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1.
Circ Cardiovasc Interv ; : e013579, 2024 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-38629273

RESUMO

BACKGROUND: The prognostic impact of left atrial appendage (LAA) patency, including those with and without visible peri-device leak (PDL), post-LAA closure in patients with atrial fibrillation, remains elusive. METHODS: Patients with atrial fibrillation implanted with the WATCHMAN 2.5 device were prospectively enrolled. The device surveillance by cardiac computed tomography angiography was performed at 3 months post-procedure. Adverse events, including stroke/transient ischemic attack (TIA), major bleeding, cardiovascular death, all-cause death, and the combined major adverse events (MAEs), were compared between patients with complete closure and LAA patency. RESULTS: Among 519 patients with cardiac computed tomography angiography surveillance at 3 months post-LAA closure, 271 (52.2%) showed complete closure, and LAA patency was detected in 248 (47.8%) patients, including 196 (37.8%) with visible PDL and 52 (10.0%) without visible PDL. During a median of 1193 (787-1543) days follow-up, the presence of LAA patency was associated with increased risks of stroke/TIA (adjusted hazard ratio for baseline differences, 3.22 [95% CI, 1.17-8.83]; P=0.023) and MAEs (adjusted hazard ratio, 1.12 [95% CI, 1.06-1.17]; P=0.003). Specifically, LAA patency with visible PDL was associated with increased risks of stroke/TIA (hazard ratio, 3.66 [95% CI, 1.29-10.42]; P=0.015) and MAEs (hazard ratio, 3.71 [95% CI, 1.71-8.07]; P=0.001), although LAA patency without visible PDL showed higher risks of MAEs (hazard ratio, 3.59 [95% CI, 1.28-10.09]; P=0.015). Incidences of stroke/TIA (2.8% versus 3.0% versus 6.7% versus 22.2%; P=0.010), cardiovascular death (0.9% versus 0% versus 1.7% versus 11.1%; P=0.005), and MAEs (4.6% versus 9.0% versus 11.7% versus 22.2%; P=0.017) increased with larger PDL (0, >0 to ≤3, >3 to ≤5, or >5 mm). Older age and discontinuing antiplatelet therapy at 6 months were independent predictors of stroke/TIA and MAEs in patients with LAA patency. CONCLUSIONS: LAA patency detected by cardiac computed tomography angiography at 3 months post-LAA closure is associated with unfavorable prognosis in patients with atrial fibrillation implanted with WATCHMAN 2.5 device. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03788941.

2.
JAMA Cardiol ; 2024 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-38630489

RESUMO

Importance: Purinergic receptor P2Y12 (P2Y12) inhibitor monotherapy after a certain period of dual antiplatelet therapy (DAPT) may be an attractive option of maintenance antiplatelet treatment for patients undergoing percutaneous coronary intervention (PCI) who are at both high bleeding and ischemic risk (birisk). Objective: To determine if extended P2Y12 inhibitor monotherapy with clopidogrel is superior to ongoing DAPT with aspirin and clopidogrel after 9 to 12 months of DAPT after PCI in birisk patients with acute coronary syndromes (ACS). Design, Setting, and Participants: This was a multicenter, double-blind, placebo-controlled, randomized clinical trial including birisk patients with ACS who had completed 9 to 12 months of DAPT after drug-eluting stent implantation and were free from adverse events for at least 6 months at 101 China centers between February 2018 and December 2020. Study data were analyzed from April 2023 to May 2023. Interventions: Patients were randomized either to clopidogrel plus placebo or clopidogrel plus aspirin for an additional 9 months. Main Outcomes and Measures: The primary end point was Bleeding Academic Research Consortium (BARC) types 2, 3, or 5 bleeding 9 months after randomization. The key secondary end point was major adverse cardiac and cerebral events (MACCE; the composite of all-cause death, myocardial infarction, stroke or clinically driven revascularization). The primary end point was tested for superiority, and the MACCE end point was tested for sequential noninferiority and superiority. Results: A total of 7758 patients (mean [SD] age, 64.8 [9.0] years; 4575 male [59.0%]) were included in this study. The primary end point of BARC types 2, 3, or 5 bleeding occurred in 95 of 3873 patients (2.5%) assigned to clopidogrel plus placebo and 127 of 3885 patients (3.3%) assigned to clopidogrel plus aspirin (hazard ratio [HR], 0.75; 95% CI, 0.57-0.97; difference, -0.8%; 95% CI, -1.6% to -0.1%; P = .03). The incidence of MACCE was 2.6% (101 of 3873 patients) in the clopidogrel plus placebo group and 3.5% (136 of 3885 patients) in the clopidogrel plus aspirin group (HR, 0.74; 95% CI, 0.57-0.96; difference, -0.9%; 95% CI, -1.7% to -0.1%; P < .001 for noninferiority; P = .02 for superiority). Conclusions and Relevance: Among birisk patients with ACS who completed 9 to 12 months of DAPT after drug-eluting stent implantation and were free from adverse events for at least 6 months before randomization, an extended 9-month clopidogrel monotherapy regimen was superior to continuing DAPT with clopidogrel in reducing clinically relevant bleeding without increasing ischemic events. Trial Registration: ClinicalTrials.gov Identifier: NCT03431142.

