AIMS: Allogeneic haematopoietic stem cell transplantation (allo-HSCT) is a vital treatment for various paediatric malignant and nonmalignant diseases. The conditioning treatment before allo-HSCT is crucial for successful engraftment. Treosulfan, a cytotoxic prodrug, has gained popularity due to its lower toxicity compared to traditional alkylating agents used for conditioning treatment. METHODS: We investigated the relationship between pharmacokinetics and pharmacodynamics of treosulfan in paediatric patients, in a substudy pooling from 2 multicentre phase 2 clinical trials. A total of 83 children with malignant and nonmalignant diseases received treosulfan-based conditioning. Treosulfan exposure and its relationship with clinical outcomes, including survival, graft failure and graft-vs.-host disease, were investigated. RESULTS: Our findings reveal no significant association between treosulfan exposure and the key clinical outcomes or toxicity (P-values between .22 and .99), if the dosing is based on the approved product information. CONCLUSION: These findings suggest that treosulfan exposure after standardized body surface area-based dosing is appropriate in paediatric allo-HSCT.
- MeSH
- alkylační protinádorové látky * škodlivé účinky aplikace a dávkování terapeutické užití farmakokinetika MeSH
- busulfan * analogy a deriváty aplikace a dávkování škodlivé účinky farmakokinetika MeSH
- dítě MeSH
- homologní transplantace * škodlivé účinky MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- nemoc štěpu proti hostiteli * prevence a kontrola MeSH
- předškolní dítě MeSH
- příprava pacienta k transplantaci * metody škodlivé účinky MeSH
- transplantace hematopoetických kmenových buněk * škodlivé účinky MeSH
- výsledek terapie MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze II MeSH
- multicentrická studie MeSH
The superiority of total body irradiation (TBI)-based vs chemotherapy conditioning for allogeneic hematopoietic stem cell transplantation (allo-HSCT) in children with acute lymphoblastic leukemia (ALL) has been established in the international, prospective phase-3 FORUM study, randomizing 417 patients aged 4-18 years in complete remission (CR), who received allo-HSCT from HLA-matched sibling or unrelated donors. Because of the unavailability of TBI in some regions and to accommodate individual contraindications, this study reports the prespecified comparison of outcomes of patients receiving busulfan (BU)- or treosulfan (TREO)-based regimens from 2013 to 2018. Overall, 180 and 128 patients received BU/thiotepa (THIO)/fludarabine (FLU) or TREO/THIO/FLU, respectively. Data were analyzed as of February 2023, with a median follow-up of 4.2 years (range, 0.3-9.1). 3-year overall survival was 0.71 (BU, 95% confidence interval [0.64-0.77]) and 0.72 (TREO, [0.63-0.79]) and 3-year event-free survival was 0.60 (BU, [0.53-0.67]) and 0.55 (TREO, [0.46-0.63]). The 3-year cumulative incidence of relapse (BU, 0.31 [0.25-0.38]; TREO, 0.36 [0.27-0.44]); and nonrelapse mortality (BU, 0.08 [0.05-0.13]; TREO, 0.09 [0.05-0.15]) were comparable. One case of fatal veno-occlusive disease occurred in each group. No significant differences in acute and chronic graft-versus-host disease (GVHD) or 3-year GVHD-free and relapse-free survival (BU, 0.48 [0.41-0.55]; TREO, 0.45 [0.37-0.54]) were recorded. Outcomes for patients in first and second CR were similar irrespective of the regimen. In conclusion, BU/THIO/FLU or TREO/THIO/FLU regimens can be an alternative to TBI for patients with ALL aged >4 years with contraindications or lack of access to TBI. This trial was registered at www.ClinicalTrials.gov as #NCT01949129.
