Early detection and prognosis evaluation for hepatocellular carcinoma by circulating tumour DNA methylation: A multicentre cohort study.

BACKGROUND: Early diagnosis of hepatocellular carcinoma (HCC) can significantly improve patient survival. We aimed to develop a blood-based assay to aid in the diagnosis, detection and prognostic evaluation of HCC. METHODS: A three-phase multicentre study was conducted to screen, optimise and validate HCC-specific differentially methylated regions (DMRs) using next-generation sequencing and quantitative methylation-specific PCR (qMSP). RESULTS: Genome-wide methylation profiling was conducted to identify DMRs distinguishing HCC tumours from peritumoural tissues and healthy plasmas. The twenty most effective DMRs were verified and incorporated into a multilocus qMSP assay (HepaAiQ). The HepaAiQ model was trained to separate 293 HCC patients (Barcelona Clinic Liver Cancer (BCLC) stage 0/A, 224) from 266 controls including chronic hepatitis B (CHB) or liver cirrhosis (LC) (CHB/LC, 96), benign hepatic lesions (BHL, 23), and healthy controls (HC, 147). The model achieved an area under the curve (AUC) of 0.944 with a sensitivity of 86.0% in HCC and a specificity of 92.1% in controls. Blind validation of the HepaAiQ model in a cohort of 523 participants resulted in an AUC of 0.940 with a sensitivity of 84.4% in 205 HCC cases (BCLC stage 0/A, 167) and a specificity of 90.3% in 318 controls (CHB/LC, 100; BHL, 102; HC, 116). When evaluated in an independent test set, the HepaAiQ model exhibited a sensitivity of 70.8% in 65 HCC patients at BCLC stage 0/A and a specificity of 89.5% in 124 patients with CHB/LC. Moreover, HepaAiQ model was assessed in paired pre- and postoperative plasma samples from 103 HCC patients and correlated with 2-year patient outcomes. Patients with high postoperative HepaAiQ score showed a higher recurrence risk (Hazard ratio, 3.33, p < .001). CONCLUSIONS: HepaAiQ, a noninvasive qMSP assay, was developed to accurately measure HCC-specific DMRs and shows great potential for the diagnosis, detection and prognosis of HCC, benefiting at-risk populations.

Head model dataset for mixed reality navigation in neurosurgical interventions for intracranial lesions.

Mixed reality navigation (MRN) technology is emerging as an increasingly significant and interesting topic in neurosurgery. MRN enables neurosurgeons to "see through" the head with an interactive, hybrid visualization environment that merges virtual- and physical-world elements. Offering immersive, intuitive, and reliable guidance for preoperative and intraoperative intervention of intracranial lesions, MRN showcases its potential as an economically efficient and user-friendly alternative to standard neuronavigation systems. However, the clinical research and development of MRN systems present challenges: recruiting a sufficient number of patients within a limited timeframe is difficult, and acquiring low-cost, commercially available, medically significant head phantoms is equally challenging. To accelerate the development of novel MRN systems and surmount these obstacles, the study presents a dataset designed for MRN system development and testing in neurosurgery. It includes CT and MRI data from 19 patients with intracranial lesions and derived 3D models of anatomical structures and validation references. The models are available in Wavefront object (OBJ) and Stereolithography (STL) formats, supporting the creation and assessment of neurosurgical MRN applications.

Association of ADP­ribosylation factor family genes with prognosis and immune infiltration of breast cancer.

Breast cancer (BC) is the most common type of cancer found in women. ADP-ribosylation factors (ARFs) are a group of small proteins that bind to GTP and are involved in controlling different cellular functions. The function and evolution of multiple ARFs in BC have remained to be fully elucidated, despite existing studies on this protein family in Homo sapiens and other species. In the present study, a systematic analysis of ARF expression levels in BC tissues compared to normal breast tissues was performed using data from The Cancer Genome Atlas database. The analysis revealed significantly higher expression of ARFs in BC tissues. In addition, the prognostic significance of ARF1 and ARF3-6 expression levels was assessed in patients with BC. Of note, elevated ARF1 expression was associated with reduced rates of distant metastasis-free survival (DMFS), overall survival (OS) and recurrence-free survival (RFS) in affected individuals. Similarly, patients with high expression levels of ARF3 had lower post-progression survival (PPS) rates. In addition, patients with higher ARF4 expression had worse PPS and patients with high ARF5 expression exhibited lower DMFS. Patients with high ARF6 expression had worse DMFS, OS, RFS and predictive power score values. Furthermore, the expression of ARF was found to be strongly linked to the infiltration of various immune cell types, namely dendritic cells, macrophages, neutrophils, CD8+ T cells and B cells. These significant associations offer a solid foundation for the potential utilization of new therapeutic targets and predictive markers for the treatment of BC.

