Добірка наукової літератури з теми "-926-217"

PPARγ (peroxisome-proliferator-activated receptor γ) is a master transcription factor involved in adipogenesis through regulating adipocyte-specific gene expression. Recently, lipin1 was found to act as a key factor for adipocyte maturation and maintenance by modulating the C/EBPα (CCAAT/enhancer-binding protein α) and PPARγ network; however, the precise mechanism by which lipin1 affects the transcriptional activity of PPARγ is largely unknown. The results of the present study show that lipin1 activates PPARγ by releasing co-repressors, NCoR1 (nuclear receptor co-repressor 1) and SMRT (silencing mediator of retinoid and thyroid hormone receptor), from PPARγ in the absence of the ligand rosiglitazone. We also identified a novel lipin1 TAD (transcriptional activation domain), between residues 217 and 399, which is critical for the activation of PPARγ, but not PPARα. Furthermore, this TAD is unique to lipin1 since this region does not show any homology with the other lipin isoforms, lipin2 and lipin3. The activity of the lipin1 TAD is enhanced by p300 and SRC-1 (steroid receptor co-activator 1), but not by PCAF (p300/CBP-associated factor) and PGC-1α (PPAR co-activator 1α). The physical interaction between lipin1 and PPARγ occurs at the lipin1 C-terminal region from residues 825 to 926, and the VXXLL motif at residue 885 is critical for binding with and the activation of PPARγ. The action of lipin1 as a co-activator of PPARγ enhanced adipocyte differentiation; the TAD and VXXLL motif played critical roles, but the catalytic activity of lipin1 was not directly involved. Collectively, these data suggest that lipin1 functions as a key regulator of PPARγ activity through its ability to release co-repressors and recruit co-activators via a mechanism other than PPARα activation.

В статье опубликованы предварительные результаты изучения нижнего строительного горизонта Краскинского городища – центра округа столичной области государства Бохай (698–926 гг.). Памятник выполнял также функцию порта, который являлся морскими воротами Бохая. От его стен начинался морской путь в Японию. Рассматриваются строительные горизонты территории храмового комплекса, жилых кварталов и дороги. Соотнесены результаты изучения нижнего горизонта жилой застройки, нижнего горизонта дороги, ведущей к храмовой территории и фундамент стены, сооруженной из каменных блоков на начальном этапе строительства фортификационных сооружений. Нижний горизонт на Краскинском городище характеризуется как ранний этап его существования, когда оно еще было поселением. Характеризуются жилые и хозяйственные сооружения, а также другие основные элементы планировочной структуры памятника. Анализируются пространственная организация и плотность застройки на изученном участке городища. Систематизируются археологические материалы, связанные с ранним этапом заселения памятника. Рассматривается характер материальной и духовной культуры населения этого периода, представленный орудиями труда, вооружением, бытовыми изделиями, монетой Кайюань тунбао, украшениями, предметами игр, обломками керамики, черепицы и отходами металлообработки. Уточняется датировка нижней границы существования памятника и определяется его функция, как поселения земледельцев, рыбаков, охотников и собирателей, ремесленников. Предполагается, что уже в этот период на поселении был сооружен первый буддийский храм. ЛИТЕРАТУРААсташенкова Е.В., Болдин В.И. Декор концевых дисков Краскинского городища // Россия и АТР. 2004. №1(43). С. 122-129.Асташенкова Е.В. Предметы изобразительного и декоративно-прикладного искусства Краскинского городища // Бохай: история и археология. Владивосток, 2010. С. 81-85.Асташенкова Е.В. 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Introduction: 8500 adult allogeneic hematopoietic stem cell transplants (alloHSCT) are performed annually in the U.S. and 17,000 in Europe. HSCT-associated thrombotic microangiopathy (TMA), defined by thrombocytopenia, microangiopathic hemolytic anemia, and organ dysfunction in the absence of disseminated intravascular coagulation, complicates some 20% of these procedures. About half of post-alloHSCT TMAs may resolve when GvHD immunoprophylaxis is modified, but three year survival rates for those with severe HSCT-TMAs are a dismal 11%. Clinical manifestations are similar to other TMAs, but their pathophysiology may be distinct. Damage to vascular endothelium, independent of loss of ADAMTS13 activity, is thought to be critical. Fibrin-rich microthrombi, often accompanied by C4d and C5b-9 (membrane attack complex) deposition, occur in the microvasculature of multiple organs (Clin Adv Hematol Oncol 2014;12:565-573; Transplantation. 