Conventional lipid-lowering agents, such as statins, ezetimibe, fibrates, bile acid sequestrants, nicotinic acid, bempedoic acid, and omega-3, play a pivotal role in managing dyslipidemia. Despite their benefits, these agents are associated with increased levels of plasma proprotein convertase subtilisin kexin 9 (PCSK9), a serine protease linked to elevated cardiovascular risk. The literature lacks comprehensive data on how these commonly used drugs collectively impact circulating PCSK9 levels alongside their lipid-modifying effects. This review addresses this gap by systematically analysing the effects of these agents on PCSK9 and lipid profiles. Following the preferred reporting items for systematic review and meta-analysis protocols guidelines, this study conducts a systematic search across multiple databases including MEDLINE, Cochrane Central, EMBASE, Web of Science, SCOPUS, and ScienceDirect. We include published, peer-reviewed randomised controlled trials (RCTs) that involve adult patients undergoing monotherapy or combination therapy with the mentioned lipid-lowering drugs for at least 2 weeks, with recorded PCSK9 levels at baseline and post-treatment. Our analysis encompasses data extraction and bias assessment independently performed by two researchers, utilising standardised mean difference for continuous data and risk ratios for dichotomous data. We also conduct subgroup and sensitivity analyses to assess treatment intensity, drug types, comorbidities, and geographical variations in study outcomes. Publication bias is evaluated through funnel plot and Egger's test. The meta-analysis includes 14 RCTs with 21 treatment arms, involving 1313 participants. Results indicate a significant increase in plasma PCSK9 levels following treatment with conventional lipid-lowering drugs (weighted mean difference: 23.25 ng/mL; 95% confidence interval: 17.00, 29.50; p < 0.01; I2 = 56%). Notably, subgroup analyses reveal significant differences based on treatment intensity, type of lipid-lowering agent, underlying diseases, and trial location. This systematic review confirms that conventional lipid-lowering drugs significantly elevate plasma PCSK9 levels. These findings highlight the necessity for clinicians to monitor PCSK9 concentrations in patients undergoing lipid-lowering treatment to optimise therapeutic strategies and mitigate associated cardiovascular risks. Our study contributes to a nuanced understanding of the biochemical effects of lipid-lowering therapies, potentially guiding future clinical practices and research in cardiovascular risk management.

The association between moyamoya syndrome (MMS) and hereditary spherocytosis (HS) is exceedingly rare, with only eight pediatric cases reported to date. This review explores the clinical intersection, pathophysiological theories, and management challenges of this dual pathology. We present a 13-year-old boy with known HS who presented with acute left limb weakness. Imaging confirmed MMS. Over a 3-year follow-up, serial magnetic resonance imaging (MRI) and digital subtraction angiography (DSA) demonstrated significant progression of cerebrovascular steno-occlusive disease. Management included chronic anemia correction, aspirin therapy, subsequent laparoscopic splenectomy, and ultimately, unilateral encephaloduroarteriosynangiosis (EDAS) revascularization surgery for symptomatic progression. This case, the ninth reported, suggests that chronic hemolysis and anemia in HS may potentiate rapid progression of MMS. It indicates the necessity of vigilant neurological monitoring in HS patients, advocates for maintaining hemoglobin levels > 110 g/L, and discusses the integrated roles of splenectomy and revascularization surgery. Early recognition and a multidisciplinary treatment strategy are crucial to mitigating stroke risk in this unique patient population.

Spatial distribution of ciliated epithelium cells in high-grade serous ovarian carcinoma

Colorectal cancer (CRC) constitutes a persistent global health burden, primarily attributed to its high propensity of metastasis and recurrence. Cancer immunotherapy has been increasingly recognized as an innovative strategy for combating this complex and challenging disease. As an attractive target for cancer immunotherapy, indoleamine 2, 3-dioxygenase (IDO)-mediated kynurenine pathway of tryptophan degradation constitutes a critical immune evasion mechanism employed by tumor cells to escape immune responses. Recent evidence has indicated that the upregulation of monoacylglycerol lipase (MGLL) leads to abnormal lipid metabolism within the tumor microenvironment (TME), significantly promoting the initiation, progression, and metastasis of CRC. Therefore, we developed an acid-responsive nanoplatform that utilizes host-guest interactions for co-encapsulation of NLG919 and MGLL siRNA. This nanosystem efficiently delivered of siRNA to silence MGLL and sustained release of NLG919 to inhibit IDO1 activity, thereby reversing the immunosuppressive TME. Furthermore, silencing MGLL enhances the accumulation of 2-arachidonoylglycerol (2-AG), promoting the migration and intratumoral infiltration of CD8+ T cells in the TME. Collectively, the immunosuppressive TME was alleviated and the host-guest nanosystem enhanced the synergistic effect of immunotherapy on tumors. This facile self-assembly nanoplatform provides an innovative strategy for the synchronized delivery of multiple therapeutic agents in cascade cancer immunotherapy.

