OBJECTIVE: We comprehensively characterized a large pediatric cohort with focal cortical dysplasia (FCD) type 1 to expand the phenotypic spectrum and to identify predictors of postsurgical outcomes. METHODS: We included pediatric patients with histopathological diagnosis of isolated FCD type 1 and at least 1 year of postsurgical follow-up. We systematically reanalyzed clinical, electrophysiological, and radiological features. The results of this reanalysis served as independent variables for subsequent statistical analyses of outcome predictors. RESULTS: All children (N = 31) had drug-resistant epilepsy with varying impacts on neurodevelopment and cognition (presurgical intelligence quotient [IQ]/developmental quotient scores = 32-106). Low presurgical IQ was associated with abnormal slow background electroencephalographic (EEG) activity and disrupted sleep architecture. Scalp EEG showed predominantly multiregional and often bilateral epileptiform activity. Advanced epilepsy magnetic resonance imaging (MRI) protocols identified FCD-specific features in 74.2% of patients (23/31), 17 of whom were initially evaluated as MRI-negative. In six of eight MRI-negative cases, fluorodeoxyglucose-positron emission tomography (PET) and subtraction ictal single photon emission computed tomography coregistered to MRI helped localize the dysplastic cortex. Sixteen patients (51.6%) underwent invasive EEG. By the last follow-up (median = 5 years, interquartile range = 3.3-9 years), seizure freedom was achieved in 71% of patients (22/31), including seven of eight MRI-negative patients. Antiseizure medications were reduced in 21 patients, with complete withdrawal in six. Seizure outcome was predicted by a combination of the following descriptors: age at epilepsy onset, epilepsy duration, long-term invasive EEG, and specific MRI and PET findings. SIGNIFICANCE: This study highlights the broad phenotypic spectrum of FCD type 1, which spans far beyond the narrow descriptions of previous studies. The applied multilayered presurgical approach helped localize the epileptogenic zone in many previously nonlesional cases, resulting in improved postsurgical seizure outcomes, which are more favorable than previously reported for FCD type 1 patients.

• MeSH
• dítě MeSH
• elektroencefalografie * metody   MeSH
• epilepsie MeSH
• fokální kortikální dysplazie MeSH
• kohortové studie MeSH
• kojenec MeSH
• lidé MeSH
• magnetická rezonanční tomografie * MeSH
• malformace mozkové kůry, skupina I * chirurgie   komplikace   diagnostické zobrazování   MeSH
• malformace mozkové kůry chirurgie   komplikace   diagnostické zobrazování   MeSH
• mladiství MeSH
• pozitronová emisní tomografie MeSH
• předškolní dítě MeSH
• refrakterní epilepsie * chirurgie   diagnostické zobrazování   patofyziologie   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

AIMS: Liver cytochromes (CYPs) play an important role in drug metabolism but display a large interindividual variability resulting both from genetic and environmental factors. Most drug dose adjustment guidelines are based on genetics performed in healthy volunteers. However, hospitalized patients are not only more likely to be the target of new prescriptions and drug treatment modifications than healthy volunteers, but will also be more subject to polypharmacy, drug-drug interactions, or to suffer from disease or inflammation affecting CYP activities. METHODS: We compared predicted phenotype based on genetic data and measured phenotype using the Geneva cocktail to determine the extent of drug metabolizing enzyme variability in a large population of hospitalized patients (>500) and healthy young volunteers (>300). We aimed to assess the correlation between predicted and measured phenotype in the two populations. RESULTS: We found that, even in cases where the genetically predicted metabolizer group correlates well with measured CYP activity at group level, this prediction lacks accuracy for the determination of individual metabolizer capacities. Drugs can have a profound impact on CYP activity, but even after combining genetic and drug treatment information, the activity of a significant proportion of extreme metabolizers could not be explained. CONCLUSIONS: Our results support the use of measured metabolic ratios in addition to genotyping for accurate determination of individual metabolic capacities to guide personalized drug prescription.

