Hepatic fibrosis progresses concomitantly with a variety of biomechanical alternations, especially increased liver stiffness. These biomechanical alterations have long been considered as pathological consequences. Recently, growing evidence proposes that these alternations result in the fibrotic biomechanical microenvironment, which drives the activation of hepatic stellate cells (HSCs). Here, an inorganic ascorbic acid-oxidase (AAO) mimicking nanozyme loaded with liquiritigenin (LQ) is developed to trigger remodeling of the fibrotic biomechanical microenvironment. The AAO mimicking nanozyme is able to consume intracellular ascorbic acid, thereby impeding collagen I deposition by reducing its availability. Simultaneously, LQ inhibits the transcription of lysyl oxidase like 2 (LOXL2), thus impeding collagen I crosslinking. Through its synergistic activities, the prepared nanosystem efficiently restores the fibrotic biomechanical microenvironment to a near-normal physiological condition, promoting the quiescence of HSCs and regression of fibrosis. This strategy of remodeling the fibrotic biomechanical microenvironment, akin to "pulling the rug out from under", effectively treats hepatic fibrosis in mice, thereby highlighting the importance of tissue biomechanics and providing a potential approach to improve hepatic fibrosis treatment.

• MeSH
• biomechanika MeSH
• buněčné mikroprostředí účinky léků   MeSH
• flavanony farmakologie   chemie   MeSH
• jaterní cirhóza * farmakoterapie   metabolismus   patologie   MeSH
• jaterní hvězdicovité buňky * metabolismus   cytologie   účinky léků   MeSH
• kolagen typu I metabolismus   MeSH
• kyselina askorbová * farmakologie   metabolismus   chemie   MeSH
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Current diabetic retinopathy (DR) treatment involves blood glucose regulation combined with laser photocoagulation or intravitreal injection of vascular endothelial growth factor (VEGF) antibodies. However, due to the complex pathogenesis and cross-interference of multiple biochemical pathways, these interventions cannot block disease progression. Recognizing the critical role of the retinal microenvironment (RME) in DR, it is hypothesized that reshaping the RME by simultaneously inhibiting primary and secondary blood-retinal barrier (BRB) injury can attenuate DR. For this, a glucose-responsive hydrogel named Cu-PEI/siMyD88@GEMA-Con A (CSGC) is developed that effectively delivers Cu-PEI/siMyD88 nanoparticles (NPs) to the retinal pigment epithelium (RPE). The Cu-PEI NPs act as antioxidant enzymes, scavenging ROS and inhibiting RPE pyroptosis, ultimately blocking primary BRB injury by reducing microglial activation and Th1 differentiation. Simultaneously, MyD88 expression silence in combination with the Cu-PEI NPs decreases IL-18 production, synergistically reduces VEGF levels, and enhances tight junction proteins expression, thus blocking secondary BRB injury. In summary, via remodeling the RME, the CSGC hydrogel has the potential to disrupt the detrimental cycle of cross-interference between primary and secondary BRB injury, providing a promising therapeutic strategy for DR.

• MeSH
• buněčné mikroprostředí účinky léků   MeSH
• diabetická retinopatie * farmakoterapie   metabolismus   MeSH
• glukosa * metabolismus   MeSH
• hematoretinální bariéra * metabolismus   účinky léků   MeSH
• hydrogely * farmakologie   MeSH
• modely nemocí na zvířatech MeSH
• myši MeSH
• nanočástice MeSH
• retina účinky léků   metabolismus   MeSH
• retinální pigmentový epitel metabolismus   účinky léků   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Nutrient or energy deprivation, especially glucose restriction, is a promising anticancer therapeutic approach. However, establishing a precise and potent deprivation strategy remains a formidable task. The Golgi morphology is crucial in maintaining the function of transport proteins (such as GLUT1) driving glycolysis. Thus, in this study, we present a "Golgi-customized Trojan horse" based on tellurium loaded with apigenin (4',5,7-trihydroxyflavone) and human serum albumin, which was able to induce GLUT1 plasma membrane localization disturbance via Golgi dispersal leading to the inhibition of tumor glycolysis. Diamond-shaped delivery system can efficiently penetrate into cells as a gift like Trojan horse, which decomposes into tellurite induced by intrinsically high H2O2 and GSH levels. Consequently, tellurite acts as released warriors causing up to 3.8-fold increase in Golgi apparatus area due to the down-regulation of GOLPH3. Further, this affects GLUT1 membrane localization and glucose transport disturbance. Simultaneously, apigenin hinders ongoing glycolysis and causes significant decrease in ATP level. Collectively, our "Golgi-customized Trojan horse" demonstrates a potent antitumor activity because of its capability to deprive energy resources of cancer cells. This study not only expands the applications of tellurium-based nanomaterials in the biomedicine but also provides insights into glycolysis restriction for anticancer therapy.

