OBJECTIVES: This study aims to identify factors possibly contributing to complications in children with acute leukaemia. Despite diverse etiological causes, similar processes trigger the process of cell malignancy. Genomic instability has received considerable attention in this context. METHOD: We conducted chromosomal analysis of bone marrow cells and measured the micronuclei (Mn) level in buccal cells over time. Statistical reliability assessment was performed using Analysis of variance (ANOVA), and the data were analyzed and visualized using the SPSS 12 statistical analysis software package. RESULTS: On the 15th day of treatment, our findings confirmed a statistically significant correlation (χ2=3.88, P=0.04) between the number of blasts in the bone marrow and unfavourable outcome in patients with a near-tetraploid chromosome clone. Additionally, on the 33rd day of treatment, we observed a correlation between an elevated number of Mn and relapses. DISCUSSION: While it is commonly believed that a hyperdiploid clone with >50 chromosomes in childhood acute lymphoblastic leukaemia confers favorable outcome, our study revealed partially heterogeneous results and poor prognosis in patients with a near-tetraploid clone. We have also identified a correlation between the Mn level on the 33rd day of treatment and the development of complications. It is possible that the increased Mn values and the occurrence of relapses were influenced by the individual patient's sensitivity to the genotoxic effect of the medication.

• MeSH
• akutní lymfatická leukemie * genetika   MeSH
• buňky kostní dřeně patologie   MeSH
• dítě MeSH
• lidé MeSH
• mikrojaderné testy MeSH
• mikrojádra chromozomálně defektní * MeSH
• mladiství MeSH
• předškolní dítě MeSH
• prognóza MeSH
• tetraploidie MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Hematopoietic stem cell transplantation (HSCT) is a life-saving procedure to treat hematopoietic disorders. Current bone marrow conditioning protocols create space for healthy donor stem cells by employing irradiation and/or chemotherapy, but carry severe toxicities, resulting in significant morbidity, mortality and substantial long-term complications. To develop a low-toxicity solution, we generated a bi-specific T-cell engager (BTCE) that targets CD117, an abundantly expressed receptor on hematopoietic stem and progenitor cells (HSPC) and leukemia-initiating cells (LICs). We show that the CD117×CD3 BTCE efficiently depletes in vitro and in vivo HSPCs and LICs. The CD117×CD3 BTCE was not toxic and facilitates highly efficient engraftment of human allogenic donor CD34+cells in humanized mice, thereby restoring hematopoiesis in vivo in both normal and leukemia-bearing humanized mice. We demonstrate here that a potent CD117×CD3 BTCE enables rapid HSCT in both benign and malignant conditions.

• MeSH
• hematopoetické kmenové buňky imunologie   metabolismus   MeSH
• imunoterapie * metody   MeSH
• leukemie * terapie   imunologie   MeSH
• lidé MeSH
• myši MeSH
• příprava pacienta k transplantaci * metody   MeSH
• protoonkogenní proteiny c-kit imunologie   metabolismus   MeSH
• transplantace hematopoetických kmenových buněk * metody   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease often associated with underlying inflammatory bowel disease (IBD). This study investigates how PSC predisposes individuals to altered inflammatory immune responses compared with IBD alone. A case-control study was conducted with a cohort of 75 patients, including 16 with PSC (14 with concomitant IBD), 39 with IBD alone, and 20 controls. Serum bile acid profile, proteomic analysis, and immune-related gene expression in the colon tissue were examined. Colonic tissue from PSC patients exhibited up-regulation of immune regulation and inflammatory signaling mRNA markers, including LGR5, IL-8, CCL2, COX2, TWIST1, and SNAIL. Additionally, PSC patients displayed a distinct proinflammatory serum proteomic signature and moderate elevation of some bile acids, such as glycochenodeoxycholic acid (GCDCA). Co-incubation of human-derived monocytes with GCDCA partially replicated the inflammatory profile observed in PSC. These findings suggest that circulating bile acids modulate the peripheral immune system proinflammatory response, contributing to the unique PSC phenotype.

• MeSH
• dospělí MeSH
• idiopatické střevní záněty * imunologie   komplikace   krev   genetika   MeSH
• kolon metabolismus   imunologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• monocyty imunologie   metabolismus   MeSH
• proteomika metody   MeSH
• sklerozující cholangitida * imunologie   krev   komplikace   genetika   MeSH
• studie případů a kontrol MeSH
• žlučové kyseliny a soli * krev   imunologie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