Effectiveness and safety of interferon α-2a combined with phototherapy for patients with early-stage mycosis fungoides - a single-arm prospective study in 13 patients.

Background: Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma.Objectives: This study was conducted to evaluate efficacy and safety of interferon (IFN) α-2a combined with phototherapy for early-stage MF.Methods: Thirteen patients with early-stage MF received subcutaneous injections of IFN α-2a at 3 million IU combined with phototherapy three times per week for 6 months. Treatment efficacy was measured by changes in body surface area (BSA) score and modified severity-weighted assessment tool (mSWAT) score at 1, 3, and 6 months after treatment. Histopathologic examinations of skin lesions were performed before and after treatment.Results: After 3 months of treatment, all 13 patients achieved a partial response, and BSA and mSWAT scores were significantly lower than those at baseline (p < 0.001). After 6 months, BSA and mSWAT scores were significantly lower than those at baseline (p < 0.001) and after 3 months (p < 0.05). Eleven patients achieved complete remission and two patients achieved a partial response (overall response rate, 100%). Histopathologic examination showed a significant decrease in the number of atypical lymphocytes in both epidermis and dermis. No severe adverse effects occurred.Conclusion: IFN α-2a in combination with phototherapy may be an effective and safe alternative modality for early-stage MF.

Rapid and sustained improvements in itch and quality of life with upadacitinib plus topical corticosteroids in adults and adolescents with atopic dermatitis: 52-week outcomes from the phase 3 AD Up study.

Purpose: Atopic dermatitis (AD) adversely impacts quality of life (QoL). We evaluated the effect of upadacitinib, an oral selective Janus kinase inhibitor approved for moderate-to-severe AD, plus topical corticosteroids (+TCS) on patient-reported outcomes (PROs) over 52 weeks.Materials and methods: In the phase 3 AD Up study (NCT03568318), adults and adolescents with moderate-to-severe AD were randomized 1:1:1 to once-daily upadacitinib 15 mg, 30 mg, or placebo + TCS. Itch, skin pain/symptoms, sleep, QoL, daily activities, emotional state, mental health, and patient impressions of disease severity/improvement/treatment satisfaction were assessed.Results: This analysis included 901 patients. Within 1-2 weeks, PRO improvements were greater with both upadacitinib doses than with placebo (p <.05). Improvements increased through weeks 4-8; rates were generally maintained through week 52. At week 52, the proportion of patients with clinically meaningful improvements in itch (Worst Pruritus Numerical Rating Scale improvement ≥4), skin pain (AD Symptom Scale Skin Pain improvement ≥4), sleep (AD Impact Scale [ADerm-IS] Sleep improvement ≥12), daily activities (ADerm-IS Daily Activities improvement ≥14), and emotional state (ADerm-IS Emotional State improvement ≥11) ranged from 62.1%-77.7% with upadacitinib 15 mg + TCS and 71.3%-83.6% with upadacitinib 30 mg + TCS.Conclusions: Upadacitinib + TCS results in rapid, sustained improvements in burdensome AD symptoms and QoL.

Regular use of fish oil supplements and course of cardiovascular diseases: prospective cohort study.

Objective: To examine the effects of fish oil supplements on the clinical course of cardiovascular disease, from a healthy state to atrial fibrillation, major adverse cardiovascular events, and subsequently death. Design: Prospective cohort study. Setting: UK Biobank study, 1 January 2006 to 31 December 2010, with follow-up to 31 March 2021 (median follow-up 11.9 years). Participants: 415 737 participants, aged 40-69 years, enrolled in the UK Biobank study. Main outcome measures: Incident cases of atrial fibrillation, major adverse cardiovascular events, and death, identified by linkage to hospital inpatient records and death registries. Role of fish oil supplements in different progressive stages of cardiovascular diseases, from healthy status (primary stage), to atrial fibrillation (secondary stage), major adverse cardiovascular events (tertiary stage), and death (end stage). Results: Among 415 737 participants free of cardiovascular diseases, 18 367 patients with incident atrial fibrillation, 22 636 with major adverse cardiovascular events, and 22 140 deaths during follow-up were identified. Regular use of fish oil supplements had different roles in the transitions from healthy status to atrial fibrillation, to major adverse cardiovascular events, and then to death. For people without cardiovascular disease, hazard ratios were 1.13 (95% confidence interval 1.10 to 1.17) for the transition from healthy status to atrial fibrillation and 1.05 (1.00 to 1.11) from healthy status to stroke. For participants with a diagnosis of a known cardiovascular disease, regular use of fish oil supplements was beneficial for transitions from atrial fibrillation to major adverse cardiovascular events (hazard ratio 0.92, 0.87 to 0.98), atrial fibrillation to myocardial infarction (0.85, 0.76 to 0.96), and heart failure to death (0.91, 0.84 to 0.99). Conclusions: Regular use of fish oil supplements might be a risk factor for atrial fibrillation and stroke among the general population but could be beneficial for progression of cardiovascular disease from atrial fibrillation to major adverse cardiovascular events, and from atrial fibrillation to death. Further studies are needed to determine the precise mechanisms for the development and prognosis of cardiovascular disease events with regular use of fish oil supplements.

