课程文献中心 更多>>

关键词： Fibroblast activation protein inhibitor   Gastric cancer   Positron emission tomography   Immunotherapy   Prognosis  

摘要： Objective This study aimed to evaluate the prognostic value of [F-18]ALF-NOTA-FAPI-04 PET/CT-derived parameters, including the maximum standardized uptake value (SUVmax), FAPI-avid tumor volume (FTV), and total lesion FAP expression (TLF), in patients with recurrent gastric cancer undergoing combined chemoimmunotherapy. We sought to establish a noninvasive imaging biomarker framework to optimize patient stratification and therapeutic decision-making. Materials and Methods This retrospective cohort study analyzed 51 patients with recurrent gastric cancer who received programmed cell death protein 1 (PD-1) inhibitors combined with chemotherapy after gastrectomy. All patients underwent [F-18]ALF-NOTA-FAPI-04 PET/CT within 14 days of chemoimmunotherapy. Semi-quantitative parameters (SUVmax, FTV, and TLF) were derived using semi-automated tumor segmentation. The primary endpoint of this study was the assessment of the clinical efficacy of chemoimmunotherapy, categorized as a durable or nondurable clinical benefit. The secondary endpoints included progression-free survival (PFS) and overall survival (OS). In a subgroup of 16 patients who underwent sequential [F-18]FDG PET/CT within seven days of [F-18]ALF-NOTA-FAPI-04 PET/CT, tracer uptake values were compared between the two PET/CT examinations. Results 51 patients were included. The median PFS and OS were 7 and 10 months, respectively. Durable clinical benefit (DCB) was observed in 30 patients and showed significantly lower SUVmax, FTV, and TLF values than non-DCB. TLF demonstrated the highest diagnostic accuracy for DCB (area under the receiver operating characteristic curve [AUC] = 0.80). Multivariable analysis identified TLF >= 188.88 SUVbw & centerdot;cm(3) as an independent factor associated with PFS (hazard ratio [HR] = 7.29, P = 0.001) and FTV >= 44.17 cm(3) as an independent factor associated with OS (HR = 5.16, P = 0.010). In the subgroup analysis of 16 patients, semi-quantitative analysis demonstrated consiste

关键词： Drp1   febrile seizures   Ginsenosides   targets   thermal proteome profiling  

摘要： Febrile seizure is a common pediatric neurological emergency that may potentially increase the risks of epilepsy and neurodevelopmental disorders. Ginsenosides are the primary active component of ginseng, demonstrating notable neuroprotective effects. However, the effects and mechanisms of Ginsenosides in febrile seizures remain poorly understood. This study aims to investigate the effects and potential molecular targets of Ginsenosides in mitigating febrile seizures and further elucidate its underlying mechanism. Seizure behaviors and EEG recordings were conducted in mice to investigate the effect of Ginsenosides on febrile seizures. Direct targets of Ginsenosides were identified through Thermal Proteome Profiling (TPP), subsequently validated by Surface Plasmon Resonance (SPR), Cellular Thermal Shift Assay (CETSA), and molecular docking. The mechanisms of Ginsenosides targeting Dynamin-related protein 1 (Drp1) in inhibiting febrile seizures were elucidated through proteomic analysis, molecular biology techniques, mitochondrial function assessments, and metabolite profiling. These findings demonstrate that Ginsenosides significantly attenuated febrile seizure severity and reduced the incidence of generalized tonic-clonic seizures (GTCS), showing a superior safety and efficacy profile compared to Ilepcimide. Using the TPP method, we identified and validated Drp1 as a promising direct target for therapeutic intervention in febrile seizures. Mechanistically, Ginsenoside-mediated Drp1 inhibition restored mitochondrial calcium homeostasis, promoting ATP production and elevating region-specific cortical levels of the endogenous anti-seizure metabolite adenosine. Moreover, Ginsenosides upregulated adenosine A1 receptor expression and suppressed the cyclic Adenosine Monophosphate (cAMP) signaling pathway, ultimately exerting anti-seizure effects. In summary, this study reveals that Ginsenosides significantly inhibit febrile seizures by directly targeting Drp1, thereby incr