2013;96:217-223). This supports a role for complement activation in HSCT-TMA, but the importance of the various complement activation pathways is unclear. Recently, narsoplimab (OMS721), a monoclonal antibody inhibitor of MBL-associated serine protease-2 (MASP-2), a principal component of lectin-dependent complement activation, received Breakthrough Therapy Designation for HSCT-TMA, based on improved survival compared to historical controls in a phase 2 study. A phase 3 program is ongoing. Chemotherapy in association with autologous HSCT is linked to a marked increase in serum MASP-2 levels, persisting for about 4 weeks post-transplant (Front Immunol 2018;9:2153). However, TMAs are rare in autologous transplants, and circulating levels of MASP-2 following alloHSCT, and the impact of TMA development on those levels, are unknown. Methods: All individuals >18 years of age scheduled to undergo alloHSCT for hematologic malignancy at New York Presbyterian Hospital-Cornell were approached to participate in this study (NCT02604420). 100 of the first 101 subjects, age 58.3 +14 yrs, were enrolled and followed for >1.5 years post-transplant. This interval is consistent with the median time to HSCT-TMA diagnosis in adults of 90 days (range 32-733 days). Plasma was obtained at baseline (defined as between the time of consent and beginning of conditioning regimen), and at each regularly scheduled visit post-transplant-day 28 +5 days; day 100 +28 days; day 180 +28 days; and day 365 +28 days-as well as at the time of TMA diagnosis, based on the Consensus Criteria of Cho et al. (Transplantation 2010;90:918-926). A commercial ELISA (MyBioSource) was used to assess MASP-2 concentrations. Results: 20 subjects met study criteria for a HSCT-TMA diagnosis, occurring a median of 69 days (range 33-289) post-transplant. Three resolved following discontinuation of GvHD prophylaxis (mTOR or calcineurin inhibitor) and switch to mycophenolate and increased corticosteroid doses, and 7 had an intercurrent infection, 6 of whom expired with ongoing severe TMA despite a change in GvHD prophylaxis (Figure). TMAs persisted in the remaining 10 subjects. Median MASP-2 levels were significantly elevated in all subjects post-transplant, assessed at the time of TMA development or, in those not developing a TMA, at day 100 + 28 days post-transplant vs. controls (n=36, 86.2ng/ml (23.3-210.9): persistent TMA (n=9 (one plasma unavailable), 154ng/ml (range 82-209)); alloHSCT subjects who did not experience a TMA (n=40 evaluated to date, 113.5ng/ml (56-430.3)). (Figure). Lack of a significant rise in MASP-2 levels in patients with persistent TMAs vs. those who did not develop a TMA, combined with a significant decrease in variance of MASP-2 levels in the former group (p=0.005), may reflect consumption of product at sites of disease activity, i.e., the microvasculature. Conclusions: There is a significant increase in MASP-2 levels, with a wide variance, in post-alloHSCT patients evaluated at a time post-transplant typical of HSCT-TMA development. At time of development of a HSCT-TMA that persists despite withdrawal of GvHD prophylaxis, MASP-2 levels remain elevated over controls, but with a significantly lower variance vs. those not developing TMA. A study of additional samples, including longitudinal specimens, from this cohort is underway to determine if a change in MASP-2 levels correlates with HSCT-TMA development post-alloHSCT. Disclosures Van Besien: Miltenyi Biotec: Research Funding.

