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PB1832: Inflammation induced coagulation in acute myeloid leukemia
Get PDFBackground: Patients with acute myeloid leukemia (AML) have an increased risk of thrombotic complications in the range of 4.2 - 5.2%.
Aims: Our hypothesis is that inflammation is responsible for deterioration of coagulation in AML.
Methods: Quantification of neutrophil extracellular traps (NETs) from peripheral blood of patients with AML by measurement of circulating cell-free DNA (cfDNA) and myeloperoxidase (MPO) activity. Inflammatory cytokines, coagulation factors and chemokines are measured by enzyme-linked immunosorbent assay (ELISA) and flow cytometry in peripheral blood, while fibrinolytic activity with fluorescent tissue-type plasminogen activator (tPA) and urokinase plasminogen activator (uPA) assays.
Results: The pro-inflammatory cytokines IL-1β and TNF-α were significantly increased in AML, but not the chemokines IL-8 and MCP-1. NETs were increased in the peripheral blood of patients with AML (p<0.05) as measured by cfDNA and MPO activity. Regarding coagulation, factor VIII (p<0.05) and adhesion molecule P-selectin (p<0.001) were increased in plasma. Fibrinolytic activity was 3-fold decreased in the plasma of patients with AML (p<0.01) as measured by tPA. In contrast, uPA levels were increased in patients with AML (p<0.05). Tissue factor (CD142+) inflammatory microparticles derived from monocytes (CD14+: 5.1±0.6, p<0.001), activated monocytes (CD14+/CD16+: 2.89±0.4%, p<0.05) and circulating endothelial cells (CD31+/CD144+: 4.08±0.5%, p<0.05) were increased in AML compared to healthy controls.
Summary/Conclusion: Chronic inflammation is present in AML in parallel with reduced fibrinolysis and increased coagulation provoking the risk of thrombosis. A panel of the applied inflammatory/ procoagulant biomarkers can be used as a predictor of thrombosis in AML
Routes of pathogens spread: phytogeographic analyses
Get PDFFilogeografija podrazumeva prostorno-vremensku rekonstrukciju evolutivne istorije različitih patogena
u cilju predviđanja pojave zaraznih bolesti, detekcijom ključnih vrsta domaćina i geografskih
područija sa kojih se patogeni šire, kao i potencijalni uticaj kretanja prirodnih rezervoara u prirodi
na dalje širenje zoonotskih bolesti. Filogeografska analiza može se raditi primenom dva različita
pristupa: filogeografija sa diskretnim lokacijama i filogeografija u kontinuiranom prostoru.
Za rekonstrukciju prostorno-vremenske evolutivne istorije koristi se Bajesova metoda implementirana
u BEAST softverski paket. Pored odgovarajućeg evolutivnog modela, izabranog na osnovu vrednosti
AIC kriterijuma u jModelTest programu, neophodno je kalibrisati i ostale parametre u BEAST
softveru (molekularni sat, demografski model) u cilju dobijanja što pouzdanijeg modela za analizu
distribucije patogena.
U studiju smo uključili 275 sekvenci NS5 gena linije 2 Virusa Zapadnog Nila (VZN), izolovanih sa
različitih geografskih lokacija u cilju analize prostorno-vremenskog širenja pomenutog patogena.
Geografska lokacija zajedno sa godinom izolacije su bile dostupne u NCBI (https://www.ncbi.nlm.
nih.gov/nucleotide/) bazi podataka. Filogeografska analiza je rađena u BEAST v1.10.4 softverskom
paketu primenom relaksiranog molekularnog sata i Gaussian Markov random field (GMRF) Skyride
modela. Za procenu konvergencije Markovljevog lanaca Monte Karlo (MCMC) i za utvrđivanje efektivne
veličine uzorka za svaki od parametara (≥200), korišćen je program TRACER v1.6. Filogenetsko
stablo konstruisano primenom Bajesove metode, analizirano je u programu FigTree v1.4.4.
Vremenski kalibrisano filogenetsko stablo NS5 gena VZN-a je pokazalo da se većina sekvenci iz Srbije
grupiše zajedno sa sekvencama iz Grčke, formirajući jedan veliki monofiletski klaster. Analizom
molekularnog sata je utvrđeno da je VZN-a ušao u Srbiju 2002. godine. Filogeografska analiza je
ukazala da je VZN najverovatnije u Srbiju ušao iz Mađarske i da je nastavio lokalno da se širi.
