Enveloping algebra valued gauge transformations for non-abelian gauge groups on non-commutative spaces

An enveloping algebra valued gauge field is constructed, its components are functions of the Lie algebra valued gauge field and can be constructed with the Seiberg-Witten map. This allows the formulation of a dynamics for a finite number of gauge field components on non-commutative spaces.Comment: 13 page

External Fields as Intrinsic Geometry

There is an interesting dichotomy between a space-time metric considered as external field in a flat background and the same considered as an intrinsic part of the geometry of space-time. We shall describe and compare two other external fields which can be absorbed into an appropriate redefinition of the geometry, this time a noncommutative one. We shall also recall some previous incidences of the same phenomena involving bosonic field theories. It is known that some such theories on the commutative geometry of space-time can be re-expressed as abelian-gauge theory in an appropriate noncommutative geometry. The noncommutative structure can be considered as containing extra modes all of whose dynamics are given by the one abelian action.Comment: 19 pages, Late

Construction of non-Abelian gauge theories on noncommutative spaces

We present a formalism to explicitly construct non-Abelian gauge theories on noncommutative spaces (induced via a star product with aconstant Poisson tensor) from a consistency relation. This results in an expansion of the gauge parameter, the noncommutative gauge potential and fields in the fundamental representation, in powers of a parameter of the noncommutativity. This allows the explicit construction of actions for these gauge theories.Comment: 11 pages; accepted for publication in European Physical Journal C; one misprint correcte

Whole genome and transcriptome amplification: practicable tools for sustainable tissue biobanking?

The use of whole genome amplification (WGA) and whole transcriptome amplification (WTA) techniques enables the enrichment of DNA and RNA from very small amounts of tissue. Here, we tested the suitability of WGA and WTA for tumor tissue biobanking. DNA and RNA from 13 standardized and seven non-standardized frozen and 12 formalin-fixed, paraffin-embedded (FFPE) clear cell renal cell carcinoma specimens (>9years old) served to test the robustness of the WGA and WTA products by reidentifying von Hippel-Lindau (VHL) gene mutations known to exist in these samples. The enrichment of DNA and RNA from frozen tissue was up to 1,291-fold and 423-fold, respectively. The sizes and yields (10- to 73-fold) of the amplified DNA obtained from the 12 FFPE samples were generally lower. The quality of the RNA from the FFPE samples was too low to reliably perform WTA. Our results demonstrate that frozen tumor tissue is very suitable for WGA and WTA. All 20 VHL mutations were verified with WGA. Notably, we were able to show that 18 of the 20 (90%) VHL mutations are also transcribed. In FFPE tumor tissue, 8 of 12 cases (67%) showed the expected mutations after the first WGA. Accurate WTA with FFPE material is sophisticated and strongly depends on the modification and degradation status of the fixed tissue. We conclude that for sustainable tissue biobanking, the use of WGA and WTA is a unique opportunity to provide researchers with sufficient amounts of nucleic acids, preferably from limited frozen tissue materia

Combining laser microdissection and microRNA expression profiling to unmask microRNA signatures in complex tissues

Neglecting tissue heterogeneity during the analysis of microRNA (miRNA) levels results in average signals from an unknown mixture of different cell types that are difficult to interpret. Here we demonstrate the technical requirements needed to obtain high-quality, quantitative miRNA expression infor- mation from tumor tissue compartments obtained by laser microdissection (LMD). Furthermore, we show the significance of disentangling tumor tissue heterogeneity by applying the newly developed protocols for combining LMD of tumor tissue compartments with RT-qPCR analysis to reveal compartment- specific miRNA expression signatures. An important advantage of this strategy is that the miRNA signature can be directly linked to histopatho logy. In summary, combining LMD and RT-qPCR is a powerful approach for spatial miRNA expression analysis in complex tissues, enabling discovery of disease mechanisms, biomarkers and drug candidates

Dual functions of SPOP and ERG dictate androgen therapy responses in prostate cancer

Driver genes with a mutually exclusive mutation pattern across tumor genomes are thought to have overlapping roles in tumorigenesis. In contrast, we show here that mutually exclusive prostate cancer driver alterations involving the ERG transcription factor and the ubiquitin ligase adaptor SPOP are synthetic sick. At the molecular level, the incompatible cancer pathways are driven by opposing functions in SPOP. ERG upregulates wild type SPOP to dampen androgen receptor (AR) signaling and sustain ERG activity through degradation of the bromodomain histone reader ZMYND11. Conversely, SPOP-mutant tumors stabilize ZMYND11 to repress ERG-function and enable oncogenic androgen receptor signaling. This dichotomy regulates the response to therapeutic interventions in the AR pathway. While mutant SPOP renders tumor cells susceptible to androgen deprivation therapies, ERG promotes sensitivity to high-dose androgen therapy and pharmacological inhibition of wild type SPOP. More generally, these results define a distinct class of antagonistic cancer drivers and a blueprint toward their therapeutic exploitation