3.
Hepatology ; 2024 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-38630500

RESUMO

BACKGROUND AND AIMS: The liver cirrhosis complications occur after long asymptomatic stages of progressive fibrosis and are generally diagnosed late. We aimed to develop a plasma metabolomic-based score tool to predict these events. APPROACH AND RESULTS: We enrolled 64,005 UK biobank participants with metabolomic profile. Participants were randomly divided into the training (n=43,734) and validation cohorts (n=20,271). Liver cirrhosis complications were defined as hospitalization for liver cirrhosis or presentation with hepatocellular carcinoma. Interpretable machine learning framework was applied to learn the metabolomic states extracted from 168 circulating metabolites in the training cohort. An integrated nomogram was developed and compared to conventional and genetic risk scores. We created three groups: low-risk, middle-risk, and high-risk through selected cut-offs of the nomogram. The predictive performance was validated through area under time-dependent receiver operating characteristic curve (time-dependent AUC), calibration curves, and decision curve analysis. The metabolomic state model could accurately predict 10-year risk of liver cirrhosis complications in the training cohort (time-dependent AUC 0.84 [95% CI 0.82-0.86]), and outperform the fibrosis-4 index (time-dependent AUC difference 0.06 [0.03-0.10]) and polygenic risk score (0.25 [0.21-0.29]). The nomogram, integrating metabolomic state, aspartate aminotransferase, platelet count, waist/hip ratio, and smoking status, showed a time-dependent AUC of 0.930 at 3 years, 0.889 at 5 years, and 0.861 at 10 years in the validation cohort, respectively. The hazard ratio in the high-risk group was 43.58 (95% CI 27.08-70.12) compared with the low-risk group. CONCLUSIONS: We developed a metabolomic state-integrated nomogram, which enables risk stratification and personalized administration of liver-related events.

4.
Phys Chem Chem Phys ; 26(15): 12003-12008, 2024 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-38576321

RESUMO

Single-walled carbon nanotubes (SWCNTs) functionalized with sparse surface chemical groups are promising for a variety of optical applications such as quantum information and bio-imaging. However, the luminescence efficiencies and stability, two key aspects, undoubtedly govern their practical usage. Herein, we assess the surface migration of oxygen and triazine groups on as-modified SWCNT fragments by adopting transition state theory and explore the de-excitation of oxygen-functionalized SWCNT fragments by performing non-adiabatic excited-state dynamics simulations. According to the predicted moderate or even small reaction barriers, the migration of both oxygen and triazine groups is feasible from an sp3 defect configuration forming an energetically more stable sp2 configuration at moderate or even room temperatures. Such isomerization leads to drastically different light emission capabilities as indicated by the large or zero oscillator strengths. During the dynamics simulations, the lowest excited singlet (S1) state rapidly decays in energy within 20 fs and then fluctuates until the end, providing insights into the emission mechanism of SWCNTs. This study highlights the potential intrinsic limitations of surface-functionalized SWCNTs for luminescence applications.