Rezultati naše studije su pokazali da je u Srbiji linija 2 VZN-a bila u cirkulaciji čitavu deceniju pre
prve epidemije 2012. godine, i time potvrdili značaj molekularno-bioinformatičkog pristupa u sagledavanju
evolutivne istorije i puteva širenja ovog patogena.Phylogeographic analysis reconstruction of evolutionary history of different pathogens aimed to
predict of emergence of infectious diseases by detecting the key host species and the geographic
areas from which pathogens spread and prediction of the impact of movement of natural reservoirs
on the spread of viral diseases. Spatiotemporal reconstructions can be assessed by two different
phylogeographic approaches; phylogeographic inference in discrete space and phylogeography in
continuous space and time. The Bayesian method implemented in the BEAST software package is
used to reconstruct the spatio-temporal evolutionary history. In addition to the appropriate evolutionary
model, chosen based on the value of the AIC criteria in the jModelTest program, it is necessary to
calibrate other parameters in the BEAST software (molecular clock, demographic model) in order to
obtain the most reliable model for distribution analysis.
In the present study we included 319 partial NS5 segment sequences of WNV, isolated from different
geographic areas with the aim to explore spatio-temporal dispersal out of Africa. Sampling time and
trapping localities for all isolates were available in NCBI (https://www.ncbi.nlm.nih.gov/nucleotide/
) public databases at the time of the study. Phylogeographic analysis was done in BEAST v1.10.4
software package using relaxed molecular clock i Gaussian Markov random field (GMRF) Skyride
model. The convergence of parameters was assessed through the ESS>200 checked using Tracer
v1.6. Phylogenetic tree was visualized using FigTree software v1.4.4.
Bayesian clade credibility (MCC) tree of the NS5 gene showed that majority of Serbian isolates was
grouped in a single large clade together with sequences from Greece and Romania, thus forming
large monophyletic clade. Molecular clock analysis estimated the time of the most recent common
ancestor (tMRCA) of the local WNV epidemic in Serbia to around 2002. Phylogeographic analysis
implied introduction of WNV-2 to Serbia from Hungary and further local spread.
Our results evidence presence and circulation of WNV-2 in Serbia a decade prior to the first evidenced
outbreak in 2012, and demonstrate the usefulness of bioinformatic methods providing a comprehensive view of the viral evolutionary history
Transplantation-related risk of Toxoplasma gondii infection: the National Reference Laboratory prospective cohort study results
Get PDFToksoplazmoza je česta ali kod pacijenata lečenih transplantacijom uglavnom zanemarena i pogrešno
dijagnostikovana oportunistička infekcija koja može ugroziti engraftment ali može i evoluirati u
životno ugrožavajuću diseminovanu infekciju. Nakon transplantacije, infekcija parazitom Toxoplasma
gondii se može razviti kao reaktivacija hronične infekcije ili može biti preneta graftom.
Naša osmogodišnja prospektivna studija bila je usmerena na dijagnostiku i monitoring toksoplazmatske
infekcije (TI) kod primalaca matičnih ćelija hematopoeze (haematopoietic stem cell
transplant, HSCT) u centru koji primenjuje protokol uzdržavanja od profilakse do engraftmenta, i
kod primalaca transplantata srca (heart transplant, HT) koji su na kontinuiranoj profilaksi trimetoprim-
sulfametoksazolom (TMP-SMX).
Cilj nam je bio utvrđivanje incidence TI u ova dva vrlo različita transplantaciona režima, i to pre nego
što evoluira u klinički manifestnu, potencijalno fatalnu bolest (Toxoplasma disease, TD). Pre-transplantacioni
serološki i qPCR skrining u post-transplantacionom toku zamenjen je redovnim qPCR
monitoringom iz uzoraka periferne krvi (peripheral blood, PB) usmerenim na Toxoplasma 529 bp gen. Kod primalaca HSCT, qPCR je rađen jednom nedeljno dok je kod primalaca HT qPCR rađen jednom
mesečno prva dva meseca post-HT i potom jednom godišnje. TI je dijagnostikovana na bazi
pozitivnog PCR rezultata iz bar jednog uzorka PB. TI je dijagnostikovana kod 21/104 (20.2%) primalaca
HSCT, prevashodno nakon alogene (19/75) i retko nakon autologne HSCT (2/29). Više od
50% slučajeva TI dijagnostikovano je tokom prvog meseca post-HSCT, pre engraftmenta odnosno
tokom uzdržavanja od profilakse. Sa druge strane, TI je dijagnostikovana kod 3/37 (8.1%) primalaca
HT. Uprkos primeni TMP-SMX, qPCR je postao pozitivan godinu dana posle HT kod dva i dve godine
post-HSCT kod trećeg pacijenta. Infekcija je bila preneta graftom kod 2/3 (seronegativni) a reaktivirana
kod 1/3 primalaca HT (seropozitivni primalac HT poreklom od seropozitivnog donora).
