Revidovaná doporučení Kidney Disease: Improving Global Outcomes (KDIGO) pro léčbu glomerulárních onemocnění jsou nyní pro možnost rychlejší reakce na aktuální poznatky publikována po jednotlivých kapitolách. V tomto článku jsou v přehledu shrnuta a komentována doporučení KDIGO z roku 2024 pro ANCA asociované vaskulitidy a lupusovou nefritidu. U ANCA asociované vaskulitidy je v indukční terapii doporučen cyklofosfamid nebo rituximab (popř. jejich kombinace) spolu s kortikosteroidy (v redukované dávce) nebo avacopanem. U závažnějšího postižení ledvin nebo u krvácení do plic s hypoxemií je možno zvážit při-dání plazmaferézy. V udržovací terapii je využíván rituximab nebo azathioprin s kortikosteroidy. U proliferativní lupusové nefritidy třídy III a IV je doporučena terapie kortikosteroidy v kombinaci s jednou z následujících možností: s analogy kyseliny mykofenolové (mykofenolát mofetilem nebo mykofenolátem sodným, dále jen MPAA), s nízkodávkovaným cyklofosfamidem, s belimumabem spolu s MPAA nebo cyklofosfamidem, s inhibitory kalcineurinu spolu s MPAA. V udržovací terapii jsou na prvním místě MPAA, al-ternativy zahrnují azathioprin či pokračování v podávání belimumabu nebo inhibitorů kalcineurinu v kombinaci se standardní tera-pií. Všichni pacienti s lupusovou nefritidou by měli být léčeni hydroxychlorochinem a pozornost je třeba věnovat také běžným opat-řením pro snížení rizika rozvoje komplikací samotného onemocnění i podané terapie.
BACKGROUND: De novo oligometastatic prostate cancer (omPCa) on prostate-specific membrane antigen (PSMA) positron emission tomography (PET) is a new disease entity and its optimal management remains unknown. OBJECTIVE: To analyze the outcomes of patients treated with cytoreductive radical prostatectomy (cRP) for omPCa on PSMA-PET. DESIGN, SETTING, AND PARTICIPANTS: Overall, 116 patients treated with cRP at 13 European centers were identified. Oligometastatic PCa was defined as miM1a and/or miM1b with five or fewer osseous metastases and/or miM1c with three or fewer lung lesions on PSMA-PET. INTERVENTION: Cytoreductive radical prostatectomy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Thirty-day complications according to Clavien-Dindo, continence rates, time to castration-resistant PCa (CRPC), and overall survival (OS) were analyzed. RESULTS AND LIMITATIONS: Overall, 95 (82%) patients had miM1b, 18 (16%) miM1a, and three (2.6%) miM1c omPCa. The median prebiopsy prostate-specific antigen was 14 ng/ml, and 102 (88%) men had biopsy grade group ≥3 PCa. The median number of metastases on PSMA-PET was 2; 38 (33%), 29 (25%), and 49 (42%) patients had one, two, and three or more distant positive lesions. A total of 70 (60%) men received neoadjuvant systemic therapy, and 37 (32%) underwent metastasis-directed therapy. Any and Clavien-Dindo grade ≥3 complications occurred in 36 (31%) and six (5%) patients, respectively. At a median follow-up of 27 mo, 19 (16%) patients developed CRPC and eight (7%) patients died. The 1-yr urinary continence rate was 82%. The 2-yr CRPC-free survival and OS were 85.8% (95% confidence interval [CI] 78.5-93.7%) and 98.9% (95% CI 96.8-100%), respectively. The limitations include retrospective design and short-term follow-up. CONCLUSIONS: Cytoreductive radical prostatectomy is a safe and feasible treatment option in patients with de novo omPCa on PSMA-PET. Despite overall favorable oncologic outcomes, some of these patients have a non-negligible risk of early progression and thus should be considered for multimodal therapy. PATIENT SUMMARY: We found that patients treated at expert centers with surgery for prostate cancer, with a limited number of metastases detected using novel molecular imaging, have favorable short-term survival, functional results, and acceptable rates of complications.