INTRODUCTION: The immunosuppressive roles of galectin-3 (Gal-3) in carcinogenesis make this lectin an attractive target for pharmacological inhibition in immunotherapy. Although current clinical immunotherapies appear promising in the treatment of solid tumors, their efficacy is significantly weakened by the hostile immunosuppressive tumor microenvironment (TME). Gal-3, a prominent TME modulator, efficiently subverts the elimination of cancer, either directly by inducing apoptosis of immune cells or indirectly by binding essential effector molecules, such as interferon-gamma (IFNγ). METHODS: N-(2-Hydroxypropyl)methacrylamide (HPMA)-based glycopolymers bearing poly-N-acetyllactosamine-derived tetrasaccharide ligands of Gal-3 were designed, synthesized, and characterized using high-performance liquid chromatography, dynamic light scattering, UV-Vis spectrophotometry, gel permeation chromatography, nuclear magnetic resonance, high-resolution mass spectrometry and CCK-8 assay for evaluation of glycopolymer non-toxicity. Pro-immunogenic effects of purified glycopolymers were tested by apoptotic assay using flow cytometry, competitive ELISA, and in vitro cell-free INFγ-based assay. RESULTS: All tested glycopolymers completely inhibited Gal-3-induced apoptosis of monocytes/macrophages, of which the M1 subtype is responsible for eliminating cancer cells during immunotherapy. Moreover, the glycopolymers suppressed Gal-3-induced capture of glycosylated IFNγ by competitive inhibition to Gal-3 carbohydrate recognition domain (CRD), which enables further inherent biological activities of this effector, such as differentiation of monocytes into M1 macrophages and repolarization of M2-macrophages to the M1 state. CONCLUSION: The prepared glycopolymers are promising inhibitors of Gal-3 and may serve as important supportive anti-cancer nanosystems enabling the infiltration of proinflammatory macrophages and the reprogramming of unwanted M2 macrophages into the M1 subtype.

• MeSH
• akrylamidy chemie   farmakologie   MeSH
• apoptóza účinky léků   MeSH
• galektin 3 * antagonisté a inhibitory   MeSH
• galektiny MeSH
• interferon gama * metabolismus   MeSH
• krevní proteiny MeSH
• lidé MeSH
• makrofágy účinky léků   MeSH
• monocyty * účinky léků   MeSH
• nádorové mikroprostředí účinky léků   MeSH
• polymery * chemie   farmakologie   MeSH
• protinádorové látky * farmakologie   chemie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

• MeSH
• Aspirin * farmakokinetika   farmakologie   terapeutické užití   MeSH
• diabetes mellitus * farmakoterapie   patologie   MeSH
• inhibitory agregace trombocytů MeSH
• komplikace diabetu MeSH
• lidé MeSH
• megakaryocyty patologie   MeSH
• trombocyty patologie   účinky léků   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• lidé MeSH

The parasitic protozoan Entamoeba histolytica secretes extracellular vesicles (EVs), but so far little is known about their function in the interaction with the host immune system. Infection with E. histolytica trophozoites can lead to formation of amebic liver abscesses (ALAs), in which pro-inflammatory immune responses of Ly6Chi monocytes contribute to liver damage. Men exhibit a more severe pathology as the result of higher monocyte recruitment and a stronger immune response. To investigate the role of EVs and pathogenicity in the host immune response, we studied the effect of EVs secreted by low pathogenic EhA1 and highly pathogenic EhB2 amebae on monocytes. Size and quantity of isolated EVs from both clones were similar. However, they differed in their proteome and miRNA cargo, providing insight into factors potentially involved in amebic pathogenicity. In addition, EVs were enriched in proteins with signaling peptides compared with the total protein content of trophozoites. Exposure to EVs from both clones induced monocyte activation and a pro-inflammatory immune response as evidenced by increased surface presentation of the activation marker CD38 and upregulated gene expression of key signaling pathways (including NF-κB, IL-17 and TNF signaling). The release of pro-inflammatory cytokines was increased in EV-stimulated monocytes and more so in male- than in female-derived cells. While EhA1 EV stimulation caused elevated myeloperoxidase (MPO) release by both monocytes and neutrophils, EhB2 EV stimulation did not, indicating the protective role of MPO during amebiasis. Collectively, our results suggest that parasite-released EVs contribute to the male-biased immunopathology mediated by pro-inflammatory monocytes during ALA formation.

