Molecular and genetic subtyping of breast cancer: the era of precision oncology

Objective: To examine and summarize the most discussed molecular targets for prognosis prediction in all histological subtypes of breast cancer. Materials and Methods: The contemporary view on breast cancer pathology as heterogeneous disease has changed the therapeutic landscape from a “one size fits all” to a subtype specific treatment approach. We conducted a wide literature review in order to simplify the various findings associated with breast cancer molecular targets and the possible routine clinical implications in the future. Results: The four intrinsic molecular subtypes of breast cancer are luminal A, luminal B, HER2/Neu-enriched and basal-like, with each subtype associated with a specific expression profile. Additionally, there are critical differences among the four molecular subtypes with regard to incidence, response to treatment, disease progression, survival, and imaging features: luminal A tumors have the most favorable prognosis of all breast cancer subtypes, whereas luminal B, HER2/Neu-enriched, and basal-like tumors have poorer clinical outcomes. Additionally, identification of expression-based tumor profiles most/least likely to respond to chemotherapy is changing the landscape of medical oncology. Conclusions: Despite the significant prognostic improvements gained using current “individualized” therapeutic approaches, not all patients benefit as there are deeper sub-classes within the intrinsic subtypes which alter treatment responses. Thus, additional gene expression profiling of each subtype is essential in providing information about more accurate behavior of the different breast tumors, thus offering hope for an even more specific precision oncology. Such potential markers must not only demonstrate analytical and clinical validity along with clinical utility, but also provide wide availability and reproducibility

Polymorphic phase transitions and ferroelectric properties in β-glycine single crystals and micro islands

The research was carried out using equipment of Ural Center for Shared Use "Modern Nanotechnologies" Ural Federal University with the financial support by the Government of the Russian Federation (Resolution 211, Contract 02.A03.21.0006). The reported study was funded by RFBR according to the research project № 18-32-00390

Stimulation of homology-directed gene targeting at an endogenous human locus by a nicking endonuclease

Homologous recombination (HR) is a highly accurate mechanism of DNA repair that can be exploited for homology-directed gene targeting. Since in most cell types HR occurs very infrequently (∼10−6 to 10−8), its practical application has been largely restricted to specific experimental systems that allow selection of the few cells that become genetically modified. HR-mediated gene targeting has nonetheless revolutionized genetics by greatly facilitating the analysis of mammalian gene function. Recent studies showed that generation of double-strand DNA breaks at specific loci by designed endonucleases greatly increases the rate of homology-directed gene repair. These findings opened new perspectives for HR-based genome editing in higher eukaryotes. Here, we demonstrate by using donor DNA templates together with the adeno-associated virus (AAV) Rep78 and Rep68 proteins that sequence- and strand-specific cleavage at a native, predefined, human locus can also greatly enhance homology-directed gene targeting. Our findings argue for the development of other strategies besides direct induction of double-strand chromosomal breaks to achieve efficient and heritable targeted genetic modification of cells and organisms. Finally, harnessing the cellular HR pathway through Rep-mediated nicking expands the range of strategies that make use of AAV elements to bring about stable genetic modification of human cells

Rhamnolipids: diversity of structures, microbial origins and roles

Rhamnolipids are glycolipidic biosurfactants produced by various bacterial species. They were initially found as exoproducts of the opportunistic pathogen Pseudomonas aeruginosa and described as a mixture of four congeners: α-L-rhamnopyranosyl-α-L-rhamnopyranosyl-β-hydroxydecanoyl-β-hydroxydecanoate (Rha-Rha-C10-C10), α-L-rhamnopyranosyl-α-L-rhamnopyranosyl-β-hydroxydecanoate (Rha-Rha-C10), as well as their mono-rhamnolipid congeners Rha-C10-C10 and Rha-C10. The development of more sensitive analytical techniques has lead to the further discovery of a wide diversity of rhamnolipid congeners and homologues (about 60) that are produced at different concentrations by various Pseudomonas species and by bacteria belonging to other families, classes, or even phyla. For example, various Burkholderia species have been shown to produce rhamnolipids that have longer alkyl chains than those produced by P. aeruginosa. In P. aeruginosa, three genes, carried on two distinct operons, code for the enzymes responsible for the final steps of rhamnolipid synthesis: one operon carries the rhlAB genes and the other rhlC. Genes highly similar to rhlA, rhlB, and rhlC have also been found in various Burkholderia species but grouped within one putative operon, and they have been shown to be required for rhamnolipid production as well. The exact physiological function of these secondary metabolites is still unclear. Most identified activities are derived from the surface activity, wetting ability, detergency, and other amphipathic-related properties of these molecules. Indeed, rhamnolipids promote the uptake and biodegradation of poorly soluble substrates, act as immune modulators and virulence factors, have antimicrobial activities, and are involved in surface motility and in bacterial biofilm development

Влияние циклопролилглицина и его аналогов на моноаминергические системы мозга мышей BALB/c