• MeSH
• dospělí MeSH
• fenotyp MeSH
• genotyp MeSH
• hospitalizace MeSH
• léčivé přípravky metabolismus   MeSH
• lékové interakce MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• senioři MeSH
• systém (enzymů) cytochromů P-450 * genetika   metabolismus   MeSH
• zdraví dobrovolníci pro lékařské studie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.SEQUOIA (ClinicalTrials.gov identifier: NCT03336333) is a phase III, randomized, open-label trial that compared the oral Bruton tyrosine kinase inhibitor zanubrutinib to bendamustine plus rituximab (BR) in treatment-naïve patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). The initial prespecified analysis (median follow-up, 26.2 months) and subsequent analysis (43.7 months) found superior progression-free survival (PFS; the primary end point) in patients who received zanubrutinib compared with BR. At a median follow-up of 61.2 months, median PFS was not reached in zanubrutinib-treated patients; median PFS was 44.1 months in BR-treated patients (hazard ratio [HR], 0.29; one-sided P = .0001). Prolonged PFS was seen with zanubrutinib versus BR in patients with mutated immunoglobulin heavy-chain variable region (IGHV) genes (HR, 0.40; one-sided P = .0003) and unmutated IGHV genes (HR, 0.21 [95% CI, 0.14 to 0.33]; one-sided P < .0001). Median overall survival (OS) was not reached in either treatment arm; estimated 60-month OS rates were 85.8% and 85.0% in zanubrutinib- and BR-treated patients, respectively. No new safety signals were detected. Adverse events were as expected with zanubrutinib; rate of atrial fibrillation was 7.1%. At a median follow-up of 61.2 months, the results supported the initial SEQUOIA findings and suggested that zanubrutinib was a favorable treatment option for untreated patients with CLL/SLL.

• MeSH
• bendamustin hydrochlorid * aplikace a dávkování   terapeutické užití   MeSH
• chronická lymfatická leukemie * farmakoterapie   mortalita   MeSH
• doba přežití bez progrese choroby MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• následné studie MeSH
• piperidiny terapeutické užití   aplikace a dávkování   škodlivé účinky   MeSH
• protokoly protinádorové kombinované chemoterapie * terapeutické užití   škodlivé účinky   MeSH
• pyrazoly * terapeutické užití   aplikace a dávkování   škodlivé účinky   MeSH
• pyrimidiny * terapeutické užití   aplikace a dávkování   škodlivé účinky   MeSH
• rituximab * aplikace a dávkování   terapeutické užití   škodlivé účinky   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH
• srovnávací studie MeSH

Despite the availability of new drugs on the clinics in recent years, drug-resistant epilepsy remains an unresolved challenge for healthcare, and one-third of epilepsy patients remain refractory to anti-seizure medications. Gene therapy in experimental models has emerged as effective treatment targeting specific neuronal populations in the epileptogenic focus. When combined with an external chemical activator using chemogenetics, it also becomes an "on-demand" treatment. Here, we evaluate a targeted and specific chemogenetic therapy, the PSAM/PSEM system, which holds promise as a potential candidate for clinical application in treating drug-resistant epilepsy. We show that the inert ligand uPSEM817, which selectively activates the chloride-permeable channel PSAM4-GlyR, effectively reduces the number of depolarization-induced action potentials in vitro. This effect is likely due to the shunting of depolarizing currents, as evidenced by decreased membrane resistance in these cells. In organotypic slices, uPSEM817 decreased the number of bursts and peak amplitude of events of spontaneous epileptiform activity. Although administration of uPSEM817 in vivo did not significantly alter electrographic seizures in a male mouse model of temporal lobe epilepsy, it did demonstrate a strong trend toward reducing the frequency of interictal epileptiform discharges. These findings indicate that PSAM4-GlyR-based chemogenetics holds potential as an anti-seizure strategy, although further refinement is necessary to enhance its efficacy.

