Permissive expansion and homing of adoptively transferred T cells in tumor-bearing hosts

Activated T cells expressing endogenous or transduced TCRs are two cell types currently used in clinical adoptive T-cell therapy. The ability of these cells to recognize their antigen, expand, and traffic to the tumor site are the initial steps necessary for successful therapy. In this study, we used in vivo bioluminescent imaging (BLI) of Renilla luciferase (RLuc) expressing T cells to evaluate the ability of adoptively transferred T cells to survive, expand and home to tumor site in vivo. Using this method, termed RT-Rack (Rluc T cell tracking), we followed T-cell response against tumors in vivo. Expansion and homing of adoptively transferred T cells were antigen dependent, but independent of the host immune status. Moreover, we successfully detected T-cell response to small and large tumors, including autochthonous liver tumors. The adoptively transferred T cells were not ignorant or excluded in a partially tolerant host, which expressed low level of the target in the periphery. Using T cell receptor-engineered T cells, we showed the ability of these cells to respond in tumor-bearing hosts by expanding and homing to the tumor site. In all these models, the host immune status, the nature of the tumor or of the antigen, the tumor size, and the presence of the targeted antigen in the periphery did not prevent the adoptively transferred T cells from responding by expanding and homing to the tumor. However, T cells had higher expression of the inhibitory receptor PD1 and reduced functional activity when a self-antigen was targeted

Two-strap RF antenna in Uragan-2M stellarator

A unshielded two-strap antenna had been installed in Uragan-2M. A vacuum chamber inner walls conditioning regime with the two-strap antenna is studied in a weak magnetic field. Plasma with the density nₑ~ (0.2…0.95)·10¹²сm⁻³ and sustained. The RF frequency was f₀~5 MHz, RF plasma was sustained in stationery magnetic field B₀≈0.01 T, at hydrogen pressure range 3·10⁻³…3·10⁻² Pa.Введена в експлуатацію на Урагані-2М багатофункціональна неекранована двонапіввиткова антена. Відпрацьована можливість роботи двонапіввиткової антени в режимі чистки внутрішніх поверхонь вакуумної камери в слабкому магнітному полі. Плазма створювалась і підтримувалась густиною nₑ~ (0.2…0.95)·10¹²сm⁻³. За робочої частоти f₀~5 МГц ВЧ-плазма створювалась у стаціонарному магнітному полі B₀≈0.01 Tл за тиску водню 3·10⁻³…3·10⁻² Па.Введена в эксплуатацию на Урагане-2М многофункциональная неэкранированная двухполувитковая антенна. Отработана возможность работы двухполувитковой антенны в режиме чистки внутренних поверхностей вакуумной камеры в малом магнитном поле Плазма создавалась и поддерживалась с плотностью ne~ (0.2…0.95)·10¹²сm⁻³. При рабочей частоте f₀~5 МГц ВЧ-плазма создавалась в стационарном магнитном поле B₀≈0.01 Tл при давлении водорода 3·10⁻³…3·10⁻² Па

Тяжесть поражения коронарных артерий у больных ишемической болезнью сердца с различными вариантами гена рецептора витамина D и уровнем обеспеченности витамином D