PPARγ Antagonists Exhibit Antitumor Effects by Regulating Ferroptosis and Disulfidptosis.

Oral squamous cell carcinoma (OSCC) stands as a prevalent subtype of head and neck squamous cell carcinoma, leading to disease recurrence and low survival rates. PPARγ, a ligand-dependent nuclear transcription factor, holds significance in tumor development. However, the role of PPARγ in the development of OSCC has not been fully elucidated. Through transcriptome sequencing analysis, we discovered a notable enrichment of ferroptosis-related molecules upon treatment with PPARγ antagonist. We subsequently confirmed the occurrence of ferroptosis through transmission electron microscopy, iron detection, etc. Notably, ferroptosis inhibitors could not completely rescue the cell death caused by PPARγ inhibitors, and the rescue effect was the greatest when disulfidptosis and ferroptosis inhibitors coexisted. We confirmed that the disulfidptosis phenotype indeed existed. Mechanistically, through qPCR and Western blotting, we observed that the inhibition of PPARγ resulted in the upregulation of heme oxygenase 1 (HMOX1), thereby promoting ferroptosis, while solute carrier family 7 member 11 (SLC7A11) was also upregulated to promote disulfidptosis in OSCC. Finally, a flow cytometry analysis of flight and multiplex immunohistochemical staining was used to characterize the immune status of PPARγ antagonist-treated OSCC tissues in a mouse tongue orthotopic transplantation tumor model, and the results showed that the inhibition of PPARγ led to ferroptosis and disulfidptosis, promoted the aggregation of cDCs and CD8+ T cells, and inhibited the progression of OSCC. Overall, our findings reveal that PPARγ plays a key role in regulating cell death in OSCC and that targeting PPARγ may be a potential therapeutic approach for OSCC.

Evaluation of parietal pleural adhesion and invasion in subpleural lung cancer: value of B-mode ultrasound and contrast-enhanced ultrasound.

Background: The parietal pleural adhesion/invasion of lung cancer can contribute substantially to poor prognosis and difficulty in surgery. The value of ultrasound in evaluating the parietal pleural adhesion or invasion (pleural adhesion/invasion) of lung cancer remains uncertain. This study investigated the value of B-mode ultrasound and contrast-enhanced ultrasound (CEUS) in diagnosing parietal pleural adhesion/invasion of subpleural lung cancer. Methods: The study animals included 40 male New Zealand white rabbits. A rabbit subpleural lung cancer model was constructed by injecting VX2 tumor tissue under ultrasound guidance. In the 1-3 weeks after subpleural lesion formation, parietal pleural adhesion/invasion of the largest subpleural lesion was evaluated with B-mode ultrasound and CEUS by two sonographers. The parietal pleural adhesion/invasion was also determined using the gold standard method of findings from anatomical and pathological examination. Results: Ultimately, 34 rabbits were subjected to complete ultrasonic evaluation. There were 20 and 14 cases with and without parietal pleural adhesion/invasion, respectively, as confirmed by anatomical and pathological evaluations. The diagnostic sensitivity, specificity, and accuracy of sonographer 1 using B-mode ultrasound were 50.0% [95% confidence interval (CI): 26.0-74.0%], 100%, and 70.6% (95% CI: 54.5-86.7%), respectively; for CEUS, they were 90.0% (95% CI: 75.6-100.0%), 100.0%, and 94.1% (95% CI: 85.8-100.0%), respectively. The diagnostic sensitivity, specificity, and accuracy of sonographer 2 using B-mode ultrasound were 45.0% (95% CI: 21.1-68.9%), 92.9% (95% CI: 77.5-100.0%), and 64.7% (95% CI: 47.8-81.6%), respectively; for CEUS, they were 85.0% (95% CI: 67.9-100.0%), 100.0%, and 91.2% (95% CI: 81.1-100.0%), respectively. The diagnostic accuracy of sonographer 1 was higher with CEUS than with B-mode ultrasound, but not significantly so (94.1% vs. 70.6%; P=0.08). The diagnostic accuracy of sonographer 2 was significantly higher with CEUS than with B-mode ultrasound (91.2% vs. 64.7%; P=0.03). The interrater reliability was higher for CEUS than for B-mode ultrasound (κ=0.941 vs. κ =0.717). Conclusions: Based on an animal model, B-mode ultrasound and CEUS both exhibited good diagnostic efficacy and interrater reliability in evaluating parietal pleural adhesion/invasion of subpleural lung cancer although CEUS outperformed B-mode ultrasound for both measures.

