BACKGROUND: To evaluate the outcomes of first-line imatinib versus nilotinib treatment for chronic myeloid leukemia in the chronic phase (CML-CP) in real-world clinical practice. METHODS: A propensity score analysis was performed to eliminate imbalances between the treatment groups. In the analysis, 163 patients in the nilotinib group and 163 patients in the matched imatinib group were retrospectively evaluated. RESULTS: Nilotinib-treated patients achieved complete cytogenetic response (CCyR) and major molecular response more rapidly than imatinib-treated patients. However, there was no significant difference in 5-year overall survival (OS) or progression-free survival (PFS) between the two groups (OS: 94.3% vs. 90.5%, p = 0.602; PFS: 92.9% vs. 88.0%, p = 0.614). Nilotinib-treated patients had a higher failure-free survival (FFS) and event-free survival (EFS) than imatinib-treated patients (FFS: 71.7% vs. 54.3%, p = 0.040; EFS: 71.7% vs. 53.5%, p = 0.025). CONCLUSIONS: This retrospective analysis from clinical practice did not confirm any benefit of frontline nilotinib treatment for OS and PFS; however, it did demonstrate higher FFS and EFS in the nilotinib cohort.

• MeSH
• chronická myeloidní leukemie * farmakoterapie   mortalita   MeSH
• doba přežití bez progrese choroby MeSH
• dospělí MeSH
• imatinib mesylát * terapeutické užití   škodlivé účinky   MeSH
• inhibitory proteinkinas terapeutické užití   škodlivé účinky   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• protinádorové látky terapeutické užití   škodlivé účinky   MeSH
• pyrimidiny * terapeutické užití   škodlivé účinky   MeSH
• retrospektivní studie MeSH
• senioři MeSH
• tendenční skóre MeSH
• výsledek terapie 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

The foundations of cell reprogramming were laid by Yamanaka and co-workers, who showed that somatic cells can be reprogrammed into pluripotent cells (induced pluripotency). Since this discovery, the field of regenerative medicine has seen advancements. For example, because they can differentiate into multiple cell types, pluripotent stem cells are considered vital components in regenerative medicine aimed at the functional restoration of damaged tissue. Despite years of research, both replacement and restoration of failed organs/ tissues have remained elusive scientific feats. However, with the inception of cell engineering and nuclear reprogramming, useful solutions have been identified to counter the need for compatible and sustainable organs. By combining the science underlying genetic engineering and nuclear reprogramming with regenerative medicine, scientists have engineered cells to make gene and stem cell therapies applicable and effective. These approaches have enabled the targeting of various pathways to reprogramme cells, i.e., make them behave in beneficial ways in a patient-specific manner. Technological advancements have clearly supported the concept and realization of regenerative medicine. Genetic engineering is used for tissue engineering and nuclear reprogramming and has led to advances in regenerative medicine. Targeted therapies and replacement of traumatized , damaged, or aged organs can be realized through genetic engineering. Furthermore, the success of these therapies has been validated through thousands of clinical trials. Scientists are currently evaluating induced tissue-specific stem cells (iTSCs), which may lead to tumour-free applications of pluripotency induction. In this review, we present state-of-the-art genetic engineering that has been used in regenerative medicine. We also focus on ways that genetic engineering and nuclear reprogramming have transformed regenerative medicine and have become unique therapeutic niches.

• MeSH
• genetické inženýrství MeSH
• indukované pluripotentní kmenové buňky metabolismus   cytologie   MeSH
• lidé MeSH
• přeprogramování buněk * MeSH
• regenerativní lékařství * MeSH
• tkáňové inženýrství MeSH
• vývojová biologie MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

