Aminophylline, a bronchodilator mainly used to treat severe asthma attacks, may induce arrhythmias. Unfortunately, the underlying mechanism is not well understood. We have recently described a significant, on average inhibitory effect of aminophylline on inward rectifier potassium current IK1, known to substantially contribute to arrhythmogenesis, in rat ventricular myocytes at room temperature. This study was aimed to examine whether a similar effect may be observed under clinically relevant conditions. Experiments were performed using the whole cell patch clamp technique at 37°C on enzymatically isolated healthy porcine and failing human ventricular myocytes. The effect of clinically relevant concentrations of aminophylline (10-100 μM) on IK1 did not significantly differ in healthy porcine and failing human ventricular myocytes. IK1 was reversibly inhibited by ∼20 and 30 % in the presence of 30 and 100 μM aminophylline, respectively, at -110 mV; an analogical effect was observed at -50 mV. To separate the impact of IK1 changes on AP configuration, potentially interfering ionic currents were blocked (L-type calcium and delayed rectifier potassium currents). A significant prolongation of AP duration was observed in the presence of 100 μM aminophylline in porcine cardiomyocytes which well agreed with the effect of a specific IK1 inhibitor Ba2+ (10 μM) and with the result of simulations using a porcine ventricular cell model. We conclude that the observed effect of aminophylline on healthy porcine and failing human IK1 might be involved in its proarrhythmic action. To fully understand the underlying mechanism, potential aminophylline impact on other ionic currents should be explored.
- MeSH
- akční potenciály účinky léků MeSH
- aminofylin * farmakologie MeSH
- draslíkové kanály dovnitř usměrňující * metabolismus MeSH
- kardiomyocyty * účinky léků metabolismus MeSH
- lidé MeSH
- metoda terčíkového zámku MeSH
- prasata MeSH
- srdeční komory účinky léků metabolismus MeSH
- srdeční selhání metabolismus farmakoterapie MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
The combination of aminophylline and salbutamol is frequently used in clinical practice in the treatment of obstructive lung diseases. While the side effects (including arrhythmias) of the individual bronchodilator drugs were well described previously, the side effects of combined treatment are almost unknown. We aimed to study the arrhythmogenic potential of combined aminophylline and salbutamol treatment in vitro. For this purpose, we used the established atomic force microscopy (AFM) model coupled with cardiac organoids derived from human pluripotent stem cells (hPSC-CMs). We focused on the chronotropic, inotropic, and arrhythmogenic effects of salbutamol alone and aminophylline and salbutamol combined treatment. We used a method based on heart rate/beat rate variability (HRV/BRV) analysis to detect arrhythmic events in the hPSC-CM based AFM recordings. Salbutamol and aminophylline had a synergistic chronotropic and inotropic effect compared to the effects of monotherapy. Our main finding was that salbutamol reduced the arrhythmogenic effect of aminophylline, most likely mediated by endothelial nitric oxide synthase activated by beta-2 adrenergic receptors. These findings were replicated and confirmed using hPSC-CM derived from two cell lines (CCTL4 and CCTL12). Data suggest that salbutamol as an add-on therapy may not only deliver a bronchodilator effect but also increase the cardiovascular safety of aminophylline, as salbutamol reduces its arrhythmogenic potential.
- MeSH
- albuterol * farmakologie MeSH
- aminofylin * farmakologie MeSH
- bronchodilatancia farmakologie MeSH
- buněčné linie MeSH
- kardiomyocyty účinky léků metabolismus MeSH
- lidé MeSH
- mikroskopie atomárních sil MeSH
- pluripotentní kmenové buňky účinky léků cytologie MeSH
- srdeční arytmie * farmakoterapie MeSH
- srdeční frekvence účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Neonatal hypoxic-ischemic (HI) brain insult is a major cause of neonatal mortality and morbidity. To assess the underlying pathological mechanisms, we mapped the spatiotemporal changes in polyamine, amino acid, and neurotransmitter levels, following HI insult (by the Rice-Vannucci method) in the brains of seven-day-old rat pups. Matrix-assisted laser desorption/ionization mass spectrometry imaging of chemically modified small-molecule metabolites by 4-(anthracen-9-yl)-2-fluoro-1-methylpyridin-1-ium iodide revealed critical HI-related metabolomic changes of 22 metabolites in 14 rat brain subregions, much earlier than light microscopy detected signs of neuronal damage. For the first time, we demonstrated excessive polyamine oxidation and accumulation of 3-aminopropanal in HI neonatal brains, which was later accompanied by neuronal apoptosis enhanced by increases in glycine and norepinephrine in critically affected brain regions. Specifically, putrescine, cadaverine, and 3-aminopropanal increased significantly as early as 12 h postinsult, mainly in motor and somatosensory cortex, hippocampus, and midbrain, followed by an increase in norepinephrine 24 h postinsult, which was predominant in the caudate putamen, the region most vulnerable to HI. The decrease of γ-aminobutyric acid (GABA) and the continuous dysregulation of the GABAergic system together with low taurine levels up to 36 h sustained progressive neurodegenerative cellular processes. The molecular alterations presented here at the subregional rat brain level provided unprecedented insight into early metabolomic changes in HI-insulted neonatal brains, which may further aid in the identification of novel therapeutic targets for the treatment of neonatal HI encephalopathy.
