Role of 3'-untranslated region translational control in cancer development, diagnostics and treatment

The messenger RNA 3'-untranslated region(3'UTR)plays an important role in regulation of gene expres-sion on the posttranscriptional level. The 3'UTR con-trols gene expression via orchestrated interactionbetween the structural components of mRNAs(cis-ele-ment) and the specific trans-acting factors(RNA bind-ing proteins and non-coding RNAs). The crosstalk ofthese factors is based on the binding sequences and/or direct protein-protein interaction, or just functionalinteraction. Much new evidence that has accumulatedsupports the idea that several RNA binding factors canbind to common mRNA targets: to the non-overlappingbinding sites or to common sites in a competitive fash-ion. Various factors capable of binding to the sameRNA can cooperate or be antagonistic in their actions.The outcome of the collective function of all factorsbound to the same mRNA 3'UTR depends on manycircumstances, such as their expression levels, affinity to the binding sites, and localization in the cell, which can be controlled by various physiological conditions. Moreover, the functional and/or physical interactions of the factors binding to 3'UTR can change the character of their actions. These interactions vary during the cell cycle and in response to changing physiological condi-tions. Abnormal functioning of the factors can lead to disease. In this review we will discuss how alterations of these factors or their interaction can affect cancer development and promote or enhance the malignant phenotype of cancer cells. Understanding these altera-tions and their impact on 3'UTR-directed posttran-scriptional gene regulation will uncover promising new targets for therapeutic intervention and diagnostics. We will also discuss emerging new tools in cancer di-agnostics and therapy based on 3'UTR binding factors and approaches to improve them.

Empty nose syndrome pathogenesis and cell-based biotechnology products as a new option for treatment

Empty nose syndrome (ENS) is a rare complication that develops after partial orcomplete turbinectomy. The main feature of ENS is paradoxical nasal obstructionfeeling despite objectively wide nasal airway. ENS pathogenesis is multifactorialand includes changes in laminar physiological airflow, disruption of mucosafunctions and deficient neural sensation. This leads to the development of ENSsymptomatology such as dyspnea, nasal dryness, nasal burning, nasalobstruction, feeling of suffocation and even comorbid psychiatric disorders thatsignificantly impairs life quality. Specific effective treatment of ENS does not existup to date. In this review we outline existing biomaterial for surgical reconstitutionof nasal anatomy and discuss the perspective of stem cell-based technologiesin ENS management. The main focus is directed to justification ofrationality application of adult mesenchymal stem cells (MSCs) from differenttissues origin and neural crest-derived stem cells (NCSCs) based on their intrinsicbiological properties. MSCs transplantation may stimulate mucosa tissueregeneration via trophic factors secretion, direct transdifferentiation into epithelialcells and pronounced immunosuppressive effect. From the other hand, NCSCsbased on their high neuroprotective properties may reconstitute nerve structureand functioning leading to normal sensation in ENS patients. We postulate thatapplication of cell-based and tissue-engineered products can help to significantlyimprove ENS symptomatology only as complex approach aimed at reconstitutionof nasal anatomy, recovery the nasal mucosa functionality and neural tissuesensation.

Pharmacophore approaches in protein kinase inhibitors design

Protein kinases constitute a superfamily of therapeutic targets for a number of human and animal diseases that include more than 500 members accordingly to sequencing data of the human genome. The well characterized nature of protein kinases makes them excellent targets for drug development. Pharmacophore approaches have become one of the major tools in the area of drug discovery. Application of pharmacophore modeling approaches allows reducing of expensive overall cost associated with drug development project. Pharmacophore models are important functional groups of atoms in the proper spatial position for interaction with target protein. Various ligand-based and structurebased methods have been developed for pharmacophore model generation. Despite the successes in pharmacophore models generation these approaches have not reached their full capacity in application for drug discovery. In the following review, we summarize the published data on pharmacophore models for inhibitorsof tyrosine protein kinases(EGFR, HER2, VEGFR, JAK2, JAK3, Syk, ZAP-70, Tie2) and inhibitors of serine/threonine kinases(Clk, Dyrk, Chk1, IKK2, CDK1, CDK2, PLK, JNK3, GSK3, m TOR, p38 MAPK, PKB). Here, we have described the achievements of pharmacophore modeling for protein kinase inhibitors, which provide key points for further application of generated pharmacophore hypotheses in virtual screening, de novo design and lead optimization.