Skuteczność terapii ruksolitynibem u pacjentki z mielofibrozą wtórną do czerwienicy prawdziwej

Przedstawiono przypadek 67-letniej kobiety, u której w 2004 roku rozpoznano czerwienicę prawdziwą, w 2011 roku pojawiły się objawy niedokrwistości hemolitycznej, a w 2016 roku stwierdzono transformację do mielofibrozy. W początkowym okresie rozpoznania czerwienicy prawdziwej (PV) pacjentkę leczono hydroksymocznikiem (HU). Od czasu wystąpienia niedokrwistości hemolitycznej, po odstawieniu HU, otrzymała prednizon i azatioprynę. Dzięki temu leczeniu uzyskano stabilne stężenie hemoglobiny (Hb 8–10 g/dl); pacjentka nie wymagała substytucji koncentratu krwinek czerwonych. Po 12 latach od rozpoznania PV, na podstawie badania patomorfologicznego szpiku kostnego, rozpoznano wtórną mielofibrozę (post-PV MF). W kolejnym 2017 roku, dzięki uzyskaniu dostępu do leku, rozpoczęto terapię ruksolitynibem. Terapię prowadzono łącznie z dalszym leczeniem niedokrwistości hemolitycznej (prednizon, azatiopryna). Stosując to skojarzone leczenie, udało się utrzymać stabilne stężenie Hb; ze względu na ograniczenie nasilenia hemolizy możliwe było zmniejszenie dawki prednizonu. W wyniku trwającej 6 miesięcy terapii uzyskano istotną poprawę jakości życia pacjentki, poprawę parametrów morfologii i zmniejszenie wielkości śledziony. Terapia ruksolitynibem jest prowadzona w pełnej dawce. Przypadek ten ukazuje, że ruksolitynib, mimo swej znanej toksyczności hematologicznej, może być lekiem skutecznym i bezpiecznym u pacjentów z wtórną MF i towarzyszącą hemolizą

Analiza efektywności techniki MLPA w inwazyjnej diagnostyce prenatalnej najczęstszych aneuploidii

Cel badania: Ustalenie efektywności metody MLPA (multiplex ligation dependent probe amplification) w prenatalnej diagnostyce najczęściej występujących aneuploidii (chromosomów 21, 18, 13, X oraz Y) oraz porównanie wyników uzyskanych tą metodą z wynikami rutynowych technik prążkowych. Materiał i metoda: Przeprowadzono badanie metodą MLPA z zastosowaniem zestawu sond SALSA MLPA P095 (MRC – Holland) na 195 próbkach DNA wyizolowanego z materiału pochodzącego z inwazyjnych badań prenatalnych wykonanych w Pracowni USG SPSK im. Prof. Orłowskiego od października 2008 r. do lipca 2012 r. u pacjentek o podwyższonym ryzyku aberracji chromosomowych u płodu oraz 5 próbkach materiału po poronieniu indukowanym. Jednocześnie prowadzono hodowle komórkowe i oceniano kariotyp klasyczną metodą cytogenetyczną. Wyniki: Kariotyp oznaczono w 192 badaniach prenatalnych (98,5%; 192/195). W 52 przypadkach (26,8%) stwierdzono nieprawidłowy kariotyp płodu – w większości proste aneuploidie chromosomów 13, 18, 21, X i Y (86,5%, 45/52). Wynik metodą MLPA udało się uzyskać w 180 próbkach DNA z materiału pobranego prenatalnie (92,3 180/195). Bezwzględna czułość i swoistość metody MLPA wyniosła 100%. W dziewięciu próbkach pobranych prenatalnie metodą MLPA nie zidentyfikowano aberracji wykrytych klasyczną metodą prążkową lub FISH. W żadnym z tych przypadków nie było możliwe uzyskanie rzeczywistego wyniku stosowanym zestawem sond. We wszystkich próbkach materiału po poronieniu udało się przeprowadzić reakcję MLPA. Wnioski: MLPA jest skuteczną metodą wykrywania najczęstszych aneuploidii w diagnostyce prenatalnej. Ze względu na małą ilość przeprowadzonych reakcji na materiale po poronieniu, ocena przydatności metody w tych przypadkach wymaga dalszych badań

Dysregulated Expression of Both the Costimulatory CD28 and Inhibitory CTLA-4 Molecules in PB T Cells of Advanced Cervical Cancer Patients Suggests Systemic Immunosuppression Related to Disease Progression