- MeSH
- krysa rodu rattus MeSH
- metabolomika MeSH
- mozek * metabolismus MeSH
- mozková hypoxie a ischemie * metabolismus patologie MeSH
- neurony metabolismus MeSH
- neurotransmiterové látky * metabolismus MeSH
- novorozená zvířata * MeSH
- polyaminy * metabolismus MeSH
- potkani Sprague-Dawley MeSH
- spektrometrie hmotnostní - ionizace laserem za účasti matrice metody MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Circulating-tumor DNA (ctDNA) and prostate-specific membrane antigen (PSMA) ligand positron-emission tomography (PET) enable minimal-invasive prostate cancer (PCa) detection and survival prognostication. The present study aims to compare their tumor discovery abilities and prognostic values. METHODS: One hundred thirty men with confirmed PCa (70.5 ± 8.0 years) who underwent [68Ga]Ga-PSMA-11 PET/CT (184.8 ± 19.7 MBq) imaging and plasma sample collection (March 2019-August 2021) were included. Plasma-extracted cell-free DNA was subjected to whole-genome-based ctDNA analysis. PSMA-positive tumor lesions were delineated and their quantitative parameters extracted. ctDNA and PSMA PET/CT discovery rates were compared, and the prognostic value for overall survival (OS) was evaluated. RESULTS: PSMA PET discovery rates according to castration status and PSA ranges did differ significantly (P = 0.013, P < 0.001), while ctDNA discovery rates did not (P = 0.311, P = 0.123). ctDNA discovery rates differed between localized and metastatic disease (P = 0.013). Correlations between ctDNA concentrations and PSMA-positive tumor volume (PSMA-TV) were significant in all (r = 0.42, P < 0.001) and castration-resistant (r = 0.65, P < 0.001), however not in hormone-sensitive patients (r = 0.15, P = 0.249). PSMA-TV and ctDNA levels were associated with survival outcomes in the Logrank (P < 0.0001, P < 0.0001) and multivariate Cox regression analysis (P = 0.0023, P < 0.0001). CONCLUSION: These findings suggest that PSMA PET imaging outperforms ctDNA analysis in detecting prostate cancer across the whole spectrum of disease, while both modalities are independently highly prognostic for survival outcomes.
- MeSH
- cirkulující nádorová DNA * krev genetika MeSH
- EDTA * analogy a deriváty MeSH
- izotopy gallia * MeSH
- lidé středního věku MeSH
- lidé MeSH
- nádory prostaty * diagnostické zobrazování genetika krev MeSH
- oligopeptidy MeSH
- PET/CT * MeSH
- prognóza MeSH
- průřezové studie MeSH
- radioizotopy galia * MeSH
- senioři MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- Publikační typ
- časopisecké články MeSH
- srovnávací studie MeSH
Multidrug resistant (MDR) bacteria are recognized to be one of the most important problems in public health. The outer membrane permeability is a critical intrinsic mechanism of bacterial resistance. In addition, bacteria produce a small number of dormant persister cells causing multidrug tolerance that reduces antimicrobial efficacy. This study aimed to evaluate the inhibitory effects of the combination of aromatic isothiocyanates (ITCs) with membrane-active agents on bacterial persisters and MDR Gram-negative bacteria. Our study demonstrated that membrane-active agents, particularly ethylenediaminetetraacetic acid (EDTA) synergistically enhanced the inhibitory activity of aromatic benzyl ITC and phenethyl ITC against most Gram-negative bacteria strains with fractional inhibitory concentration index values ranging from 0.18 to 0.5 and 0.16 to 0.5, respectively, and contributed to an 8- to 64-fold minimal inhibitory concentration reduction compared with those of aromatic ITCs alone. The EDTA-aromatic ITCs combination effectively reduced the survival rates of tested bacteria and significantly eradicated bacterial persisters (p = 0.033 and 0.037, respectively). The growth kinetics analysis also supported the enhanced inhibitory effect of EDTA-aromatic ITCs combination against tested bacteria. Our results suggested an alternate treatment strategy against Gram-negative bacteria, promoting the entry of aromatic ITCs into bacterial cytoplasm to facilitate bacterial clearance and thus preventing the development of bacterial resistance.