• MeSH
• antitumorózní látky aplikace a dávkování   farmakologie   MeSH
• apigenin * aplikace a dávkování   farmakologie   MeSH
• buněčná membrána * metabolismus   účinky léků   MeSH
• glukosa metabolismus   MeSH
• glykolýza * účinky léků   MeSH
• Golgiho aparát * metabolismus   účinky léků   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nádory farmakoterapie   metabolismus   patologie   MeSH
• přenašeč glukosy typ 1 * metabolismus   MeSH
• telur * aplikace a dávkování   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Liver fibrosis is a reversible pathological process caused by chronic liver damage and a major risk factor for hepatocellular carcinoma (HCC). Hepatic stellate cell (HSC) activation is considered the main target for liver fibrosis therapy. However, the efficiency of this strategy is limited due to the complex microenvironment of liver fibrosis, including excessive extracellular matrix (ECM) deposition and hypoxia-induced imbalanced ECM metabolism. Herein, nilotinib (NIL)-loaded hyaluronic acid (HA)-coated Ag@Pt nanotriangular nanozymes (APNH NTs) were developed to inhibit HSCs activation and remodel the microenvironment of liver fibrosis. APNH NTs efficiently eliminated intrahepatic reactive oxygen species (ROS) due to their inherent superoxide dismutase (SOD) and catalase (CAT) activities, thereby downregulating the expression of NADPH oxidase-4 (NOX-4) and inhibiting HSCs activation. Simultaneously, the oxygen produced by the APNH NTs further alleviated the hypoxic microenvironment. Importantly, the released NIL promoted collagen depletion by suppressing the expression of tissue inhibitor of metalloproteinase-1 (TIMP-1), thus synergistically remodeling the microenvironment of liver fibrosis. Notably, an in vivo study in CCl4-induced mice revealed that APNH NTs exhibited significant antifibrogenic effects without obvious long-term toxicity. Taken together, the data from this work suggest that treatment with the synthesized APNH NTs provides an enlightening strategy for remodeling the microenvironment of liver fibrosis with boosted antifibrogenic activity.

• Publikační typ
• časopisecké články MeSH

Intestinal milieu disorders are strongly related to the occurrence of inflammatory bowel diseases (IBDs), which results from mucosa destruction, epithelium disruption, and tight junction (TJ) proteins loss. Excess of H2 S in the intestinal milieu produced by the sulfate-reducing bacteria metabolism contributes to development of IBDs via epithelial barrier breakdown. Conventional interventions, such as surgery and anti-inflammatory medications, are considered not completely effective because of frequent recurrence and other complications. Herein, a novel oral delivery system, a hydroxypropyl methylcellulose acetate succinate (HPMCAS)-based polymer-coated Zr-based metal-organic framework (UiO-66) with a Cux -rhodamine B (CR) probe (hereinafter referred to as HUR), is produced via a co-flow microfluidic approach with the ability to reduce H2 S levels, thus restoring the intestinal lumen milieu. HPMCAS serves as an enteric coating that exposes UiO-66@CR at the pH of the intestine but not the acidic pH of the stomach. The synthesized HUR exhibits notable therapeutic efficacy, including mucosa recovery, epithelium integrity restoration, and TJ proteins upregulation via H2 S scavenging to protect against intestinal barrier damage and microbiome dysbiosis. Thus, HUR is verified to be a promising theranostic platform able to decrease the H2 S content for intestinal milieu disorder treatment. The presented study therefore opens the door for further exploitation for IBDs therapy.