• MeSH
• akční potenciály účinky léků   MeSH
• epilepsie patofyziologie   genetika   farmakoterapie   terapie   metabolismus   MeSH
• genetická terapie metody   MeSH
• hipokampus * metabolismus   MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• myši MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Mismatch repair-deficient (dMMR) endometrial cancer (EC) is an inflamed phenotype with poor outcomes when meeting high-risk criteria and limited treatment options in the adjuvant setting. We report protocol-prespecified subgroup analysis of patients with dMMR tumors from the phase III ENGOT-en11/GOG-3053/KEYNOTE-B21 study (ClinicalTrials.gov identifier: NCT04634877) in newly diagnosed, high-risk EC after surgery with curative intent. Patients were randomly assigned to pembrolizumab 200 mg or placebo (six cycles) plus carboplatin-paclitaxel (four to six cycles) once every 3 weeks, then pembrolizumab 400 mg or placebo once every 6 weeks (six cycles), respectively. MMR status was a stratification factor. Patients received radiotherapy at investigator discretion. Investigator-assessed disease-free survival (DFS) was a primary end point. No formal hypothesis testing was performed for subgroup analysis. In the intention-to-treat population, 141 patients in the pembrolizumab arm and 140 in the placebo arm had dMMR tumors. At this interim analysis, hazard ratio for DFS favored pembrolizumab (0.31 [95% CI, 0.14 to 0.69]); median DFS was not reached in either group. Two-year DFS rates were 92.4% (95% CI, 84.4 to 96.4) and 80.2% (95% CI, 70.8 to 86.9), respectively. No new safety signals occurred. Longer-term follow-up of outcomes will be evaluated at final analysis. Preplanned subgroup analysis on the basis of the study's stratification factors suggests that pembrolizumab plus chemotherapy improves DFS and is clinically relevant for patients with dMMR tumors in the curative-intent setting.

• MeSH
• adjuvantní chemoterapie MeSH
• dospělí MeSH
• dvojitá slepá metoda MeSH
• humanizované monoklonální protilátky * terapeutické užití   aplikace a dávkování   škodlivé účinky   MeSH
• karboplatina aplikace a dávkování   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádory endometria * patologie   farmakoterapie   mortalita   terapie   MeSH
• oprava chybného párování bází DNA * MeSH
• paclitaxel * aplikace a dávkování   MeSH
• přežití bez známek nemoci MeSH
• protokoly protinádorové kombinované chemoterapie * terapeutické užití   MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH

The rapid evolution and spread of multidrug resistance among bacterial pathogens has significantly outpaced the development of new antibiotics, underscoring the urgent need for alternative therapies. Antimicrobial photodynamic therapy and antimicrobial sonodynamic therapy have emerged as promising treatments. Antimicrobial photodynamic therapy relies on the interaction between light and a photosensitizer to produce reactive oxygen species, which are highly cytotoxic to microorganisms, leading to their destruction without fostering resistance. Antimicrobial sonodynamic therapy, a novel variation, substitutes ultrasound for light to activate the sonosensitizers, expanding the therapeutic reach. To increase the efficiency of antimicrobial photodynamic therapy and antimicrobial sonodynamic therapy, the combination of these two methods, known as antimicrobial photo-sonodynamic therapy, is currently being explored and considered a promising approach. Recent advances, particularly in the application of nanomaterials, have further enhanced the efficacy of these therapies. Nanosensitizers, due to their improved reactive oxygen species generation and targeted delivery, offer significant advantages in overcoming the limitations of conventional sensitizers. These breakthroughs provide new avenues for treating bacterial infections, especially multidrug-resistant strains and biofilm-associated infections. Continued research, including comprehensive clinical studies, is crucial to optimizing nanomaterial-based antimicrobial photo-sonodynamic therapy for clinical use, ensuring their effectiveness in real-world applications.