- MeSH
- antigeny povrchové metabolismus MeSH
- cytoredukční chirurgie MeSH
- glutamátkarboxypeptidasa II metabolismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- metastázy nádorů MeSH
- nádory prostaty * patologie chirurgie MeSH
- pozitronová emisní tomografie * metody MeSH
- prostatektomie * metody MeSH
- prostatický specifický antigen krev MeSH
- retrospektivní studie MeSH
- senioři MeSH
- výsledek terapie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- Geografické názvy
- Evropa MeSH
Physiology-based pharmacokinetic modeling suggests that rifabutin can out-balance P-glycoprotein (P-gp) induction by concurrent P-gp inhibition. However, clinical or experimental evidence for this Janus-faced rifabutin effect is missing. Consequently, LS180 cells were exposed to a moderately (2 μM) and strongly (10 μM) P-gp-inducing concentration of rifampicin or rifabutin for 6 days. Cellular accumulation of the fluorescent P-gp substrate rhodamine 123 was evaluated using flow cytometry, either without (induction only) or with adding rifamycin drug to the cells during the rhodamine 123 efflux phase (induction + potential inhibition). Rhodamine 123 accumulation was decreased similarly by both drugs after 6-day exposure (2 μM: 55% residual fluorescence compared to non-induced cells, P < 0.01; 10 μM: 30% residual fluorescence compared to non-induced cells, P < 0.001), indicating P-gp induction. Rhodamine 123 influx transporters mRNA expressions were not affected, excluding off-target effects. Acute re-exposure to rifabutin, however, considerably re-increased rhodamine 123 accumulation (2 μM induction: re-increase by 55%, P < 0.01; 10 μM induction: 49% re-increase, P < 0.001), suggesting P-gp inhibition. In contrast, rifampicin only had weak effects (2 μM induction: no re-increase; 10 μM induction: 16% re-increase; P < 0.05). Molecular docking analysis eventually revealed that rifabutin has a higher binding affinity to the inhibitor binding site of P-gp than rifampicin (ΔG (kcal/mol) = -11.5 vs -5.3). Together, this study demonstrates that rifabutin can at least partly mask P-gp induction by P-gp inhibition, mediated by high affinity binding to the inhibitory site of P-gp.
BACKGROUND: Cerebral palsy (CP) is the most common cause of physical disability in childhood defined as a group of permanent disorders of movement. The aim of this study was to determine the effects of 12-week aquatic exercise program on gross motor function, swimming skills, and walking ability in children with cerebral palsy. METHODS: Eighteen children (mean±SD age: 12.3±3 years) with cerebral palsy classified at levels I, II and III on the Gross Motor Function Classification System were allocated to one group, where the first 12 weeks were a control period while another 12 weeks were an experimental period. The participants underwent the same battery of tests focusing gross motor function, swimming skills, and walking ability on three occasions. RESULTS: Control period was stable with no significant changes in any of measurements. After the 12-week experimental program, a statistically significant improvement was determined in gross motor function (P=0.005), swimming skills (P=0.000), walking endurance and walking velocity (P=0.000). No significant differences (P>0.05) were observed for walking efficiency. CONCLUSIONS: The 12-week aquatic exercise program (3/week, 60 minutes), combining Halliwick method, swimming and walking activities may improve the gross motor function, swimming skills, walking endurance and velocity in ambulatory children with cerebral palsy.