Transwell migration and invasion assays in HOC7 and SKOV3 cells following SDC4 knockdown

Tumor regions annotated by H&E staining and integrated with cell-type composition across spatial domains in high-grade serous ovarian carcinoma

RATIONALE:Vertebral artery stenosis (VAS), which refers to the narrowing of the vertebral artery, is a significant cause of posterior circulation ischaemic stroke. Medical treatment involves managing risk factors and using medications, while endovascular treatment typically consists of percutaneous transluminal angioplasty, which may be performed with or without stenting. Despite these available options, optimal management of people with symptomatic vertebral artery stenosis has not yet been established. OBJECTIVES:To assess the benefits and harm of percutaneous transluminal angioplasty, with or without stenting, plus medical treatment (MT), compared with MT alone, in people with episodes of vertebrobasilar ischaemia due to vertebral artery stenosis. SEARCH METHODS:We searched MEDLINE, Embase, BIOSIS, and two other indexes on the Web of Science, China Biological Medicine Database, Chinese Science and Technique Journals Database, China National Knowledge Infrastructure and Wanfang Data, as well as ClinicalTrials.gov trials register and the World Health Organisation (WHO) International Clinical Trials Registry Platform to 9 Dec 2025. ELIGIBILITY CRITERIA:We included all randomised controlled trials (RCTs) that compared endovascular therapy (ET) plus MT with MT alone in treating people aged 18 years or over with symptomatic VAS. We included all types of ET modalities, such as angioplasty alone, balloon-mounted stenting, and angioplasty followed by the placement of a self-expanding stent. The MT regimen encompassed risk-factor control, antiplatelet therapy, lipid-lowering therapy, and individualised management for patients with hypertension or diabetes. OUTCOMES:Our outcomes were 30-day post-randomisation death or stroke; fatal or non-fatal stroke in the territory of the treated vertebral artery from 30 days after randomisation to the end of follow-up; stroke (ischaemic or haemorrhagic) during the entire follow-up period; death during the entire follow-up period; stroke or transient ischaemic attack (TIA) during the entire follow-up period; and ≥ 50% restenosis of the treated vertebral artery documented by conventional cerebral angiography. All strokes and TIAs were newly diagnosed events. We evaluated all important outcomes during the entire follow-up period. RISK OF BIAS:We assessed risk of bias in RCTs using version 1 of the Cochrane tool (RoB 1). SYNTHESIS METHODS:Two review authors independently screened studies, extracted data, and assessed risk of bias. For dichotomous outcomes, we calculated risk ratios with 95% confidence intervals and pooled results using fixed-effect meta-analysis when studies were sufficiently similar; otherwise, we provided a narrative synthesis. We used GRADE methods to assess the certainty of evidence and summarised key outcomes in a summary of findings table. INCLUDED STUDIES:We included a total of four multicentre RCTs with 429 participants who had symptomatic vertebral artery stenosis, all comparing endovascular treatment plus medical treatment versus medical treatment alone in adults with recent posterior circulation transient ischaemic attack or non-disabling ischaemic stroke. SYNTHESIS OF RESULTS:We included four RCTs with 429 participants who had symptomatic vertebral artery stenosis, with a mean age of 63.4 years. Three of the four RCTs (VAST, VIST, and SAMMPRIS) were stopped early, and all trials had a high risk of performance bias because blinding of the endovascular therapy was not feasible, which limits the precision of treatment-effect estimates. Overall, the certainty of the evidence is low, mainly due to the high risk of performance bias, early termination of three of the four trials, small sample sizes, and imprecision of the effect estimates. There was no clear evidence of a difference in 30-day post-randomisation deaths/strokes between ET plus MT and MT alone (risk ratio (RR) 2.02, 95% confidence interval (CI) 0.73 to 5.55; 4 studies, 429 participants; low-certainty evidence). There was no clear evidence of a difference between ET plus MT and MT alone in fatal/non-fatal strokes in the territory of the treated vertebral artery stenosis after 30 days post-randomisation to completion of follow-up (RR 0.54, 95% CI 0.29 to 1.01; 4 studies, 429 participants; low-certainty evidence); in ischaemic or haemorrhagic stroke during the entire follow-up period (RR 0.76, 95% CI 0.46 to 1.26; 4 studies, 429 participants; low-certainty evidence); or in death during the entire follow-up period (RR 0.83, 95% CI 0.41 to 1.66; 4 studies, 429 participants; low-certainty evidence). Low-certainty evidence suggests that ET plus MT may make little or no difference to stroke or transient ischaemic attack during follow-up (RR 0.65, 95% CI 0.39 to 1.06; 2 studies, 234 participants; low-certainty evidence). Of the prespecified outcomes, no included study reported restenosis or good functional outcome, so these outcomes could not be analysed. AUTHORS' CONCLUSIONS:Based on four RCTs including 429 participants, there may be little to no difference between endovascular treatment plus medical treatment and medical treatment alone in 30-day post-randomisation death/stroke, fatal/non-fatal stroke in the territory of the treated vertebral artery stenosis after 30 days post-randomisation to completion of follow-up, stroke (ischaemic or haemorrhagic) during the entire follow-up period, death during the entire follow-up period, and stroke or transient ischaemic attack during the entire follow-up period. Overall, the certainty of the evidence is low. We found no reliable evidence that endovascular treatment plus medical treatment is superior to medical treatment alone in preventing stroke or death. Confidence intervals are wide and compatible with either modest benefit or modest harm from the addition of endovascular treatment. FUNDING:This work was supported by the National Natural Science Foundation of China (grant number: 82301468 and 82501574), the Beijing Nova Program (grant number: 20230484336), the Beijing Hospitals Authority's Ascent Plan (grant number: DFL20220702), the Xuanwu Hospital Talent Seed Program (grant number: YC20250107), and the Beijing Hospitals Authority Clinical Medicine Development of Special Funding Support (grant number: ZLRK202320). REGISTRATION:The protocol to this review has not been published. The original review can be accessed as: DOI: 10.1002/14651858.CD013692.pub2.