• MeSH
• antibakteriální látky * farmakologie   MeSH
• Bacteria účinky léků   MeSH
• bakteriální infekce * farmakoterapie   mikrobiologie   terapie   MeSH
• biofilmy účinky léků   MeSH
• fotochemoterapie * metody   MeSH
• fotosenzibilizující látky * farmakologie   MeSH
• lidé MeSH
• nanočástice chemie   MeSH
• nanostruktury chemie   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• ultrazvuková terapie MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Článek se zabývá definicí a kategorizací digitálních her. Nejprve analyzuje dosavadní dostupné definice a upozorňuje na jejich úskalí v přesnosti a následné použitelnosti pro vymezení pojmu digitální hra. V návaznosti na tuto analýzu si klade za cíl poskytnout přesnější a komplexnější definici digitálních her založenou na kompilaci předešlých teoretických tezí. Dále se článek věnuje problematice kategorizace digitálních her, upozorňuje na nejednoznačnost označování herních žánrů, která může vést k zavádějícím označením a neshodám v herní komunitě i mezi odborníky. Digitální hry často kombinují prvky několika žánrů, což činí jejich tradiční zařazení obtížným. V reakci na tuto situaci přináší článek návrh alternativní kategorizace se zaměřením na primární herní smyčku, díky čemuž reflektuje současné trendy v herním průmyslu a umožňuje flexibilnější rozdělení her podle jejich dominantních mechanismů. Základní kategorizaci pak doplňuje žánrovými kombinacemi, specifickými doplňkovými žánry, otevřeností herního světa, sociálními aspekty, platebními modely a perspektivami pohledu. Článek reaguje na aktuální společenskou a odbornou potřebu zpřehlednění terminologie v oblasti digitálních her, což je nezbytné nejen pro vědecké bádání, ale i pro preventivní intervence a efektivní pedagogickou praxi. Systematické vymezení pojmů a žánrových kategorií přispívá k lepší orientaci odborníků napříč různými oblastmi, umožňuje přesnější diagnostiku fenoménu nadměrného hraní a zvyšuje srozumitelnost komunikace mezi výzkumníky, terapeuty, odborníky v praxi a jejich klienty. Článek tak nabízí důležitý nástroj pro mezioborové porozumění a efektivní aplikaci poznatků v praxi. Závěrem studie zdůrazňuje nutnost průběžné revize definic i způsobů kategorizace digitálních her s ohledem na jejich nepřetržitý vývoj. Digitální hry se neustále proměňují a rozšiřují o nové prvky, a proto je důležité, aby i teoretické rámce reflektovaly tyto změny a umožňovaly přesnější uchopení tohoto dynamického fenoménu.

The article focuses on the definition and categorization of digital games. It first analyzes existing definitions and highlights their shortcomings in terms of accuracy and applicability for defining the concept of a digital game. Following this analysis, the paper aims to provide a more precise and comprehensive definition of digital games, based on a synthesis of previous theoretical approaches. The article further examines the challenges of categorizing digital games, emphasizing the ambiguity in labeling game genres, which can lead to misleading classifications and disagreements within both the gaming community and experts. Digital games frequently combine elements from multiple genres, making their traditional classification difficult. In response to this issue, the article proposes an alternative categorization approach centred on the primary gameplay loop, reflecting current trends in the gaming industry and enabling a more flexible classification of games based on their dominant mechanics. This core categorization is complemented by genre combinations, specific sub-genres, game world openness, social aspects, monetization models, and perspectives of gameplay. The article responds to the current social and professional need to clarify terminology in the field of digital games, which is essential not only for scientific research but also for preventive interventions and effective pedagogical practice. The systematic definition of terms and genre categories contributes to better orientation for experts across different fields, enables more accurate diagnosis of the phenomenon of excessive gaming, and increases the clarity of communication between researchers, therapists, practitioners, and their clients. The article thus offers an important tool for interdisciplinary understanding and the effective application of knowledge in practice. Finally, the article emphasizes the necessity of continuously revising the definitions and classification methods of digital games in light of their ongoing evolution. As digital games constantly change and incorporate new elements, it is crucial that theoretical frameworks adapt to these transformations, ensuring a more accurate understanding of this dynamic phenomenon.

