Mechanisms of action of immunomodulatory drugs in plasma cell myeloma

Szpiczak plazmocytowy jest chorobą przebiegającą wieloetapowo, która cechuje się rozrostem monoklonalnych plazmocytów. Ostatnie dekady okazały się przełomowe w leczeniu szpiczaka pod względem stosowania nowych leków i schematów terapeutycznych istotnie wydłużających przeżycie chorych na tę nieuleczalną chorobę. Pierwszym lekiem z grupy leków immunomodulujących wykazującym skuteczność w leczeniu pacjentów ze szpiczakiem był talidomid. Identyfikacja jego działań immunomodulujących, przeciwzapalnych i antyangiogennych zaowocowała opracowaniem analogów o zwiększonej aktywności i mniejszej toksyczności, co doprowadziło do wprowadzenia lenalidomidu do praktyki klinicznej. Lenalidomid okazał się lekiem immunomodulującym, zdolnym do regulacji zarówno humoralnej, jak i komórkowej odpowiedzi układu immunologicznego poprzez zmianę produkcji cytokin, regulację kostymulacji limfocytów T i zwiększania cytotoksyczności komórek NK. Wykazuje również istotne właściwości antyangiogenne. Wyniki ostatnich badań wykazały, że kolejny lek immunomodulujący — pomalidomid — cechuje się silną aktywnością przeciwszpiczakową in vitro i in vivo, działając bezpośrednio na komórki szpiczaka i na komórki mikrośrodowiska szpiku kostnego. Przytoczone dane z literatury wskazują na wysoką skuteczność talidomidu, lenalidomidu i pomalidomidu w leczeniu szpiczaka plazmocytowego. Hematologia 2011; 2, 2: 105–115Plasma cell myeloma is a multi-stage disease that is characterized by monoclonal proliferation of plasma cells. The last decades brought a major breakthrough in the treatment of multiple myeloma, concerning the new medicine and the therapeutic schema which vitally lengthen the lifespan of patients suffering from this incurable disease. Thalidomide has been the first within the group of the immunomodulatory drugs which proved its efficacy in the treatment of patients with myeloma. Identification of its immunomodulatory, anti-inflammatory and antiangiogenic activity resulted in the development of analogues of enhanced activity and lesser toxicity which caused the rapid introduction of lenalidomide into clinical practice. Lenalidomide has turned out to be an immunomodulatory agent able to regulate both the cellular and humoral immune responses by altering cytokine production, it regulates T cell costimulation and augments the NK cell cytotoxicity. It also shows to have anti-angiogenic properties. The latest studies have demonstrated that another immunomodulatory drug — pomalidomide — has a potent anti-myeloma activity in vitro and in vivo, acting both directly on myeloma cells and on the cells in the bone marrow microenvironment. The aforementioned data of the literature suggest high efficacy of thalidomide, lenalidomide and pomalidomide in the treatment of myeloma. Hematologia 2011; 2, 2: 105–11

Under the eye of the spectator and the voyeur

Les contributions réunies dans le présent volume se proposent d’interroger les modalités de visibilité les plus diverses. Elles reflètent également la variété des directions dans lesquelles sont poursuivies les recherches en littérature, arts visuels (film, peinture) ou en linguistique. Les reportages, la presse aussi bien que le roman et la poésie manipulent l’image, régissent la matière par le regard et, en fonction des résultats, exercent un pouvoir sur le public. Le potentiel performatif de celui ou celle qui regarde et qui témoigne de ce qu’il/elle a vu, observé, scruté – se manifeste dans les textes de culture des pays et des époques divers

Development of the natural working fluid‐based refrigeration system for domestic scale freeze‐dryer

In this work, the analysis of the refrigeration system designed for the FrostX 10 freeze‐dryer is presented. The main goal of this study was to experimentally investigate the reference R452a freeze‐dryer and prepare recommendations for a machine based on the R290 refrigeration unit. In order to guarantee the temperature requirements and efficient operation of that unit, the analysis of suitable natural refrigerants was performed. Consequently, propane (R290) was selected. In addition, a number of modifications were introduced for the prototype system. System analysis showed that the replacement of the refrigerant in the existing system improves the system energy efficiency by approximately 18%. During the experimental campaign of the basic refrigeration unit, an unstable operation of the evaporator was found. The concept of a new cooling system for a prototype device was presented. The configuration and type of heat exchanger to maximise the performance of the ice trap of the freeze‐dryer were proposed.Development of the natural working fluid‐based refrigeration system for domestic scale freeze‐dryeracceptedVersio

Programmed Death-1 and Its Ligand Are Novel Immunotolerant Molecules Expressed on Leukemic B Cells in Chronic Lymphocytic Leukemia

