Impact of STAT Proteins in Tumor Progress and Therapy Resistance in Advanced and Metastasized Prostate Cancer

Signal transducers and activators of transcription (STATs) are a family of transcription factors involved in several biological processes such as immune response, cell survival, and cell growth. However, they have also been implicated in the development and progression of several cancers, including prostate cancer (PCa). Although the members of the STAT protein family are structurally similar, they convey different functions in PCa. STAT1, STAT3, and STAT5 are associated with therapy resistance. STAT1 and STAT3 are involved in docetaxel resistance, while STAT3 and STAT5 are involved in antiandrogen resistance. Expression of STAT3 and STAT5 is increased in PCa metastases, and together with STAT6, they play a crucial role in PCa metastasis. Further, expression of STAT3, STAT5, and STAT6 was elevated in advanced and high-grade PCa. STAT2 and STAT4 are currently less researched in PCa. Since STATs are widely involved in PCa, they serve as potential therapeutic targets. Several inhibitors interfering with STATs signaling have been tested unsuccessfully in PCa clinical trials. This review focuses on the respective roles of the STAT family members in PCa, especially in metastatic disease and provides an overview of STAT-inhibitors evaluated in clinical trials.

RNA Modifications in Pathogenic Bacteria: Impact on Host Adaptation and Virulence

RNA modifications are involved in numerous biological processes and are present in all RNA classes. These modifications can be constitutive or modulated in response to adaptive processes. RNA modifications play multiple functions since they can impact RNA base-pairings, recognition by proteins, decoding, as well as RNA structure and stability. However, their roles in stress, environmental adaptation and during infections caused by pathogenic bacteria have just started to be appreciated. With the development of modern technologies in mass spectrometry and deep sequencing, recent examples of modifications regulating host-pathogen interactions have been demonstrated. They show how RNA modifications can regulate immune responses, antibiotic resistance, expression of virulence genes, and bacterial persistence. Here, we illustrate some of these findings, and highlight the strategies used to characterize RNA modifications, and their potential for new therapeutic applications.

Involvement of hpap2 and dgkA Genes in Colistin Resistance Mediated by mcr Determinants

Plasmid-mediated colistin resistance (mcr) determinants are challenging the efficacy of polymyxins against Gram-negative pathogens. Among 10 mcr genes described so far, the major determinants mcr-1 and mcr-3 are found closely linked to hpap2 or dgkA genes, encoding a hypothetical phosphatidic acid phosphatase of type 2 (PAP2) and a diacylglycerol kinase, respectively, whose functions are still unknown. In this study, mcr-1, mcr-1–hpap2, mcr-3, and mcr-3–dgkA were expressed in Escherichia coli, and recombinant strains were analyzed to detect antimicrobial susceptibility and changes in the expression of genes involved in phospholipid metabolism. The mcr-1 or mcr-3 single genes were enough to drive growth on colistin selective media, although co-expression of linked genes conferred maximal antibiotic resistance. Expression of mcr determinants downregulated endogenous genes involved in lipopolysaccharide (LPS) modification or phospholipid recycling, although to different extents of repression: strong for arnB, ybjG, and pmrR; medium for eptA, lpxT, and dgkA; small for bacA and pgpB. Four of these genes (bacA, lpxT, pgpB, and ybjG) encode undecaprenyl pyrophosphate (UPP) phosphatases. In these conditions, cells presented resistance against bacitracin, an antibiotic that sequesters UPP from PAP2 enzymes. The hpap2 and dgkA genes might play a role in colistin resistance by compensating for phospholipid metabolism functions altered during LPS modification by colistin resistance determinants.

Methodical Considerations and Resistance Evaluation against F. graminearum and F. culmorum Head Blight in Wheat. The Influence of Mixture of Isolates on Aggressiveness and Resistance Expression

In resistance tests to Fusarium head blight (FHB), the mixing of inocula before inoculation is normal, but no information about the background of mixing was given. Therefore, four experiments (2013–2015) were made with four independent isolates, their all-possible (11) mixtures and a control. Four cultivars with differing FHB resistance were used. Disease index (DI), Fusarium damaged kernels (FDK) and deoxynivalenol (DON) were evaluated. The isolates used were not stable in aggressiveness. Their mixtures did not also give a stable aggressiveness; it depended on the composition of mix. The three traits diverged in their responses. After the mixing, the aggressiveness was always less than that of the most pathogenic component was. However, in most cases it was significantly higher than the arithmetical mean of the participating isolates. A mixture was not better than a single isolate was. The prediction of the aggressiveness level is problematic even if the aggressiveness of the components was tested. Resistance expression is different in the mixing variants and in the three traits tested. Of them, DON is the most sensitive. More reliable resistance and toxin data can be received when instead of one more independent isolates are used. This is important when highly correct data are needed (genetic research or cultivar registration).

Methodical Considerations and Resistance Evaluation against Fusarium graminearum and F. culmorum Head Blight in Wheat. Part 3. Susceptibility Window and Resistance Expression

Flowering is the most favorable host stage for Fusarium infection in wheat, which is called the susceptibility window (SW). It is not known how long it takes, how it changes in different resistance classes, nor how stable is the plant reaction in the SW. We have no information, how the traits disease index (DI), Fusarium-damaged kernel rate (FDK), and deoxynivalenol (DON) respond within the 16 days period. Seven winter wheat genotypes differing in resistance were tested (2013–2014). Four Fusarium isolates were used for inoculation at mid-anthesis, and 4, 8, 11, 13, and 16 days thereafter. The DI was not suitable to determine the length of the SW. In the Fusarium-damaged kernels (FDK), a sharp 50% decrease was found after the 8th day. The largest reduction (above 60%) was recorded for DON at each resistance level between the 8th and 11th day. This trait showed the SW most precisely. The SW is reasonably stable in the first 8–9 days. This fits for all resistance classes. The use of four isolates significantly improved the reliability and credit of the testing. The stable eight-day long SW helps to reduce the number of inoculations. The most important trait to determine the SW is the DON reaction and not the visual symptoms.

THE EXPRESSIONS OF FREEDOM AND RESISTANCE IN GUNS N’ ROSES’ APPETITE FOR DESTRUCTION

Music and song lyrics are artistic works for people from any social group to listen to and read. Song lyrics have been situated in various social contexts. Social realities or circumstances, for example, have often been the source of inspiration for song lyrics. This kind of social aspect is apparent in Guns N’ Roses’ album Appetite for Destruction. The album presents songs with lyrics that portray various social and cultural issues in contemporary society. Through the stories of survival from the physical and mental abuse since childhood, the portrayal of those issues represents the freedom of expression and resistance. Freedom and resistance are a response to abusive behavior and social establishment. This kind of response represents the attitude demonstrated by subculture groups. The present article studies the song lyrics in Appetite for Destruction with the above mentioned topic. The topic is discussed using John Rowe’s postnationalist approach and analyzed using Charles Sanders Peirce’s semiotic method. The discussion also draws on the concept of subculture as described by Dick Hebdigie. The primary data are the words and sentences in the album that signify expressions of freedom and resistance. The study led to the finding that the album reveals freedom and resistance from the perspective of the victims of physical and mental abuse since childhood. The spirit of freedom and resistance is their anchor throughout their survival from abuses and pitfalls in society. It also found that the song lyrics describe the social realities of subculture groups with the same spirit in surviving life predicaments and the social establishment.Keywords: song lyrics; resistance; expression of freedom; abuse; Appetite for Destruction