Cervical cancer (CC) occurs more frequently in women who are immunosuppressed, suggesting that both local and systemic immune abnormalities may be involved in the evolution of the disease. Costimulatory CD28 and inhibitory CTLA-4 molecules expressed in T cells play a key role in the balanced immune responses. There has been demonstrated a relation between CD28, CTLA-4, and IFN genes in susceptibility to CC, suggesting their importance in CC development. Therefore, we assessed the pattern of CD28 and CTLA-4 expression in T cells from PB of CC patients with advanced CC (stages III and IV according to FIGO) compared to controls. We also examined the ability of PBMCs to secrete IFN-gamma. We found lower frequencies of freshly isolated and ex vivo stimulated CD4 + CD28+ and CD8 + CD28+ T cells in CC patients than in controls. Loss of CD28 expression was more pronounced in the CD8+ T subset. Markedly increased proportions of CTLA-4+ T cells in CC patients before and after culture compared to controls were also observed. In addition, patients’ T cells exhibited abnormal kinetics of surface CTLA-4 expression, with the peak at 24 h of stimulation, which was in contrast to corresponding normal T cells, revealing maximum CTLA-4 expression at 72 h of stimulation. Of note, markedly higher IFN-gamma concentrations were shown in supernatants of stimulated PBMCs from CC patients. Conclusions: Our report shows the dysregulated CD28 and CTLA-4 expression in PB T cells of CC patients, which may lead to impaired function of these lymphocytes and systemic immunosuppression related to disease progression

The Evaluation of DHPMs as Biotoxic Agents on Pathogen Bacterial Membranes

Herein, we present biological studies on 3,4-dihydropyrimidin-2(1H)-ones (DHPMs) obtained via Biginelli reaction catalyzed by NH4Cl under solvent-free conditions. Until now, DHPMs have not been tested for biological activity against pathogenic E. coli strains. We tested 16 newly synthesized DHPMs as antimicrobial agents on model E. coli strains (K12 and R2–R4). Preliminary cellular studies using MIC and MBC tests and digestion of Fpg after modification of bacterial DNA suggest that these compounds may have greater potential as antibacterial agents than typically used antibiotics, such as ciprofloxacin (ci), bleomycin (b) and cloxacillin (cl). The described compounds are highly specific for pathogenic E. coli strains based on the model strains used and may be engaged in the future as new substitutes for commonly used antibiotics in clinical and nosocomial infections in the pandemic era

Engineering and Performance of Ruthenium Complexes Immobilized on Mesoporous Siliceous Materials as Racemization Catalysts

Dynamic kinetic resolution (DKR) is one of the most attractive routes to enantioselective synthesis, and ruthenium complexes are often applied as racemization catalysts. Two substituted cyclopentadienyl ruthenium complexes were immobilized covalently and non-covalently on mesoporous silica of mesocellular foam (MCF) and Santa Barbara Amorphous (SBA)-15 type functionalized with a 3 carbon spacer and 4-(chloromethyl)-N-amidobenzoate moiety. The catalysts were studied in a model reaction of secondary alcohol racemization. The immobilization decreased catalyst activity, considerably more for SBA-15 than for MCFs, and complete racemization of 1-phenylethanol was achieved within 24 h with the MCF-supported catalyst. The catalyst could be recovered and reused, thus paving the way for further development of the DKR process. The synthesized materials were fully characterized by Fourier-transform infrared spectroscopy analysis, thermogravimetry analysis, inductively cou-pled plasma optical emission spectrometry, and nitrogen adsorption at 77 K

Real-life experience with bortezomib-based regimens in elderly comorbid patients with newly diagnosed multiple myeloma : Polish retrospective multicenter analysis

Bortezomib was the first proteasome inhibitor approved for the therapy of multiple myeloma (MM). Currently, VMP (bortezomib, melphalan, prednisone) is one of the standard regimens recommended as the first‑line therapy for patients with MM ineligible for high‑dose chemotherapy (HDT) with autologous stem‑cell transplantation (auto‑SCT). Participants of clinical trials are highly selected populations; therefore, the aim of this study was to present observations from real practice that might provide important information for practitioners. We retrospectively analyzed the data on the efficacy and safety of bortezomib‑based regimens in 154 patients with newly diagnosed MM ineligible for HDT with auto‑SCT (median age, 73 years; range, 39-89 years) with particular attention to the effect of age, performance status, and concomitant diseases. Patients aged 75 years or older constituted 53.2% of the study cohort. Performance status was impaired in 34.4% of the patients, according to the Eastern Cooperative Oncology Group scale. Comorbidities were reported in 83.8% of the patients (mainly arterial hypertension and atherosclerotic vascular disease). A total of 798 courses of bortezomib‑based regimens (mainly VMP, 86%) were administered. The overall response rate was 81.7%, including 12.7% for complete response and 29.6% for very good partial response. The median progression‑free survival (PFS) and event‑free survival were 17.3 and 7.1 months, respectively. The impaired performance status and age of 75 or older were negative predictors of PFS. The most common severe adverse events were neuropathy (19.4%), infections (19.2%), and neutropenia (14.9%). Bortezomib‑based regimens are effective and well tolerated in the first‑line therapy of elderly patients with MM and comorbidities, with advanced disease, and light chain MM. A more detailed assessment of patients' frailty is needed to increase the efficacy of treatment