Naši rezultati potvrđuju da je sistemski qPCR monitoring iz uzoraka PB dragocen u dijagnostici TI
ne samo kod primalaca HSCT već i kod primalaca solidnih organa, posebno nakon HT. Učestalost
qPCR monitoringa se mora adaptirati shodno specifičnostima transplantacionog protokola, pre
svega primeni profilakse ali i osnovnoj dijagnozi, na način koji omogućava pravovremenu primenu
specifične terapije u svakom slučaju TI.Toxoplasmosis is a common but often neglected and misdiagnosed opportunistic infection in transplant
recipients, which can not only compromise the engraftment, but also evolve into life-threatening
disseminated infection. Post-transplantation, Toxoplasma gondii infection can develop as a reactivation
of chronic infection or could be graft-transmitted. We conducted an eight-year-long prospective
study on the diagnosis and monitoring of Toxoplasma infection (TI) in haematopoietic stem cell
transplant (HSCT) recipients in a setting that withholds prophylaxis until engraftment, and in heart
transplant (HT) recipients on continuous trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis.
The objective was to determine the incidence of TI before it evolves into clinical, potentially fatal
Toxoplasma disease (TD), in these two very different transplantation settings. Pre-transplantation
serological and qPCR screening was followed by post-transplantation peripheral blood (PB)-based
qPCR monitoring targeting the Toxoplasma 529 bp gene. In HSCT recipients, qPCR was performed
weekly while in HT recipients, qPCR was performed monthly for two months post-HT and then
yearly. TI was diagnosed based on a positive PCR result in at least one PB sample.
TI was diagnosed in 21/104 (20.2%) HSCT recipients, predominantly after allogeneic (19/75) and
rarely after autologous HSCT (2/29). Over 50% of TI cases were diagnosed during the first month
post-HSCT, while awaiting engraftment without prophylaxis. On the other hand, TI was diagnosed
in 3/37 (8.1%) HT recipients. Regardless of the TMP-SMX prophylaxis, qPCR became positive one
year after HT in two and two years post-HSCT in third patient. Infection was graft-transmitted in 2/3
(seronegative) and reactivated in 1/3 OHT (seropositive recipient of a seropositive donor’s heart
transplant).
The presented results show that systematic PB-based qPCR monitoring is a valuable resource for
the diagnosis of TI not only in HSCT but also in solid organ recipients, especially after HT. Frequency
of qPCR monitoring should be adjusted according to the specificity of the transplantation setting,
especially in terms of prophylaxis but also an underlying diagnosis, in a manner allowing for prompt
introduction of specific treatment in each case of TI
Nischarin expression may have differing roles in male and female melanoma patients
Get PDFDue to the development of resistance to previously effective therapies, there is a constant need for novel treatment modalities for metastatic melanoma. Nischarin (NISCH) is a druggable scaffolding protein reported as a tumor suppressor and a positive prognostic marker in breast and ovarian cancers through regulation of cancer cell survival, motility and invasion. The aim of this study was to examine the expression and potential role of nischarin in melanoma. We found that nischarin expression was decreased in melanoma tissues compared to the uninvolved skin, and this was attributed to the presence of microdeletions and hyper-methylation of the NISCH promoter in the tumor tissue. In addition to the previously reported cytoplasmic and membranous localization, we observed nischarin in the nuclei in melanoma patients’ tissues. NISCH expression in primary melanoma had favorable prognostic value for female patients, but, unexpectedly, high NISCH expression predicted worse prognosis for males. Gene set enrichment analysis suggested significant sex-related disparities in predicted association of NISCH with several signaling pathways, as well as with different tumor immune infiltrate composition in male and female patients. Taken together, our results imply that nischarin may have a role in melanoma progression, but that fine-tuning of the pathways it regulates is sex-dependent.This is the submitted version of the article: Ostojić, M.; Jevrić, M.; Mitrović-Ajtić, O.; Živić, K.; Tanić, M.; Čavić, M.; Srdić-Rajić, T.; Grahovac, J. Nischarin Expression May Have Differing Roles in Male and Female Melanoma Patients. J Mol Med 2023, 101 (8), 1001–1014. https://doi.org/10.1007/s00109-023-02339-y
Phospholipid Fatty Acid Profiles of Plasma and Erythrocyte Membranes in Dogs Fed with Commercial Granulated Food