Abstract Introduction: ASP2215, a new tyrosine kinase inhibitor with activity against FMS-like receptor tyrosine kinase-3 (FLT3) and AXL receptor tyrosine kinase, is currently in development for the treatment of acute myeloid leukemia (AML). Methods: In an ongoing, first-in-human Phase 1/2, dose-escalation/dose-expansion study, the pharmacokinetic (PK) profile and pharmacodynamic (PD) effects of ASP2215 were evaluated under fasting conditions in patients with relapsed or refractory AML (R/R AML). Patients who met study criteria were assigned to treatment in the dose-escalation cohorts or were randomized to an open dose level in the dose-expansion cohorts. The dose-escalation cohort was a modified 3+3 with accelerated titration design that evaluated ascending oral doses of ASP2215 (20-450 mg), the dose-expansion cohort was a parallel, multi-dose-expansion cohort. Blood samples were collected and safety/tolerability assessments, including 12-lead electrocardiogram, were evaluated at protocol-specified time points for both cohorts. Effect of increasing ASP2215 exposure on inhibition of FLT3 phosphorylation, assessed via plasma inhibitory assay (PIA), was evaluated using an inhibitory PK/PD Emaxmodel. PK/PD analyses were performed to evaluate the relationship between ASP2215 exposure and changes from baseline in QTcF intervals (ΔQTcF) and changes from baseline in clinical laboratory values (e.g., creatinine kinase [ΔCK], aspartate aminotransferase [ΔAST]). Results: Data from an interim analysis of the dose-escalation/dose-expansion study were available from 215 subjects (n=23 [dose escalation], n=192 [dose expansion]). The ASP2215 PK parameters across the dose range (20-450 mg), evaluated after both single- and multiple-dose administration, are presented (Table); statistical analyses suggest the ASP2215 PK parameters are dose proportional from 20-450 mg. Median time to maximal concentration (Tmax) was observed between 2 hr and 6 hr after single and repeated oral dosing. The estimated median half-life (t1/2) ranged from approximately 45 hr to 159 hr based on the accumulation ratio; ASP2215 accumulation was extensive after multiple dose administration as reflected by the accumulation index (Rac) ranging from approximately 3.2-10. A strong correlation was shown for ASP2215 exposure-related inhibition of FLT3 phosphorylation, with >90% FLT3 inhibition observed by Day 8 at ASP2215 doses of ≥80 mg. Although a positive slope was observed between ΔQTcF and ASP2215 exposure, only 5% of the study population were reported as having a maximum post-baseline QTcF interval >500 msec. A similar trend was observed with ASP2215 concentration-related increases in ΔCK and ΔAST; however, <10% of all subjects experienced a Grade ≥3 shift from baseline in CK or AST concentrations. Conclusions: ASP2215 has demonstrated exposure-related FLT3 inhibition and a pharmacokinetic profile that support once-daily oral administration for the treatment of AML in subjects who relapsed after, or are refractory to, induction or salvage treatment. Table. ASP2215 Pharmacokinetic Parameters after Multiple-Dose Administration 20 mg (n=4) 40 mg (n=3) 80 mg (n=3) 120 mg (n=3) 200 mg (n=2) 300 mg (n=3) 450 mg (n=3) Cmax(ng/mL) 45.6 (30.5, 137) 106 (76.7, 140) 396 (217, 516) 282 (248, 593) 1460 (886, 2040) 1260 (1040, 2280) 1150 (776, 1530) Tmax(hr) 4.01 (4.00, 6.00) 3.87 (0.500, 6.00) 4.33 (4.00, 4.42) 2.02 (1.95, 5.75) 6.03 (6.00, 6.07) 6.05 (4.08, 6.07) 5.00 (4.07, 5.93) AUC0-24(ng·h/mL) 926 (543, 2480) 2460 (1750, 2800) 6280 (4160, 10600) 6190 (4200, 11300) 31500 (16500, 46600) 28700 (22300, 43300) 11500 (8070, 14900) t1/2 (hr) 52.8 (39.7, 83.1) 83.7 (68.5, 243) 91.5 (60.9, 108) 45.3 (30.5, 63.3) 143 (99.7, 186) 159 (83.3, 187) 56.9 (51.5, 62.3) Rac 3.70 (2.92, 5.51) 5.55 (4.64, 15.1) 6.02 (4.18, 7.02) 3.25 (2.38, 4.33) 9.08 (6.51, 11.7) 10.1 (5.53, 11.7) 3.94 (3.62, 4.27) Data are presented as median (minimum, maximum). AUC0-24, area under the concentration-time curve between 0-24 hr; Cmax, maximal concentration; t1/2, elimination half-life; Tmax, time to maximal concentration; Rac, accumulation ratio. Disclosures Smith: Astellas: Research Funding; Plexxikon: Research Funding. Off Label Use: ASP2215 is an investigational product for the treatment of AML. Perl:Astellas US Pharma Inc.: Consultancy; Ambit/Daichi Sankyo: Consultancy; Arog Pharmaceuticals: Consultancy; Asana Biosciences: Consultancy; Actinium Pharmaceuticals: Consultancy. Altman:Novartis: Other: Advisory board; BMS: Other: Advisory board; Seattle Genetics: Other: Advisory board; Spectrum: Other: Advisory board; Ariad: Other: Advisory board; Astellas: Other: Advisory board; assistance with abstract preparation. Gill:Astellas Pharma US, Inc: Employment. Kadokura:Astellas Pharma Global Development: Employment, Other: Personal fees. Yuen:Astellas Pharma, Inc.: Employment. Fisniku:Astellas: Employment. Liu:Astellas: Employment. Nagase:Astellas: Employment. Sargent:Astellas Pharma US, Inc: Employment. Bahceci:Astellas Pharma Global Development: Employment.

