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Bone Marrow Adipose Tissue: Regulation of Osteoblastic Niche, Hematopoiesis and Hematological Malignancies
No full textBone marrow adipose tissue (BMAT) creates a specific microniche within multifunctional bone marrow (BM) ecosystem which imposes changes in surrounding cells and at systemic level. Moreover, BMAT contributes to spatial and temporal separation and metabolic compartmentalization of BM, thus regulating BM homeostasis and diseases. Recent findings have identified novel progenitor subsets of bone marrow adipocytes (BMAd)s recruited during the BM adipogenesis within different skeletal and hematopoietic stem cell niches. Potential of certain mesenchymal BM cells to differentiate into both osteogenic and adipogenic lineages, contributes to the complex interplay of BMAT with endosteal (osteoblastic) niche compartments as an important cellular player in bone tissue homeostasis. Targeting and ablation of BMAT cells at certain states might be an optional and promising strategy for improvement of bone health. Additionally, recent findings demonstrated spatial distribution of BMAds related to hematopoietic cells and pointed out important functional roles in the vital processes such as long-term hematopoiesis. BM adipogenesis appears to be an emergency phenomenon that follows the production of hematopoietic stem and progenitor cell niche factors, thus regulating physiological, stressed, and malignant hematopoiesis. Lipolytic and secretory activity of BMAds can influence survival and proliferation of hematopoietic cells at different maturation stages. Due to their different lipid status, constitutive and regulated BMAds are important determinants of normal and malignant hematopoietic cells. Further elucidation of cellular and molecular players involved in BMAT expansion and crosstalk with malignant cells is of paramount importance for conceiving the new therapies for improvement of BM health
Activation of coagulation factors and prothrombic properties of endothelium in hematological malignancies
Get PDFIntroduction: Patients with hematological malignancies have an increased risk of thrombotic complications, ranging from 3-5% in patients with lymphoma and acute myeloid leukemia (AML). The presented study observed the onset of thrombus formation to predict risk factors for thrombosis in lymphoid and myeloid malignancies. Methods: Coagulation factors, inflammatory signaling pathways and adhesion molecules have been observed in patients with Hodgkin lymphoma (HL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and AML. Their mononuclear cells (MNC) trans-endothelial migration through human microvascular endothelial cells (HMEC-1) monolayer is observed by Boyden chamber.
Results: Thrombin was in positive correlation with tumor necrosis factor alpha (TNF-α) in HL, while with P-selectin (p<0.001), tumor growth factor-beta (TGF-β) and factor VIII (p<0.05) in DLBCL and AML. Transendothelial migration of MNC was increased by TNF-α (p<0.001) in DLBCL regardless of previous thrombosis. Regarding coagulation, factor VIII was increased in HL and AML (p<0.05), while tissue factor in non-Hodgkin lymphomas (DLBCL and FL, p<0.05). Tissue factor was in positive correlation with adhesion molecule P-selectin and factor VIII (p<0.05). P-selectin was increased in non-Hodgkin lymphomas (p<0.0001), while TGF-β only in FL (p<0.001). Fibrinolytic activity was decreased in plasma of patients with HL, DLBCL, and FL (p<0.05), but largely in AML (p<0.01) as measured by tissue-type plasminogen activator. Inflammatory NF-κB signaling has been activated in HL and DLBCL, while p38 signaling only in HL. Conclusion: Coagulation factors and inflammation are increased in hematological malignancies along with the interaction of the endothelium and circulating cells that predispose to thrombus formatio
Using Transcranial Electrical Stimulation to modulate gambling-related cognitive functions: A systematic review and study protocol