INTRODUCTION: Malignant diseases challenge clinicians to balance treatment intensity and patient quality of life. Regular physical activity positively impacts mental and physical health, benefiting sleep patterns, heart rate, and overall health. Moreover, telehealth physical exercise training represents a viable option for maintaining intrinsic capacity. The American Cancer Society highlights exercise's role in helping patients cope with anti-cancer treatment side effects. In the Czech Republic, there is no fitness-promoting protocol for cancer patients, despite recognized benefits. Exercise may also enhance immune function, with moderate-intensity exercise potentially positively affecting immune cell counts. OBJECTIVE: This study aimed to analyze the long-term effects of exercise on circulating immune cells in patients undergoing treatment for solid malignancies. PATIENTS AND METHODS: 49 participants were recruited at the Masaryk Memorial Cancer Institute, Czech Republic, starting September 2021. Participants were randomized into an experimental (SAPA = undergoing monitored exercise program) group (N = 16; madian age: 46,6; median BMI: 25,1) and a control (CO) group (N = 33; madian age: 52,0; median BMI: 25,3). Flow cytometry was used to examine cellular immunological profiles. The exercise program involved thrice-weekly sessions conducted online. RESULTS: SAPA group showed stable lymphocyte counts post-exercise (percentage chance: +0,5 %; p = 0,256; effect size r = -0,284), while the CO group exhibited a significant drop (percentage chance: -23,0 %; p = 0,015; effect size r = -0,423). B lymphocyte numbers were significantly higher in the SAPA group post-exercise compared to the CO group (p = 0,003; effect size r = -0,422). The number of Th-lymphocytes, T-c lymphocytes, T-gamma/delta lymphocytes, and NK cells remained stable in SAPA but dropped in CO group. CONCLUSION: Exercise's impact on the immune system in cancer patients shows promise, with differences noted between acute and chronic exercise effects. Previous studies on acute exercise indicate a rise in immune cell counts, supporting our findings of stable or increased immune cells with controlled exercise in cancer patients. Controlled physical activity stabilizes or increases certain immune cell populations in patients undergoing chemotherapy for solid malignancies, highlighting the potential benefits of incorporating exercise into cancer treatment protocols.
- Publikační typ
- časopisecké články MeSH
Given the significant prevalence of FLT3 receptor and its mutations in acute myeloid leukemia (AML) pathogenesis, we present a novel series of furo[2,3-d]pyrimidin-1,3,4-thiadiazole-urea derivatives, designed to exhibit FLT3-ITD inhibitory activity. These compounds demonstrated cytotoxicity in FLT3-ITD expressing AML cell lines MOLM-13 and MV4-11 in the nanomolar range, with significant selectivity over the K562 cell line. In-depth evaluations of example compound 49 revealed its efficacy in suppressing FLT3 phosphorylation and the downstream signaling molecules, including STAT5 and ERK1/2. Notably, compound 49 demonstrated cytotoxic effects in Ba/F3 cells expressing FLT3-ITD or FLT3-ITD-F691L mutant, exceeding the potency of both sorafenib and quizartinib. Molecular docking studies suggest that this compound binds to the active site of FLT3 in a type II manner. The study suggests that substituted furo[2,3-d]pyrimidines could be useful additions to the growing field of FLT3-targeted therapy for AML. These compounds have the potential to serve as novel FLT3-ITD inhibitors and may offer insights for developing future therapeutic strategies in AML.