5.
Zhongguo Zhong Yao Za Zhi ; 49(3): 625-633, 2024 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-38621866

RESUMO

Extracts are important intermediates in the production of traditional Chinese medicines preparations. The drying effect of extracts will directly affect the subsequent production process and the quality of the preparation. To meet the requirements of high drug loading, short time consumption, and simple production process of personalized traditional Chinese medicine preparations, this study explored the application of multi-program microwave vacuum drying process in the extract drying of personalized traditional Chinese medicine preparations. The influencing factors of microwave vacuum drying process were investigated for 5 excipients and 40 prescriptions. Taking the feasibility of drying, drying rate, drying time, and dried extract status as indicators, this study investigated the feeding requirements of microwave vacuum drying. With the dried extract status as the evaluation indicator, the three drying programs(A, B, and C) were compared to obtain the optimal drying condition. The experimental results showed that the optimal feeding conditions for microwave vacuum drying were material layer thickness of 2 cm and C program(a total of 7 drying processes), which solved the problem of easy scorching in microwave drying with process management. Furthermore, the preset moisture content of the dried extract in microwave drying should be 4%-5%, so that the dried extract of traditional Chinese medicine preparation had uniform quality, complete drying, and no scorching. This study lays a foundation for the application of microwave drying in the production of traditional Chinese medicine preparations, promoting the high-quality development of personalized traditional Chinese medicine preparations.


Assuntos
Medicina Tradicional Chinesa , Micro-Ondas , Vácuo , Dessecação/métodos , Extratos Vegetais
6.
Zhongguo Zhong Yao Za Zhi ; 49(3): 770-778, 2024 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-38621881

RESUMO

This paper aims to study the therapeutic effect of Massa Medicata Fermentata on hyperlipidemia model rats and investigate its mechanism of hypolipidemic effect with the help of non-targeted metabolomics. The mixed hyperlipidemia model rats were constructed by giving high-fat chow. After successful modeling, the rats were divided into the model group, pravastatin sodium group(4.4 mg·kg~(-1)), lipotropic group(0.1 g·kg~(-1)), high-dose group(2.4 g·kg~(-1)), medium-dose group(1.2 g·kg~(-1)), and low-dose group(0.6 g·kg~(-1)) of Massa Medicata Fermentata, and they were administered for four weeks once daily. An equal volume of ultrapure water was given to the blank group and model group. Serum lipid level and liver hematoxylin-eosin(HE) staining were used as indicators to estimate the intervention effect of Massa Medicata Fermentata on mixed hyperlipidemia, and the changes in metabolites in plasma of mixed hyperlipidemia model rats were analyzed by non-targeted metabolomics. The mechanism of the hypolipidemic effect of Massa Medicata Fermentata was analyzed through metabolite pathway enrichment. The results showed that compared with the model group, the Massa Medicata Fermentata administration group, especially the high-dose group, could significantly reduce the content of total cholesterol(TC), triglyceride(TG), and low-density lipoprotein cholesterol(LDL-c)(P<0.05 or P<0.01), and liver HE staining revealed that the number of adipocytes in the high-dose group was reduced to some extent. The potential biomarkers obtained by non-targeted metabolomics screening included glycerol 3-phosphate, sphingomyelin, sphingosine 1-phosphate, and deoxyuridine, which were mainly involved in the sphingolipid metabolism process, glycerophospholipid metabolism process, glycerol ester metabolism pathway, and pyrimidine metabolism pathway, totaling four possible metabolic pathways related to lipid metabolism. This study provides a reference for an in-depth investigation of the hypolipidemic mechanism of Massa Medicata Fermentata, which is of great significance for further promoting the clinical application of Massa Medicata Fermentata and increasing the indications.