Get PDFGambling represents a reward-based activity that many people engage in for fun and leisure. However, excessive gambling may lead to Gambling Disorder (GD), the most prevalent behavioural addiction. There is evidence that neural circuits behind some of the cognitive processes that drive GD can be modulated by Transcranial Electrical Stimulation (tES). To comprehensively understand the potential of tES in targeting cognitive mechanisms implicated in GD, we conducted a PRISMA-guided systematic review of studies that applied tES to modulate gambling-related cognitive processes in a diverse range of population samples, including healthy participants, participants with GD, as well as other addictions. Most of the studies used transcranial direct current stimulation (tDCS) to target dorsolateral prefrontal cortex (DLPFC). While 70% of studies showed neuromodulatory effects, the results varied considerably depending on the stimulation parameters, sample characteristics, as well as outcome measures used. We noticed that studies predominantly focused on the DLPFC without providing a clear rationale, even though other brain regions have shown greater relevance to the cognitive functions affected in GD. Furthermore, we have identified a gap in the existing literature regarding the use of tES among participants with gambling-related issues. Based on these findings, we propose a study protocol for investigating the effects of tES on cognitive functions affected in GD, in a sample of at-risk gamblers. In a sham-controlled, parallel-group study we will use multichannel tDCS to modulate the activity of anterior cingulate cortex, due to its key role in gambling-related cognitive processes. The electrode montage will be optimized based on current flow modeling. We will test the effects on cognitive tasks measuring risk-taking, impulsivity, inhibition, and decision-making. In addition to at risk-gamblers, we will sample control participants with no gambling-related issues. This approach will enable us to examine whether and how this factor may determine the responsiveness to tES
SARS-CoV-2 specific antibody response after an mRNA vaccine as the third dose: homologous versus heterologous boost
Get PDFImplementacija treće doze vakcine protiv SARS-CoV-2 u preporuke širom sveta otvorila je polje
istraživanja heterologog pristupa revakcinaciji, odnosno kombinacije primarne serije vakcine i treće
doze različite vakcinalne platforme. Iako je literatura bogata radovima na temu heterologog pristupa,
imunogenost i trajanje humoralnog imunskog odgovora nakon kombinacije inaktivisane BBIBPCorV
i iRNK vakcine nisu dovoljno istraženi. Stoga, cilj ove studije bio je ispitivanje razlike u imunogenosti
i dugotrajnosti humoralnog imunskog odgovora u okviru perioda od šest meseci nakon
treće doze kod homologog (tri doze BNT162b2) i heterologog (BBIBP-CorV/BNT162b2) pristupa
revakcinaciji tokom Omikron talasa u Srbiji. U studiju je uključen 91 ispitanik, od kojih se 55 odlučilo
za homologi a 36 za heterologi pristup.
Serumi ispitanika analizirani su u četiri vremenske tačke: šest meseci nakon prve doze, a zatim tri nedelje,
tri meseca i šest meseci nakon treće doze. IgG antitela specifična za receptor-vezujući domen “šiljastog”
(eng. spike) proteina detektovana su BioMerieux VIDAS SARS-CoV-2 IgG testom. Tri nedelje
nakon treće doze, oba pristupa revakcinaciji dovela su do značajnog porasta u koncentraciji antitela
(p<0.0001). Štaviše, ispitanici koji su se opredelili za heterologu kombinaciju imali su statistički
značajno više koncentracije antitela od homologe grupe, u kontrolnim vremenskim tačkama na tri
nedelje i tri meseca nakon treće doze (p=0.025, p=0.0006). Međutim, značajan pad humoralnog
imunskog odgovora zapažen je tokom vremena kod oba pristupa. Većina infekcija nakon vakcinacije
registrovana je u periodu između tri i šest meseci nakon treće doze (n=22), a ukupna incidencija
ovih infekcija za posmatrani period iznosila je 36.36% (20/55) nakon homologog i 16.67% (6/36)
nakon heterologog pristupa.