- MeSH
- akutní lymfatická leukemie * terapie mortalita MeSH
- busulfan * analogy a deriváty terapeutické užití MeSH
- dítě MeSH
- homologní transplantace MeSH
- lidé MeSH
- mladiství MeSH
- nemoc štěpu proti hostiteli * etiologie MeSH
- předškolní dítě MeSH
- příprava pacienta k transplantaci * metody MeSH
- transplantace hematopoetických kmenových buněk * škodlivé účinky MeSH
- vidarabin analogy a deriváty terapeutické užití aplikace a dávkování MeSH
- výsledek terapie MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- randomizované kontrolované studie MeSH
- srovnávací studie MeSH
The human body gets exposed to a variety of toxins intentionally or unintentionally on a regular basis from sources such as air, water, food, and soil. Certain toxins can be synthetic, while some are biological. The toxins affect the various parts of the body by activating numerous pro-inflammatory markers, like oxidative stresses, that tend to disturb the normal function of the organs ultimately. Nowadays, people use different types of herbal treatments, viz., herbal drinks that contain different spices for detoxification of their bodies. One such example is turmeric, the most commonly available spice in the kitchen and used across all kinds of households. Turmeric contains curcumin, which is a natural polyphenol. Curcumin is a medicinal compound with different biological activities, such as antioxidant, antineoplastic, anti-inflammatory, and antibacterial. Hence, this review gives a comprehensive insight into the promising potential of curcumin in the detoxification of heavy metals, carbon tetrachloride, drugs, alcohol, acrylamide, mycotoxins, nicotine, and plastics. The review encompasses diverse animal-based studies portraying curcumin's role in nullifying the different toxic effects in various organs of the body (especially the liver, kidney, testicles, and brain) by enhancing defensive signaling pathways, improving antioxidant enzyme levels, inhibiting pro-inflammatory markers activities and so on. Furthermore, this review also argues over curcumin's safety assessment for its utilization as a detoxifying agent.
- MeSH
- akrylamid toxicita MeSH
- antioxidancia farmakologie MeSH
- Curcuma chemie MeSH
- kurkumin * farmakologie chemie MeSH
- lidé MeSH
- metabolická inaktivace MeSH
- mykotoxiny toxicita MeSH
- nikotin MeSH
- oxidační stres účinky léků MeSH
- těžké kovy toxicita MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
While the immunomodulation effects of per- and polyfluoroalkyl substances (PFASs) are described on the level of clinical signs in epidemiological studies (e.g., suppressed antibody response after vaccination), the underlying mechanism has still not been fully elucidated. To reveal mechanisms of PFAS exposure on immunity, we investigated the genome-wide transcriptomic changes of peripheral blood mononuclear cells (PBMCs) responding to PFAS exposure (specifically, exposure to PFPA, PFOA, PFNA, PFDA, PFUnDA, PFHxS, and PFOS). Blood samples and the chemical load in the blood were analyzed under the cross-sectional CELSPAC: Young Adults study. The overall aim of the study was to identify sensitive gene sets and cellular pathways conserved for multiple PFAS chemicals. Transcriptome networks related to adaptive immunity were perturbed by multiple PFAS exposure (i.e., blood levels of at least four PFASs). Specifically, processes tightly connected with late B cell development, such as B cell receptor signaling, germinal center reactions, and plasma cell development, were shown to be affected. Our comprehensive transcriptome analysis identified the disruption of B cell development, specifically the impact on the maturation of antibody-secreting cells, as a potential mechanism underlying PFAS immunotoxicity.
- MeSH
- fluorokarbony * toxicita MeSH
- kyseliny alkansulfonové * MeSH
- látky znečišťující životní prostředí * MeSH
- leukocyty mononukleární MeSH
- lidé MeSH
- mladý dospělý MeSH
- průřezové studie MeSH
- transkriptom MeSH
- Check Tag
- lidé MeSH
- mladý dospělý MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Česká republika MeSH
Despite covering <5% of Earth's terrestrial area, peatlands are crucial for global carbon storage and are hot spots of methane cycling. This study examined the dynamics of aerobic and anaerobic methane oxidation in two undisturbed peatlands: a fen and a spruce swamp forest. Using microcosm incubations, we investigated the effect of ammonium addition, at a level similar to current N pollution processes, on aerobic methane oxidation. Our findings revealed higher methane consumption rates in fen compared to swamp peat, but no effect of ammonium amendment on methane consumption was found. Members of Methylocystis and Methylocella were the predominant methanotrophs in both peatlands. Furthermore, we explored the role of ferric iron and sulfate as electron acceptors for the anaerobic oxidation of methane (AOM). AOM occurred without the addition of an external electron acceptor in the fen, but not in the swamp peat. AOM was stimulated by sulfate and ferric iron addition in the swamp peat and inhibited by ferric iron in the fen. Our findings suggest that aerobic methane oxidizers are not N-limited in these peatlands and that there is an intrinsic potential for AOM in these environments, partially facilitated by ferric iron and sulfate acting as electron acceptors.