The aim of this study was to conduct QuantiFERON Monitor (QFM) testing in patients with multiple sclerosis (MS), which is used to monitor the state of the immune system through the non-specific stimulation of leukocytes followed by determining the level of interferon-gamma (IFN-γ) released from activated cells. Additionally, we tested the level of selected cytokines (IFN-α, IFN-γ, IL-1α, IL-1β, IL-1ra, IL-2, IL-3, IL-4, IL-6, IL-7, IL-10, IL-15, IL-33, VEGF) from stimulated blood samples to further understand the immune response. This study builds upon a previously published study, utilizing activated serum samples that were initially used for IFN-γ determination. However, our current focus shifts from IFN-γ to exploring other cytokines that could provide further insights into the immune response. A screening was conducted using Luminex technology, which yielded promising results. These results were then further elaborated upon using ELISA to provide a more detailed understanding of the cytokine profiles involved. This study, conducted from August 2019 to June 2023, included 280 participants: 98 RRMS patients treated with fingolimod (fMS), 96 untreated patients with progressive MS (pMS), and 86 healthy controls (HC). Our results include Violin plots showing elevated IL-1α in pMS and fMS. Statistical analysis indicated significant differences in the interleukin levels between groups, with IL-1ra and age as key predictors in differentiating HC from pMS and IL-1ra, IL-1α, age, and EDSS in distinguishing pMS from fMS. These findings suggest cytokines' potential as biomarkers in MS progression and treatment response.

• MeSH
• antagonista receptoru pro interleukin 1 MeSH
• cytokiny MeSH
• imunitní systém MeSH
• interferon gama MeSH
• lidé MeSH
• roztroušená skleróza * diagnóza   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: It remains unknown whether severe mental disorders contribute to fatally harmful effects of physical illness. AIMS: To investigate the risk of all-cause death and loss of life-years following the onset of a wide range of physical health conditions in people with severe mental disorders compared with matched counterparts who had only these physical health conditions, and to assess whether these associations can be fully explained by this patient group having more clinically recorded physical illness. METHOD: Using Czech national in-patient register data, we identified individuals with 28 physical health conditions recorded between 1999 and 2017, separately for each condition. In these people, we identified individuals who had severe mental disorders recorded before the physical health condition and exactly matched them with up to five counterparts who had no recorded prior severe mental disorders. We estimated the risk of all-cause death and lost life-years following each of the physical health conditions in people with pre-existing severe mental disorders compared with matched counterparts without severe mental disorders. RESULTS: People with severe mental disorders had an elevated risk of all-cause death following the onset of 7 out of 9 broadly defined and 14 out of 19 specific physical health conditions. People with severe mental disorders lost additional life-years following the onset of 8 out 9 broadly defined and 13 out of 19 specific physical health conditions. The vast majority of results remained robust after considering the potentially confounding role of somatic multimorbidity and other clinical and sociodemographic factors. CONCLUSIONS: A wide range of physical illnesses are more likely to result in all-cause death in people with pre-existing severe mental disorders. This premature mortality cannot be fully explained by having more clinically recorded physical illness, suggesting that physical disorders are more likely to be fatally harmful in this patient group.

• MeSH
• dospělí MeSH
• duševní poruchy * epidemiologie   MeSH
• kohortové studie MeSH
• komorbidita MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• příčina smrti * MeSH
• registrace statistika a číselné údaje   MeSH
• senioři MeSH
• zdravotní stav 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
• Geografické názvy
• Česká republika MeSH

Chronically inflamed mucosa in inflammatory bowel disease (IBD) is associated with an increased risk of cancer. Besides IBD-associated dysplasia, there are non-conventional mucosal changes that may act as potential precursors. The aim of the study was to retrospectively review samples from IBD patients focusing on detection of such lesions with evaluation of their immunohistochemical and molecular properties. Surgical specimens and/or endoscopical biopsy samples of IBD patients examined during a 10-year period were reviewed. Detected mucosal lesions were divided into three groups-group 1 (non-conventional or putative precursor lesions - PPLs) with serrated or villous hypermucinous morphology, group 2 (true serrated polyps fulfilling valid criteria), and group 3 (IBD-associated neoplasia). Lesions from all groups were analyzed with antibodies against MLH1, p53, and MGMT and by molecular testing of KRAS, NRAS, and BRAF mutation. Samples from 309 IBD patients were reviewed. A total of 88 mucosal lesions were found in 51 patients. Most common were lesions from group 1 with superficial serrated epithelial change seen in 41 samples (46.6%) and villous hypermucinous change in 6 (6.8%). Group 2 consisted of 15 true serrated polyps. Six conventional IBD-dysplasia cases and 11 carcinomas were seen in group 3. Six lesions from group 1 were associated with invasive carcinoma whereas two shared the same mutation in KRAS or BRAF. Lesions from group 1 were characterized by loss of MGMT expression in 44.6%, aberrant p53 expression, and by mutations in KRAS gene in 42.9% of cases. This study proves the existence of mucosal changes other than conventional IBD-dysplasia and extends the knowledge about their immunohistochemical and molecular properties and relation to carcinoma further supporting their potential role in IBD-related carcinogenesis.