Effects of chronic cycloprolylglycine (CPG) and its analogues GZK-001 and GZK-002 treatment at the doses 1 and 2 mg/kg on levels of monoamines and their metabolites in BALB/c mice brain were determined by HPLC. Neurochemical data demonstrated that antidepressant-like effects of the peptides are mediated by an increase in NA and decrease in DA content in frontal cortex. Alterations in striatal monoamine metabolism were observed predominantly after CPG's analogues treatment: the concentration of DA was increased, although its rate of turnover was diminished. In hippocampus more active was CPG: the levels of NE, DA, 5-HT, and its metabolite 5-HIAA were decreased. GZK-001 (1 mg/kg) caused a decrease in the concentration of DA and 5-HIAA. The present results suggest that antidepressant-like effects of CPG and its analogues are associated with DA, NE, and 5-HT systems.Методом ВЭЖХ изучено влияние хронического введения циклопролилглицина (ЦПГ) и его аналогов ГЗК-001 и ГЗК-002 в дозах 1 и 2 мг/кг на содержание и метаболизм (5-HT), дофамина (ДА) и норадреналина (НА) в структурах мозга мышей BALB/c. Было показано, что антидепрессивноподобное действие пептидов сопровождается увеличением уровня НА и уменьшением содержания ДА во фронтальной коре. В стриатуме преобладало влияние аналогов ЦПГ: увеличивался уровень ДА и снижалась скорость его метаболизма. В гиппокампе напротив активнее был ЦПГ: уменьшалось содержание НА, ДА, 5-НТ и его метаболита 5-ГИУК. Под влиянием ГЗК-001 в дозе 1 мг снижался уровень ДА и 5-ГИУК. На основании полученных данных можно заключить, что в механизме антидепрессивноподобного эффекта ЦПГ и его аналогов принимают участие серотонинергическая, норадреналинергическая и дофаминергическая системы мозга

Изучение фармакокинетики [3Н]-циклопролилглицина в крови крыс

Resume. The objective of this study is to evaluate pharmacokinetic parameters of tritium-labeled cycloprolylglycine [3H] -CPG following intravenous bolus administration of 5.7 μg (2 mCi). [3H] -CPG was prepared by solid-state catalytic isotopic exchange with spillover-tritium. It was found that plasma concentration-time profile of [3H] -CPG is adequately fit by a two-compartment model. The pharmacokinetic parameter estimates revealed rapid а-phase (distribution phase) (T1/2α min) followed by a slower β-phase of elimination (T1/2β 80 min). These findings are consistent with previous results of pharmacokinetic study of CPG as a noopept metabolite. CPG is differ significantly from other therapeutic peptides in pharmacokinetic profile (T1/2 , MRT, etc), which implies that CPG has a more prolonged duration of action.Изучена фармакокинетика меченого по тритию метаболита ноопепта циклопролилглицина [3Н]-ЦПГ после внутривенного болюсного введения в дозе 5,7 мкг (2 мКи). Мечение субстанции ЦПГ проводили с помощью реакции высокотемпературного твердофазного каталитического изотопного обмена. Обнаружено, что временной характер изменений концентрации [3Н]-ЦПГ в крови крыс подчиняется двухкамерной модели. Расчёт фармакокинетических параметров показал, что α-фаза (фаза распределения) протекает очень быстро, а β-фаза элиминации [3Н]-ЦПГ достаточно продолжительна. При этом величина Т1/2α составляет 1 мин, а Т1/2β - 80 мин. Эти данные согласуются с ранее полученными результатами по фармакокинетике ЦПГ как метаболита, образующегося из лекарственного препарата ноопепт. ЦПГ существенно отличается от других дипептидных соединений по величинам фармакокинетических параметров (Т1/2e , MRT и др.), что предполагает наличие у него большей продолжительности фармакологического действия

Tau association with synaptic vesicles causes presynaptic dysfunction

Tau is implicated in more than 20 neurodegenerative diseases, including Alzheimer's disease. Under pathological conditions, Tau dissociates from axonal microtubules and missorts to pre- and postsynaptic terminals. Patients suffer from early synaptic dysfunction prior to Tau aggregate formation, but the underlying mechanism is unclear. Here we show that pathogenic Tau binds to synaptic vesicles via its N-terminal domain and interferes with presynaptic functions, including synaptic vesicle mobility and release rate, lowering neurotransmission in fly and rat neurons. Pathological Tau mutants lacking the vesicle binding domain still localize to the presynaptic compartment but do not impair synaptic function in fly neurons. Moreover, an exogenously applied membrane-permeable peptide that competes for Tau-vesicle binding suppresses Tau-induced synaptic toxicity in rat neurons. Our work uncovers a presynaptic role of Tau that may be part of the early pathology in various Tauopathies and could be exploited therapeutically.status: publishe

Certified reference materials for radionuclides in Bikini Atoll sediment (IAEA-410) and Pacific Ocean sediment (IAEA-412)

The preparation and characterization of certified reference materials (CRMs) for radionuclide content in sediments collected offshore of Bikini Atoll (IAEA-410) and in the open northwest Pacific Ocean (IAEA-412) are described and the results of the certification process are presented. The certified radionuclides include: 40K, 210Pb (210Po), 226Ra, 228Ra, 228Th, 232Th, 234U, 238U, 239Pu, 239+240Pu and 241Am for IAEA-410 and 40K, 137Cs, 210Pb (210Po), 226Ra, 228Ra, 228Th, 232Th, 235U, 238U, 239Pu, 240Pu and 239+240Pu for IAEA-412. The CRMs can be used for quality assurance and quality control purposes in the analysis of radionuclides in sediments, for development and validation of analytical methods and for staff training