Introduction. Vitamin D deficiency may be an independent predictor of coronary heart disease (CHD) and the severity of coronary atherosclerosis. The results of studies of the association of various polymorphisms of the vitamin D receptor (VDR) gene with the risk and severity of CHD are contradictory, which necessitates the study of genetic variants of the VDR gene and the characteristics of the clinical course of CHD in the Russian population.The objective was to determine the distribution of genotypes of TaqI, BsmI and ApaI of polymorphic variants of the VDR gene and the level of vitamin D sufficiency in CHD patients with varying severity of CHD, residents of St. Petersburg.Methods and materials. The study included 407 CHD patients and 318 patients without clinical signs of CHD of comparable age (p>0.05). All CHD patients underwent coronary angiography. Typing of the VDR gene variants was performed by polymerase chain reaction and subsequent restriction analysis. Determination of the level of 25(OH)D blood serum was carried out by enzyme immunoassay.Results. Vitamin D deficiency was detected in 82 % of CHD patients, the content of 25(OH)D in blood serum was lower in CHD patients who had 2 or more myocardial infarctions (MI) than in those who had one MI (p=0.03). Vitamin D deficiency is associated with a 3.6-fold increased risk of multivessel disease (p=0.01). The presence of the aa genotype and the a allele (ApaI), the bb genotype and the b allele of the VDR gene (BsmI) is associated with an increased risk of CHD and the severity of atherosclerotic lesions of the coronary arteries.Conclusion. Vitamin D deficiency is typical for CHD patients and is associated with the severity of coronary atherosclerosis. The presence of aa genotype and a allele (ApaI polymorphism), bb genotype and b allele of the VDR gene (BsmI polymorphism) is associated with an increased risk of CHD and the severity of atherosclerotic lesions of the coronary arteries. TaqI polymorphism of the VDR gene is not associated with the risk of CHD.Актуальность. Дефицит витамина D может быть независимым предиктором ишемической болезни сердца (ИБС) и тяжести коронарного атеросклероза. Результаты исследований связи различных полиморфизмов гена рецептора витамина D (VDR) с риском и тяжестью ИБС противоречивы, что обуславливает необходимость изучения генетических вариантов гена VDR и особенностей клинического течения ИБС в российской популяции.Введение. Дефицит витамина D может быть независимым предиктором ишемической болезни сердца (ИБС) и тяжести коронарного атеросклероза. Результаты исследований связи различных полиморфизмов гена рецептора витамина D (VDR) с риском и тяжестью ИБС противоречивы, что обуславливает необходимость изучения генетических вариантов гена VDR и особенностей клинического течения ИБС в российской популяции.Цель – определить распределения генотипов TaqI, BsmI и ApaI полиморфных вариантов гена рецептора витамина D и уровня обеспеченности витамином D у больных ИБС с различной тяжестью поражения коронарных артерий, жителей Санкт-Петербурга.Методы и материалы. В исследование включены 407 больных ИБС и 318 обследованных без клинических признаков ИБС, сопоставимого возраста (р>0,05). Всем больным ИБС была выполнена коронарография. Типирование вариантов гена VDR проводили методом полимеразной цепной реакции и последующего рестрикционного анализа. Определение уровня 25(OH)D сыворотки крови проводили иммуноферментным методом.Результаты. У 82 % больных ИБС выявлен дефицит витамина D, содержание 25(ОН)D сыворотки крови было ниже у больных ИБС, перенесших два и более инфаркта миокарда (ИМ), чем у перенесших один ИМ (р=0,03). Дефицит витамина D ассоциируется с повышением риска многососудистого поражения в 3,6 раза (р=0,01). Наличие aa­генотипа и а-аллеля (АраI), bb-генотипa и b-аллеля гена VDR (BsmI) ассоциируется с повышением риска ИБС и с тяжестью атеросклеротического поражения коронарных артерий.Заключение. Дефицит витамина D характерен для больных ИБС и ассоциируется с тяжестью коронарного атеросклероза. Наличие aa-генотипа и а-аллеля (АраI-полиморфизм), bb-генотипa и b-аллеля гена VDR (BsmI-полиморфизм) ассоциируется с повышением риска ИБС и с тяжестью атеросклеротического поражения коронарных артерий. TaqI-полиморфизм гена VDR не ассоциирован с риском ИБС

Efficacy of CAR T-cell Therapy in Large Tumors Relies upon Stromal Targeting by IFN gamma

Adoptive T-cell therapy using chimeric antigen receptor-modified T cells (CAR-T therapy) has shown dramatic efficacy in patients with circulating lymphoma. However, eradication of solid tumors with CAR-T therapy has not been reported yet to be efficacious. In solid tumors, stroma destruction, due to MHC-restricted cross-presentation of tumor antigens to T cells, may be essential. However, CAR-Ts recognize antigens in an MHC-independent manner on cancer cells but not stroma cells. In this report, we show how CAR-Ts can be engineered to eradicate large established tumors with provision of a suitable CD28 costimulatory signal. In an HER2-dependent tumor model, tumor rejection by HER2-specific CAR-Ts was associated with sustained influx and proliferation of the adoptively transferred T cells. Interestingly, tumor rejection did not involve natural killer cells but was associated instead with a marked increase in the level of M1 macrophages and a requirement for IFN gamma receptor expression on tumor stroma cells. Our results argue that CAR-T therapy is capable of eradicating solid tumors through a combination of antigen-independent stroma destruction and antigen-specific tumor cell targeting. (C) 2014 AACR

Operation and upgrade of diagnostic neutral beam injector RUDI at TEXTOR tokamak

The status and the executing modernization of RUssian Diagnostic Injector (RUDI) are described. The ion source consists of arc plasma emitter and multiaperture four-electrode ion optical system. The present ion optical system with round beamlets is to be replaced by new slit apertures system for the reducing beam angular divergence in one direction. Due to enlarged dimensions and transparency of new ion optical system the extracted ion beam current will be by 50% increased. For the extension of beam pulse duration from 4 s to 8-10 s an optimized metal-ceramic arc-discharge channel is introduced. In the paper, the optical measurements results of beam parameters, including the profile of species distribution, scanned by custom-built multichannel spectroscope, are also presented

Holocene fire and occupation in Amazonia: records from two lake districts

While large-scale pre-Columbian human occupation and ecological disturbance have been demonstrated close to major Amazonian waterways, less is known of sites in terra firme settings. Palaeoecological analyses of two lake districts in central and western Amazonia reveal long histories of occupation and land use. At both locations, human activity was centred on one of the lakes, while the others were either lightly used or unused. These analyses indicate that the scale of human impacts in these terra firme settings is localized and probably strongly influenced by the presence of a permanent open-water body. Evidence is found of forest clearance and cultivation of maize and manioc. These data are directly relevant to the resilience of Amazonian conservation, as they do not support the contention that all of Amazonia is a ‘built landscape’ and therefore a product of past human land use