive UC. Therefore, urinary CXCL16 may serve as a useful, simple and non-invasive tool to identify high-risk UC with increased risk of progression at the molecular level.
The autonomous migration of specialized cells is an essential characteristic in both physiological and pathological functions in the adult human organism. Leukocytes, fibroblasts, and stem cells, but ...also tumor cells, are thus the subject of intense investigation in a broad range of research fields. A wide spectrum of methods have therefore been established to analyze chemokinetic and chemotactic cell migration, ranging from easy-to-handle two-dimensional surface migration assays to highly specialized three-dimensional and intravital analysis methods. It is now manifest that the results obtained with these various migration assays substantially differ. This review therefore gives an overview of the migration assays which are currently in use, describes the methods, and critically enlightens the particular advantages and disadvantages of each method.
In order to assess the seismic risk for Switzerland, and particularly for the city of Basel, the seismic vulnerability of the existing buildings needs to be evaluated. Since no major damaging ...earthquake has occurred in Switzerland in recent times, vulnerability functions from observed damage patterns are not available. A simple evaluation method based on engineering models of the building structures suitable for the evaluation of a larger number of buildings is therefore proposed. The method is based on a nonlinear static approach acknowledging the importance of the nonlinear deformation capacity of the buildings subjected to seismic action. Eighty-seven residential buildings in a small target area in Basel were evaluated. The results are vulnerability functions that express the expected damage as a function of the spectral displacement. In order to extrapolate the results to other residential areas of the town, building classes were defined for which the vulnerability is presented in a probabilistic form that can be used directly for earthquake scenario projects.
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