Gram-positive bacteria are responsible for a wide range of infections in humans. In most Gram-positive bacteria, sortase A plays a significant role in attaching virulence factors to the bacteria's cell wall. These cell surface proteins play a significant role in virulence and pathogenesis. Even though antibiotics are available to treat these infections, there is a continuous search for an alternative strategy due to an increase in antibiotic resistance. Thus, using anti-sortase drugs to combat these bacterial infections may be a promising approach. Here, we describe a method for targeting Gram-positive bacterial infection by combining curcumin and trans-chalcone as sortase A inhibitors. We have used curcumin and trans-chalcone alone and in combination as a sortase A inhibitor. We have seen ~78%, ~43%, and ~94% inhibition when treated with curcumin, trans-chalcone, and a combination of both compounds, respectively. The compounds have also shown a significant effect on biofilm formation, IgG binding, protein A recruitment, and IgG deposition. We discovered that combining curcumin and trans-chalcone is more effective against Gram-positive bacteria than either compound alone. The present work demonstrated that a combination of these natural compounds could be used as an antivirulence therapy against Gram-positive bacterial infection.
- MeSH
- aminoacyltransferasy * antagonisté a inhibitory metabolismus MeSH
- antibakteriální látky * farmakologie chemie MeSH
- bakteriální proteiny * metabolismus antagonisté a inhibitory MeSH
- biofilmy * účinky léků MeSH
- chalkon * farmakologie chemie MeSH
- cysteinové endopeptidasy * metabolismus MeSH
- faktory virulence metabolismus MeSH
- grampozitivní bakteriální infekce farmakoterapie mikrobiologie MeSH
- grampozitivní bakterie účinky léků MeSH
- kurkumin * farmakologie chemie MeSH
- lidé MeSH
- mikrobiální testy citlivosti MeSH
- virulence účinky léků MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Optimal conditioning prior to allogeneic hematopoietic stem cell transplantation for children with non-malignant diseases is subject of ongoing research. This prospective, randomized, phase 2 trial compared safety and efficacy of busulfan with treosulfan based preparative regimens. Children with non-malignant diseases received fludarabine and either intravenous (IV) busulfan (4.8 to 3.2 mg/kg/day) or IV treosulfan (10, 12, or 14 g/m2/day). Thiotepa administration (2 × 5 mg/kg) was at the investigator's discretion. Primary endpoint was freedom from transplantation (treatment)-related mortality (freedom from TRM), defined as death between Days -7 and +100. Overall, 101 patients (busulfan 50, treosulfan 51) with at least 12 months follow-up were analyzed. Freedom from TRM was 90.0% (95% CI: 78.2%, 96.7%) after busulfan and 100.0% (95% CI: 93.0%, 100.0%) after treosulfan. Secondary outcomes (transplantation-related mortality [12.0% versus 3.9%]) and overall survival (88.0% versus 96.1%) favored treosulfan. Graft failure was more common after treosulfan (n = 11), than after busulfan (n = 2) while all patients were rescued by second procedures except one busulfan patient. CTCAE Grade III adverse events were similar in both groups. This study confirmed treosulfan to be an excellent alternative to busulfan and can be safely used for conditioning treatment in children with non-malignant disease.
