Regulatory T Cells Restrain Interleukin-2- and Blimp-1-Dependent Acquisition of Cytotoxic Function by CD4⁺ T Cells

In addition to helper and regulatory potential, CD4+ T cells also acquire cytotoxic activity marked by granzyme B (GzmB) expression and the ability to promote rejection of established tumors. Here, we examined the molecular and cellular mechanisms underpinning the differentiation of cytotoxic CD4+ T cells following immunotherapy. CD4+ transfer into lymphodepleted animals or regulatory T (Treg) cell depletion promoted GzmB expression by tumor-infiltrating CD4+, and this was prevented by interleukin-2 (IL-2) neutralization. Transcriptional analysis revealed a polyfunctional helper and cytotoxic phenotype characterized by the expression of the transcription factors T-bet and Blimp-1. While T-bet ablation restricted interferon-γ (IFN-γ) production, loss of Blimp-1 prevented GzmB expression in response to IL-2, suggesting two independent programs required for polyfunctionality of tumor-reactive CD4+ T cells. Our findings underscore the role of Treg cells, IL-2, and Blimp-1 in controlling the differentiation of cytotoxic CD4+ T cells and offer a pathway to enhancement of anti-tumor activity through their manipulation

CD25-Treg-depleting antibodies preserving IL-2 signaling on effector T cells enhance effector activation and antitumor immunity.

Intratumoral regulatory T cell (Treg) abundance associates with diminished anti-tumor immunity and poor prognosis in human cancers. Recent work demonstrates that CD25, the high affinity receptor subunit for IL-2, is a selective target for Treg depletion in mouse and human malignancies; however, anti-human CD25 antibodies have failed to deliver clinical responses against solid tumors due to bystander IL-2 receptor signaling blockade on effector T cells, which limits their anti-tumor activity. Here we demonstrate potent single-agent activity of anti-CD25 antibodies optimized to deplete Tregs whilst preserving IL-2-STAT5 signaling on effector T cells, and demonstrate synergy with immune checkpoint blockade in vivo. Pre-clinical evaluation of an anti-human CD25 (RG6292) antibody with equivalent features demonstrates, in both non-human primates and humanized mouse models, efficient Treg depletion with no overt immune-related toxicities. Our data supports the clinical development of RG6292 and evaluation of novel combination therapies incorporating non-IL-2 blocking anti-CD25 antibodies in clinical studies

Numerical simulations of deep drawing for control of product qualiy

: Już w fazie projektowania procesów głębokiego tłoczenia blach dąży się do eliminacji lub przynajmniej minimalizacji przewidywanych niedokładności kształtu i wymiarów produktu, spowodowanych wieloma różnymi warunkami samego procesu jak i własnościami odkształcanego materiału. Wyróżnić można wiele czynników opisujących końcową jakość produktu (zjawisko nawrotu sprężystego, utrata spójności materiału, czy fałdowanie powierzchni. W artykule przedstawiono szeregu wad wytłoczek, które mogą być opisane poprzez odpowiednie wskaźniki ilościowe i jakościowe. W przeciwieństwie do tradycyjnych metod laboratoryjnych wykorzystywanych do poprawy jakości wytłoczek popularnym narzędziem i mniej kosztownym narzędziem stają się symulacje numeryczne połączone z automatycznymi metodami optymalizacji. W pracy przedstawiono dwa pakiety oparte o Metodę Elementów Skończonych (MES): ABAQUS/Explicit i Eta/Dynaform 5.2, oraz dokonano porównania wyników symulacji przykładowego procesu tłoczenia prostokątnej puszki stalowej, uzyskanych z tych programów. Przedstawiono również analizę wyników symulacji numerycznych pod kątem oceny jakości wytłoczki poprzez zdefiniowanie odpowiednich wskaźników oraz możliwości zastosowania procedur automatycznej optymalizacji w celu jej poprawy. Dokonano oceny dokładności obliczeń w porównaniu z wynikami eksperymentalnymi. Ponadto przedstawiono wrażliwość zjawiska odsprężynowania powrotnego na zastosowanie dodatkowych sił oporowych działających na kołnierz wytłoczki podczas procesu, oraz zastosowanie metody odwrotnej do wyznaczenia wartości tych sił w celu zminimalizowania wielkości nawrotu sprężystego.There are many important factors (springback, thinning/thickening, wrinkling) which determine the quality of deep drawing processes products. Inaccuracies of shape and dimensions of products, which are caused by various process conditions, should be minimized or even eliminated. However, it is a difficult task, which can be solved by different methods. The proper drawing dies design, which is the most important part of the process design, is preceded by series of physical or numerical tests. Thus, accurate numerical models for such parameters as friction, stress and strain state in the material, strain hardening, etc. are needed. Development of models is based on plastometric tests and the inverse anlalysis for their interpretation. Dedicated finite element software equipped with quality factors evaluation and control is used for simulations of drawing processes. In this work, two FEM based programs, ABAQUS/Explicit and the Eta/Dynaform 5.2, are presented and compared using deep drawing of the 3D part as an example. The analysis of results of numerical simulation is presented in the paper. The accuracy of calculations and specific quality factors are evaluated. Beyond this, the sensitivity of springback to changes of forces causing flow resistance of the sheet, as well as application of the inverse method to evaluate these forces for minimal values of springback deformation, is presented