Adjuvants enhance and prolong the immune response to therapeutic agents, such as drugs and vaccines. However, conventional adjuvants have limitations in terms of immune specificity and duration. Nanoadjuvants can leverage their nanoscale size to increase the capture efficacy of antigens by antigen-presenting cells and improve immunogen presentation for targeted delivery. Furthermore, noninvasive visualization of bifunctional nanoadjuvants with integrated efficacy and imaging postdelivery can provide insights into in vivo distribution and performance, aiding in the optimization and design of new dosage forms. This review systematically summarizes the structure, assembly, and function of nanoadjuvants alongside contrast agents. It delves into the impact of complex structures formed by nanoadjuvant-contrast agent interactions on antigen presentation, migration, imaging tracking, and visualization of immune cell recruitment. It also discusses how imaging can determine optimal immune intervals, vaccine safety, and toxicity while enabling diagnostic and therapeutic integration. Moreover, this paper discusses potential applications of novel adjuvants and promising imaging technologies that could have implications for future vaccine and drug development endeavors.

This randomized clinical trial investigates if intra-arterial alteplase improves clinical outcomes in patients with acute ischemic stroke (AIS) of the posterior circulation within 24 hours of symptom onset and after successful mechanical recanalization. QuestionAmong patients with acute basilar artery occlusion treated within 24 hours of symptom onset and achieving successful mechanical recanalization, does intra-arterial alteplase improve clinical outcomes?FindingsIn this randomized clinical trial including 246 patients, functional independence at 90 days was achieved in approximately half of patients in both the intra-arterial alteplase and control groups. Rates of symptomatic intracranial hemorrhage were similar across groups.MeaningStudy results show that adjunctive intra-arterial alteplase after successful endovascular recanalization for acute stroke due to basilar artery occlusion seems safe but did not improve functional outcomes at 90 days. ImportanceThe impact of adjunctive intra-arterial alteplase after successful endovascular thrombectomy (EVT) in patients with acute ischemic stroke due to large-vessel occlusion (AIS-LVO) in the posterior circulation requires further investigation.ObjectiveTo assess the efficacy and safety of intra-arterial alteplase after successful EVT for AIS-LVO in the posterior circulation.Design, Setting, and ParticipantsThis was a multicenter, prospective, randomized, open-label, blinded-end point (PROBE design) clinical trial. The study was conducted between September 5, 2023, and November 29, 2024, with the 3-month follow-up completed on February 18, 2025. The trial was conducted in 37 comprehensive stroke centers in China. Patients in China with acute basilar artery occlusion presenting within 24 hours of the time last known well were randomly assigned to the treatment group or control group. Eligible participants were adults who achieved successful recanalization after EVT.InterventionsEligible patients were randomly assigned to the intra-arterial alteplase group (0.225 mg/kg, maximum dose limit 22.5 mg infused at a concentration of 1.0 mg/mL within 15 minutes distal to the origin of posterior inferior cerebellar artery) or control group (no intra-arterial thrombolysis).Main Outcomes and MeasuresThe primary efficacy outcome was the proportion of patients achieving functional independence (modified Rankin Scale score of 0-2) at 90 days. The primary safety outcomes were mortality at 90 days and incidence of symptomatic intracranial hemorrhage within 48 hours.ResultsA total of 247 patients were enrolled, and 1 patient was excluded from the full analysis set due to basilar artery reocclusion before intra-arterial alteplase. The remaining 246 patients (median [IQR] age, 65.0 [56.0-72.0] years; 176 male [71.5%]) were included in this analysis, 124 (50.4%) in the treatment group and 122 (49.6%) in the control group. Among the patients recruited and followed up, functional independence at 90 days was achieved in 52 (41.9%) in the intra-arterial alteplase group and 57 (46.7%) in the control group (adjusted risk ratio, 0.93; 95% CI, 0.73-1.18; P = .55). Mortality at 90 days (29.6% vs 27.0%, respectively; adjusted hazard ratio, 1.07; 95% CI, 0.71-1.61; P = .75) and incidence of symptomatic intracranial hemorrhage (2.4% vs 2.5%, respectively; unadjusted risk ratio, 0.98; 95% CI, 0.20-4.74; P = .97) were similar across groups.Conclusions and RelevanceResults of this randomized clinical trial reveal that in patients with posterior circulation stroke due to acute basilar artery occlusion, intra-arterial alteplase after successful endovascular recanalization appeared to be safe but was not associated with improvement of functional outcomes at 90 days.Trial RegistrationClinicalTrials.gov Identifier: NCT05897554

Validation of the TNFα–SAA1/2–APOE signaling axis in 16 public HGSOC slices

Introduction Circulating proprotein convertase subtilisin/kexin 9 (PCSK9) levels may differ by sex and geographic region, but evidence remains inconsistent. This systematic review and meta-analysis quantifies these differences in adults with hyperlipidaemia, atherosclerotic cardiovascular disease (ASCVD) or elevated ASCVD risk.Methods We searched MEDLINE, Web of Science, Cochrane Central and EMBASE through August 2024 for studies reporting plasma PCSK9 in ≥10 adults. Two reviewers extracted data and assessed bias. Random-effects models pooled standardised mean differences (SMDs) or means; heterogeneity was evaluated by I2, with subgroup and sensitivity analyses exploring its sources.Results For gender, 13 studies (5 706 participants) showed significantly higher PCSK9 in females than males (SMD −0.35, 95% CI −0.49 to −0.20; p=0.033; I2=54%). Single-sex studies corroborated this: female-only mean 350.66 ng/mL (95% CI 301.86 to 399.46) versus male-only 228.36 ng/mL (95% CI 176.33 to 280.39). For region, 63 studies (34 802 participants) from Asia, Europe and North America yielded no significant overall difference (p=0.569); after outlier exclusion, pooled means were 250.39 (95% CI 217.70 to 283.08), 269.27 (95% CI 230.24 to 308.31) and 301.76 (95% CI 194.28 to 409.23) ng/mL, with I2=0% within subgroups. Sensitivity analyses confirmed robustness; most studies were high quality. GRADE (Grading of Recommendations, Assessment, Development and Evaluation) certainty was moderate for sex and low for region.Conclusions In these clinical populations, women have higher circulating PCSK9 levels than men, while regional differences were not statistically significant. These findings support gender-conscious interpretation of baseline PCSK9 values but do not establish PCSK9 inhibitor dosing or treatment strategies.