Međutim, ispitanici sa potvrđenom infekcijom nakon vakcinacije nisu imali pneumoniju niti su bili
hospitalizovani. Iako je heterologi pristup indukovao više koncentracije antitela, naši rezultati ukazuju
da su i heterologi i homologi pristup indukovali potentan humoralni imunski odgovor i odgovarajuću
zaštitu od hospitalizacije i smrtnog ishoda tokom Omikron talasa. Međutim, opadanje imunskog
odgovora opaženo kod oba vakcinalna pristupa u periodu od šest meseci, kao i konstantna opasnost
od pojave novih pretećih varijanti, ukazuje na potrebu preispitivanja trenutne vakcinalne strategije.Worldwide implementation of the third dose of vaccine against SARS-CoV-2 opened a new field of
research concerning the heterologous boost i.e., the combination of the primary vaccine series and
a different vaccinal platform for the third dose. Although literature is replete with studies of heterologous
boosts, longevity and immunogenicity of the inactivated BBIBP-CorV and mRNA BNT162b2
combination remains under-explored. Thus, the aim of this study was to evaluate the differences in
immunogenicity and longevity of the humoral immune response within six months after the third
dose in both homologous (BNT162b2) and heterologous (BBIBP-CorV/BNT162b2) vaccination setting,
and to assess the real-life data in the middle of the Omicron surge in Serbia.
A total of 91 individuals were included in this study, of which 55 received homologous and 36 heterologous
boost. Serum samples were analyzed at four timepoints: six months after the first dose;
three weeks, three months, and six months after the third dose. Specific IgG antibodies against the
receptor-binding domain of the spike protein were detected using BioMerieux VIDAS SARS-CoV-2
IgG kit. Both groups showed a highly significant increase in antibody concentrations (p<0.0001)
three weeks after the boost.
Furthermore, comparison per timepoint has shown that recipients of heterologous boost had significantly
higher antibody concentrations than homologous group, at three weeks and three months
after the boost (p=0.025, p=0.0006). However, a significant decline in antibody response over time
was noted for both strategies. The majority of breakthrough infections were registered in the period
between three and six months after the boost (n=22).Furthermore, total incidence was estimated at 36.36% (20/55) for homologous group, and 16.67%
(6/36) for heterologous group. Most importantly, none of the recipients of the third dose developed
pneumonia during the breakthrough infection, and none were hospitalized. In conclusion, although
heterologous approach resulted in higher antibody concentrations, our findings imply that both
homologous and heterologous boost induce potent humoral immune response and adequate protection
against hospitalization and death in the Omicron setting. However, waning immune
response registered for both types of boosts within six months and constant threats of new emerging
variants, calls for an update of vaccine strategy
High Prevalence and Genetic Variability of Hepatozoon canis in Grey Wolf (Canis lupus L. 1758) Population in Serbia
Get PDFWild canids are globally recognised as hosts and reservoirs of a large number of ecto- and endoparasites. Data that reveal the importance of the grey wolf (Canis lupus L.1758) in the spread of hepatozoonosis are very scarce. There are a large number of different potential host species that can be infected by Hepatozoon canis, but the most common are domestic and wild carnivores, such as dogs, jackals, foxes, and wolves. In this study, the epidemiological significance of the grey wolf as a host for the pathogen was analysed for the first time in Serbia, as well as the genetic variability of H. canis. The presence of H. canis in wolf spleens has been demonstrated using molecular methods. A total of 107 wolf spleen samples from 30 localities in Serbia were analysed. The presence of H. canis was confirmed in 62 (57.94%) individuals from 26 out of 30 localities. According to the analysis, the sampled H. canis sequences were found to be characterised by a certain heterogeneity. Based on five mutated nucleotide sites in the sequences, H. canis could be divided into five sequence types, S1 to S5. The five sequence types can potentially circulate in grey wolf populations as well as among other domestic and wild canids. This study is the first confirmation of the presence of H. canis in grey wolf populations in Serbia. Considering that the role of this vector-borne disease is poorly researched in wild carnivores, it is very important to indicate the role of this species in the circulation of this pathogen in natural ecosystems