- MeSH
- busulfan terapeutické užití MeSH
- dítě MeSH
- lidé MeSH
- nemoc štěpu proti hostiteli * etiologie MeSH
- příprava pacienta k transplantaci metody MeSH
- prospektivní studie MeSH
- transplantace hematopoetických kmenových buněk * metody MeSH
- vidarabin terapeutické užití MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze II MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
Effective treatment of patients with autism spectrum disorder (ASD) is still absent so far. Taurine exhibits therapeutic effects towards the autism-like behaviour in ASD model animals. Here, we determined the mechanism of taurine effect on hippocampal neurogenesis in genetically inbred BTBR T+ tf/J (BTBR) mice, a proposed model of ASD. In this ASD mouse model, we explored the effect of oral taurine supplementation on ASD-like behaviours in an open field test, elevated plus maze, marble burying test, self-grooming test, and three-chamber test. The mice were divided into four groups of normal controls (WT) and models (BTBR), who did or did not receive 6-week taurine supplementation in water (WT, WT+ Taurine, BTBR, and BTBR+Taurine). Neurogenesis-related effects were determined by Ki67 immunofluorescence staining. Western blot analysis was performed to detect the expression of phosphatase and tensin homologue deleted from chromosome 10 (PTEN)/mTOR/AKT pathway-associated proteins. Our results showed that taurine improved the autism-like behaviour, increased the proliferation of hippocampal cells, promoted PTEN expression, and reduced phosphorylation of mTOR and AKT in hippocampal tissue of the BTBR mice. In conclusion, taurine reduced the autism-like behaviour in partially inherited autism model mice, which may be associa-ted with improving the defective neural precursor cell proliferation and enhancing the PTEN-associated pathway in hippocampal tissue.
- MeSH
- autistická porucha * metabolismus farmakoterapie MeSH
- chování zvířat účinky léků MeSH
- fosfohydroláza PTEN * metabolismus MeSH
- hipokampus * metabolismus účinky léků MeSH
- modely nemocí na zvířatech MeSH
- myši MeSH
- neurogeneze * účinky léků MeSH
- poruchy autistického spektra metabolismus farmakoterapie MeSH
- proliferace buněk účinky léků MeSH
- protoonkogenní proteiny c-akt * metabolismus MeSH
- signální transdukce * účinky léků MeSH
- taurin * farmakologie MeSH
- TOR serin-threoninkinasy * metabolismus MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
The purpose of this study was to investigate the acute effect of low, moderate, or high doses of taurine on anaerobic and physiological performance in female rugby players. A total of 16 sub-elite female rugby athletes (21.3 ± 1.5 yr, 168.0 ± 4.9 cm, 62.1 ± 3.5 kg mean ± SD) participated in this research. Following familiarization, participants attended 4 successive tests separated by 72 h in a randomized, counter-balanced, crossover research design. Following an over night fast, participants completed a 5-min 60 Watt warm-up followed by a 30-s Wingate anaerobic test on a cycle ergometer after ingestion of either 2 g taurine (LOWTAU), 4 g (MODTAU), 6 g (HIGHTAU) or placebo (PLA) 1 h before the test. Peak (PP) and mean power (MP) along with heart rate (HR), rating of perceived exertion (RPE), capillary lactate and blood glucose were measured. LOWTAU did not affect PP, MP, HR, lactate and glucose compared to PLA (p > 0.05), while MODTAU improved MP and HIGHTAU improved PP and MP compared to PLA and LOWTAU (p < 0.05). MODTAU and HIGHTAU had little effect on HR, blood lactate and glucose (p > 0.05). A single dose of taurine (MODTAU or HIGHTAU) 1 h prior to competition or training would provide an ergogenic effect on subsequent power output.
- MeSH
- americký fotbal * fyziologie MeSH
- anaerobní práh účinky léků MeSH
- dvojitá slepá metoda MeSH
- klinické křížové studie * MeSH
- krevní glukóza účinky léků metabolismus MeSH
- kyselina mléčná * krev MeSH
- látky zvyšující výkon aplikace a dávkování farmakologie MeSH
- lidé MeSH
- mladý dospělý MeSH
- potravní doplňky MeSH
- sportovní výkon * fyziologie MeSH
- srdeční frekvence * účinky léků MeSH
- taurin * aplikace a dávkování farmakologie MeSH
- tělesná námaha fyziologie účinky léků MeSH
- zahřívací cvičení MeSH
- zátěžový test MeSH
- Check Tag
- lidé MeSH
- mladý dospělý MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- randomizované kontrolované studie MeSH