• MeSH
• adenokarcinom patologie   MeSH
• adenom diagnóza   patologie   MeSH
• dítě MeSH
• dospělí MeSH
• idiopatické střevní záněty diagnóza   patologie   MeSH
• kolorektální nádory diagnóza   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mutace genetika   MeSH
• nádorové biomarkery analýza   MeSH
• polypy tlustého střeva diagnóza   patologie   MeSH
• protoonkogenní proteiny B-raf genetika   MeSH
• retrospektivní studie MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Heavy metals are naturally occurring components of the Earth's crust and persistent environmental pollutants. Human exposure to heavy metals occurs via various pathways, including inhalation of air/dust particles, ingesting contaminated water or soil, or through the food chain. Their bioaccumulation may lead to diverse toxic effects affecting different body tissues and organ systems. The toxicity of heavy metals depends on the properties of the given metal, dose, route, duration of exposure (acute or chronic), and extent of bioaccumulation. The detrimental impacts of heavy metals on human health are largely linked to their capacity to interfere with antioxidant defense mechanisms, primarily through their interaction with intracellular glutathione (GSH) or sulfhydryl groups (R-SH) of antioxidant enzymes such as superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), glutathione reductase (GR), and other enzyme systems. Although arsenic (As) is believed to bind directly to critical thiols, alternative hydrogen peroxide production processes have also been postulated. Heavy metals are known to interfere with signaling pathways and affect a variety of cellular processes, including cell growth, proliferation, survival, metabolism, and apoptosis. For example, cadmium can affect the BLC-2 family of proteins involved in mitochondrial death via the overexpression of antiapoptotic Bcl-2 and the suppression of proapoptotic (BAX, BAK) mechanisms, thus increasing the resistance of various cells to undergo malignant transformation. Nuclear factor erythroid 2-related factor 2 (Nrf2) is an important regulator of antioxidant enzymes, the level of oxidative stress, and cellular resistance to oxidants and has been shown to act as a double-edged sword in response to arsenic-induced oxidative stress. Another mechanism of significant health threats and heavy metal (e.g., Pb) toxicity involves the substitution of essential metals (e.g., calcium (Ca), copper (Cu), and iron (Fe)) with structurally similar heavy metals (e.g., cadmium (Cd) and lead (Pb)) in the metal-binding sites of proteins. Displaced essential redox metals (copper, iron, manganese) from their natural metal-binding sites can catalyze the decomposition of hydrogen peroxide via the Fenton reaction and generate damaging ROS such as hydroxyl radicals, causing damage to lipids, proteins, and DNA. Conversely, some heavy metals, such as cadmium, can suppress the synthesis of nitric oxide radical (NO·), manifested by altered vasorelaxation and, consequently, blood pressure regulation. Pb-induced oxidative stress has been shown to be indirectly responsible for the depletion of nitric oxide due to its interaction with superoxide radical (O2·-), resulting in the formation of a potent biological oxidant, peroxynitrite (ONOO-). This review comprehensively discusses the mechanisms of heavy metal toxicity and their health effects. Aluminum (Al), cadmium (Cd), arsenic (As), mercury (Hg), lead (Pb), and chromium (Cr) and their roles in the development of gastrointestinal, pulmonary, kidney, reproductive, neurodegenerative (Alzheimer's and Parkinson's diseases), cardiovascular, and cancer (e.g. renal, lung, skin, stomach) diseases are discussed. A short account is devoted to the detoxification of heavy metals by chelation via the use of ethylenediaminetetraacetic acid (EDTA), dimercaprol (BAL), 2,3-dimercaptosuccinic acid (DMSA), 2,3-dimercapto-1-propane sulfonic acid (DMPS), and penicillamine chelators.