Assuntos
Medicamentos de Ervas Chinesas , Hiperlipidemias , Ratos , Animais , Medicamentos de Ervas Chinesas/farmacologia , Fígado , Hiperlipidemias/tratamento farmacológico , Metabolômica , Colesterol , Dieta Hiperlipídica/efeitos adversos
7.
Artigo em Inglês | MEDLINE | ID: mdl-38625818

RESUMO

There is a paucity of data on the surgical or medical treatment for abscess/fistula complicating Crohn's disease after successful nonsurgical management. We conducted a cohort study to investigate the long-term outcomes and the risk factors for the requirement of subsequent surgical intervention in Crohn's disease patients with complicating fistulas/abscess following successful nonsurgical management. Data were collected on penetrating Crohn's disease experiencing successful nonsurgical treatment between December 2012 and December 2021. Long-term outcomes and risk factors of surgery were assessed by univariate and multivariate analysis, and subgroup analysis was performed based on penetrating phenotype including abscess, fistula, and phlegmon. A total of 523 penetrating Crohn's disease patients; there were 390, 125, and 60 patients complicated with fistulas, abscess, and phlegmon, respectively. Long-term outcomes showed that BMI < 18.5 (kg/m2), the recurrent abscess, and stricture were independent risk factors of surgery. Biologics and resolution of abscess were independent protective factors of surgery. Furthermore, in 399 patients undergoing early surgery, stricture and BMI < 18.5 (kg/m2) were independent risk factors, and biologics and abscess resolution were protective of the early surgery. Subgroup analysis based on fistula, abscess, and phlegmon phenotype also demonstrated that concomitant stricture was an independent risk factor and the use of biologics was protective of surgical resection. Our data indicate that biologics can delay the requirement of surgery and may be given to patients with penetrating complicating Crohn's disease who have been successfully treated nonoperatively, but surgical resection should be considered in the setting of malnutrition and stenosis formation.

8.
Org Biomol Chem ; 2024 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-38623862

RESUMO

Asp-based lactam cyclic peptides are considered promising drug candidates. However, using Fmoc solid-phase peptide synthesis (Fmoc-SPPS) for these peptides also causes aspartimide formation, resulting in low yields or even failure to obtain the target peptides. Here, we developed a diaminodiacid containing an amide bond as a ß-carboxyl-protecting group for Asp to avoid aspartimide formation. The practicality of this diaminodiacid has been illustrated by the synthesis of lactam cyclic peptide cyclo[Lys9,Asp13] KIIIA7-14 and 1Y.

9.
Cancer Cell ; 2024 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-38608702

RESUMO

With limited treatment options, cachexia remains a major challenge for patients with cancer. Characterizing the interplay between tumor cells and the immune microenvironment may help identify potential therapeutic targets for cancer cachexia. Herein, we investigate the critical role of macrophages in potentiating pancreatic cancer induced muscle wasting via promoting TWEAK (TNF-like weak inducer of apoptosis) secretion from the tumor. Specifically, depletion of macrophages reverses muscle degradation induced by tumor cells. Macrophages induce non-autonomous secretion of TWEAK through CCL5/TRAF6/NF-κB pathway. TWEAK promotes muscle atrophy by activating MuRF1 initiated muscle remodeling. Notably, tumor cells recruit and reprogram macrophages via the CCL2/CCR2 axis and disrupting the interplay between macrophages and tumor cells attenuates muscle wasting. Collectively, this study identifies a feedforward loop between pancreatic cancer cells and macrophages, underlying the non-autonomous activation of TWEAK secretion from tumor cells thereby providing promising therapeutic targets for pancreatic cancer cachexia.