Interplay between Comprehensive Inflammation Indices and Redox Biomarkers in Testicular Germ-Cell Tumors
Get PDFSustained and dysregulated inflammation, concurrent tumor-induced immune suppression, and oxidative stress are profoundly involved in cancer initiation, presentation, and perpetuation. Within this prospective study, we simultaneously analyzed the preoperative indices of systemic inflammatory response and the representative byproducts of oxidative DNA, protein, and lipid damage with the aim of evaluating their clinical relevance among patients diagnosed with testicular germ-cell tumors (GCT). In the analytical cohort (n = 88, median age 34 years), neutrophil-to-lymphocyte ratio (NLR), derived neutrophil-to-lymphocyte ratio (dNLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), systemic immune-inflammation index (SII), systemic inflammation response index (SIRI), and C-reactive protein (CRP) were significantly altered in patients with a higher tumor stage (p < 0.05). Highly suggestive correlations were found between NLR, dNLR, and SII and modified nucleoside 8-OHdG. CRP and albumin-to-globulin ratio (AGR) significantly correlated with thiols group level and maximal tumor dimension (p < 0.05). Based on receiver operating characteristic (ROC) curve analyses, all the evaluated pre-orchiectomy inflammation markers demonstrated strong performance in predicting metastatic disease; optimal cut-off points were determined for each indicator. Although further large-scale studies are warranted, inflammatory and redox indices may both complement the established tumor markers and standard clinicopathological prognostic variables and contribute to enhanced personalized risk-assessment among testicular GCT patients
Утицај инхибиције активности CD73 ензима на вијабилност и диференцијациони потенцијал мезенхимских матичних ћелија костне сржи
No full textCD73, екто-5′ нуклеотидаза, има важну улогу у процесу продукције аденозина и регулације имуносупресије. Истовремено, CD73 је маркер мезенхимских матичних ћелија (ММЋ), међутим значај његове активности за регенеративни потенцијал ММЋ није расветљен. У овој студији испитиван је ефекат инхибиције активности CD73 на вијабилност и диференцијациони потенцијал ММЋ костне сржи (КС-
ММЋ). Резултати МТТ теста показују да инхибиција активности CD73 нема утицај на вијабилност КС-ММЋ с обзиром да нису уочене промене у метаболичкој
активности након третмана различитим концентрацијама инхибитора, α,β-метилен AДП-а (APCP – 10, 20 и 50 μg/ml). Како би се потврдио инхибиторни ефекат ових концентрација APCP на активност CD73, одређена је количина неорганског фосфата, методом са малахит зеленим. Утврђено је да све три испитиване концентрације APCP већ након 15 минута значајно инхибирају активност CD73 ензима. Потенцијал диференцијације КС-ММЋ одређиван је одговарајућим хистохемијским бојењем. Показано је да је активност CD73 превасходно од значаја за остеогену диференцијацију, док код хондрогенезе и адипогенезе нису уочене промене. Наиме, након 7 дана индукције остеогене диференцијације, експресија ензима алкалне фосфатазе значајно је стимулисана при инхибицији активности CD73. Насупрот томе, анализа касне остеогенезе показује да APCP значајно инхибира степен минерализације ванћелијског матрикса, што указује да активност CD73 ензима може имати значајну улогу у регулацији остеогеног потенцијала КС-ММЋ.CD73, ekto-5′ nukleotidaza, ima važnu ulogu u procesu produkcije adenozina i regulacije imunosupresije. Istovremeno, CD73 je marker mezenhimskih matičnih ćelija (MMĆ), međutim značaj njegove aktivnosti za regenerativni potencijal MMĆ nije rasvetljen. U ovoj studiji ispitivan je efekat inhibicije aktivnosti CD73 na vijabilnost i diferencijacioni potencijal MMĆ kostne srži (KS- MMĆ). Rezultati MTT testa pokazuju da inhibicija aktivnosti CD73 nema uticaj na vijabilnost KS-MMĆ s obzirom da nisu uočene promene u metaboličkoj aktivnosti