Metoda I-SCAN w ocenie nacisku wywieranego przez wyroby włókiennicze

The capabilities of the I-SCAN (TekScan) system for pressure measurements were tested in in vivo and in vitro condition using hosiery articles at a pressure of 18-21mmHg, as declared by the manufacturers. For two types of knee-length socks with the same structure and slight difference in composition (polyamide/elastomer 78/22% and 64/36%) the pressure was measured on the ankle and calf in four positions (1-front, 2-inner side, 3-back, 4-outer side). The highest pressure values were found for the 1-front position and the lowest for the 2-inner side position. It was shown that there is a correlation between the in vivo and in vitro tests. The I-SCAN method allows to take measurements in various place and to create maps of the pressure distribution.Nacisk wyrobów włókienniczych może powodować niepożądany wpływ na użytkownika lub działać profilaktycznie. W obu przypadkach ocena nacisku wymaga odpowiednich metod dostosowanych do przeznaczenia wyrobu. Badano możliwości systemu I-SCAN (TekScan) w warunkach in vivo i in vitro, na przykładzie wyrobów pończoszniczych należących do pierwszej klasy nacisku 18-21mmHg. W przeciwieństwie do powszechnie stosowanych metod, metoda I-SCAN bazująca na elastycznych matach pomiarowych umożliwia pomiar w dowolnym miejscu i tworzenie map nacisku. Dla dwóch rodzajów podkolanówek o zbliżonym składzie (poliamid/elastomer 78/22% i poliamid/elastomer 64/36%), i takiej samej strukturze zmierzono nacisk na wysokości kostki i łydki w czterech pozycjach (1–przód, 2-strona wewnętrzna, 3–tył, 4–strona zewnętrzna). Największy nacisk na kostce i łydce występował w pozycji 1-przód, a najmniejszy w pozycji 2-strona wewnętrzna. Wykazano, że dla metody I-SCAN istnieje korelacja między badaniami in vivo i in vitro

Escherichia coli bacteraemias in intensive care unit patients

BACKGROUND: Although bacterial infections are common in critically ill patients, isolation of bacteria from the sample is not always unambiguous. The authors addressed Escherichia coli bacteraemia in patients treated in the Intensive Care Unit in the Teaching Hospital in Gdansk in 2002−2009. METHODS: Using a computer database, the names of Escherichia coli positive patients and dates of blood sampling were found, followed by a retrospective assessment whether positive blood cultures were accompanied by the clinical features of sepsis or asymptomatic bacteraemia. RESULTS: Positive cultures were found in 40 blood samples (36 patients). Bacteraemia was diagnosed in 11, sepsis in 10, severe sepsis in 6 and septic shock in 13 cases. In the bacteraemia group, the condition originated from the gastrointestinal tract — 4 cases; from the lungs — 1; while in 6 cases, the aetiology was not detected. In patients with an infection, the likely source was the gastrointestinal tract — 12 cases; the lungs — 4; and pyothorax — 2. In 11 cases, the aetiology remained unidentified. In 3 patients in the bacteraemia group, cultures of other microorganisms were found to be positive, while there were 4 cases among the septic patients. In the bacteraemia group, 8 patients died in the intensive care unit, without relation to bacteraemia. Amongst septic patients 17 died, including 12 whose death was probably attributable to Escherichia coli infection. CONCLUSIONS: Escherichia coli bacteraemias and infections have been and will remain an everyday problem in hospital wards. The differentiation of asymptomatic bacteraemia from infection is essential for rational antibiotic therapy, which is particularly important considering the increasing resistance of microorganisms.  BACKGROUND: Although bacterial infections are common in critically ill patients, isolation of bacteria from the sample is not always unambiguous. The authors addressed Escherichia coli bacteraemia in patients treated in the Intensive Care Unit in the Teaching Hospital in Gdansk in 2002−2009. METHODS: Using a computer database, the names of Escherichia coli positive patients and dates of blood sampling were found, followed by a retrospective assessment whether positive blood cultures were accompanied by the clinical features of sepsis or asymptomatic bacteraemia. RESULTS: Positive cultures were found in 40 blood samples (36 patients). Bacteraemia was diagnosed in 11, sepsis in 10, severe sepsis in 6 and septic shock in 13 cases. In the bacteraemia group, the condition originated from the gastrointestinal tract — 4 cases; from the lungs — 1; while in 6 cases, the aetiology was not detected. In patients with an infection, the likely source was the gastrointestinal tract — 12 cases; the lungs — 4; and pyothorax — 2. In 11 cases, the aetiology remained unidentified. In 3 patients in the bacteraemia group, cultures of other microorganisms were found to be positive, while there were 4 cases among the septic patients. In the bacteraemia group, 8 patients died in the intensive care unit, without relation to bacteraemia. Amongst septic patients 17 died, including 12 whose death was probably attributable to Escherichia coli infection. CONCLUSIONS: Escherichia coli bacteraemias and infections have been and will remain an everyday problem in hospital wards. The differentiation of asymptomatic bacteraemia from infection is essential for rational antibiotic therapy, which is particularly important considering the increasing resistance of microorganisms.