11.
JMIR Serious Games ; 12: e46789, 2024 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-38596827

RESUMO

Background: Removable partial denture (RPD) design is crucial to long-term success in dental treatment, but shortcomings in RPD design training and competency acquisition among dental students have persisted for decades. Digital production is increasing in prevalence in stomatology, and a digital RPD (D-RPD) module, under the framework of the certified Objective Manipulative Skill Examination of Dental Technicians (OMEDT) system reported in our previous work, may improve on existing RPD training models for students. Objective: We aimed to determine the efficacy of a virtual 3D simulation-based progressive digital training module for RPD design compared to traditional training. Methods: We developed a prospective cohort study including dental technology students at the Stomatology College of Chongqing Medical University. Cohort 1 received traditional RPD design training (7 wk). Cohort 2 received D-RPD module training based on text and 2D sketches (7 wk). Cohort 3 received D-RPD module pilot training based on text and 2D sketches (4 wk) and continued to receive training based on 3D virtual casts of real patients (3 wk). RPD design tests based on virtual casts were conducted at 1 month and 1 year after training. We collected RPD design scores and the time spent to perform each assessment. Results: We collected the RPD design scores and the time spent to perform each assessment at 1 month and 1 year after training. The study recruited 109 students, including 58 (53.2%) female and 51 male (56.8%) students. Cohort 1 scored the lowest and cohort 3 scored the highest in both tests (cohorts 1-3 at 1 mo: mean score 65.8, SD 21.5; mean score 81.9, SD 6.88; and mean score 85.3, SD 8.55, respectively; P<.001; cohorts 1-3 at 1 y: mean score 60.3, SD 16.7; mean score 75.5, SD 3.90; and mean score 90.9, SD 4.3, respectively; P<.001). The difference between cohorts in the time spent was not statistically significant at 1 month (cohorts 1-3: mean 2407.8, SD 1370.3 s; mean 1835.0, SD 1329.2 s; and mean 1790.3, SD 1195.5 s, respectively; P=.06) but was statistically significant at 1 year (cohorts 1-3: mean 2049.16, SD 1099.0 s; mean 1857.33, SD 587.39 s; and mean 2524.3, SD 566.37 s, respectively; P<.001). Intracohort comparisons indicated that the differences in scores at 1 month and 1 year were not statistically significant for cohort 1 (95% CI -2.1 to 13.0; P=.16), while cohort 3 obtained significantly higher scores 1 year later (95% CI 2.5-8.7; P=.001), and cohort 2 obtained significantly lower scores 1 year later (95% CI -8.8 to -3.9; P<.001). Conclusions: Cohort 3 obtained the highest score at both time points with retention of competency at 1 year, indicating that progressive D-RPD training including virtual 3D simulation facilitated improved competency in RPD design. The adoption of D-RPD training may benefit learning outcomes.

12.
Nat Commun ; 15(1): 3208, 2024 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-38615045

RESUMO

Investigations of one-dimensional segmented heteronanostructures (1D-SHs) have recently attracted much attention due to their potentials for applications resulting from their structure and synergistic effects between compositions and interfaces. Unfortunately, developing a simple, versatile and controlled synthetic method to fabricate 1D-SHs is still a challenge. Here we demonstrate a stress-induced axial ordering mechanism to describe the synthesis of 1D-SHs by a general under-stoichiometric reaction strategy. Using the continuum phase-field simulations, we elaborate a three-stage evolution process of the regular segment alternations. This strategy, accompanied by easy chemical post-transformations, enables to synthesize 25 1D-SHs, including 17 nanowire-nanowire and 8 nanowire-nanotube nanostructures with 13 elements (Ag, Te, Cu, Pt, Pb, Cd, Sb, Se, Bi, Rh, Ir, Ru, Zn) involved. This ordering evolution-driven synthesis will help to investigate the ordering reconstruction and potential applications of 1D-SHs.

13.
Front Pharmacol ; 15: 1375522, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38628639

RESUMO

Accurate calculation of drug-target affinity (DTA) is crucial for various applications in the pharmaceutical industry, including drug screening, design, and repurposing. However, traditional machine learning methods for calculating DTA often lack accuracy, posing a significant challenge in accurately predicting DTA. Fortunately, deep learning has emerged as a promising approach in computational biology, leading to the development of various deep learning-based methods for DTA prediction. To support researchers in developing novel and highly precision methods, we have provided a comprehensive review of recent advances in predicting DTA using deep learning. We firstly conducted a statistical analysis of commonly used public datasets, providing essential information and introducing the used fields of these datasets. We further explored the common representations of sequences and structures of drugs and targets. These analyses served as the foundation for constructing DTA prediction methods based on deep learning. Next, we focused on explaining how deep learning models, such as Convolutional Neural Networks (CNNs), Recurrent Neural Networks (RNNs), Transformer, and Graph Neural Networks (GNNs), were effectively employed in specific DTA prediction methods. We highlighted the unique advantages and applications of these models in the context of DTA prediction. Finally, we conducted a performance analysis of multiple state-of-the-art methods for predicting DTA based on deep learning. The comprehensive review aimed to help researchers understand the shortcomings and advantages of existing methods, and further develop high-precision DTA prediction tool to promote the development of drug discovery.