- MeSH
- antibakteriální látky * farmakologie MeSH
- EDTA * farmakologie MeSH
- gramnegativní bakterie * účinky léků MeSH
- isothiokyanatany * farmakologie MeSH
- mikrobiální testy citlivosti * MeSH
- mikrobiální viabilita účinky léků MeSH
- mnohočetná bakteriální léková rezistence * účinky léků MeSH
- permeabilita buněčné membrány účinky léků MeSH
- synergismus léků MeSH
- vnější bakteriální membrána účinky léků MeSH
- Publikační typ
- časopisecké články MeSH
Functional imaging with prostate-specific membrane antigen (PSMA) ligands has emerged as the standard imaging method for prostate cancer (PCA). In parallel, the analysis of blood-derived, cell-free DNA (cfDNA) has been shown to be a promising quantitative biomarker of PCA aggressiveness and patient outcome. This study aimed to evaluate the relationship and prognostic value of cfDNA concentrations and the PSMA-positive tumor volume (PSMA-TV) in men with PCA undergoing [68Ga]Ga-PSMA-11 PET/CT imaging. Methods: We recruited 148 men with histologically proven PCA (mean age, 70.7 ± 7.7 y) who underwent [68Ga]Ga-PSMA-11 PET/CT (184.9 ± 18.9 MBq) and blood sampling between March 2019 and August 2021. Among these, 74 (50.0%) had hormone-sensitive PCA and 74 (50.0%) had castration-resistant PCA (CRPC). All patients provided written informed consent before blood sample collection and imaging. The cfDNA was extracted and quantified, and PSMA-expressing tumor lesions were delineated to extract the PSMA-TVs. The Spearman coefficient assessed correlations between PSMA-TV and cfDNA concentrations and cfDNA's relation with clinical parameters. The Kruskal-Wallis test examined the mean cfDNA concentration differences based on PSMA-TV quartiles for significantly correlated patient groups. Log-rank and multivariate Cox regression analyses evaluated the prognostic significance of high and low cfDNA and PSMA-TV levels for overall survival. Results: Weak positive correlations were found between cfDNA concentration and PSMA-TV in the overall group (r = 0.16, P = 0.049) and the CRPC group (r = 0.31, P = 0.007) but not in hormone-sensitive PCA patients (r = -0.024, P = 0.837). In the CRPC cohort, cfDNA concentrations significantly differed between PSMA-TV quartiles 4 and 1 (P = 0.002) and between quartiles 4 and 2 (P = 0.016). Survival outcomes were associated with PSMA-TV (P < 0.0001, P = 0.004) but not cfDNA (P = 0.174, P = 0.12), as per the log-rank and Cox regression analysis. Conclusion: These findings suggest that cfDNA might serve as a biomarker of advanced, aggressive CRPC but does not reliably reflect total tumor burden or prognosis. In comparison, [68Ga]Ga-PSMA-11 PET/CT provides a highly granular and prognostic assessment of tumor burden across the spectrum of PCA disease progression.