The small-molecule alkaloid halofuginone (HF) is obtained from febrifugine. Recent studies on HF have aroused widespread attention owing to its universal range of noteworthy biological activities and therapeutic functions, which range from parasite infections and fibrosis to autoimmune diseases. In particular, HF is believed to play an excellent anticancer role by suppressing the proliferation, adhesion, metastasis, and invasion of cancers. This review supports the goal of demonstrating various anticancer effects and molecular mechanisms of HF. In the studies covered in this review, the anticancer molecular mechanisms of HF mainly included transforming growth factor-β (TGF-β)/Smad-3/nuclear factor erythroid 2-related factor 2 (Nrf2), serine/threonine kinase proteins (Akt)/mechanistic target of rapamycin complex 1(mTORC1)/wingless/integrated (Wnt)/β-catenin, the exosomal microRNA-31 (miR-31)/histone deacetylase 2 (HDAC2) signaling pathway, and the interaction of the extracellular matrix (ECM) and immune cells. Notably, HF, as a novel type of adenosine triphosphate (ATP)-dependent inhibitor that is often combined with prolyl transfer RNA synthetase (ProRS) and amino acid starvation therapy (AAS) to suppress the formation of ribosome, further exerts a significant effect on the tumor microenvironment (TME). Additionally, the combination of HF with other drugs or therapies obtained universal attention. Our results showed that HF has significant potential for clinical cancer treatment.

• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Personalizace a individualizace terapie a diagnostiky pomocí pokročilých in vitro modelů využívajících tkáň pacienta je budoucností klinické medicíny. Tyto modely zahrnují organoidy, tedy trojrozměrné in vitro modely odvozené z dospělých nebo indukovaných pluripotentních kmenových buněk, modely orgánů na čipu a další kombinované modely. Kmenové buňky pro založení těchto kultur lze získat od pacienta za pomocí minimálně invazivních metod a expandovat in vitro pro následná personalizovaná využití. Tento přehledový článek shrnuje charakteristiky jednotlivých přístupů a jejich potenciální využití zejména v transplantační terapii diabetu mellitu a diabetického onemocnění ledvin. Oproti současným metodám transplantace pankreatu a pankreatických ostrůvků, respektive transplantace ledvin, nabízí tyto přístupy řadu výhod. Na závěr jsou prezentována současná klinická využití těchto modelů v prediktivním testování léčebné odpovědi a transplantační terapii s prvními klinickými studiemi využívajícími tyto modely v kauzální léčbě diabetu mellitu.

Personalization and individualization of therapy and diagnostics using advanced in vitro models utilizing patient tissue is the future of clinical medicine. These models include organoids, i.e., three-dimensional in vitro models derived from adult or induced pluripotent stem cells, organ-on-a-chip models, and other combination models. Stem cells for establishing these cultures can be obtained from the patient using minimally invasive methods and expanded in vitro for subsequent personalized applications. This review article summarizes the characteristics of each approach and their potential applications, particularly in transplantation therapy for diabetes mellitus and diabetic kidney disease. Compared with current approaches to pancreas and pancreatic islet transplantation and kidney transplantation, respectively, these approaches offer a number of potential advantages. In conclusion, the current clinical applications of these models in predictive testing of treatment response and transplantation therapy are presented, with the first clinical trials using these models in the causal treatment of diabetes mellitus.

Signální dráha PI3K/AKT/mTOR hraje zásadní roli v řadě buněčných procesů a rovněž v karcinogenezi. V tuto chvíli máme k dispozici několik molekul, které jsou schopny cílit na přenos signálu v rámci této dráhy a účinně blokovat nádorový růst. Kapivasertib představuje novou molekulu blokující alterovaný gen pro PIK3CA/AKT1/PTEN a podle klinické studie CAPItello-291 získal registraci pro pacienty předléčené hormonální léčbou, v kombinaci s fulvestrantem a současně s přítomností minimálně jedné výše uvedené mutace.

PI3K/AKT/mTOR signaling pathway plays a key role in several cell processes and also in the carcinogenesis. At this moment there are several molecules which can target cell signaling in this pathway and effectively blockade cancer progression. Capivasertib represents a new drug which target the altered gen for PIK3CA/AKT1/PTEN and according to the results of the clinical trial CAPItello-291 gained registration for the previously treated breast cancer patients in combination with fulvestrant and harboring at least one above mentioned mutation.