• MeSH
• amébový absces jater imunologie   parazitologie   MeSH
• cytokiny metabolismus   MeSH
• entamébóza imunologie   parazitologie   MeSH
• Entamoeba histolytica * imunologie   patogenita   genetika   MeSH
• extracelulární vezikuly * imunologie   metabolismus   MeSH
• lidé MeSH
• monocyty * imunologie   parazitologie   MeSH
• signální transdukce * MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Kontext: Procento nezralých granulocytů (immature granulocytes, iG%) je časným markerem zánětu s prognostickou hodnotou u řady onemocnění. Cíl: V této studii jsme se pokusili zjistit, zda má procento nezralých granulocytů prognostickou hodnotu z hlediska 28denní mortality pacientů s akutním koronárním syndromem (AKS). Metoda: Jednalo se o retrospektivní studii provedenou v období mezi 1. lednem 2019 a 30. červnem 2019 na Klinice urgentní medicíny lékařské fakulty univerzity v tureckém Mersinu. Do studie byli zařazeni všichni pacienti ve věku nad 18 let, kteří byli dopraveni na kliniku urgentní medicíny s bolestí na hrudi a hospitalizováni s předběžnou diagnózou AKS. Pacienti byli rozděleni do dvou skupin, na ty, kteří přežili, a ty, kteří nepřežili. Byly zaznamenány hodnoty iG% a dalších laboratorních parametrů a následně byl analyzován vztah mezi hodnotami iG% a 28denní mortalitou. Kromě toho byla pro srovnání diagnostické přesnosti hodnot iG% a dalších proměnných provedena analýza roc. Výsledky: Do studie bylo zařazeno celkem 617 pacientů, z tohoto počtu bylo 423 (68,6 %) mužů. Průměrný věk pacientů dosahoval 63,9 ± 12,7 roku. hodnota iG% byla vyšší u nepřeživších pacientů (1,2 ± 1,4) než u přeživších (0,5 ± 0,5 ) (p = 0,007). V predikci 28denní mortality, pokud byla mezní hodnota iG% > 0,6, byla zjištěna specificita ve výši 93,70 % a senzitivita 54,55 % (Auc = 0,717; p = 0,000). V predikci 28denní mortality na AKS představovalo iG% nezávislý rizikový faktor (poměr rizik [hazard ratio, hr] 632,962; 95% interval spolehlivosti 3,389–118 206,572; p = 0,016). Závěr: u pacientů s AKS může hodnota iG% souviset s 28denní mortalitou.

Background: The percentage of immature granulocytes (IG%) is an early marker of inflammation and has a prognostic significance in many diseases. Objective: In this study, we tried to investigate whether the percentage of immature granulocytes has a prognostic value in 28-day mortality in patients with acute coronary syndrome (ACS). Method: This study was carried out retrospectively between 1.1.2019 and 30.6.2019 at Mersin University Faculty of Medicine, Department of Emergency Medicine. Patients older than 18 years who applied to the emergency department with chest pain and were hospitalized with a preliminary diagnosis of ACS were included in the study. The patients were divided into two groups as survivors and non-survivors. IG% and other laboratory parameters were recorded. The relationship between IG% and 28-day mortality was analyzed. In addition, ROC analysis was performed to compare the diagnostic accuracy of IG% and other variables. Results: A total of 617 patients, including 423 (68.6%) men, were included in the study. The mean age of the patients were 63.9 ± 12.7. IG% was higher in non-survivor patients (1.2 ± 1.4) than in surviving patients (0.5 ± 0.5) (p = 0.007). In predicting 28-day mortality, when the cut-off value for IG% was >0.6, the specifi- city was found to be 93.70% and the sensitivity to be 54.55% (AUC = 0.717, p = 0.000). In predicting 28-day mortality for ACS, IG% was an independent risk factor (hazard ratio [HR] 632.962, 95% confidence interval 3.389-118206.572, p = 0.016). Conclusion: IG% may be associated with a 28-day mortality in patients with ACS.

• MeSH
• akutní koronární syndrom * krev   mortalita   MeSH
• biologické markery MeSH
• granulocyty * patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• prognóza MeSH
• proporcionální rizikové modely MeSH
• ROC křivka MeSH
• senioři MeSH
• statistika jako téma MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• klinická studie MeSH

The molecular basis of increased hemoglobin in Andean Aymara highlanders is unknown. We conducted an integrative analysis of whole-genome-sequencing and granulocytes transcriptomics from Aymara and Europeans in Bolivia to explore genetic basis of the Aymara high hemoglobin. Differentially expressed and spliced genes in Aymaras were associated with inflammatory and hypoxia-related pathways. We identified transcripts with 4th or 5th exon skipping of NFKB1 (AS-NFKB1), key part of NF-kB complex, and their splicing quantitative trait loci; these were increased in Aymaras. AS-NFKB1 transcripts correlated with both transcripts and protein levels of inflammatory and HIF-regulated genes, including hemoglobin. While overexpression of the AS-NFKB1 variant led to increased expression of inflammatory and HIF-targeted genes; under inflammatory stress, NF-kB protein translocation to the nucleus was attenuated, resulting in reduced expression of these genes. Our study reveals AS-NFKB1 splicing events correlating with increased hemoglobin in Aymara and their possible protective mechanisms against excessive inflammation.