• MeSH
• antioxidancia metabolismus   MeSH
• bioakumulace MeSH
• látky znečišťující životní prostředí toxicita   MeSH
• lidé MeSH
• oxidační stres * účinky léků   MeSH
• těžké kovy * toxicita   MeSH
• vystavení vlivu životního prostředí škodlivé účinky   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

INTRODUCTION: The dismal prognosis of pancreatic ductal adenocarcinoma (PDAC) highlights the urgent need for novel therapeutic strategies. Immune checkpoint inhibitors (ICIs) seem to be ineffective in most PDAC studies. Therefore, we conducted an open-label, multicenter phase 1/2 study (CA209-9KH) to evaluate the safety of stereotactic radiotherapy (SRT) and sequential ICI therapy in PDAC, as well as to validate the efficacy of this regimen as a potential activator of antitumor immunity. METHODS: Patients aged ≥ 18 years with unresectable non-metastatic PDAC following four FOLFIRINOX induction cycles were included. Treatment comprised SRT (4 × 8 Gy) and sequential nivolumab administration until disease progression or unacceptable toxicity. The primary endpoints were safety and toxicity assessment. Secondary endpoints included progression-free survival (PFS), overall survival (OS), biomarker evaluation, and quality of life (QoL) analysis. RESULTS: Twenty-two patients were screened, with 15 enrolled. Eleven (median) nivolumab cycles were administered. SRT demonstrated low and clinically nonsignificant toxicity, whereas nivolumab toxicity aligned with prior safety profiles, without grade 4-5 events observed. Three patients discontinued therapy owing to toxicity. Median PFS and OS were 8.1 and 13.0 months, respectively, with 12-month PFS and OS rates of 0% and 66.7%, respectively, and a 24-month OS rate of 8.9%. Biomarker levels correlated with clinical or radiological disease control. Patient-reported QoL remained acceptable, deteriorating with disease progression. CONCLUSION: SRT and nivolumab therapy exhibited manageable toxicity profiles consistent with previous findings; however, long-term treatment responses were not achieved with this regimen in locally advanced PDAC. Another strategy to trigger antitumor immunity in PDAC needs to be sought. TRIAL REGISTRATION: EudraCT: 2017-003404-52; ClinicalTrials.gov: NCT04098432.

• Publikační typ
• časopisecké články MeSH

Two new minor Amaryllidaceae alkaloids were isolated from Hippeastrum × hybridum cv. Ferrari and Narcissus pseudonarcissus cv. Carlton. The chemical structures were identified by various spectroscopic (one- and two-dimensional (1D and 2D) NMR, circular dichroism (CD), high-resolution mass spectrometry (HRMS) and by comparison with literature data of similar compounds. Both isolated alkaloids were screened for their human acetylcholinesterase (hAChE) and butyrylcholinesterase (hBuChE) inhibition activity. One of the new compounds, a heterodimer alkaloid of narcikachnine-type, named narciabduliine (2), showed balanced inhibition potency for both studied enzymes, with IC50 values of 3.29 ± 0.73 µM for hAChE and 3.44 ± 0.02 µM for hBuChE. The accommodation of 2 into the active sites of respective enzymes was predicted using molecular modeling simulation.