Using microdispensing to manufacture a customized cell dish for microbeam irradiation of single, living cells

In this paper is described the preparation of patterned cell dishes to be used in studies of low dose irradiation effects on living cells. Using a droplet microdispenser, an 8 mu m thick polypropylene cell substrate, to which cells do not naturally adhere, was coated in a matrix pattern with the cell adhesive mussel protein Cell-Tak. Cells were shown to adhere and grow on the protein-coated spots, but not on the uncoated parts, providing for guided cell growth. Cultivation of isolated cell colonies provides an opportunity to study how low doses of ionizing radiation affect neighbouring un-irradiated cell colonies. (C) 2009 Elsevier B.V. All rights reserved

New Dinuclear Macrocyclic Copper(II) Complexes as Potentially Fluorescent and Magnetic Materials

Two dinuclear copper(II) complexes with macrocyclic Schiff bases K1 and K2 were prepared by the template reaction of (R)-(+)-1,1′-binaphthalene-2,2′-diamine and 2-hydroxy-5-methyl-1,3-benzenedicarboxaldehyde K1, or 4-tert-butyl-2,6-diformylphenol K2 with copper(II) chloride dihydrate. The compounds were characterized by spectroscopic methods. X-ray crystal structure determination and DFT calculations confirmed their geometry in solution and in the solid phase. Moreover, intermolecular interactions in the crystal structure of K2 were analyzed using 3D Hirshfeld surfaces and the related 2D fingerprint plots. The magnetic study revealed very strong antiferromagnetic CuII-CuII exchange interactions, which were supported by magneto-structural correlation and DFT calculations conducted within a broken symmetry (BS) framework. Complexes K1 and K2 exhibited luminescent properties that may be of great importance in the search for new OLEDs. Both K1 and K2 complexes showed emissions in the range of 392–424 nm in solutions at various polarities. Thin materials of the studied compounds were deposited on Si(111) by the spin-coating method or by thermal vapor deposition and studied by scanning electron microscopy (SEM/EDS), atomic force microscopy (AFM), and fluorescence spectroscopy. The thermally deposited K1 and K2 materials showed high fluorescence intensity in the range of 318–531 nm for K1/Si and 326–472 nm for the K2/Si material, indicating that they could be used in optical devices

Bendamustine-Based Regimens as Salvage Therapy in Refractory/Relapsed Multiple Myeloma Patients: A Retrospective Real-Life Analysis by the Polish Myeloma Group

Multiple myeloma (MM) is an incurable disease and patients become refractory to the treatment in the course of the disease. Bendamustine-based regimens containing steroids and other agents are among the therapeutic options offered to MM patients. Here, we investigated the safety and the efficacy of bendamustine used in patients with refractory/relapsed MM (RRMM). The patients were treated with bendamustine and steroids (n = 52) or bendamustine, steroids and immunomodulatory agents or proteasome inhibitors (n = 53). Response rates, progression-free survival (PFS), overall survival (OS) and frequency of adverse events were compared between both study groups. Most efficacy measurements were better in patients treated with three-drug regimens: overall response rate (55% versus 37%, p = 0.062), median PFS (9 months versus 4 months, p p = 0.679). The benefit from combining bendamustine and steroids with an additional agent was found in subgroups previously treated with both lenalidmide and bortezomib, with stem cell transplant and with more than two previous therapy lines. Toxicity was similar in both study groups and bendamustine-based therapies were generally well-tolerated. Our study suggests that bendamustine may be an effective treatment for patients with RRMM. Three-drug regimens containing bendamustine, steroids and novel agents produced better outcomes and had acceptable toxicity. The efficacy of bendamustine combined with steroids was limited