PA28γ induces dendritic cell maturation and activates T-cell immune responses in oral lichen planus.

Oral lichen planus (OLP) is a common chronic inflammatory disease of the oral mucosa, the mechanism of its inflammatory progression has not yet been fully elucidated. PA28γ plays a significant role in a variety of immune-related diseases. However, the exact role of PA28γ in the pathogenesis of OLP remains unclear. Here, we demonstrated that PA28γ is overexpressed in epithelial cells and inflammatory cells of OLP tissues but has no significant relationship with OLP subtypes. Functionally, keratinocytes with high PA28γ expression could induce dendritic cell (DC) maturation and promote the T-cell differentiation into Th1 cells in response to the immune response. In addition, we found that a high level of PA28γ expression is associated with high numbers of infiltrating mature DCs and activated T-cells in OLP tissues. Mechanistically, keratinocytes with high PA28γ expression could promote the secretion of C-C motif chemokine (CCL)5, blocking CCL5 or/and its receptor CD44 could inhibit the induction of T-cell differentiation by keratinocytes with high PA28γ expression. In conclusion, we reveal that keratinocytes with high expression of PA28γ in OLP can induce DC maturation and promote T-cell differentiation through the CCL5-CD44 pathway, providing previously unidentified mechanistic insights into the mechanism of inflammatory progression in OLP.

Elevated remnant cholesterol is a risk factor for acute ischemic stroke.

OBJECTIVES: Remnant cholesterol (RC) is thought to be an important pathogenic risk factor for atherosclerosis, however, the relationship between RC and acute ischemic stroke (AIS) is still unclear. This study aimed to determine whether fasting blood RC level is an independent risk factor for AIS. MATERIALS AND METHODS: A retrospective analysis was performed on 650 patients with AIS and 598 healthy controls during the same time period. The association between RC and AIS was investigated using binary logistic regression, and the relationship between RC and AIS risk was demonstrated using Restricted Cubic Splines (RCS). RESULTS: RC was significantly higher in the AIS group compared with control group, and was an independent risk factor for AIS when the covariates were not adjusted;After adjusting some covariates, RC was still an independent risk factor for AIS. The RCS analysis found the risk was non-linear: when RC concentration was less than 0.69 mol/L, the risk of AIS increased with the elevation of RC, and when RC concentration was more than or equal to 0.69 mol/L, the risk of AIS was insignificant with the elevation of RC. Correlation analysis revealed that RC was associated with diabetes and fasting glucose. Further analysis revealed that the incidence of AIS in diabetic patients increased significantly with the increase of RC, and RCS analysis revealed that the risk of AIS in diabetic patients increased with the increase of RC when RC was more than 1.15 mol/L. CONCLUSIONS: This study confirms RC as an independent risk factor for AIS, which highlights a distinct non-linear association between RC levels and AIS risk. These findings suggest the need for targeted AIS risk assessment strategies, especially in diabetic patients, and underscore the relevance of RC as a biomarker in AIS risk stratification.

In Situ Symbiosis of Cerium Oxide Nanophase for Enhancing the Oxygen Electrocatalysis Performance of Single-Atom Fe─N─C Catalyst with Prolonged Stability for Zinc-Air Batteries.