• MeSH
• alkaloidy amarylkovitých chemie   farmakologie   MeSH
• alkaloidy chemie   farmakologie   MeSH
• Alzheimerova nemoc MeSH
• butyrylcholinesterasa chemie   ultrastruktura   MeSH
• cholinesterasové inhibitory chemie   farmakologie   MeSH
• cholinesterasy chemie   ultrastruktura   MeSH
• cirkulární dichroismus MeSH
• katalytická doména účinky léků   MeSH
• lidé MeSH
• molekulární struktura MeSH
• simulace molekulového dockingu MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Alzheimer's disease (AD) is a complex disorder with unknown etiology. Currently, only symptomatic therapy of AD is available, comprising cholinesterase inhibitors and N-methyl-d-aspartate (NMDA) receptor antagonists. Drugs targeting only one pathological condition have generated only limited efficacy. Thus, combining two or more therapeutic interventions into one molecule is believed to provide higher benefit for the treatment of AD. In the presented study, we designed, synthesized, and biologically evaluated 15 novel fluoren-9-amine derivatives. The in silico prediction suggested both the oral availability and permeation through the blood-brain barrier (BBB). An initial assessment of the biological profile included determination of the cholinesterase inhibition and NMDA receptor antagonism at the GluN1/GluN2A and GluN1/GluN2B subunits, along with a low cytotoxicity profile in the CHO-K1 cell line. Interestingly, compounds revealed a selective butyrylcholinesterase (BChE) inhibition pattern with antagonistic activity on the NMDARs. Their interaction with butyrylcholinesterase was elucidated by studying enzyme kinetics for compound 3c in tandem with the in silico docking simulation. The docking study showed the interaction of the tricyclic core of new derivatives with Trp82 within the anionic site of the enzyme in a similar way as the template drug tacrine. From the kinetic analysis, it is apparent that 3c is a competitive inhibitor of BChE.

• MeSH
• Alzheimerova nemoc farmakoterapie   enzymologie   genetika   patologie   MeSH
• butyrylcholinesterasa chemie   účinky léků   genetika   MeSH
• CHO buňky MeSH
• cholinesterasové inhibitory chemie   farmakologie   MeSH
• Cricetulus MeSH
• fluoreny chemie   farmakologie   MeSH
• hematoencefalická bariéra účinky léků   MeSH
• inhibitory enzymů farmakologie   MeSH
• lidé MeSH
• počítačová simulace MeSH
• receptory N-methyl-D-aspartátu antagonisté a inhibitory   genetika   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

OBJECTIVES: This retrospective study aimed to analyze the trend of mortality due to thoracic aortic ruptures caused by deceleration injuries that occurred within the catchment area of Hradec Kralove University Hospital. MATERIALS AND METHODS: The study sample comprised 175 patients who had sustained thoracic aortic ruptures caused by deceleration injuries and were transported to Hradec Kralove University Hospital in 2009-2014. The small proportion of patients enrolled in this retrospective study were diagnosed and treated at the emergency department (ED). However, the overwhelming majority of the sample comprised of patients who died at the accident scene and later underwent an autopsy at the Institute of Forensic Medicine in our hospital. RESULTS: Of 175 patients, 150 underwent an autopsy. Of these, 139 individuals (79%) died at the incident scene, and 11 (6%) were transported to the ED and later died of their injuries. A total of 36 patients were admitted to the hospital; 29 were admitted primary (11 later died), and 7 were transferred. No deaths occurred in the group of secondary admissions. Thus, 31% of all patients hospitalized died following transport to the hospital. Of 175 patients, 15% (or 69% of all hospitalized patients) survived their injuries. Among patients who died as a result of thoracic aortic injury, no unexpected deaths were recorded (i.e., no deaths among patients with survival probability more than 50% = PS > 0.5). CONCLUSION: Our results suggested that the lethality of thoracic aortic injuries might be minimized by transporting triage-positive patients directly to trauma centers. Accurate diagnoses and treatments were supported by admission chest X-rays, a massive transfusion protocol, and particularly, CT angiography, which is not routinely included in primary surveys. An additional prognostic parameter was clinical collaboration between an experienced trauma surgeon, an interventional radiologist, and a vascular or thoracic surgeon.

• MeSH
• aorta thoracica diagnostické zobrazování   zranění   MeSH
• dopravní nehody mortalita   statistika a číselné údaje   MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• radiografie MeSH
• retrospektivní studie MeSH
• ruptura aorty diagnostické zobrazování   epidemiologie   etiologie   mortalita   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• traumatologická centra statistika a číselné údaje   MeSH
• zpomalení škodlivé účinky   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Hongkong MeSH