关键词： plasma polymerization   nanoparticles   fibrillin-1   re-endothelialization  

摘要： Small diameter vascular grafts made from expanded polytetrafluoroethylene (ePTFE) dominate clinical practice but are prone to high failure rates due to poor endothelialization, acute thrombosis or mid-term neointimal hyperplasia. The highly hydrophobic surface of ePTFE inhibits endothelial cell attachment and proliferation, making timely recovery of the protective endothelial layer a key challenge. Chemically inert, highly hydrophobic polymers such as ePTFE are amongst the most difficult to improve with biofunctionalization. To address this, a novel surface coating comprising a new class of plasma polymerized nanoparticles (PPN) functionalized with bioactive PF8, a recombinant fibrillin-1 peptide is developed. PPN surface modification significantly reduces ePTFE hydrophobicity, enabling efficient surface coating of PPN-PF8 and promoting endothelial attachment and proliferation in vitro. In a rat abdominal aortic interposition model, PPN-PF8 functionalized ePTFE grafts rapidly re-endothelialized, with extensive coverage of endothelial cells at 3 weeks post-implantation. This leads to increased tissue plasminogen activator (tPA) secretion and reduced fibrin deposition, indicating the formation of a healthy, functional endothelial layer. These findings highlight the potential of plasma-polymerized nanoparticles presenting fibrillin-1 to drive rapid re-endothelialization, offering an accessible and scalable method for improving the performance of small-diameter vascular grafts.

关键词： angiosarcoma   twins   cryptogenic cirrhosis   germline mutation   MAF gene  

摘要： Primary hepatic angiosarcoma (HAS) is an exceedingly rare tumor that is often idiopathic and usually fatal. It typically occurs in a bimodal age distribution, in older adults or very young children. We describe a unique case of HAS arising at an unusual age, in an adolescent who was one of a pair of identical twins affected by cryptogenic cirrhosis and who were found to have germline loss-of-function variant in MAF, a gene that has recently been shown through animal models to be crucial in the specification of liver sinusoidal endothelial cells (LSECs). The case is the first known report of liver disease in the setting of germline MAF variants. It implicates LSEC dysfunction in both non-neoplastic and neoplastic liver disease and lends insight into the importance of LSECs in liver health and homeostasis.

关键词： Cotton wool spot   Endothelial dysfunction   Endothelin-1   Retinal vein occlusion   Vasospasm  

摘要： IntroductionTo determine the incidence, clinical characteristics, and spatial associations of retinal arterial vasospasm in retinal vein occlusion (RVO), and to explore its relationship with aqueous humor endothelin-1 (ET-1) *** retrospective cohort study included 58 eyes with RVO that underwent wide-field fluorescein angiography (FA) within 1 month of presentation. In addition, aqueous humor samples were prospectively collected from a subset of 18 treatment-na & iuml;ve RVO eyes. Arterial vasospasm was defined as a focal narrowing of the arterial lumen on early-phase FA. Cotton wool spots (CWS) and retinal hemorrhage were evaluated using color fundus photography and electronic medical records. Topographic concordance was assessed using quadrant-based, horizontal, and vertical hemifield classifications. Aqueous humor samples were analyzed for ET-1 concentration using enzyme-linked immunosorbent assay (ELISA).ResultsArterial vasospasm was identified in 21 eyes (36.2%), including six eyes with central RVO and 15 eyes with branch RVO. Vasospasm was most commonly observed in the superotemporal quadrant and predominantly on second-order arteriolar branches (78.6%). CWS were more frequent in eyes with vasospasm compared with those without (81.0% vs. 54.1%;p = 0.050). Significant spatial concordance between vasospasm and CWS was observed in the vertical hemifield (p = 0.049), with no concordance observed with retinal hemorrhage location or severity. Exploratory aqueous humor analysis showed higher ET-1 concentrations in eyes with vasospasm (8.37 +/- 4.59 vs. 5.74 +/- 1.88 pg/mL), although statistical interpretation was limited by the sample *** arterial vasospasm is a relatively common but under-recognized feature of RVO. Its association with CWS and higher ET-1 levels suggests localized arterial endothelial dysfunction. Vasospasm may represent an arterial component of RVO pathophysiology and warrants further investigation.

关键词： Zhigancao decoction   myocardial ischemia-reperfusion injury   JAK2/STAT3/HIF-1 alpha   oxidative stress   inflammation   traditional Chinese medicine  

摘要： Objective Zhigancao Decoction (ZGCD), a classic traditional Chinese formula, is widely used for cardiovascular disorders, but its role in myocardial ischemia-reperfusion injury (MIRI) is unclear. This study evaluated the cardioprotective effects of ZGCD in rats and investigated the association with JAK2/STAT3/HIF-1 alpha signaling. Methods A left anterior descending coronary artery ligation-reperfusion model was established in rats, which were randomized to sham, MIRI, low- and high-dose ZGCD, JAK2 inhibitor, or JAK2 inhibitor + ZGCD groups. After 4 weeks of gavage, cardiac function and infarct size were assessed, and myocardial histology, inflammatory and oxidative stress markers, and JAK2/STAT3/HIF-1 alpha protein expression were measured. Results ZGCD improved left ventricular ejection fraction and reduced infarct size, attenuated histological damage, decreased serum TNF-alpha, IL-1 beta, malondialdehyde and myocardial reactive oxygen species, and increased IL-10 and superoxide dismutase activity compared with MIRI alone. ZGCD also enhanced myocardial p-JAK2/JAK2 and p-STAT3/STAT3 ratios and HIF-1 alpha expression, whereas the JAK2 inhibitor largely counteracted these functional and molecular benefits. Conclusion ZGCD attenuates MIRI in rats, which is accompanied by coordinated anti-inflammatory and antioxidant effects and enhanced JAK2/STAT3/HIF-1 alpha signaling, supporting its potential as an adjunctive cardioprotective strategy.

