Telomerase - future drug target enzyme?

Problem pomnoževanja koncev evkariontskih kromosomov (telomer) so uspešno rešili z odkritjem encima telomeraze konec 80. let prejšnjega stoletja, za odkritje so leta 2009 podelili tudi Nobelovo nagrado za medicino in fiziologijo. Izražanje telomeraze pri rakavih boleznih in človeške sanje o večni mladosti so močno pospešile razvoj farmakoloških telomeraznih inhibitorjev in aktivatorjev, vendar pa kljub 15-letnemu raziskovanju zdravila še niso dostopna na trgu. V članku smo glede na podatke v svetovnih medijih in literaturi naredili pregled farmakoloških učinkovin v zgodnjih fazah kliničnih preskušanj, ki specifično uravnavajo aktivnost telomeraze. Načrtovana protitumorska zdravila večinoma ne bodo namenjena samostojni uporabi, saj telomerazne inhibitorje klinično preskušajo v kombinaciji z obstoječimi kemoterapevtskimi sredstvi, protitelomerazna cepiva pa v kombinaciji z imunostimulansi. Poleg raka in staranja v prispevku navajamo ostala bolezenska stanja, ki so povezana s telomerazo/telomerami, hkrati pa opisujemo tudi tehnično-pravne probleme pri razvoju novih zdravil. Glede na dinamiko razvoja lahko prva protitelomerazna zdravila na trgu pričakujemo v naslednjih petih letih.Eucaryotic chromosome endings (telomeres) replication problem was solved in the 1980\u27s by discovery of the telomerase enzyme. The Nobel Prize in Physiology or Medicine was awarded in 2009 for the discovery of telomerase. Altered telomerase expression in cancer, and human dream of eternal youth haveaccelerated the development of pharmacological telomerase inhibitors and activators. However, after 15 years of development they are still not available on the market. In the present article we reviewed pharmacological agents that target telomerase activity, which have entered clinical trials. Current drugs in development are mostly not intended to be used alone, as telomerase inhibitors under clinical trials are used in combination with the existing chemotherapeutics and anti-telomerase vaccines in combination with immuno-stimulants. Apart from cancer and aging, there are other diseases linked to deregulated activity of telomerasežtelomeres and we also discuss technical and legal problems that researchers encounter in developing anti-telomerase therapy. Given the pace of development, first anti-telomerase drugs might appear on the market in the next 5 years

Classification of subsystems for graded-local nets with trivial superselection structure

We classify Haag-dual Poincar\'e covariant subsystems \B\subset \F of a graded-local net \F on 4D Minkowski spacetime which satisfies standard assumptions and has trivial superselection structure. The result applies to the canonical field net \F_\A of a net \A of local observables satisfying natural assumptions. As a consequence, provided that it has no nontrivial internal symmetries, such an observable net \A is generated by (the abstract versions of) the local energy-momentum tensor density and the observable local gauge currents which appear in the algebraic formulation of the quantum Noether theorem. Moreover, for a net \A of local observables as above, we also classify the Poincar\'e covariant local extensions \B \supset \A which preserve the dynamics.Comment: 38 pages, LaTe

News from the Virasoro algebra

It is shown that the local quantum field theory of the chiral energy- momentum tensor with central charge $c=1$ coincides with the gauge invariant subtheory of the chiral $SU(2)$ current algebra at level 1, where the gauge group is the global $SU(2)$ symmetry. At higher level, the same scheme gives rise to $W$-algebra extensions of the Virasoro algebra.Comment: 4 pages, Latex, DESY 93-11

1943-09-16, Phillip to Ann

https://digitalcommons.chapman.edu/avolk_correspondence/1000/thumbnail.jp

1943-10-05, Larry to Ann

https://digitalcommons.chapman.edu/avolk_correspondence/1001/thumbnail.jp

Quarks, gluons, colour: Facts or fiction?

A general method is presented which allows one to determine from the local gauge invariant observables of a quantum field theory the underlying particle and symmetry structures appearing at the lower (ultraviolet) end of the spatio--temporal scale. Particles which are confined to small scales, i.e., do not appear in the physical spectrum, can be uncovered in this way without taking recourse to gauge fields or indefinite metric spaces. In this way notions such as quark, gluon, colour symmetry and confinement acquire a new and intrinsic meaning which is stable under gauge or duality transformations. The method is illustrated by the example of the Schwinger model.Comment: 22 pages, ams-latex; the article had to be replaced because of tex problems, there are no changes in the tex

Effect of hydrolysable tannins on proliferation of small intestinal porcine and human enterocytes

The aim of the study was to investigate the concentration dependent impact of chestnut and oak extracts with high concentration of hydrolysable tannins on the growth of animal and human small intestinal enterocyte cell lines.In our study, four tannin extracts from oak and sweet chestnut were used (GALLIC ACID, FARMATAN, CONTAN, TANEX). Tannins were tested on normal porcine small intestinal cell lines (PSI, IPEC-J2, CLAB), human normal (H4) and human cancerogenic (Caco-2) cell line. Proliferation of cells was followed in 96-well plate by colony count assay. In this assay, a small number of cells was initially seeded into wells and growth of cell colonies in the presence of tannins supplemented in a wide range of concentrations (0.5 μg/mL–500.0 μg/mL) was followed up to 5 days. Experiments were stopped before cell colonies started to fuse and counted using the microscope. Colony count served as an indicator for comparison between control and assay experiments. GALLIC ACID was very effective at growth inhibition of cancerogenic Caco-2 cells. Inhibition up to 20% was observed in the concentration interval 0.98 to 31.25 μg/mL. FARMATAN accelerated proliferation of IPEC-J2 and Caco-2 cell lines up to 31.25 μg/mL. CONTAN was most potent in promoting growth of IPEC-J2 in the range of 1–62.5 μg/mL. In contrast, in a range between 1–62.5 μg/mL TANEX accelerated growth of human normal cell line H4, while having little effects on other cell lines. The obtained results suggest potentially beneficial use of chestnut and oak extract in the diet of humans and animals. In lower concentrations tannins could be used for the purpose of accelerated recovery of small intestinal epithelium, but further research is needed for elucidation of the mechanisms responsible for the observed effects on cell proliferation

Localization and the interface between quantum mechanics, quantum field theory and quantum gravity I (The two antagonistic localizations and their asymptotic compatibility)

It is shown that there are significant conceptual differences between QM and QFT which make it difficult to view the latter as just a relativistic extension of the principles of QM. At the root of this is a fundamental distiction between Born-localization in QM (which in the relativistic context changes its name to Newton-Wigner localization) and modular localization which is the localization underlying QFT, after one separates it from its standard presentation in terms of field coordinates. The first comes with a probability notion and projection operators, whereas the latter describes causal propagation in QFT and leads to thermal aspects of locally reduced finite energy states. The Born-Newton-Wigner localization in QFT is only applicable asymptotically and the covariant correlation between asymptotic in and out localization projectors is the basis of the existence of an invariant scattering matrix. In this first part of a two part essay the modular localization (the intrinsic content of field localization) and its philosophical consequences take the center stage. Important physical consequences of vacuum polarization will be the main topic of part II. Both parts together form a rather comprehensive presentation of known consequences of the two antagonistic localization concepts, including the those of its misunderstandings in string theory.Comment: 63 pages corrections, reformulations, references adde