The differentiation potential of individual clones of fibroblast CFU (CFU-F) was studied and the relative expression level of genes was analyzed in the culture of CFU-F from the bone marrow in ...patients with non-severe and severe forms of aplastic anemia at the onset of the disease. The differentiation potential of CFU-F clones was determined by the relative expression of marker genes using quantitative PCR. In aplastic anemia, the ratio of CFU-F clones with different differentiation potential changes, but the molecular mechanisms of this phenomenon are different in non-severe and severe aplastic anemia. In the culture of CFU-F in non-severe and severe aplastic anemia, the relative expression level of genes associated with the maintenance of the hematopoietic stem cell in the bone marrow niche changes, but the decrease in the expression of immunoregulatory genes occurs in severe form only, which may reflect differences in the pathogenesis of non-severe and severe aplastic anemia.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The properties of bone marrow-derived multipotent mesenchymal stromal cells (MSC) of patients with aplastic anemia at the onset of the disease are studied insufficiently. The aim of this work was to ...test the ability of MSC from patients with aplastic anemia to maintain hematopoietic precursors and to analyze the expression of genes associated with hematopoiesis and immune response. The ability of MSC to maintain hematopoietic precursors was determined by counting cobblestone area-forming cells; gene expression was analyzed by quantitative PCR. It was shown that MSC of patients with aplastic anemia preserve their ability to maintain hematopoietic precursors. Pronounced changes in the expression of the
VEGFA
and
ANGPT1
genes were found. MSC from aplastic anemia patients with PNH clone significantly differ from those from aplastic anemia patients without PNH clone in terms of the expression of the
SDF1
,
IL1R
, and
VEGFA
genes. Changes in gene expression can be associated with the pathogenesis of the disease.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Green fluorescent protein (eGFP) gene was transferred into mouse mesenchymal stem cells
in vivo
using a lentiviral vector. In 2 months after injection of the lentivirus into the cavity of the femoral ...bone, up to 30% fibroblast CFU in the bone marrow of infected mice contained the alien gene. The transferred gene was found in more than 50% of adherent layers of longterm bone marrow cultures formed by mesenchymal stem cells from the infected mice bone marrow; 4% fibroblast CFU obtained from these layers were labeled. Ectopic hemopoiesis foci developed after transplantation of the bone marrow from infected mice under the renal capsule of syngeneic recipients contained bone tissue labeled with the alien gene in 57% cases and labeled fibroblast CFU in 11%. The data confirm the possibility of gene transfer with the lentiviral vectors into the mesenchymal stem cells
in vivo
.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Murine mesenchymal stem cells in long-term bone marrow culture were genetically labeled using lentiviral vector carrying enhanced green fluorescent protein (eGFP) reporter gene under SFFV promoter or ...without it. We studied the developmental fate of labeled mesenchymal stem cells in stromal cell layers of long-term bone marrow culture and in ectopic hemopoietic foci formed by these stromal layers under the renal capsule of syngeneic mice. The frequency of labeled polypotent stromal precursors (fibroblast CFU) was analyzed in adherent cell layers of long-term culture and ectopic foci formed from them. The proportion of labeled fibroblast CFU in ectopic foci increased by 10 times in case of implantation of adherent cell layers infected with lentivirus containing eGFP reporter gene without promoter. eGFP expression leads to rejection of labeled stromal cells. Labeling with eGFP-carrying vector without promoter makes possible long-term tracking of mesenchymal stromal cells.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
We studied the effect of natural glucocorticosteroid hydrocortisone on total cell production, cloning efficiency, and expression of genes important for the function of mesenchymal stromal cells. ...Addition of hydrocortisone to the culture medium reduces the total cell yield by 2 times and significantly increased cloning efficiency by 2–3 times; this effect was more pronounced in multipotent mesenchymal stromal cells obtained from female donors. Hydrocortisone had no effect on the expression of immunomodulatory factors produced by multipotent mesenchymal stromal cells. Hydrocortisone inhibits the expression of bone differentiation markers, increases the expression of the early adipocyte differentiation marker at the beginning of culturing, and dramatically stimulates the expression of the late adipocyte differentiation marker throughout the culturing period. The findings suggest that hydrocortisone activates multipotent mesenchymal stromal cells.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
When combined with immunotherapy, image-guided targeted delivery of chemotherapeutic agents is a promising direction for combination cancer theranostics, but this approach has so far produced only ...limited success due to a lack of molecular targets on the cell surface and low therapeutic index of conventional chemotherapy drugs. Here, we demonstrate a synergistic strategy of combination immuno/chemotherapy in conditions of dual regioselective targeting, implying vectoring of two distinct binding sites of a single oncomarker (here, HER2) with theranostic compounds having a different mechanism of action. We use: (i) PLGA nanoformulation, loaded with an imaging diagnostic fluorescent dye (Nile Red) and a chemotherapeutic drug (doxorubicin), and functionalized with affibody ZHER2:342 (8 kDa); (ii) bifunctional genetically engineered DARP-LoPE (42 kDa) immunotoxin comprising of a low-immunogenic modification of therapeutic Pseudomonas exotoxin A (LoPE) and a scaffold targeting protein, DARPin9.29 (14 kDa). According to the proposed strategy, the first chemotherapeutic nanoagent is targeted by the affibody to subdomain III and IV of HER2 with 60-fold specificity compared with nontargeted particles, while the second immunotoxin is effectively targeted by DARPin molecule to subdomain I of HER2. We demonstrate that this dual targeting strategy can enhance anticancer therapy of HER2-positive cells with a very strong synergy, which made possible 1000-fold decrease of effective drug concentration in vitro and a significant enhancement of HER2 cancer therapy compared to monotherapy in vivo. Moreover, this therapeutic combination prevented the appearance of secondary tumor nodes. Thus, the suggested synergistic strategy utilizing dual targeting of the same oncomarker could give rise to efficient methods for aggressive tumors treatment.