• MeSH
• alternativní sestřih * genetika   MeSH
• dospělí MeSH
• exony genetika   MeSH
• faktor 1 indukovatelný hypoxií - podjednotka alfa genetika   metabolismus   MeSH
• granulocyty metabolismus   MeSH
• hemoglobiny * metabolismus   genetika   MeSH
• lidé MeSH
• lokus kvantitativního znaku MeSH
• NF-kappa B - podjednotka p50 * metabolismus   genetika   MeSH
• regulace genové exprese MeSH
• transkriptom MeSH
• zánět * genetika   metabolismus   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Bolívie MeSH

The intestine hosts the largest immune system and peripheral nervous system in the human body. The gut‒brain axis orchestrates communication between the central and enteric nervous systems, playing a pivotal role in regulating overall body function and intestinal homeostasis. Here, using a human three-dimensional in vitro culture model, we investigated the effects of serotonin, a neuromodulator produced in the gut, on immune cell and intestinal tissue interactions. Serotonin attenuated the tumor necrosis factor-induced proinflammatory response, mostly by affecting the expression of chemokines. Serotonin affected the phenotype and distribution of tissue-migrating monocytes, without direct contact with the cells, by remodeling the intestinal tissue. Collectively, our results show that serotonin plays a crucial role in communication among gut-brain axis components and regulates monocyte migration and plasticity, thereby contributing to gut homeostasis and the progression of inflammation. In vivo studies focused on the role of neuromodulators in gut inflammation have shown controversial results, highlighting the importance of human experimental models. Moreover, our results emphasize the importance of human health research in human cell-based models and suggest that the serotonin signaling pathway is a new therapeutic target for inflammatory bowel disease.

• MeSH
• lidé MeSH
• monocyty metabolismus   imunologie   MeSH
• pohyb buněk MeSH
• serotonin * metabolismus   MeSH
• signální transdukce MeSH
• střevní sliznice * metabolismus   patologie   MeSH
• TNF-alfa metabolismus   MeSH
• zánět metabolismus   patologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

INTRODUCTION: A critical step preceding the potential biomedical application of nanoparticles is the evaluation of their immunomodulatory effects. Such nanoparticles are expected to enter the bloodstream where they can be recognized and processed by circulating monocytes. Despite the required biocompatibility, this interaction can affect intracellular homeostasis and modulate physiological functions, particularly inflammation. This study focuses on titanium dioxide (TiO2) as an example of relatively low cytotoxic nanoparticles with potential biomedical use and aims to evaluate their possible modulatory effects on the inflammasome-based response in human primary monocytes. METHODS: Monocyte viability, phenotypic changes, and cytokine production were determined after exposure to TiO2 (diameter, 25 nm; P25) alone. In the case of the modulatory effects, we focused on NLRP3 activation. The production of IL-1β and IL-10 was evaluated after (a) simultaneous activation of monocytes with bacterial stimuli muramyl dipeptide (MDP), or lipopolysaccharide (LPS), and TiO2 (co-exposure model), (b) prior activation with TiO2 alone and subsequent exposure to bacterial stimuli MDP or LPS. The differentiation of TiO2-treated monocytes into macrophages and their polarization were also assessed. RESULTS: The selected TiO2 concentration range (30-120 μg/mL) did not induce any significant cytotoxic effects. The highest dose of TiO2 promoted monocyte survival and differentiation into macrophages, with the M2 subset being the most prevalent. Nanoparticles alone did not induce substantial production of inflammatory cytokines IL-1β, IL-6, or TNF-α. The immunomodulatory effect on NLRP3 depended on the type of costimulant used. While co-exposure of monocytes to MDP and TiO2 boosted NLRP3 activity, co-exposure to LPS and TiO2 inhibited NLRP3 by enhancing IL-10 release. The inhibitory effect of TiO2 on NLRP3 based on the promotion of IL-10 was confirmed in a post-exposure model for both costimulants. CONCLUSION: This study confirmed a non-negligible modulatory effect on primary monocytes in their inflammasome-based response and differentiation ability.

• MeSH
• acetylmuramyl-alanyl-isoglutamin farmakologie   MeSH
• buněčná diferenciace účinky léků   MeSH
• cytokiny metabolismus   MeSH
• inflamasomy účinky léků   MeSH
• interleukin-10 metabolismus   MeSH
• interleukin-1beta metabolismus   MeSH
• kovové nanočástice chemie   toxicita   MeSH
• kultivované buňky MeSH
• lidé MeSH
• lipopolysacharidy * farmakologie   MeSH
• makrofágy účinky léků   MeSH
• monocyty * účinky léků   MeSH
• nanočástice chemie   toxicita   MeSH
• protein NLRP3 * metabolismus   MeSH
• titan * chemie   farmakologie   toxicita   MeSH
• viabilita buněk * účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH