Ultra-fast Glyco-coating of Non-biological Surfaces

The ability to glycosylate surfaces has medical and diagnostic applications, but there is no technology currently recognized as being able to coat any surface without the need for prior chemical modification of the surface. Recently, a family of constructs called function-spacer-lipids (FSL) has been used to glycosylate cells. Because it is known that lipid-based material can adsorb onto surfaces, we explored the potential and performance of cell-labelling FSL constructs to “glycosylate” non-biological surfaces. Using blood group A antigen as an indicator, the performance of a several variations of FSL constructs to modify a large variety of non-biological surfaces was evaluated. It was found the FSL constructs when optimised could in a few seconds glycosylate almost any non-biological surface including metals, glass, plastics, rubbers and other polymers. Although the FSL glycan coating was non-covalent, and therefore temporary, it was sufficiently robust with appropriate selection of spacer and surface that it could capture anti-glycan antibodies, immobilize cells (via antibody), and withstand incubation in serum and extensive buffer washing, making it suitable for diagnostic and research applications

Neoglycolipids Micelle-like Structures as a Basis for Drug Delivery Systems

Targeted drug delivery is one of the most promising tasks of nanomedicine, as this is a real way to increase the effectiveness of therapeutic effects against many diseases. In this regard, the development of new inexpensive highly effective stimulating and non-immunogenic drug delivery systems (DDS) is of great importance. In this work new molecular candidates were proposed and studied for the creation of such systems based on the use of new compounds, neoglycolipids. It is shown that these compounds are capable of self-association in aqueous solutions and can serve as potential carriers of drug compounds with targeted delivery determined by their terminal groups (in particular, glycans). The processes of their associates formation and features of their structure are investigated. The results show that these selforganizing nanoscale systems can be used as a basis for developing new drug delivery systems. Keywords: neoglycolipids, micelle-like structures, small-angle X-ray scattering, molecular dynamics simulatio

Three deaf mice: mouse models for TECTA-based human hereditary deafness reveal domain-specific structural phenotypes in the tectorial membrane

Tecta is a modular, non-collagenous protein of the tectorial membrane, an extracellular matrix of the cochlea essential for normal hearing. Missense mutations in Tecta cause dominant forms of nonsyndromic deafness and a genotype-phenotype correlation has been reported in humans, with mutations in different Tecta domains causing mid- or high-frequency hearing impairments that are either stable or progressive. Three mutant mice were created as models for human Tecta mutations; the TectaL1820F, G1824D/+ mouse for zona pellucida (ZP) domain mutations causing stable mid-frequency hearing loss in a Belgian family, the TectaC1837G/+ mouse for a ZP-domain mutation underlying progressive mid-frequency hearing loss in a Spanish family, and the TectaC1619S/+ mouse for a zonadhesin-like (ZA) domain mutation responsible for progressive, high-frequency hearing loss in a French family. Mutations in the ZP and ZA domains generate distinctly different changes in the structure of the tectorial membrane. ABR thresholds in the 8-40 kHz range are elevated by 30-40 dB in the ZP-domain mutants, whilst those in the ZA-domain mutant are elevated by 20-30 dB. The phenotypes are stable and no evidence has been found for a progressive deterioration in tectorial membrane structure or auditory function. Despite elevated auditory thresholds, the Tecta mutant mice all exhibit an enhanced tendency to have audiogenic seizures in response to white noise stimuli at low sound pressure levels (≤84 dB SPL), revealing a previously unrecognised consequence of Tecta mutations. These results, together with those from previous studies, establish an allelic series for Tecta unequivocally demonstrating an association between genotype and phenotype

ПЛАНИРУЕМОЕ МНОГОЦЕНТРОВОЕ РАНДОМИЗИРОВАННОЕ КЛИНИЧЕСКОЕ ИССЛЕДОВАНИЕ II ФАЗЫ: НЕОАДЪЮВАНТНАЯ ХИМИОЛУЧЕВАЯ ТЕРАПИЯ С ПОСЛЕДУЮЩЕЙ ГАСТРЭКТОМИЕЙ D2 И АДЪЮВАНТНОЙ ХИМИОТЕРАПИЕЙ У БОЛЬНЫХ МЕСТНОРАСПРОСТРАНЕННЫМ РАКОМ ЖЕЛУДКА

Introduction. The prognosis for surgical treatment of locally advanced gastric cancer remains disappointing. Neoadjuvant chemo-radiation therapy is relatively new and the least researched method of treatment, it is attracting more and more attention, mainly abroad in recent years. The aims of neoadjuvant therapy is the earliest start of systemic therapy, damage of the primary tumor and regional metastases, an increase in the percentage of radical operations, improving treatment outcome. Material and methods. The planning study is a multicenter, randomized clinical phase II trial. Patients of the first (experimental) group will be treated as the followes: neoadjuvant chemo-radiotherapy (total tumor dose of 46 Gy in 23 fractions with the concurrent modified CapOX scheme) followed by D2 gastrectomy and adjuvant chemotherapy. Patients of the second (control) group will be treated with D2 gastrectomy and adjuvant chemotherapy. Adjuvant chemotherapy will be carried out under the following schemes (optional for the researchers): CapOX or FOLFOX. Toxicity evaluation of neoadjuvant chemo-radiotherapy and adjuvant chemotherapy will be conducted with NCI CTC Toxicity Scale Version 3.0. The main objectives of the trial are to assess the safety and immediate effectiveness of neoadjuvant chemo-radiotherapy according to the criteria of the frequency and severity of postoperative complications and mortality, and tumor response. We are planning to include 80 patients with morphologically confirmed gastric cancer сT2–4N1–3, сT3–4N0–3; М0. The proposed trial will be carried out in accordance with the principles of the Helsinki Declaration, it has been approved by local ethic committees of the participated institutions. Results. As a result of this multicenter randomized trial it is planned to show the reproducibility of obtained in MRRC and a number of foreign centers results – that is, the safety and high immediate effectiveness of neoadjuvant chemo-radiotherapy in patients with locally advanced gastric cancer. Conclusion. If we reach the goals of the planning trial, the results would allow to reasonably recommend the start of large international phase III trials for the final evaluation of the proposed neoadjuvant treatment as a standard one in patients with locally advanced gastric cancer.Введение. Прогноз при хирургическом лечении местнораспространенного рака желудка остается неутешительным. Неоадъювантная химиолучевая терапия является относительно новым и наименее исследованным методом лечения, привлекающим к себе в последние годы все большее внимание, преимущественно за рубежом. Цели неоадъювантной терапии состоят в максимально раннем начале системной терапии, повреждении первичной опухоли и регионарных метастазов, увеличении процента выполнения радикальных операций, улучшении результатов лечения. Материал и методы. Исследование является многоцентровым рандомизированным клиническим исследованием II фазы. Больным первой (исследуемой) группы будет проведено лечение в составе: неоадъювантная химиолучевая терапия (СОД 46 Гр за 23 фракции на фоне модифицированного режима CapOX) с последующей гастрэктомией D2 и адъювантной химиотерапией. Больным второй (контрольной) группы будет выполнена гастрэктомия D2 и адъювантная химиотерапия. Адъювантная химиотерапия будет проводиться по следующим схемам (на выбор исследователя): САРОX или FOLFOX. Оценка токсичности неоадъювантной химиолучевой терапии и адъювантной химиотерапии будет проводиться с помощью шкалы токсичности NCI CTC, версия 3.0. Основные цели состоят в оценке безопасности и непосредственной эффективности неоадъювантной химиолучевой терапии по критерию частоты и степени выраженности послеоперационных осложнений и летальности, и терапевтического патоморфоза. Планируется включение 80 больных морфологически верифицированным раком желудка сT2–4N1–3, сT3–4N0–3; М0. Исследование выполняется в соответствии с принципами Хельсинкской декларации, оно одобрено локальными этическими комитетами учреждений-соисполнителей. Результаты. В результате проведения данного многоцентрового рандомизированного исследования планируется показать воспроизводимость полученных в МРНЦ и ряде зарубежных Центров результатов – то есть безопасность и высокую непосредственную эффективность неоадъювантной химиолучевой терапии у больных местнораспространенным раком желудка. Заключение. В случае достижения поставленных целей полученные результаты позволят обоснованно рекомендовать проведение крупных международных исследований III фазы для окончательного изучения предложенного метода в качестве стандартного у больных местнораспространенным раком желудка

Вариант вируса гриппа в, адаптированный к мышам, для изучения лечебной и профилактической эффективности противовирусных препаратов in vitro и in vivo