• MeSH
• mikrofluidika MeSH
• porézní koordinační polymery * metabolismus   MeSH
• střeva MeSH
• střevní sliznice metabolismus   MeSH
• sulfan chemie   MeSH
• těsný spoj MeSH
• Publikační typ
• časopisecké články MeSH

PURPOSE: To test the hypothesis that intensity modulated radiation therapy (IMRT) reduces acute hematologic and gastrointestinal (GI) toxicity for patients with locoregionally advanced cervical cancer. METHODS AND MATERIALS: We enrolled patients with stage IB-IVA cervical carcinoma in a single-arm phase II trial involving 8 centers internationally. All patients received weekly cisplatin concurrently with once-daily IMRT, followed by intracavitary brachytherapy, as indicated. The primary endpoint was the occurrence of either acute grade ≥3 neutropenia or clinically significant GI toxicity within 30 days of completing chemoradiation therapy. A preplanned subgroup analysis tested the hypothesis that positron emission tomography-based image-guided IMRT (IG-IMRT) would lower the risk of acute neutropenia. We also longitudinally assessed patients' changes in quality of life. RESULTS: From October 2011 to April 2015, 83 patients met the eligibility criteria and initiated protocol therapy. The median follow-up was 26.0 months. The incidence of any primary event was 26.5% (95% confidence interval [CI] 18.2%-36.9%), significantly lower than the 40% incidence hypothesized a priori from historical data (P=.012). The incidence of grade ≥3 neutropenia and clinically significant GI toxicity was 19.3% (95% CI 12.2%-29.0%) and 12.0% (95% CI 6.7%-20.8%), respectively. Compared with patients treated without IG-IMRT (n=48), those treated with IG-IMRT (n=35) had a significantly lower incidence of grade ≥3 neutropenia (8.6% vs 27.1%; 2-sided χ(2)P=.035) and nonsignificantly lower incidence of grade ≥3 leukopenia (25.7% vs 41.7%; P=.13) and any grade ≥3 hematologic toxicity (31.4% vs 43.8%; P=.25). CONCLUSIONS: IMRT reduces acute hematologic and GI toxicity compared with standard treatment, with promising therapeutic outcomes. Positron emission tomography IG-IMRT reduces the incidence of acute neutropenia.

• MeSH
• adenokarcinom diagnostické zobrazování   patologie   terapie   MeSH
• antitumorózní látky terapeutické užití   MeSH
• brachyterapie metody   MeSH
• celková dávka radioterapie MeSH
• chemoradioterapie metody   MeSH
• cisplatina terapeutické užití   MeSH
• gastrointestinální trakt účinky záření   MeSH
• incidence MeSH
• kostní dřeň * MeSH
• léčba šetřící orgány metody   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádory děložního čípku diagnostické zobrazování   patologie   terapie   MeSH
• neutropenie epidemiologie   prevence a kontrola   MeSH
• radiosenzibilizující látky terapeutické užití   MeSH
• radioterapie řízená obrazem metody   MeSH
• radioterapie s modulovanou intenzitou metody   MeSH
• spinocelulární karcinom diagnostické zobrazování   patologie   terapie   MeSH
• studie proveditelnosti MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze II MeSH
• multicentrická studie MeSH