摘要： Autophagy is part of the innate immune arsenal to fight viruses, including HIV-1. We previously reported that HIV-1 Gag is targeted for autophagy-mediated degradation. Here, we identify HIV-1 Vpr, an important virulence factor, as an autophagy target in HIV-1 NL4-3, a lab adapted molecular clone. Notably, Vpr proteins from a collection of transmitted/founder viruses (TFVs) were resistant to autophagy. Based on this observation, we identified residues at positions 37, 45, 77, 83-86, 93-94 in NL4-3 Vpr as responsible for its susceptibility to autophagy. Importantly, differences between NL4-3 and TFV Vpr proteins at these positions impact their interaction with the autophagy receptors NDP52, SQSTM1/p62 and TAX1 BP1. By engineering NL4-3 molecular clones harboring either autophagy-sensitive or -resistant vpr, we found that in 2D and 3D in vitro systems virus spread was significantly reduced for the virus carrying autophagy-sensitive Vpr. In conclusion, our study identifies Vpr as a novel autophagy target and suggests that Vpr susceptibility to autophagy impacts HIV-1 spread.

关键词： C(sp3)-N bond cleavage   C-H bond activation   RFTA   Visible-light photocatalysis   Green solvent  

摘要： Riboflavin 2 ',3 ',4 ',5 '-tetraacetate (RFTA) is a classic enzyme-mimetic photocatalyst that has demonstrated excellent catalytic performance in various oxidation reactions. In this study, we found that RFTA, in the presence of visible light and oxygen, can promote the cleavage of C(sp3)-N bonds and achieve one-pot oxidative amidation to construct 3,4-dihydroisoquinolin-1(2H)-one, a heterocyclic core widely present in many bioactive molecules, with a yield of 72 %. The reaction proceeds smoothly at room temperature and atmospheric pressure under 520 nm light irradiation using N-benzyl-1,2,3,4-tetrahydroisoquinoline as the substrate, without the need for precious metals, stoichiometric oxidants, or added bases, and is operationally simple. Preliminary mechanistic studies suggest that the reaction may first undergo single-electron transfer (SET), followed by a light-induced proton-coupled electron transfer (PCET) process, which cooperatively achieves the selective cleavage of the C (sp3)-N bond and the site-specific oxidation of the C(sp3)-H bond, thereby obtaining high chemical selectivity. Although this method still has certain limitations, we hope that this initial exploration can provide a useful supplement to the application of RFTA in biomimetic photocatalysis and offer a mild and practical new strategy for the synthesis of dihydroisoquinolinone skeletons with drug value.

关键词： polycystic ovary syndrome   obesity   GLP-1 receptor agonists   systematic review   meta-analysis  

摘要： Objective To assess the effect of treatment with glucagon-like peptide-1 receptor agonists (GLP1-RAs) on weight-related, metabolic, and reproductive outcomes and health economics in women with polycystic ovary syndrome (PCOS).Design Systematic review and meta-analysis, Prospero CRD42024535096Methods Cochrane Library, EMBASE, and Medline were searched on September 20, 2024 for studies including women with PCOS, comparing GLP1-RAs with no treatment, placebo, lifestyle intervention, combined oral contraceptives, antiandrogenic drugs, or metformin in randomized controlled trials (RCTs).Results A total of 9654 studies were identified, 365 read in full text and 11 RCTs were included. GLP1-RAs as an add-on showed a reduction in BMI compared to the control group, mean difference (95% CI), -1.38 (-2.39 to -0.38) kg/m2 (low certainty). For LDL cholesterol and triglycerides, no difference was noted between the groups (low certainty), whereas evidence was insufficient to draw conclusion regarding glucose, insulin, hirsutism, and menstrual regularity. No studies were identified assessing quality of life, mental health, or cost-effectiveness *** GLP-1-RAs are associated with modest short-term weight loss in women with PCOS and overweight or obesity. Evidence for benefits on metabolic, reproductive, or psychological outcomes remains uncertain due to low-quality data, and no studies have evaluated *** registration The protocol for the systematic review was registered prospectively in Prospero, CRD42024535096.