14.
Front Oncol ; 14: 1372123, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38628666

RESUMO

Background: Portal vein tumor thrombus (PVTT) seriously affects the prognosis of hepatocellular carcinoma (HCC). However, whether bile duct tumor thrombus (BDTT) significantly affects the prognosis of HCC as much as PVTT remains unclear. We aimed to compare the long-term surgical outcomes of HCC with macroscopic PVTT (macro-PVTT) and macroscopic BDTT (macro-BDTT). Methods: The data of HCC patients with macro-BDTT or macro-PVTT who underwent hemihepatectomy were retrospectively reviewed. A propensity score matching (PSM) analysis was performed to reduce the baseline imbalance. The recurrence-free survival (RFS) and overall survival (OS) rates were compared between the cohorts. Results: Before PSM, the PVTT group had worse RFS and OS rates than the BDTT group (P = 0.043 and P = 0.008, respectively). Multivariate analyses identified PVTT (hazard ratio [HR] = 1.835, P = 0.016) and large HCC (HR = 1.553, P = 0.039) as independent risk factors for poor OS and RFS, respectively. After PSM, the PVTT group had worse RFS and OS rates than the BDTT group (P = 0.037 and P = 0.004, respectively). The 3- and 5-year OS rates were significantly higher in the BDTT group (59.5% and 52.1%, respectively) than in the PVTT group (33.3% and 20.2%, respectively). Conclusion: Aggressive hemihepatectomy provides an acceptable prognosis for HCC patients with macro-BDTT. Furthermore, the long-term surgical outcomes of HCC patients with macro-BDTT were significantly better than those of HCC patients with macro-PVTT.

15.
Colloids Surf B Biointerfaces ; 238: 113915, 2024 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-38631281

RESUMO

Hydrogels have emerged as a new type of wound dressing materials that involved in different stages of the healing processes. However, most of the existing wound dressings mainly offer a protective and moisturizing layer to prevent cross-infection, while the anti-inflammatory and anti-oxidative properties are frequently induced by extra addition of other bioactive molecules. Here, a novel type of sulfated glyco-functionalized hydrogels for wound dressing was prepared through the hybrid supramolecular co-assembly of carbohydrate segments (FG, FGS and FG3S), fluorenylmethoxycarbonyl-diphenylalanine (Fmoc-FF), and diphenylalanine-dopamine (FFD). Implanting sulfated carbohydrates can mimic the structure of glycosaminoglycans (GAGs), promoting cell proliferation and migration, along with anti-inflammatory effects. In situ polymerization of FFD introduced a secondary covalent network to the hydrogel, meanwhile, providing anti-oxidation and adhesion properties to wound surfaces. Furthermore, the dynamic supramolecular interactions within the hydrogels also confer self-healing capabilities to the wound dressing materials. In vivo experiments further demonstrated significantly accelerated healing rates with the multifunctional hydrogel FG3S-FFD, indicating high application potential.

16.
Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi ; 38(4): 422-425, 2024 Apr 15.
Artigo em Chinês | MEDLINE | ID: mdl-38632060