Background Building on our previous isolation of plaque-derived small extracellular vesicles (sEVs) from carotid atherosclerotic stenosis (CAS) patients, this study aimed to identify plasma sEV-encapsulated miRNAs that reflect plaque vulnerability and predict clinical outcomes, based on differentially expressed miRNAs identified in sEVs from stable versus vulnerable plaques. Methods CAS patients were retrospectively enrolled into four complementary cohorts: (1) a sequencing cohort (n=12) for miRNA profiling of plaque-derived sEVs; (2) a discovery cohort (n=62) to identify candidate plasma-derived sEV miRNAs associated with plaque vulnerability; and (3) validation cohort 1 (n=180; endarterectomy cases) and (4) validation cohort 2 (n=326; stenting cases) for validating the diagnostic efficacy of the identified plasma-derived sEV miRNAs. Candidate miRNAs were quantified using a High-throughput nano-bio chip integrated system (HNCIB). Their associations with plaque vulnerability and 3-year post-endarterectomy major adverse cardiovascular events (MACE) were analyzed. Results MiRNA sequencing revealed significant upregulation of miR-660-5p in vulnerable plaque-derived sEVs. Its expression levels showed a significant positive correlation between matched plaque- and plasma-derived sEVs from the same patient. Moreover, plasma-derived sEV miR-660-5p levels were independently associated with carotid plaque vulnerability in both validation cohorts, defined either by histopathological criteria (endarterectomy cases) or the clinically validated Plaque-Reporting and Data System (RADS) criteria (stenting cases). Additionally, elevated plasma-derived sEV miR-660-5p levels were also associated with a higher risk of 3-year post-endarterectomy MACE. Conclusion Plasma-derived sEV miR-660-5p represents a promising non-invasive biomarker for assessing carotid plaque vulnerability and predicting 3-year MACE risk following carotid endarterectomy, offering potential for improved risk stratification and therapeutic targeting.

The persistent discharge of antibiotic contaminants into aquatic environments promotes antimicrobial resistance (AMR), posing significant ecological and public health risks. Toward this objective, ciprofloxacin (CIP)-contaminated water was treated via visible-light-assisted photocatalysis using curcumin-derived carbon quantum dots (Cur-CQDs) paired magnetic-carbon nitride lateral heterostructures (LMCN@Cur-CDs) to evaluate their degradation efficiency. The resulting lateral heterostructure (LHS) exhibited a larger surface area (SBET=154.8 m2‧g− 1), abundant defect sites (ID/IG=1.06), and yielded efficient peroxydisulfate (PDS) activation under visible light. Consequently, rapid CIP degradation (94.86

The rapid proliferation of tumor cells is driven by metabolic reprogramming and redox regulation. Realtime monitoring of glutathione (GSH)/adenosine-5' -triphosphate (ATP) provides a dynamic perspective for tumor metabolism and is crucial for guiding precision treatment. We report a dual-site activatable fluorescent probe M901 for simultaneously detecting GSH and ATP without spectral overlap, and the detection range (GSH: 0-7 mmol/L, ATP: 0-6.5 mmol/L) matching the physiological concentration range. Based on this, M901 visualizes a bidirectional regulatory relationship between ATP synthesis ,. (energy imbalance) H electron transport chain dysfunction H reactive oxygen species (ROS) T H GSH ,. (oxidative stress). Additionally, M901 reveals for the first time the dynamic compensatory mechanism between GSH and ATP in cellular oxidative stress induced by the inhibition of solute carrier family 7 member 11 (SLC7A11) or glutathione peroxidase 4 (GPX4). In vivo imaging further confirms oxidative stress and mitochondrial dysfunction are core pathological mechanisms leading to liver injury, with treatment efficacy positively correlated with GSH/ATP levels. Importantly, the dynamic visualization of GSH/ATP by M901 enables real-time evaluation of the anti-tumor effects of ferroptosis inducers and cisplatin, guiding successful precision resection of invasive malignant tumors (negative margins < 0.2 mm). This study confirms the potential of M901 as a clinical visualization tool for diagnosing, treating and monitoring a variety of diseases.

Transdermal drug delivery systems (TDDS), as an important alternative to oral and injectable administration, offer significant advantages including non-invasive delivery, avoidance of first-pass metabolism, and the ability to achieve sustained drug release. However, the physicochemical properties of the skin impose multiple barriers and limitations on transdermal drug delivery, which has motivated extensive research efforts to overcome these bottlenecks. This review focuses on the fundamental principles of transdermal drug transport and summarizes major technological approaches, including passive diffusion systems, active enhancement strategies, microneedle-based delivery platforms, and nanocarrier systems. In addition, recent advances in the application of TDDS for the treatment of skin diseases, immune disorders, neurological diseases, and cardiovascular diseases are reviewed. Finally, key challenges and future perspectives toward intelligent, personalized, and multifunctional TDDS are discussed, with an emphasis on clinical translation issues such as interindividual variability in skin barrier function, formulation design, safety, and regulatory considerations, underscoring the potential of TDDS in modern medicine.