Programmed death-1 (PD-1) is an immunoreceptor predominantly expressed on exhausted T cells, which through an interaction with its ligand (PD-L1), controls peripheral tolerance by limiting effector functions of T lymphocytes. qRT-PCR for PD-1, PD-L1 and their splicing forms as well as flow cytometric assessment of surface expression was performed in a cohort of 58 chronic lymphocytic leukemia (CLL) patients. In functional studies, we assessed the influence of the proliferative response of leukemic B-cells induced by IL-4 and CD40L on PD-1 transcripts and expression on the protein level. The median level of PD-1, but not PD-L1, transcripts in CLL patients was higher in comparison to healthy volunteers (HVs, n = 43, p = 0.0057). We confirmed the presence of PD-1 and PD-L1 on the CLL cell surface, and found the expression of PD-1, but not PD-L1, to be higher among CLL patients in comparison to HVs (47.2% vs. 14.8%, p<0.0001). The Kaplan-Meier curves for the time to progression and overall survival in groups with high and low surface expression of PD-1 and PD-L1 revealed no prognostic value in CLL patients. After stimulation with IL-4 and CD40L, protein expression of PD-1 was significantly increased in samples that responded and up-regulated CD38. PD-1, which is aberrantly expressed both at mRNA and cell surface levels in CLL cells might represent a novel immunotolerant molecule involved in the pathomechanism of the disease, and could provide a novel target for future therapies

Badger <i>Meles meles</i> as Ecosystem Engineer and Its Legal Status in Europe

The European badger plays an important role as a natural factor shaping species diversity in forests. Its extensive setts can be used by many other animals as shelters. Soil perturbations in their setts support plant communities that differ from the matrix landscape. The badger is also an effective seed disperser. We investigated its role as an ecosystem engineer in preserving species diversity and discussed its legal status across Europe. In most European countries (69.3% of the continent), the badger is hunted, sometimes year-round. The hunting season lasting through winter until early spring may have a negative effect on badger populations, especially when cubs are born in February. Although this species is Red Listed in 19 European countries (with categories ranging from LC to EN), the badger is strictly protected by law in 30.7% of its European range. A reduction in badger populations may limit its ecosystem services (seed dispersal, topsoil disturbances, microhabitat creation). Much new data on the importance of badgers in ecosystem engineering has allowed us to reconsider how we manage badger populations

Badger Meles meles as Ecosystem Engineer and Its Legal Status in Europe

The European badger plays an important role as a natural factor shaping species diversity in forests. Its extensive setts can be used by many other animals as shelters. Soil perturbations in their setts support plant communities that differ from the matrix landscape. The badger is also an effective seed disperser. We investigated its role as an ecosystem engineer in preserving species diversity and discussed its legal status across Europe. In most European countries (69.3% of the continent), the badger is hunted, sometimes year-round. The hunting season lasting through winter until early spring may have a negative effect on badger populations, especially when cubs are born in February. Although this species is Red Listed in 19 European countries (with categories ranging from LC to EN), the badger is strictly protected by law in 30.7% of its European range. A reduction in badger populations may limit its ecosystem services (seed dispersal, topsoil disturbances, microhabitat creation). Much new data on the importance of badgers in ecosystem engineering has allowed us to reconsider how we manage badger populations

Bibliography of Polish Dialectology (from 1986 to 1995, including additions for previous years)