PURPOSE: To demonstrate an efficient method for training and validation of a knowledge-based planning (KBP) system as a radiation therapy clinical trial plan quality-control system. METHODS AND MATERIALS: We analyzed 86 patients with stage IB through IVA cervical cancer treated with intensity modulated radiation therapy at 2 institutions according to the standards of the INTERTECC (International Evaluation of Radiotherapy Technology Effectiveness in Cervical Cancer, National Clinical Trials Network identifier: 01554397) protocol. The protocol used a planning target volume and 2 primary organs at risk: pelvic bone marrow (PBM) and bowel. Secondary organs at risk were rectum and bladder. Initial unfiltered dose-volume histogram (DVH) estimation models were trained using all 86 plans. Refined training sets were created by removing sub-optimal plans from the unfiltered sample, and DVH estimation models… and DVH estimation models were constructed by identifying 30 of 86 plans emphasizing PBM sparing (comparing protocol-specified dosimetric cutpoints V10 (percentage volume of PBM receiving at least 10 Gy dose) and V20 (percentage volume of PBM receiving at least 20 Gy dose) with unfiltered predictions) and another 30 of 86 plans emphasizing bowel sparing (comparing V40 (absolute volume of bowel receiving at least 40 Gy dose) and V45 (absolute volume of bowel receiving at least 45 Gy dose), 9 in common with the PBM set). To obtain deliverable KBP plans, refined models must inform patient-specific optimization objectives and/or priorities (an auto-planning "routine"). Four candidate routines emphasizing different tradeoffs were composed, and a script was developed to automatically re-plan multiple patients with each routine. After selection of the routine that best met protocol objectives in the 51-patient training sample (KBPFINAL), protocol-specific DVH metrics and normal tissue complication probability were compared for original versus KBPFINAL plans across the 35-patient validation set. Paired t tests were used to test differences between planning sets. RESULTS: KBPFINAL plans outperformed manual planning across the validation set in all protocol-specific DVH cutpoints. The mean normal tissue complication probability for gastrointestinal toxicity was lower for KBPFINAL versus validation-set plans (48.7% vs 53.8%, P<.001). Similarly, the estimated mean white blood cell count nadir was higher (2.77 vs 2.49 k/mL, P<.001) with KBPFINAL plans, indicating lowered probability of hematologic toxicity. CONCLUSIONS: This work demonstrates that a KBP system can be efficiently trained and refined for use in radiation therapy clinical trials with minimal effort. This patient-specific plan quality control resulted in improvements on protocol-specific dosimetric endpoints.

• MeSH
• klinické zkoušky jako téma normy   MeSH
• kostní dřeň MeSH
• kritické orgány * MeSH
• léčba šetřící orgány metody   normy   MeSH
• lidé MeSH
• močový měchýř MeSH
• nádory děložního čípku patologie   radioterapie   MeSH
• pánevní kosti MeSH
• plánování radioterapie pomocí počítače metody   normy   MeSH
• radioterapie s modulovanou intenzitou metody   normy   MeSH
• rektum MeSH
• řízení kvality * MeSH
• střeva MeSH
• tumor burden MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• validační studie MeSH

BACKGROUND: To test the hypothesis that atlas-based active bone marrow (ABM)-sparing intensity modulated radiation therapy (IMRT) yields similar dosimetric results compared to custom ABM-sparing IMRT for cervical cancer patients. METHODS: We sampled 62 cervical cancer patients with pre-treatment FDG-PET/CT in training (n=32) or test (n=30) sets. ABM was defined as the subvolume of the pelvic bone marrow (PBM) with standardized uptake value (SUV) above the mean on the average FDG-PET image (ABMAtlas) vs. the individual's PET (ABMCustom). Both were deformed to the planning CT. Overlap between the two subvolumes was measured using the Dice coefficient. Three IMRT plans designed to spare PBM, ABMAtlas, or ABMCustomwere compared for 30 test patients. Dosimetric parameters were used to evaluate plan quality. RESULTS: ABMAtlasand ABMCustomvolumes were not significantly different (p=0.90), with a mean Dice coefficient of 0.75, indicating good agreement. Compared to IMRT plans designed to spare PBM and ABMCustom, ABMAtlas-sparing IMRT plans achieved excellent target coverage and normal tissue sparing, without reducing dose to ABMCustom(mean ABMCustomdose 29.4Gy vs. 27.1Gyvs. 26.9Gy, respectively; p=0.10); however, PTV coverage and bowel sparing were slightly reduced. CONCLUSIONS: Atlas-based ABM sparing IMRT is clinically feasible and may obviate the need for customized ABM-sparing as a strategy to reduce hematologic toxicity.

• MeSH
• celková dávka radioterapie MeSH
• dospělí MeSH
• fluorodeoxyglukosa F18 MeSH
• kostní dřeň účinky záření   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádory děložního čípku radioterapie   MeSH
• PET/CT MeSH
• plánování radioterapie pomocí počítače metody   MeSH
• radioterapie s modulovanou intenzitou škodlivé účinky   metody   MeSH
• senioři MeSH
• studie proveditelnosti MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

The publication contains papers and articles that focus on the treatment of burns, including current research. Intended for professional public.

• MeSH
• komorbidita MeSH
• popálení terapie   MeSH

• Konspekt
• Patologie. Klinická medicína
• NLK Obory
• popáleninová medicína
• NLK Publikační typ
• kolektivní monografie