RESUMO

Objective: To investigate the effectiveness of anatomical locking plate in the treatment of Rockwood type Ⅰ-Ⅲ patella fractures. Methods: The clinical data of 16 patients with patella fractures who were admitted between November 2021 and January 2023 and met the selection criteria was retrospectively analyzed. There were 14 males and 2 females, with an average age of 44.5 years (range, 19-72 years). Causes of injuries included tumble in 12 cases and traffic accident in 4 cases. The fractures were rated as type Ⅰ in 2 cases, type Ⅱ in 9 cases, and type Ⅲ in 5 cases according to Rockwood classification criteria. The time from injury to operation ranged from 6 to 15 days, with an average of 9 days. After fracture reduction, an appropriate anatomical locking plate was selected for internal fixation. The operation time, intraoperative blood loss, and incision healing were recorded; the Lysholm score, Böstman patella fracture efficacy score, knee joint mobility, and visual analogue scale (VAS) score were used to evaluate the knee joint function and pain degree; X-ray films were used to review the fracture reduction and healing. Results: The operation time was 65-100 minutes (mean, 75.3 minutes); the intraoperative blood loss was 10-35 mL (mean, 25.6 mL). All incisions healed by first intention after operation. All patients were followed up 11-26 months (mean, 19.7 months). X-ray films showed that the fractures were reduced satisfactorily, and all achieved bony healing with healing time of 3-5 months. At last follow-up, the Lysholm score was 90-95 (mean, 93.0); the Böstman patella fracture efficacy score was 27-30 (mean, 28.8), of which 12 cases were excellent and 4 were good; the VAS score was 0-1 (mean, 0.3). There was no significant difference in the range of motion of the knee joint between the healthy and affected sides [145° (140°, 150°) vs 145° (140°, 145°); Z=1.890, P=0.059]. Conclusion: Choosing anatomical locking plates for Rockwood typeⅠ-Ⅲ patella fractures can achieve strong fixation with minimal surgical trauma, rapid recovery of knee joint function, and mild pain after operation.

17.
Chem Commun (Camb) ; 60(33): 4475-4478, 2024 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-38563956

RESUMO

A hydrogen-bonded organic framework (HOF) consisting of a 9,10-diphenylanthracene carboxylic derivative, DPACOOH, was developed for solid state triplet-triplet annihilation upconversion (TTA-UC). The HOF sample shows a 70% increase in upconversion quantum yield and a lower threshold value of 126.0 mW cm-2 compared to those of the disordered powder sample, due to a 43% longer triplet diffusion length in HOF than that in the powder sample.

18.
J Immunother Cancer ; 12(4)2024 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-38580335

RESUMO

BACKGROUND: Ovarian cancer is the most lethal gynecological malignancy, with limited treatment options after failure of standard therapies. Despite the potential of poly(ADP-ribose) polymerase inhibitors in treating DNA damage response (DDR)-deficient ovarian cancer, the development of resistance and immunosuppression limit their efficacy, necessitating alternative therapeutic strategies. Inhibitors of poly(ADP-ribose) glycohydrolase (PARG) represent a novel class of inhibitors that are currently being assessed in preclinical and clinical studies for cancer treatment. METHODS: By using a PARG small-molecule inhibitor, COH34, and a cell-penetrating antibody targeting the PARG's catalytic domain, we investigated the effects of PARG inhibition on signal transducer and activator of transcription 3 (STAT3) in OVCAR8, PEO1, and Brca1-null ID8 ovarian cancer cell lines, as well as in immune cells. We examined PARG inhibition-induced effects on STAT3 phosphorylation, nuclear localization, target gene expression, and antitumor immune responses in vitro, in patient-derived tumor organoids, and in an immunocompetent Brca1-null ID8 ovarian mouse tumor model that mirrors DDR-deficient human high-grade serous ovarian cancer. We also tested the effects of overexpressing a constitutively activated STAT3 mutant on COH34-induced tumor cell growth inhibition. RESULTS: Our findings show that PARG inhibition downregulates STAT3 activity through dephosphorylation in ovarian cancer cells. Importantly, overexpression of a constitutively activated STAT3 mutant in tumor cells attenuates PARG inhibitor-induced growth inhibition. Additionally, PARG inhibition reduces STAT3 phosphorylation in immune cells, leading to the activation of antitumor immune responses, shown in immune cells cocultured with ovarian cancer patient tumor-derived organoids and in immune-competent mice-bearing mouse ovarian tumors. CONCLUSIONS: We have identified a novel antitumor mechanism underlying PARG inhibition beyond its primary antitumor effects through blocking DDR in ovarian cancer. Furthermore, targeting PARG activates antitumor immune responses, thereby potentially increasing response rates to immunotherapy in patients with ovarian cancer.