Get PDFIntake of long-chain n-3 polyunsaturated fatty acids (PUFA) benefits human and animal health. Our study aimed to analyze the long-chain n-3 PUFA content of two types of food and their effect on plasma and erythrocyte phospholipids of Belgian Shepherd dogs. A total of 10 dogs were fed commercial granulated food (Food 1), and another 10 were provided commercial Premium granulated food of high quality (Food 2). All the analyses were performed using gas-liquid chromatography. Our results showed that Food 1 contained more n-3 PUFA than Food 2, which was reflected in higher n-3 PUFA in plasma and erythrocyte phospholipids. Because long-chain n-3 PUFA in phospholipids are precursors for antioxidative molecules, further studies should investigate the effects of the analyzed commercial granulated food rich in n-3 on oxidative stress parameters in dogs
Existing knowledge on Zn status biomarkers (1963–2021) with a particular focus on FADS1 and FADS2 diagnostic performance and recommendations for further research
Get PDFThe role of Zn in human health was discovered 60 years ago, and despite remarkable research efforts, a sufficiently sensitive and specific biomarker of Zn status is still lacking. Plasma/serum Zn, currently the best available and most accepted population Zn status indicator, responds well to severe Zn deficiency, yet, mild to moderate Zn deficiency states usually remain unrecognized. Identifying early-stage Zn deficiency requires additional robust markers of Zn status. This paper discusses the sensitivity, specificity, and responsiveness of plasma Zn concentrations to Zn interventions. It describes the biochemical and dietary basis for the causal association between Zn and fatty acid desaturases activity, FADS1 and FADS2, based on data collected through studies performed in animals and/or humans. The influence of potential confounders and covariates on the observed relationships is considered. Additional potential Zn biomarkers are discussed and suggestions for further research in this area are provided
Effect of Dietary Supplements with ω-3 Fatty Acids, Ascorbic Acid, and Polyphenolic Antioxidant Flavonoid on Gene Expression, Organ Failure, and Mortality in Endotoxemia-Induced Septic Rats
Get PDFSepsis syndrome develops through enhanced secretion of pro-inflammatory cytokines and the generation of reactive oxygen species (ROS). Sepsis syndrome is characterized by vascular hyperpermeability, hypotension, multiple organ dysfunction syndrome (MODS), and increased mortality, among others. Endotoxemia-derived sepsis is an important cause of sepsis syndrome. During endotoxemia, circulating endotoxin interacts with endothelial cells (ECs), inducing detrimental effects on endothelium function. The endotoxin induces the conversion of ECs into fibroblasts, which are characterized by a massive change in the endothelial gene-expression pattern. This downregulates the endothelial markers and upregulates fibrotic proteins, mesenchymal transcription factors, and extracellular matrix proteins, producing endothelial fibrosis. Sepsis progression is modulated by the consumption of specific nutrients, including ω-3 fatty acids, ascorbic acid, and polyphenolic antioxidant flavonoids. However, the underlying mechanism is poorly described. The notion that gene expression is modulated during inflammatory conditions by nutrient consumption has been reported. However, it is not known whether nutrient consumption modulates the fibrotic endothelial gene-expression pattern during sepsis as a mechanism to decrease vascular hyperpermeability, hypotension, MODS, and mortality. Therefore, the aim of this study was to investigate the impact of the consumption of dietary ω-3 fatty acids, ascorbic acid, and polyphenolic antioxidant flavonoid supplements on the modulation of fibrotic endothelial gene-expression patterns during sepsis and to determine the effects on sepsis outcomes. Our results indicate that the consumption of supplements based on ω-3 fatty acids and polyphenolic antioxidant flavonoids was effective for improving endotoxemia outcomes through prophylactic ingestion and therapeutic usage. Thus, our findings indicated that specific nutrient consumption improves sepsis outcomes and should be considered in treatment
Effects of Transcranial Electrical Stimulation on Gambling and Gaming: A Systematic Review of Studies on Healthy Controls, Participants with Gambling/Gaming Disorder, and Substance Use Disorder