Expression and amplification of therapeutic target genes in retinoblastoma

Purpose: We set out to evaluate alterations of the therapeutic target genes KIT (CD 117), EGFR, and HER-2 in human retinoblastoma. Methods: Ninety-five formalin-fixed, paraffin-embedded retinoblastomas were brought into a tissue microarray (TMA) format. Immunohistochemistry was performed to analyze the expression of CD117, EGFR, and HER-2. Fluorescence in situ hybridization (FISH) was utilized for detection of EGFR amplifications. Three tumors with strong CD117 positivity were sequenced for KIT exon 11 mutations. Results: Detectable CD117 expression was seen in 19% of all interpretable cases. Sequence analysis of the three tumors with the strongest CD117 expression revealed no mutations. EGFR was positive in 14% of all cases. No EGFR amplification was observed by FISH, however. All tumors were negative for HER-2 expression. Conclusions: Our data suggest that selected cases of retinoblastoma may be candidates for anti-EGFR and imatinib mesylate (STI571) therap

Altered cytoplasmic and nuclear ADP-ribosylation levels analyzed with an improved ADP-ribose binder are a prognostic factor in renal cell carcinoma

ADP-ribosylation (ADPR) of proteins is catalyzed by ADP-ribosyltransferases, which are targeted by inhibitors (i.e. poly(ADP-ribose) polymerase inhibitors [PARPi]). Although renal cell carcinoma (RCC) cells are sensitive in vitro to PARPi, studies on the association between ADPR levels and somatic loss of function mutations in DNA damage repair genes are currently missing. Here we observed, in two clear cell RCC (ccRCC) patient cohorts (n = 257 and n = 241) stained with an engineered ADP-ribose binding macrodomain (eAf1521), that decreased cytoplasmic ADPR (cyADPR) levels significantly correlated with late tumor stage, high-ISUP (the International Society of Urological Pathology) grade, presence of necrosis, dense lymphocyte infiltration, and worse patient survival (p < 0.01 each). cyADPR proved to be an independent prognostic factor (p = 0.001). Comparably, absence of nuclear ADPR staining in ccRCC correlated with absence of PARP1 staining (p < 0.01) and worse patient outcome (p < 0.05). In papillary RCC the absence of cyADPR was also significantly associated with tumor progression and worse patient outcome (p < 0.05 each). To interrogate whether the ADPR status could be associated with genetic alterations in DNA repair, chromatin remodeling, and histone modulation, we performed DNA sequence analysis and identified a significant association of increased ARID1A mutations in ccRCC$^{cyADPR+++/PARP1+}$ compared with ccRCC$^{cyADPR-/PARP1-}$ (31% versus 4%; p < 0.05). Collectively, our data suggest the prognostic value of nuclear and cytoplasmic ADPR levels in RCC that might be further influenced by genetic alterations

Analysis of the PARP1, ADP-Ribosylation, and TRIP12 Triad With Markers of Patient Outcome in Human Breast Cancer

PARP inhibitors (PARPi) are increasingly used in breast cancer therapy, including high-grade triple-negative breast cancer (TNBC) treatment. Varying treatment responses and PARPi resistance with relapse currently limit the efficacy of PARPi therapy. The pathobiological reasons why individual patients respond differently to PARPi are poorly understood. In this study, we analyzed the expression of PARP1, the main target of PARPi, in normal breast tissue, breast cancer, and its precursor lesions using human breast cancer tissue microarrays covering a total of 824 patients, including more than 100 TNBC cases. In parallel, we analyzed nuclear adenosine diphosphate (ADP)-ribosylation as a marker of PARP1 activity and TRIP12, an antagonist of PARPi-induced PARP1 trapping. Although we found PARP1 expression generally increased in invasive breast cancer, PARP1 protein levels and nuclear ADP-ribosylation were lower in higher tumor grade and TNBC samples than non-TNBCs. Cancers with low levels of PARP1 and low levels of nuclear ADP-ribosylation were associated with significantly reduced overall survival. This effect was even more pronounced in cases with high levels of TRIP12. These results indicate that PARP1-dependent DNA repair capacity may be compromised in aggressive breast cancers, potentially fueling enhanced accumulation of mutations. Moreover, the results revealed a subset of breast cancers with low PARP1, low nuclear ADP-ribosylation, and high TRIP12 levels, which may compromise their response to PARPi, suggesting a combination of markers for PARP1 abundance, enzymatic activity, and trapping capabilities might aid patient stratification for PARPi therapy

Sequence analysis and high-throughput immunhistochemical profiling of KIT (CD 117) expression in uveal melanoma using tissue microarrays

We aimed to immunohistochemically examine the expression of KIT (CD 117) in human posterior uveal melanoma and to analyze KIT-positive tumors for gene mutations. Brought into a tissue microarray (TMA) format were 101 formalin-fixed, paraffin-embedded posterior uveal melanomas. Immunhistochemistry was performed using the polyclonal anti-CD117 antibody from Dako (A4502). In ten selected KIT-positive tumors, exons 2, 8, 9, 11, 13 and 17 were sequenced. Of the 101 cases, 89 (88%) could be evaluated on the TMAs. Immunohistochemistry for CD 117 was weakly positive in 5 cases (6%), moderately positive in 10 cases (12%) and strongly positive in 57 cases (69%). No KIT mutations were detected in the analyzed exons. In conclusion, human posterior uveal melanoma frequently expresses CD117 at high levels. Although KIT mutations could not be found, it appears justified to investigate the utility of imatinib mesylate in the treatment of these patient