Monografia pt. Bibliografia dialektologii polskiej (od roku 1986 do 1995 włącznie wraz z uzupełnieniami za lata poprzednie), pod redakcją Agaty Kwaśnickiej-Janowicz, Anny Piechnik, Janusza Strutyńskiego to cenne poznawczo i metodologicznie studium leksykograficzne i leksykologiczne, ujmujące zgromadzony materiał badawczy w sposób wyważony i zgodny z najnowszymi ustaleniami metodologicznymi. […] Nieocenioną zaletą pracy jest bogactwo materiału, obejmującego 6447 numerowanych pozycji hasłowych, ułożonych według ściśle określonych zasad merytorycznych i wydawniczych, z podziałem na 11 działów tematycznych. Są to: 1. Bibliografie. 2. Generalia. 3. Materiały. 4. Słownictwo i frazeologia. 5. Fonetyka i fonologia. 6. Fleksja. 7. Słowotwórstwo. 8. Składnia. 9. Stosunek dialektów do innych systemów językowych. 10. Dialektologia historyczna. 11. Recenzje wydawnictw ciągłych i opracowań zbiorowych. Całość wpisuje się w sprawdzoną strukturę metodologiczną (zgodnie z zasadami wydanych już trzech tomów Bibliografii dialektologii polskiej) i stanowi cenne dopełnienie danych dialektologicznych, usystematyzowanych naukowo i konceptualizacyjnie. […] Układ jest spójny kompozycyjnie i kompletny pod względem jakościowym i ilościowym, a opracowanie ma walor użyteczności społecznej i praktycznej parametryzacji zasobów materiałowych o wyjątkowej ważności naukowej i przydatności dla szerokiego kręgu uczonych, a także osób spoza kręgu nauki, zainteresowanych dziedzictwem językowym i kulturowym. [Jest] to opracowanie wyjątkowe w polskiej strukturze naukowej, społecznie użyteczne i bardzo potrzebne. Publikacja od kilku lat była oczekiwana i zainteresuje spore grono językoznawców, studentów filologii polskiej i innych nauk humanistycznych, nauczycieli języka polskiego i dziedzictwa kulturowego oraz pracowników regionalnych jednostek kultury. Jest to wydawnictwo niepowtarzalne i jedyne na polskim rynku wydawniczym, a fakt jego opublikowania w wersji elektronicznej bazy danych jest dodatkowym atutem, który z pewnością powiększy krąg zainteresowanych.The monograph Bibliography of Polish Dialectology (from 1986 to 1995, including additions for previous years) edited by Agata Kwaśnicka-Janowicz, Anna Piechnik and Janusz Strutyński is a cognitively and methodologically valuable lexicographical and lexicological study which presents the collected research material in a balanced manner and in accordance with the latest methodological findings. [...] An invaluable advantage of the work is the wealth of material, which includes 6447 numbered entries, arranged according to strictly defined substantive and publishing rules, divided into 11 thematic sections. These are: 1. Bibliographies. 2. Generalia. 3. Materials. 4. Vocabulary and phraseology 5. Phonetics and phonology. 6. Inflection. 7. Word Formation 8. Syntax. 9. The relation of dialects to other language systems. 10. Historical dialectology. 11. Reviews of serial and collective publications. The book as a whole follows a proven methodological structure (in accordance with the principles of the already published three volumes of Bibliografia dialektologii polskiej) and constitutes a valuable complement to dialectological data, which are scientifically systematized and conceptualized. [...] The layout is coherent in terms of composition and complete in terms of quality and quantity, and the study has the value of social utility and practical parameterization of material resources of exceptional scientific validity and usefulness to a wide circle of scholars, as well as non-scientists interested in the linguistic and cultural heritage. It is a truly unique study in the Polish scientific structure, socially useful and much needed. The publication has been expected for several years and will be of interest to a large group of linguists, students of Polish philology and other humanities, teachers of Polish language and cultural heritage, and employees of regional cultural units. It is a unique, one of its kind publication on the Polish publishing market, and the fact that it is published in the electronic version of the database is an additional advantage which will certainly extend the circle of interested parties

PD-1 expression after CLL cells stimulation with CD40L and IL-4.

<p>Figure displays analysis of PD-1 expression on both transcript and protein levels on CLL cells after stimulation with CD40L and IL-4. (A) PD-1 mRNA expression level in stimulated cells and non-stimulated control (0.22 vs. 0.24, p = 0.54). (B) PD-1 MFI in stimulated and non-stimulated cells (82.22 vs. 69.34, p = 0.48). (C) Difference of PD-1 mRNA expression levels between stimulated cells and non-stimulated control assessed using qRT-PCR (2^−ΔΔCt) and correlated with CD38 MFI, with samples segregated into up-regulation or down-regulation of CD38 upon stimulation (0.637 vs. 0.326; p = 0.34). (D) Change of PD-1 MFI between stimulated and non-stimulated cells, with patients segregated as in (C) (6.240 vs. −6.670, p = 0.0093).</p

Primer sequences.

<p>F, forward; R, reverse; fl_PD-1, full length PD-1; Δex2_PD-1, PD-1 lacking exon 2; Δex3_PD-1; PD-1 lacking exon 3; Δex2,3_PD-1, PD-1 lacking exons 2 and 3; Δex2,3,4_PD-1, PD-1 lacking exons 2, 3 and 4; fl_PD-L1, full length PD-L1; Δex2_PD-L1, PD-L1 lacking exon 2.</p

Surface expression of PD-1 and PD-L1 on cells from CLL patients and HVs.

<p>Figure displays a flow cytometric analysis of PD-1 and PD-L1 expression on CLL cells and normal B cells. (A) Median PD-1 expression of PD-1 on CD5⁺CD19⁺ CLL cells and control B cells of healthy volunteers (HVs) (47.2% vs. 14.81%, p<0.0001). (B) The mean fluorescence intensity MFI of PD-1 on CD5⁺CD19⁺ CLL cells and control B cells of HVs (12.49 vs. 8.59, respectively, p = 0.078). (C) Median PD-L1 expression on CD5⁺CD19⁺ CLL cells and control B cells of HVs (median: 52.52%, range 10.8%–97.3%, p = 0.22). (D) PD-L1 MFI of CD5⁺CD19⁺ CLL cells and control B cells of HVs (9.96 vs. 7.93, p = 0.017). (E) Correlation of MFI of PD-1 positive CLL cells with PD-L1 positive CLL cells (r² = 0.34, p<0.05). MFI of PD-1 and PD-L1 on CD5⁺CD19⁺ leukemic cells and on CD19⁺ control B cells was defined by flow cytometric analysis (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0035178#pone.0035178.s002" target="_blank">Figure S2</a>).</p