- MeSH
- biologické markery MeSH
- EDTA MeSH
- hormony MeSH
- izotopy gallia MeSH
- lidé středního věku MeSH
- lidé MeSH
- nádory prostaty rezistentní na kastraci * diagnostické zobrazování MeSH
- nádory prostaty * diagnostické zobrazování patologie MeSH
- PET/CT metody MeSH
- prognóza MeSH
- prospektivní studie MeSH
- radioizotopy galia MeSH
- retrospektivní studie MeSH
- senioři MeSH
- tumor burden MeSH
- volné cirkulující nukleové kyseliny * MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- Publikační typ
- časopisecké články MeSH
Impairments of N-methyl-D-aspartate receptor (NMDAR) activity have been implicated in several neuropsychiatric disorders, with pharmacological inhibition of NMDAR-mediated currents and associated neurobehavioral changes considered as a model of schizophrenia. We analyzed the effects of brief and long-term exposure of rat cortical cultures to the most prevalent endogenous modulators of NMDAR (kynurenic acid, pregnenolone sulfate, spermidine, and zinc) on neuronal viability, stimulation-induced release of glutamate, and dendritic morphology with synaptic density. Both, glutamate release and neuronal viability studies revealed no difference between the test and control groups. No differences were also observed in the number of dendritic branching and length, or density of synaptic connections and neuronal soma size. Comparison of the extent of dendritic projections and branching patterns, however, revealed enhanced distal arborization with the expansion of the dendritic area under prolonged treatment of cultures with physiological concentrations of NMDAR modulators, with differences reaching significance in spermidine and pregnenolone sulfate tests. Measurements of the density of glutamatergic synapses showed consistency across all neuronal groups, except those treated with pregnenolone sulfate, which showed a reduction of PSD-95-positive elements. Overall, our data suggest that constitutive glutamatergic activity mediated by NMDAR controls the dendritic field expansion and can influence the integrative properties of cortical neurons.
Pancreatic polypeptide cell hyperplasia (PPY-H) is a multiplication of the neuroendocrine cells producing pancreatic polypeptide (PPY). The development and role of PPY-H and its corresponding clinical and imaging findings still need to be fully elucidated. We present 12 cases of PPY-H accompanying pancreatic neuroendocrine neoplasias (NEN). PPY-H was analyzed with the help of immunohistochemistry and confocal microscopy; preoperative clinical data and imaging studies were evaluated retrospectively. We observed PPY-H emerging from pancreatic ducts, and in some cases, we observed simultaneous NKX6.1 positivity in ducts and PPY-H. Additional clinical-pathological correlations suggests that gastrointestinal symptoms (e.g., epigastric pain and cholestasis) could be more related to PPY-H than to NEN hormonal production. In particular cases, SSTR2 expression was strong in PPY-H and correlated with distinguishable accumulation of activity next to NEN on 99 mTc EDDA/Hynic-TOC SPECT/CT. In another case, 18F-FDG-PET/CT showed increased metabolic activity in the area of PPY-H surrounding NEN. Our data suggest that PPY-H originates in the lining of pancreatic ducts. Confirmation of SSTR2 in PPY-H, using immunohistochemistry, suggests the utility of 99 mTc EDDA/Hynic-TOC or 68Ga-DOTA radiotracers in clinical diagnostics; however, studies with larger cohort are needed.
- MeSH
- EDTA analogy a deriváty MeSH
- hyperplazie MeSH
- lidé MeSH
- nádory slinivky břišní * patologie MeSH
- neuroendokrinní nádory * patologie MeSH
- nukleární lékařství * MeSH
- organotechneciové sloučeniny MeSH
- pankreatický polypeptid MeSH
- PET/CT MeSH
- retrospektivní studie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Androgen deprivation therapy (ADT) is known to influence the prostate-specific membrane antigen (PSMA) expression of prostate cancer, potentially complicating the interpretation of PSMA ligand PET findings and affecting PSMA radioligand therapy. However, the impact of ADT on PSMA ligand biodistribution in nontumorous organs is not well understood. Methods: Men (n = 112) with histologically proven prostate cancer who underwent 68Ga-PSMA-HBED-CC (68Ga-PSMA-11) PET/CT between November 2015 and July 2021 at the Medical University Vienna with known ADT status were retrospectively recruited. Fifty-six patients were on gonadotropin-releasing hormone-interfering ADT at the time of imaging (ADT group), whereas 56 patients with no history of ADT served as a control group. Physiologically PSMA-expressing organs (salivary glands, kidneys, liver, and spleen) were delineated, and their uptake was compared according to their data distributions. Multivariate regression analysis assessed the relationship between renal, hepatic, splenic, and salivary gland uptake and the explanatory variables metabolic tumor volume, glomerular filtration rate, and ADT status. Results: ADT was associated with lower levels of PSMA uptake in the kidneys (SUVmean: Δ[ADT - control] = -7.89; 95% CI, -10.73 to -5.04; P < 0.001), liver (SUVpeak: Δ[ADT - control] = -2.3; 95% CI, -5.72 to -0.93; P = 0.003), spleen (SUVpeak: Δ[ADT - control] = -1.27; 95% CI, -3.61 to -0.16; P = 0.033), and salivary glands (SUVmean: Δ[ADT - control] = -1.04; 95% CI, -2.48 to -0.13; P = 0.027). In a multivariate analysis, ADT was found to be associated with lower renal (SUVmean: β = -7.95; 95% CI, -11.06 to -4.84; P < 0.0001), hepatic (SUVpeak: β = -7.85; 95% CI, -11.78 to -3.91; P < 0.0001), splenic (SUVpeak: β = -5.83; 95% CI, -9.95 to -1.7; P = 0.006), and salivary gland (SUVmean: β = -1.47; 95% CI, -2.76 to -0.17; P = 0.027) uptake. A higher glomerular filtration rate was associated with a higher renal SUVmean (β = 0.16; 95% CI, 0.05 to 0.26; P = 0.0034). Conclusion: These findings suggest that ADT systemically modulates PSMA expression, which may have implications for treatment-optimizing and side-effect-minimizing strategies for PSMA radioligand therapies, particularly those using more potent 225Ac-labeled PSMA conjugates.