Get PDFGambling disorder (GD) and internet gaming disorder (IGD) are formally recognized behavioral addictions with a rapidly growing prevalence and limited treatment options. Recently, transcranial electrical stimulation (tES) techniques have emerged as potentially promising interventions for improving treatment outcomes by ameliorating cognitive functions implicated in addictive behaviors. To systematize the current state of evidence and better understand whether and how tES can influence gambling and gaming-related cognitive processes, we conducted a PRISMA-guided systematic review of the literature, focusing on tES effects on gaming and gambling in a diverse range of population samples, including healthy participants, participants with GD and IGD, as well as participants with substance abuse addictions. Following the literature search in three bibliographic databases (PubMed, Web of Science, and Scopus), 40 publications were included in this review, with 26 conducted on healthy participants, 6 focusing on GD and IGD patients, and 8 including participants with other addictions. Most of the studies targeted the dorsolateral prefrontal cortex, using transcranial direct current stimulation (tDCS), and assessed the effects on cognition, using gaming and gambling computerized cognitive tasks measuring risk taking and decision making, e.g., balloon analogue risk task, Iowa gambling task, Cambridge gambling task, etc. The results indicated that tES could change gambling and gaming task performances and positively influence GD and IGD symptoms, with 70% of studies showing neuromodulatory effects. However, the results varied considerably depending on the stimulation parameters, sample characteristics, as well as outcome measures used. We discuss the sources of this variability and provide further directions for the use of tES in the context of GD and IGD treatment
New Iron Twist to Chloroquine─Upgrading Antimalarials with Immunomodulatory and Antimicrobial Features
No full textHerein, upgraded chloroquine (CQ) derivatives capable of overcoming Plasmodium resistance and, at the same time, suppressing excessive immune response and risk of concurrent bacteremia were developed. Twelve new ferrocene-CQ hybrids tethered with a small azathia heterocycle (1,3-thiazolidin-4-one, 1,3-thiazinan-4-one, or 5-methyl-1,3-thiazolidin-4-one) were synthesized and fully characterized. All hybrids were evaluated for their in vitro antiplasmodial, antimicrobial, and immunomodulatory activities. Additional assays were performed on selected hybrids to gain insights into their mode of action. Although only hybrid 4a was more potent than the parent drug toward CQ-resistant Dd2 Plasmodium falciparum strain, several other hybrids (such as 6b, 6c, and 6d) manifested substantially improved antimicrobial and immunomodulatory properties. Interesting structure-activity relationship data were obtained, hinting at future research for the development of new multitarget chemotherapies for malaria and other infectious diseases complicated by drug resistance, bacterial co-infection, and immune-driven pathology issues
Anti-inflammatory effect of combining fish oil and evening primrose oil supplementation on breast cancer patients undergoing chemotherapy: a randomized placebo-controlled trial
Get PDFBreast cancer is the most common malignant tumor and one of the leading causes of cancer-related death in women throughout the world. This study is a parallel, randomized, double-blind, controlled, 12-week supplementation trial, investigating the anti-inflammatory effects of dietary intake of fish oil and evening primrose oil (EPO), in patients with breast cancer undergoing chemotherapy. The primary outcomes were changes in the nutritional status and inflammatory cytokines of patients during the study. The secondary outcomes were changes in hematological and biochemical parameters and fatty acid profile. Of the 32 eligible patients, half of them is randomly assigned to a treatment arm with fish oil and EPO (n = 16), or a control arm (n = 16) with mineral oil as a placebo. The intervention group was taking 2 gel capsules of fish oil and 3 gel capsules of EPO (400 mg eicosapentaenoic acid, 600 mg docosahexaenoic acid, and 351 mg gamma-linolenic acid) fish oil and evening primrose oil for 12 weeks, during their chemotherapy. The control/placebo group was taking 5 gel capsules of 1g of mineral oil. One of the patients dropped out due to discontinuation of the treatment (in the placebo group) and two did not show up at the post-treatment measurements (in the intervention group), thus, 29 women completed the study. The results showed an increase in plasma levels of docosapentaenoic acid (22:5n-3), docosahexaenoic acid (22:6n-3), total n-3PUFA, vaccenic acid (18:1n-7), and a decrease in n-6/n-3 PUFA ratio in the intervention group. An increase in the plasma level of dihomo-gamma-linolenic acid (20:3n-6) was observed in the placebo group. There was no difference in plasma levels of interleukin (IL) IL-8, IL-10, and tumor necrosis factor-alpha, while the level of IL-6 decreased in both groups and was significantly lower in the intervention group at the end of the study. In conclusion, this supplementation improved the PUFA status and decreased the level of IL-6 in breast cancer patients undergoing chemotherapy. Consequently, this treatment may help reduce cancer complications resulting from impaired lipid metabolism and inflammation. ClinicalTrials.gov Identifier: NCT03516253. Date of registration 04/05/2018