Objective: to develop a new antigenic relevance influenza B virus suitable for modeling influenza infection in mice to assess of in vivo and in vitro therapeutic and preventive efficacy of antiviral drugs.Materials and methods: was carried out an adaptation of influenza B virus in BALB/c mice. Was performed, comparative assessment of in vivo and in vitro pathogenicity of the parenta! virus and. adapted, influenza B virus. Was assessed, inhibition of neuraminidase with antiviral drugs (oseltamivir ethoxyacrylate and. Tamiflu) in relation to the adapted, influenza B virus.Results: adapted  influenza B virus (B/Novosibirsk/40/2017-MA strain) models non-lethal influenza infection with pronounced, clinical signs of the disease in experimental animals. Were described the destructive changes in lungs and. brain that increases during infection. Analysis of internal organs (lungs, brain, liver, heart, kidneys, spleen) were revealed viral load only in the lungs. Were evaluated, in vivo and in vitro efficacy of antiviral drugs (oseltamivir ethoxysuccinate and Tamiflu®) on the model of influenza infection. Were proved, the high, efficiency of the innovative drug — oseltamivir ethoxysuccinate.Conclusion: the antigen-relevant adapted, influenza B virus (B/Novosibirsk/40/2017-MA strain) can be used, to assess the drug effectiveness against influenza, as well as an additional tool for predicting the effectiveness of the vaccine against drifting strains.Цель: разработка нового, обладающего антигенной актуальностью, штамма вируса гриппа типа В, пригодного для моделирования гриппозной инфекции у экспериментальных мышей для оценки лечебной и профилактической эффективности противовирусных препаратов in vivo и in vitro.Mатериалы и методы: была проведена адаптация вируса гриппа В на мышах линии BALB/c. Выполнена сравнительная оценка патогенности родительского и адаптированного вариантов вируса гриппа В в экспериментах in vivo и in vitro. Используя адаптированный вариант вируса гриппа В, проведена оценка ингибирования нейраминидазы с помощью противовирусных лекарственных средств (осельтамивира этоксисукцинат, и Тамифлю®).Результаты: полученный адаптированный вариант, вируса гриппа В штамм. В/Novosibirsk/40/2017-MA моделирует у экспериментальных животных нелетальную гриппозную инфекцию с выраженными клиническими признаками заболевания. Описаны, деструктивные изменения в лёгких и головном, мозге, нарастающие в ходе инфекции. Вирусологический анализ внутренних органов (лёгкие, головной мозг, печень, сердце, почки, селезёнка) выявил репликацию вируса гриппа только в лёгких. На данной модели гриппозной инфекции проведена оценка эффективности противовирусных лекарственных средств (осель-тамивира этоксисукцинат, и Тамифлю®) in vivo и in vitro. Доказана высокая эффективность инновационного лекарственного средства осельтамивира этоксисукцинат..Заключение: полученный антигенно актуальный вирус гриппа В штамм В/Novosibirsk/40/2017-MA может, быть использован, для оценки эффективности противогриппозных препаратов, а также в качестве дополнительного инструмента прогнозирования эффективности вакцины, против дрейфующих штаммов

THE WAYS TO OPTIMIZE CLINICAL OUTCOMES OF PHOTODYNAMIC THERAPY BY OPTICAL IMAGING TECHNIQUES

Background: Photodynamic therapy (PDT) is a  modern minimally invasive technique for treatment of a wide range of diseases, including malignancies. One of directions for PDT development is the individualization of exposure modes that can be achieved with effective treatment monitoring. There are a  number of approaches employing imaging techniques, the most promising of them being optical ones. Aim: To analyze factors affecting clinical outcomes of PDT in non-melanoma skin tumors, and to evaluate the prospects of optical imaging techniques for PDT planning and monitoring. Materials and methods: We retrospectively analyzed various aspects of the results PDT obtained in 855 patients with non-melanoma skin tumors. PDT was performed with systemic chlorine photosensitizers. As a  source of irradiation, the laser at a wavelength of 662 nm was used following exposure modes: mean power density 0.3 W/cm², the laser irradiation dose of 200 J/cm² for basal cancer and 300 J/cm² for squamous cell carcinoma. Clinical evaluation was performed based on tumor response according to RECIST criteria, by the presence or absence of recurrence during long term follow up and by the presence or absence of cosmetic defects. Fluorescence imaging and optical coherence tomography were used as non-invasive imaging techniques. Results: It was found that clinical predictors of treatment failure included tumor recurrence, squamous type of tumor, and advanced exophytic or infiltrative component. Fluorescence imaging showed an association between clinical outcomes of PDT and fluorescence characteristics of the photosensitizer. The best clinical outcomes were achieved in 147 patients with a combination of high contrast fluorescence (FC>1.2) and a high degree of photobleaching of the agent (ΔIt/IN >25%): the number of complete tumor responses was 94% (138 of 147), with recurrence seen in 3 (2%) patients only with the follow up from 6 to 53 month duration. Clinical predictors of PDT cosmetic failures are tumor recurrence and tumor stage above T2. The most vulnerable zones are the outer ear and nose wings; this fact is related to an involvement of the cartilage located directly beneath the thin skin in the photodynamic reaction. This was demonstrated by optical coherence tomography. Conclusion: Presence of clinical predictors of PDT failure justifies correction of light exposure modes that can be optimally implemented with techniques for objective evaluation of the tumor borders, photosensitizer accumulation and photobleaching. Dynamic non-invasive monitoring of PDT procedure with fluorescence imaging and optical coherence tomography seems promising for implementation of an individual approach resulting in optimal oncological and functional outcomes

Synthesis of blood group Forssman pentasaccharide GalNAcα1-3GalNAcβ1-3Galα1-4Galβ1-4Glcβ–R

Synthesis of the glycan part of Forssman glycolipid GalNAcα1-3GalNAcβ1-3Galα1-4Galβ1-4Glc–Cer in the form of 2-aminoethyl glycoside has been carried out. The glycoside has been converted into a lipophilic derivative capable of controlled inserting into erythrocytes. The obtained surface-modified cells, termed kodecytes, revealed a high level of the blood group system FORS serological activity