New insights into the synergism of nucleoside analogs with radiotherapy

Nucleoside analogs have been frequently used in combination with radiotherapy in the clinical setting, as it has long been understood that inhibition of DNA repair pathways is an important means by which many nucleoside analogs synergize. Recent advances in our understanding of the structure and function of deoxycytidine kinase (dCK), a critical enzyme required for the anti-tumor activity for many nucleoside analogs, have clarified the mechanistic role this kinase plays in chemo- and radio-sensitization. A heretofore unrecognized role of dCK in the DNA damage response and cell cycle machinery has helped explain the synergistic effect of these agents with radiotherapy. Since most currently employed nucleoside analogs are primarily activated by dCK, these findings lend fresh impetus to efforts focused on profiling and modulating dCK expression and activity in tumors. In this review we will briefly review the pharmacology and biochemistry of the major nucleoside analogs in clinical use that are activated by dCK. This will be followed by discussions of recent advances in our understanding of dCK activation via post-translational modifications in response to radiation and current strategies aimed at enhancing this activity in cancer cells

Modern media and sports : how the popularity of handball has been changed by technological development and mass media?

In der Bachelorarbeit soll bewiesen werden welchen Einfluss die modernen Medien auf die Sportart Handball haben. Dazu wird zuerst die Entwicklung der modernen Medien anhand zweier Tabellen gezeigt. Des Weiteren erfolgt eine Erklärung zum Medium Online sowie zum Medium Fernsehen. Da es in dieser Wissenschaftlichen Arbeit um diese Bereiche geht. Zusätzlich wird der Handballsport kurz vorgestellt hier erfolgt eine Definition und eine Zusammenfassung der wichtigsten Daten, sowie Änderungen in diesem Sport. Anschließend wird mittels einer Analyse das Verhalten sowie die Veränderung des Auftrittes der DKB Handball-Bundesliga auf der Social Media-Plattform Facebook untersucht. Dazu werden zwei Zeiträume untersucht, der erste Zeitraum ist nach dem Eintritt auf Facebook gewählt. .

The fdx gene encoding the [2Fe--2S] ferredoxin of Halobacterium salinarium (H. halobium).

The gene encoding the [2Fe--2S] ferredoxin (fdx gene) was isolated from Halobacterium salinarium using two oligonucleotides deduced from the ferredoxin sequence as probes. Cosmid DNAs exhibiting hybridization were isolated, the fdx gene was localized to smaller subfragments and the nucleotide sequence determined. The 390 bp coding sequence is located in the halobacterial FI-DNA and transcribed as a 440 nucleotide mRNA. S1 mapping indicated that the 5' terminus of the mRNA maps immediately upstream of the ATG start codon. The promoter box A, centred around position -25 (5' AC-TATG 3'), and box B (TG) elements at the start of the transcript resemble the sequences of a typical archaeal promoter. The restriction pattern of an approximately 50 kb region surrounding the fdx gene is conserved in various Halobacterium species. The halobacterial ferredoxin and the major gas vesicle protein GvpA exhibit up to 70% similarity to their respective counterparts in cyanobacteria suggesting lateral gene transfer between the organisms. These similarities prompted a more detailed investigation of the relative positions of the genes in the halobacterial genome

Evaluating the Therapeutic Potential of a Non-Natural Nucleotide That Inhibits Human Ribonucleotide Reductase

Human ribonucleotide reductase (hRR) is the key enzyme involved in de novo dNTP synthesis and thus represents an important therapeutic target against hyperproliferative diseases, most notably cancer. The purpose of this study was to evaluate the ability of non-natural indolyl-2’-deoxynucleoside triphosphates to inhibit the activity of hRR. The structural similarities of these analogs with dATP predicted that they would inhibit hRR activity by binding to its allosteric sites. In silico analysis and in vitro characterization identified one particular analog designated as 5-nitro-indolyl-2'-deoxyribose triphosphate (5-NITP) that inhibits hRR. 5-NITP binding to hRR was determined by isothermal titration calorimetry. X-ray crystal structure of 5-NITP bound to RR1 was determined. Cell-based studies demonstrated the anti-cancer effects of the corresponding non-natural nucleoside against leukemia cells. 5-NITP binds to hRR with micromolar affinity. Binding does not induce hexamerization of hRR1 like dATP, the native allosteric inhibitor of hRR that binds with high affinity to the A-site. The X-ray crystal structure of S. cerevisiae RR1-5-NITP (ScRR1-5-NITP) complex determined to 2.3 Å resolution shows that 5-NITP does not bind to the A-site but rather at the S-site. Regardless, 5-NIdR produces cytostatic and cytotoxic effects against human leukemia cells by altering cell-cycle progression. Our studies provide useful insights towards developing new inhibitors with improved potency and efficacy against hRR