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IJS, KILJ, NUK, PNG, UL, UM
Due to the absence of labels and fast analyses, optical biosensors promise major advances in biomedical diagnostics, security, environmental, and food safety applications. However, the sensitivity of ...the most advanced plasmonic biosensor implementations has a fundamental limitation caused by losses in the system and/or geometry of biochips. Here, we report a “scissor effect” in topologically dark metamaterials which is capable of providing ultrahigh-amplitude sensitivity to biosensing events, thus solving the bottleneck sensitivity limitation problem. We explain how the “scissor effect” can be realized via the proper design of topologically dark metamaterials and describe strategies for their fabrication. To validate the applicability of this effect in biosensing, we demonstrate the detection of folic acid (vitamin important for human health) in a wide 3-log linear dynamic range with a limit of detection of 0.22 nM, which is orders of magnitude better than those previously reported for all optical counterparts. Our work provides possibilities for designing and realizing plasmonic, semiconductor, and dielectric metamaterials with ultrasensitivity to binding events.
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IJS, KILJ, NUK, PNG, UL, UM
Developing combined cancer therapy strategies is of utmost importance as it can enhance treatment efficacy, overcome drug resistance, and ultimately improve patient outcomes by targeting multiple ...pathways and mechanisms involved in cancer growth and progression. Specifically, the potential of developing a combination chemo&photothermal therapy using targeted polymer nanoparticles as nanocarriers offers a promising approach for synergistic cancer treatment by combining the benefits of both therapies, such as targeted drug delivery and localized hyperthermia. Here, we report the first targeted anti-HER2 PLGA nanocarriers, called targosomes, that simultaneously possess photothermal, chemotherapeutic and diagnostic properties using only molecular payloads. Biocompatible poly(lactic-co-glycolic acid), PLGA, nanoparticles were loaded with photosensitizer phthalocyanine, diagnostic dye Nile Blue, and chemotherapeutic drug irinotecan, which was chosen as a result of screening a panel of theragnostic nanoparticles. The targeted delivery to cell surface oncomarker HER2 was ensured by nanoparticle modification with the anti-HER2 monoclonal antibody, trastuzumab, using the one-pot synthesis method without chemical conjugation. The irradiation tests revealed prominent photothermal properties of nanoparticles, namely heating by 35 °C in 10 min. Nanoparticles exhibited a 7-fold increase in binding and nearly an 18-fold increase in cytotoxicity for HER2-overexpressing cells compared to cells lacking HER2 expression. This enhancement of cytotoxicity was further amplified by >20-fold under NIR light irradiation. In vivo studies proved the efficacy of nanoparticles for bioimaging of primary tumor and metastasis sites and demonstrated 93% tumor growth inhibition, making these nanoparticles excellent candidates for translation into theragnostic applications.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Introduction.
Pulmonary Arterial Thromboembolism (PATE), which is characterised by low prognosis probability and potentially high danger, ranks third in the mortality structure of cardiovascular ...diseases. The primary method for treating PATE is recanalisation of the pulmonary arteries affected by embolism. Although the destruction of thromboemboli with thrombolytic drugs has proven effective, the right ventricular failure progresses faster in a majority of patients with massive pulmonary embolism. The aim of the present study is to evaluate the long-term results of surgical treatment of PATE by balloon angioplasty in combination with thrombolytic therapy in comparison with isolated systemic thrombolysis.
Materials and methods.
The treatment of 80 patients with pulmonary embolism was analysed. Depending on the selected treatment approaches, the patients were divided into 2 groups as follows: group 1 — 39 patients, conducted by the BAP LA, in combination with thrombolysis; group 2 — 41 patients who underwent conservative treatment (thrombolysis and subsequent anticoagulation therapy).
Results.
Despite the small sample and short period of observation, we may note the significantly better results of treatment in group 1 of the study. Positive dynamics of ECG indicators — in particular, pulmonary hypertension, RV KDR, functional class of heart failure NYHA as well as the reduction of right ventricular overload according to the ECG — indicates that the BAP LA method for the surgical treatment of pulmonary embolism, in combination with thrombolytic therapy, is effective and safe.
Conclusions.
Balloon angioplasty of pulmonary arteries in combination with thrombolytic therapy can significantly reduce the degree of pulmonary hypertension (рχ2 = 0.034), as well as helping to normalise the size of the right ventricle (рχ2 < 0.001) and improvement in functional class of heart failure NYHA (рχ2 = 0.026) in patients with pulmonary embolism compared with patients with isolated thrombolytic therapy.
Nanostructured materials and systems find various applications in biomedical fields. Hybrid organo-inorganic nanomaterials are intensively studied in a wide range of areas, from visualization to drug ...delivery or tissue engineering. One of the recent trends in material science is biomimetic approaches toward the synthesis or modification of functional nanosystems. Here, we describe an approach toward multifunctional nanomaterials through the biomimetic polymerization of dopamine derivatives. Magnetite nanoparticles were modified with a combination of dopamine conjugates to give multifunctional magneto-fluorescent nanocomposites in one synthetic step. The obtained material showed excellent biocompatibility at concentrations up to 200 μg/mL and an in vivo biodistribution profile typical for nanosized formulations. The synthesized systems were conjugated with antibodies against HER2 to improve their selectivity toward HER2-positive cancer cells. The produced material can be used for dual magneto-optical in vivo studies or targeted drug delivery. The applied synthetic strategy can be used for the creation of various multifunctional hybrid nanomaterials in mild conditions.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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