- MeSH
- antagonisté androgenů terapeutické užití MeSH
- EDTA MeSH
- lidé MeSH
- ligandy MeSH
- nádory prostaty * patologie MeSH
- PET/CT metody MeSH
- radioizotopy galia MeSH
- retrospektivní studie MeSH
- tkáňová distribuce MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
To investigate the use of kinetic parameters derived from direct Patlak reconstructions of [68Ga]Ga-PSMA-11 positron emission tomography/computed tomography (PET/CT) to predict the histological grade of malignancy of the primary tumor of patients with prostate cancer (PCa). Thirteen patients (mean age 66 ± 10 years) with a primary, therapy-naïve PCa (median PSA 9.3 [range: 6.3-130 μg/L]) prior radical prostatectomy, were recruited in this exploratory prospective study. A dynamic whole-body [68Ga]Ga-PSMA-11 PET/CT scan was performed for all patients. Measured quantification parameters included Patlak slope (Ki: absolute rate of tracer consumption) and Patlak intercept (Vb: degree of tracer perfusion in the tumor). Additionally, the mean and maximum standardized uptake values (SUVmean and SUVmax) of the tumor were determined from a static PET 60 min post tracer injection. In every patient, initial PSA (iPSA) values that were also the PSA level at the time of the examination and final histology results with Gleason score (GS) grading were correlated with the quantitative readouts. Collectively, 20 individual malignant prostate lesions were ascertained and histologically graded for GS with ISUP classification. Six lesions were classified as ISUP 5, two as ISUP 4, eight as ISUP 3, and four as ISUP 2. In both static and dynamic PET/CT imaging, the prostate lesions could be visually distinguished from the background. The average values of the SUVmean, slope, and intercept of the background were 2.4 (±0.4), 0.015 1/min (±0.006), and 52% (±12), respectively. These were significantly lower than the corresponding parameters extracted from the prostate lesions (all p < 0.01). No significant differences were found between these values and the various GS and ISUP (all p > 0.05). Spearman correlation coefficient analysis demonstrated a strong correlation between static and dynamic PET/CT parameters (all r ≥ 0.70, p < 0.01). Both GS and ISUP grading revealed only weak correlations with the mean and maximum SUV and tumor-to-background ratio derived from static images and dynamic Patlak slope. The iPSA demonstrated no significant correlation with GS and ISUP grading or with dynamic and static PET parameter values. In this cohort of mainly high-risk PCa, no significant correlation between [68Ga]Ga-PSMA-11 perfusion and consumption and the aggressiveness of the primary tumor was observed. This suggests that the association between SUV values and GS may be more distinctive when distinguishing clinically relevant from clinically non-relevant PCa.
- MeSH
- EDTA analogy a deriváty MeSH
- izotopy gallia MeSH
- lidé středního věku MeSH
- lidé MeSH
- nádory prostaty * diagnostické zobrazování chirurgie patologie MeSH
- PET/CT * metody MeSH
- pilotní projekty MeSH
- prospektivní studie MeSH
- prostatektomie * metody MeSH
- prostatický specifický antigen metabolismus krev MeSH
- radiofarmaka MeSH
- radioizotopy galia * MeSH
- senioři MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- Publikační typ
- časopisecké články MeSH