Assuntos
Glicosídeo Hidrolases , Neoplasias Ovarianas , Fator de Transcrição STAT3 , Animais , Feminino , Humanos , Camundongos , Linhagem Celular , Imunidade , Neoplasias Ovarianas/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Fator de Transcrição STAT3/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo , Glicosídeo Hidrolases/antagonistas & inibidores , Glicosídeo Hidrolases/metabolismo
19.
Commun Biol ; 7(1): 418, 2024 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-38582945

RESUMO

Fuchs endothelial corneal dystrophy (FECD) is a leading indication for corneal transplantation, but its molecular etiology remains poorly understood. We performed genome-wide association studies (GWAS) of FECD in the Million Veteran Program followed by multi-ancestry meta-analysis with the previous largest FECD GWAS, for a total of 3970 cases and 333,794 controls. We confirm the previous four loci, and identify eight novel loci: SSBP3, THSD7A, LAMB1, PIDD1, RORA, HS3ST3B1, LAMA5, and COL18A1. We further confirm the TCF4 locus in GWAS for admixed African and Hispanic/Latino ancestries and show an enrichment of European-ancestry haplotypes at TCF4 in FECD cases. Among the novel associations are low frequency missense variants in laminin genes LAMA5 and LAMB1 which, together with previously reported LAMC1, form laminin-511 (LM511). AlphaFold 2 protein modeling, validated through homology, suggests that mutations at LAMA5 and LAMB1 may destabilize LM511 by altering inter-domain interactions or extracellular matrix binding. Finally, phenome-wide association scans and colocalization analyses suggest that the TCF4 CTG18.1 trinucleotide repeat expansion leads to dysregulation of ion transport in the corneal endothelium and has pleiotropic effects on renal function.


Assuntos
Distrofia Endotelial de Fuchs , Humanos , Distrofia Endotelial de Fuchs/genética , Distrofia Endotelial de Fuchs/metabolismo , Estudo de Associação Genômica Ampla , Fator de Transcrição 4/genética , Colágeno , Laminina/genética
20.
Int J Biol Sci ; 20(6): 1965-1977, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38617544

RESUMO

Osteoarthritis (OA) is the most prevalent degenerative joint disorder, causing physical impairments among the elderly. Core binding factor subunit ß (Cbfß) has a critical role in bone homeostasis and cartilage development. However, the function and mechanism of Cbfß in articular cartilage and OA remains unclear. We found that Cbfßf/fAggrecan-CreERT mice with Cbfß-deficiency in articular cartilage developed a spontaneous osteoarthritis-like phenotype with articular cartilage degradation. Immunofluorescence staining showed that Cbfßf/fAggrecan-CreERT mice exhibited a significant increase in the expression of articular cartilage degradation markers and inflammatory markers in the knee joints. RNA-sequencing analysis demonstrated that Cbfß orchestrated Hippo/Yap, TGFß/Smad, and Wnt/ß-catenin signaling pathways in articular cartilage, and Cbfß deficiency resulted in the abnormal expression of downstream genes involved in maintaining articular cartilage homeostasis. Immunofluorescence staining results showed Cbfß deficiency significantly increased active ß-catenin and TCF4 expression while reducing Yap, TGFß1, and p-Smad 2/3 expression. Western blot and qPCR validated gene expression changes in hip articular cartilage of Cbfß-deficient mice. Our results demonstrate that deficiency of Cbfß in articular cartilage leads to an OA-like phenotype via affecting Hippo/Yap, TGFß, and Wnt/ß-catenin signaling pathways, disrupting articular cartilage homeostasis and leading to the pathological process of OA in mice. Our results indicate that targeting Cbfß may be a potential therapeutic target for the design of novel and effective treatments for OA.


Assuntos
Cartilagem Articular , Osteoartrite , Animais , Camundongos , Agrecanas , beta Catenina/genética , Osteoartrite/genética , Fenótipo , Fator de Crescimento Transformador beta , Via de Sinalização Wnt/genética
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