Importance:The impact of adjunctive intra-arterial alteplase after successful endovascular thrombectomy (EVT) in patients with acute ischemic stroke due to large-vessel occlusion (AIS-LVO) in the posterior circulation requires further investigation. Objective:To assess the efficacy and safety of intra-arterial alteplase after successful EVT for AIS-LVO in the posterior circulation. Design, Setting, and Participants:This was a multicenter, prospective, randomized, open-label, blinded-end point (PROBE design) clinical trial. The study was conducted between September 5, 2023, and November 29, 2024, with the 3-month follow-up completed on February 18, 2025. The trial was conducted in 37 comprehensive stroke centers in China. Patients in China with acute basilar artery occlusion presenting within 24 hours of the time last known well were randomly assigned to the treatment group or control group. Eligible participants were adults who achieved successful recanalization after EVT. Interventions:Eligible patients were randomly assigned to the intra-arterial alteplase group (0.225 mg/kg, maximum dose limit 22.5 mg infused at a concentration of 1.0 mg/mL within 15 minutes distal to the origin of posterior inferior cerebellar artery) or control group (no intra-arterial thrombolysis). Main Outcomes and Measures:The primary efficacy outcome was the proportion of patients achieving functional independence (modified Rankin Scale score of 0-2) at 90 days. The primary safety outcomes were mortality at 90 days and incidence of symptomatic intracranial hemorrhage within 48 hours. Results:A total of 247 patients were enrolled, and 1 patient was excluded from the full analysis set due to basilar artery reocclusion before intra-arterial alteplase. The remaining 246 patients (median [IQR] age, 65.0 [56.0-72.0] years; 176 male [71.5%]) were included in this analysis, 124 (50.4%) in the treatment group and 122 (49.6%) in the control group. Among the patients recruited and followed up, functional independence at 90 days was achieved in 52 (41.9%) in the intra-arterial alteplase group and 57 (46.7%) in the control group (adjusted risk ratio, 0.93; 95% CI, 0.73-1.18; P = .55). Mortality at 90 days (29.6% vs 27.0%, respectively; adjusted hazard ratio, 1.07; 95% CI, 0.71-1.61; P = .75) and incidence of symptomatic intracranial hemorrhage (2.4% vs 2.5%, respectively; unadjusted risk ratio, 0.98; 95% CI, 0.20-4.74; P = .97) were similar across groups. Conclusions and Relevance:Results of this randomized clinical trial reveal that in patients with posterior circulation stroke due to acute basilar artery occlusion, intra-arterial alteplase after successful endovascular recanalization appeared to be safe but was not associated with improvement of functional outcomes at 90 days. Trial Registration:ClinicalTrials.gov Identifier: NCT05897554.

Deep eutectic solvents (DESs) represent a burgeoning class of versatile media with significant potential to enhance the solubility, stability, and bioavailability of poorly water-soluble antineoplastic active pharmaceutical ingredients (AAPIs). However, the rational design of API-specific DES formulations remains impeded by an insufficient mechanistic understanding of the molecular-level interactions that govern API-DES compatibility. To address this critical gap, our study pioneers an integrated multi-scale computational strategy, synergizing free volume analysis, binding energy calculations, and hydrogen-bonding network quantification to unravel the supramolecular interplay between diverse DESs and a panel of clinically relevant AAPIs (including 5-FU, p-toluenesulfonamide (PTS), trigonelline, piperine, phloretin, nonivamide, curcumin, and erlotinib). We demonstrate that the free volume of DESs, formed from choline chloride or betaine with various hydrogen bond donors (HBDs), is dynamically altered upon AAPI incorporation, exhibiting either a "tightening" or "loosening" effect that correlates with dissolution enhancement or molecular stabilization. Interaction total energy (ΔEt) profiles reveal strong dependencies on [HBA][HBD][AAPI] combinations, with glycerol-based DESs showing superior affinity for most AAPIs, while zwitterionic HBDs (e.g. glycine) form less stable complexes. The investigated [DES][AAPI] systems were classified into four ranks (I-IV) representing a descending gradient of predictive certainty and overall solubilization/stabilization potential. DESs such as [ChCl][PG], [ChCl][Glycerol], or [Betaine][Glycerol] appear more frequently in Classes I and IV than in Classes II and III. Given that Class I represents superior performance and Class IV represents high predictive uncertainty (rather than poor performance), the predominance of these DESs in Class I suggests a higher probability of favorable outcomes across diverse AAPIs.These insights provide a predictive framework for the rational design of DES systems tailored to specific APIs, enabling optimized solubility, stability, and controlled release in next-generation drug delivery applications.