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Abstract Background The completeness of Medical Record (MR) is an indicator of the quality of care provided. IMFR (Medical and Physical Rehabilitation Institute), a hospital part of the Udine Healthcare Trust with 400 discharges yearly, launched at the end of 2017 a MR-quality program based on the involvement of Link Professionals (LP): doctors, nurses and therapists specifically trained. The main aim of this study is to determine if involving LP would improve MR completeness and would keep it over time. The second aim is to describe the 1-year experience of MR completeness and professional attitude toward recording medical information in it. Methods In December 2017 a new MR was introduced at the IMFR and its completeness was evaluated in January 2018. From January to April 2018, 17 LP educated all colleagues on the recording behavior through periodic meetings and focus groups. Then, LP peer-reviewed 20 inpatients paper-based MRs, assessing completeness, in April 2018 and then quarterly until January 2019. The evaluation was performed with a tool including a total of 73 items, divided in pertinence to the three professional figures involved. Feedbacks on MR completeness were given to professionals by LP in two-weeks. External data validation was performed to ensure data consistency. Significance (p &lt; 0.01) was assessed by Cochran-Armitage test for trends. Results The overall completeness of MR improved significantly from 59.6% (552 items out of 926; Jan-18) to 77.0% (738/959; Apr-18), settling to 78.3% (696/889) in January-19, with an overall trend of + 18.7%. Items pertaining to doctors improved significantly from 56.4% (217/385) to 81.4% (1173/1441), nurses’ from 60.7% (165/272) to 78.6% (740/941), therapists’ from 79.0% (79/100) to 91.7% (277/302). External validation results in 75% of agreement. Conclusions The involvement of LP proved effectiveness in encouraging professionals behavior, supporting the MR completeness improvement and keep it over one year time. Key messages Professionals involvement and short-term feedbacks contribute to the healthcare quality improvement. Peer-reviewing medical records improves professionals attitude in recording behavior.

Дисертація на здобуття наукового ступеня кандидата технічних наук за спеціальністю 05.18.05 – технологія цукристих речовин та продуктів бродіння. – Національний університет харчових технологій Міністерства освіти і науки, Київ, 2014. Дисертаційну роботу присвячено удосконаленню технології пива з використанням антиоксидантів з рослинної сировини. Розглянуто окиснення ізо-альфа-кислот при кип’ятінні сусла з хмелем або хмелепродуктами за ланцюговим вільнорадикальним механізмом. Визначено шляхи сповільнення окиснення в результаті додавання антиоксидантів з рослинної сировини. На основі вивчення кінетики окиснення компонентів хмельових смол озонованим повітрям розчинів СО₂-екстракту хмелю підібрано умови, що забезпечують прискорене окиснення компонентів хмельових смол. Доведено ефективність застосування антиоксидантів із рослинної сировини для захисту від окиснення компонентів хмельових смол. Встановлено найефективніші антиоксиданти та рекомендовану кількість їх внесення. Виявлено, що добавка АО із листя м'яти перцевої та кори дуба в сусло в процесі його кип'ятіння із хмелем найбільш ефективно сприяє коагуляції білків сусла й освітленню пива і дає можливість економити 10 % хмелю або його концентратів та збільшити фізіологічну цінність пива. Виявлено, що АО з трави звіробою та кори дуба впливають на вміст летких метаболітів окиснювального обміну, зокрема зменшують вміст діацетилу та ацетальдегіду в молодому та готовому пиві. Запропоновано технологію застосування антиоксидантів з рослинної сировини на стадіях кип’ятіння і охолодження сусла. Визначено технологічні режими внесення антиоксидантів з рослинної сировини і хмелепродуктів. Проведено виробничі випробування технології різних сортів пива з використанням рослинних антиоксидантів на заводі Харківського відділення ПАТ «CАН ІнБев Україна». Виготовлено дослідно-промислову партію об’ємом 10000 дал.
The thesis for a scientific degree of candidate of technical sciences on specialty 05.18.05 – technology of sugary substances and fermentation products. – National University of Food Technologies, Ministry of Education and Science of Ukraine, Kуiv, 2014. The dissertation paper is devoted to the improvement of beer technology with the use of plant-extracted antioxidants. Iso-alpha acids oxidation by free-radical-chain mechanism during wort boiling with hop or hop products is discussed. The ways to inhibit the oxidation due to the addition of plant-extracted antioxidants are determined. Based on the analysis of kinetics of ozonized air oxidation of hop resins components in methanol CO₂ hop extract solution, the conditions are found that provide accelerated oxidation of hop resins components. The efficiency of application of plant-extracted antioxidants for anti-oxygenation of hop resins components is proved. The most effective antioxidants and their dosing rate have been determined. It is revealed that adding antioxidants extracted from peppermint leaves and oak bark into boiling wort with hop is most effective for wort proteins coagulation and beer clarification, this provides up to 10 % savings in hop or its extracts and increases the physiological value of the beer. It is found that antioxidants extracted from Hypericum and oak bark influence the contents of volatile metabolites of the oxidizing exchange; specifically they reduce the diacetyl and acetic aldehyde content in young and finished beer. The technology of plant-extracted antioxidants application at the stages of wort boiling and cooling is proposed. The conditions of plant-extracted antioxidants and hop products dozing are determined. Industrial tests of production technology for different beer types with the use of plant-extracted antioxidants were performed at the Kharkov branch of the PJSC «SUN InBev Ukraine». An experimental industrial batch of 10,000 dal was produced.