nakon tretmana različitim koncentracijama inhibitora, α,β-metilen ADP-a (APCP – 10, 20 i 50 μg/ml). Kako bi se potvrdio inhibitorni efekat ovih koncentracija APCP na aktivnost CD73, određena je količina neorganskog fosfata, metodom sa malahit zelenim. Utvrđeno je da sve tri ispitivane koncentracije APCP već nakon 15 minuta značajno inhibiraju aktivnost CD73 enzima. Potencijal diferencijacije KS-MMĆ određivan je odgovarajućim histohemijskim bojenjem. Pokazano je da je aktivnost CD73 prevashodno od značaja za osteogenu diferencijaciju, dok kod hondrogeneze i adipogeneze nisu uočene promene. Naime, nakon 7 dana indukcije osteogene diferencijacije, ekspresija enzima alkalne fosfataze značajno je stimulisana pri inhibiciji aktivnosti CD73. Nasuprot tome, analiza kasne osteogeneze pokazuje da APCP značajno inhibira stepen mineralizacije vanćelijskog matriksa, što ukazuje da aktivnost CD73 enzima može imati značajnu ulogu u regulaciji osteogenog potencijala KS-MMĆ
Diagnostic accuracy of magnetic resonance imaging targeted biopsy techniques compared to transrectal ultrasound guided biopsy of the prostate: a systematic review and meta-analysis
Get PDFBackground: Multiparametric MRI localizes cancer in the prostate, allowing for MRI guided biopsy (MRI-GB) 43 alongside transrectal ultrasound-guided systematic biopsy (TRUS-GB). Three MRI-GB approaches exist; visual estimation (COG-TB); fusion software-assisted (FUS-TB) and MRI ‘in-bore’ biopsy (IB-TB). It is unknown whether any of these are superior. We conducted a systematic review and meta-analysis to address three questions. First, whether MRI-GB is superior to TRUS-GB at detecting clinically significant PCa (csPCa). Second, whether MRI-GB is superior to TRUS-GB at avoiding detection of insignificant PCa. Third, whether any MRI-GB strategy is superior at detecting csPCa. Methods: A systematic literature review from 2015 to 2019 was performed in accordance with the START recommendations. Studies reporting PCa detection rates, employing MRI-GB and TRUS-GB were included and evaluated using the QUADAS-2 checklist. 1553 studies were found, of which 43 were included in the meta-analysis. Results: For csPCa, MRI-GB was superior in detection to TRUS-GB (0.83 vs. 0.63 [p = 0.02]). MRI-GB was superior in detection to TRUS-GB at avoiding detection of insignificant PCa. No MRI-GB technique was superior at detecting csPCa (IB-TB 0.87; COG TB 0.81; FUS-TB 0.81, [p = 0.55]). There was significant heterogeneity observed between the included studies. Conclusions: In patients with suspected PCa on MRI, MRI-GB offers superior rates of csPCa detection and reduces detection of insignificant PCa compared to TRUS-GB. No individual MRI-GB technique was found to be better in csPCa detection. Prospective adequately powered randomized controlled trials are required
Modulation of Functional Characteristics of Mesenchymal Stromal Cells by Acellular Preparation of Porcine Hemoglobin
Get PDFExploring the potential usage of the acellular preparation of porcine hemoglobin (PHb) isolated from slaughterhouse blood as a cell culture media component, we have tested its effects on the functional characteristics of stromal cells of mesodermal origin. Human peripheral blood mesenchymal stromal cells (PB-MSCs) were used in this study as a primary cell model system, along with three mouse cell lines (ATDC5, MC3T3-E1, and 3T3-L1), which represent more uniform model systems. We investigated the effect of PHb at concentrations of 0.1, 1, and 10 μM on these cells’ proliferation, cycle, and clonogenic and migratory potential, and found that PHb’s effect depended on both the cell type and its concentration. At the lowest concentration used (0.1 μM), PHb showed the least evident impact on the cell growth and migration; hence, we analyzed its effect on mesenchymal cell multilineage differentiation capacity at this concentration. Even under conditions that induce a specific type of MSC differentiation (cultivation in particular differentiation media), PHb modulated chondrogenic, osteogenic, and adipogenic differentiation, making it a potential candidate for a supplement of MSC culture. Through a model of porcine hemoglobin, these findings also contribute to improving the knowledge of extracellular hemoglobin’s influence on MSCs in vivo