PURPOSE:Interventional skill and assessment are essential for vascular interventionalists prior to performing clinical procedures. However, traditional surgical assessments often fail to deliver objective and accurate results. To address these issues, our study proposes a simulator and an analytical framework for evaluating endovascular procedural performance. METHODS:A custom interventional operation simulator included an in vitro silicone phantom, mock circulation loop, visual module, force-sensing module, and custom software for kinematic and force data post-processing. An in vitro study was conducted to deliver medical guidewire to four target vessels by thirty interventionalists and ten medical novices. Four types of features (i.e., vascular morphological, device-vascular model interaction, kinematic and force) were obtained from the interventional tasks. An operational force prediction model was developed and trained using long short-term memory (LSTM) networks based on multi-modal feature datasets. Furthermore, features with significant differences were applied for qualitative and quantitative evaluation via support vector machine and Mahalanobis distance. RESULTS:The well-trained LSTM model could predict the operation force, force and torque between instruments and vascular model. The qualitative assessment achieved an overall accuracy of 84.17% for two-class classification to distinguish the novice and expert attempts, and the quantitative assessment could assign effective scores for all attempts. CONCLUSIONS:This work provides an approach for the prediction and assessment of intervention performance behaviors, and results demonstrate the effectiveness of this method for promoting the development of interventional skill assessment.

Spatial feature plots of the distribution and enrichment of the GP1 molecular subtype (differentiated-invasive) in high-grade serous ovarian carcinoma

Carotid atherosclerosis is a kind of systemic atherosclerosis in the carotid arteries. It remains one of the leading causes of ischemic stroke. However, the efficiency of treatment is insufficient. Thus, it is urgent to deepen the understanding of the underlying mechanisms in carotid atherosclerosis, which may facilitate the development of effective therapeutic interventions. Phenotypic switching of vascular smooth muscle cells (VSMCs) is recognized as a central process in atherosclerosis progression. However, the key regulatory genes involved in this process during carotid atherosclerosis are not fully understood. Three gene expression datasets, GSE43292, GSE100927, and GSE28829 were downloaded from Gene Expression Omnibus (GEO) database, covering carotid atherosclerosis and control groups. we integrated bioinformatics analysis with three machine learning algorithms to identify the hub genes associated with carotid atherosclerosis. Subsequent validation using clinical specimens and murine atherosclerosis confirmed the expression of the hub genes at both the mRNA and protein levels. Furthermore, in vitro phenotypic switching model using human aortic smooth muscle cells (HASMCs) treated with pro‑atherogenic stimuli was established to identify the expression of hub genes and to investigate how knockdown of these hub genes in HASMCs influences VSMCs phenotypic switching. Through the integration of bioinformatics analysis and three machine learning algorithms, we identified PALS2 and CASQ2 as consistently downregulated genes in carotid atherosclerotic plaques compared to normal tissues. Gene interaction network analysis suggested that PALS2 and CASQ2 may cooperatively regulate calcium homeostasis and calcification in VSMCs. This finding was further supported by consistent downregulation of both genes in clinical atherosclerotic samples, murine atherosclerosis, and in HASMCs exposed to pro‑atherogenic stimuli. Functionally, knockdown of either gene enhanced VSMCs phenotypic switching, calcium deposition and amplifies CREB1 phosphorylation, collectively demonstrating their protective role in mitigating atherosclerosis. This study identifies PALS2 and CASQ2 as novel regulators involved in the VSMCs phenotypic switching and calcification in carotid atherosclerosis. Both genes are consistently downregulated in atherosclerotic plaques and function as upstream suppressors of a calcium-CREB1 calcification axis. These findings provide novel insights into the molecular mechanisms of atherosclerosis and highlight PALS2 and CASQ2 as potential therapeutic targets for intervention.