- MeSH
- akutní myeloidní leukemie farmakoterapie patologie metabolismus MeSH
- antitumorózní látky * farmakologie chemie chemická syntéza MeSH
- inhibitory proteinkinas * farmakologie chemie chemická syntéza MeSH
- léky antitumorózní - screeningové testy * MeSH
- lidé MeSH
- molekulární struktura MeSH
- nádorové buněčné linie MeSH
- proliferace buněk účinky léků MeSH
- pyrimidiny chemie farmakologie chemická syntéza MeSH
- simulace molekulového dockingu * MeSH
- thiadiazoly * chemie farmakologie chemická syntéza MeSH
- tyrosinkinasa 3 podobná fms * antagonisté a inhibitory metabolismus MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
A subpopulation of astrocytes on the brain's surface, known as subpial astrocytes, constitutes the "glia limitans superficialis" (GLS), which is an interface between the brain parenchyma and the cerebrospinal fluid (CSF) in the subpial space. Changes in connexin-43 (Cx43) and aquaporin-4 (AQP4) proteins in subpial astrocytes were examined in the medial prefrontal cortex at postoperative day 1, 3, 7, 14, and 21 after sham operation and sciatic nerve compression (SNC). In addition, we tested the altered uptake of TRITC-conjugated 3 kDa dextran by reactive subpial astrocytes. Cellular immunofluorescence (IF) detection and image analysis were used to examine changes in Cx43 and AQP4 protein levels, as well as TRITC-conjugated 3 kDa dextran, in subpial astrocytes. The intensity of Cx43-IF was significantly increased, but AQP4-IF decreased in subpial astrocytes of sham- and SNC-operated rats during all survival periods compared to naïve controls. Similarly, the uptake of 3 kDa dextran in the GLS was reduced following both sham and SNC operations. The results suggest that both sciatic nerve injury and peripheral tissue injury alone can induce changes in subpial astrocytes related to the spread of their reactivity across the cortical surface mediated by increased amounts of gap junctions. At the same time, water transport and solute uptake were impaired in subpial astrocytes.
- MeSH
- akvaporin 4 * metabolismus MeSH
- astrocyty * metabolismus MeSH
- dextrany * metabolismus MeSH
- konexin 43 * metabolismus MeSH
- krysa rodu rattus MeSH
- nervus ischiadicus * zranění metabolismus MeSH
- potkani Sprague-Dawley MeSH
- prefrontální mozková kůra * metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Several Ranunculaceae species are used in folk medicine to eliminate pathologies associated with oxidative stress as well as parasitic infections; however, a number of studies confirming their pharmacological properties is limited. In this study, 19 ethanolic extracts obtained from 16 Ranunculaceae species were assayed for in vitro antioxidant, antiproliferative, and antiparasitic potential. The maximum antioxidant potential in both oxygen radical absorbance capacity (ORAC) and 2,2-diphenyl-1-picrylhydrazyl (DPPH) assays was observed for Aconitum toxicum extract [half-maximal inhibitory concentration (IC50) 18.7 and 92.6 μg/mL]. Likewise, Anemone transsilvanica extract exerted the most promising antiproliferative activity against Caco-2 (IC50 46.9 μg/mL) and HT29 (IC50 70.2 μg/mL) cell lines in 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Additionally, a dual antioxidant and cytotoxicity effect was demonstrated for Aconitum moldavicum and Caltha palustris extracts. Whilst the efficacy of extracts was modest against Trypanosoma brucei (IC50 ranging from 88.8 to 269.3 μg/mL), several extracts exhibited high potency against Leishmania infantum promastigotes (Aconitum vulparia IC50 18.8 μg/mL). We also tested them against the clinically relevant intracellular stage and found extract of A. vulparia to be the most effective (IC50 29.0 ± 1.1 μg/mL). All tested extracts showed no or low toxicity against FHs 74Int normal cell line (IC50 ranging from 152.9 to >512 μg/mL). In conclusion, we suggest the above-mentioned plant extracts as potential candidates for development of novel plant-based antioxidant and/or antiproliferative and/or antileishmanial compounds.
- MeSH
- antioxidancia * farmakologie chemie MeSH
- antiparazitární látky farmakologie chemie MeSH
- buňky HT-29 MeSH
- Caco-2 buňky MeSH
- léčivé rostliny chemie MeSH
- lidé MeSH
- proliferace buněk * účinky léků MeSH
- Ranunculaceae chemie MeSH
- rostlinné extrakty * farmakologie chemie MeSH
- tradiční lékařství MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Rumunsko MeSH
- MeSH
- chirurgie operační * MeSH
- klimatické změny * MeSH
- lidé MeSH
- nezletilí * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- dopisy MeSH
- Geografické názvy
- Řecko MeSH