The Fenton reaction, induced by the H2O2 formed during the oxygen reduction reaction (ORR) process leads to significant dissolution of Fe, resulting in unsatisfactory stability of the iron-nitrogen-doped carbon catalysts (Fe-NC). In this study, a strategy is proposed to improve the ORR catalytic activity while eliminating the effect of H2O2 by introducing CeO2 nanoparticles. Transmission electron microscopy and subsequent characterizations reveal that CeO2 nanoparticles are uniformly distributed on the carbon substrate, with atomically dispersed Fe single-atom catalysts (SACs) adjacent to them. CeO2@Fe-NC achieves a half-wave potential of 0.89 V and a limiting current density of 6.2 mA cm-2, which significantly outperforms Fe-NC and commercial Pt/C. CeO2@Fe-NC also shows a half-wave potential loss of only 1% after 10 000 CV cycles, which is better than that of Fe-NC (7%). Further, H2O2 elimination experiments show that the introduction of CeO2 significantly accelerate the decomposition of H2O2. In situ Raman spectroscopy results suggest that CeO2@Fe-NC significantly facilitates the formation of ORR intermediates compared with Fe-NC. The Zn-air batteries utilizing CeO2@Fe-NC cathodes exhibit satisfactory peak power density and open-circuit voltage. Furthermore, theoretical calculations show that the introduction of CeO2 enhances the ORR activity of Fe-NC SAC. This study provides insights for optimizing SAC-based electrocatalysts with high activity and stability.

The Chinese Version of the Compensatory ADHD Behaviors Scale (CABS): A Study on Reliability, Validity, and Clinical Utility.

Purpose: With the further development of attention-deficit/hyperactivity disorder (ADHD) research, more and more assessment tools related to ADHD have been used. However, there is still no measurement instrument to evaluate the compensatory behavior of ADHD in China. This study aimed to examine the reliability and validity of the Compensatory ADHD Behaviors Scale (CABS) adapted in Chinese and explore ecological characteristics in adults with ADHD using the CABS. Patients and Methods: Data were collected from a sample of 306 adults (Mage = 26.43 years, SD = 5.32; 46.08% male). The original version CABS was translated into Chinese using the forward and backward translation procedures. Participants completed the CABS and questionnaires assessing ADHD symptoms and executive function. We utilized content validity, exploratory factor analysis (EFA), confirmatory factor analysis (CFA), and criterion validity to test the validity. Internal consistency and test-retest reliability were employed to test the reliability. Analysis of variance (ANOVA) was employed to compare ADHD subgroups based on gender, ADHD subtype, comorbidities, and medication status, while controlling for demographic variables as covariates. Results: CABS exhibited good construct validity (two factors: present-oriented and future-oriented), content validity (content validity index: 0.98), internal consistency reliability (Cronbach's alpha coefficient: 0.85 to 0.87) and test-retest reliability (intraclass correlation coefficient: 0.59 to 0.88). The results of CFA showed acceptable fitness for each subscale. CABS demonstrated significant associations with inattention symptoms and plan/organizational abilities. Medicated ADHD individuals scored higher on future-oriented effectiveness subscale of CABS than non-medicated (F = 6.106, p = 0.014). Conclusion: The results indicate that the Chinese CABS exhibited good validity and reliability. It can be considered a valid tool for assessing compensatory behaviors in Chinese adults with ADHD. Further research is needed to explore the connection between medication and compensatory behavior.

Measurement Methods for Droplet Adhesion Characteristics and Micrometer-Scale Quantification of Contact Angle on Superhydrophobic Surfaces: Challenges and Opportunities.

Inspired by nature, superhydrophobic surfaces have been widely studied. Usually the wettability of a superhydrophobic surface is quantified by the macroscopic contact angle. However, this method has various limitations, especially for precision micro devices with superhydrophobic surfaces, such as biomimetic artificial compound eyes and biomimetic water strider robots. These precision micro devices with superhydrophobic surfaces proposed a higher demand for the quantification of contact angles, requiring contact angle quantification technology to have micrometer-scale measurement capabilities. In this review, it is proposed to achieve micrometer-scale quantification of superhydrophobic surface contact angles through droplet adhesion characteristics (adhesion force and contact radius). Existing contact angle quantification techniques and droplet characteristics' measurement methods were described in detail. The advancement of micrometer-scale quantification technology for the contact angle of superhydrophobic surfaces will enhance our understanding of superhydrophobic surfaces.

Catalytically Relevant Organocopper(III) Complexes Formed through Aryl-Radical-Enabled Oxidative Addition.

Stepwise oxidative addition of copper(I) complexes to form copper(III) species via single electron transfer (SET) events has been widely proposed in copper catalysis. However, direct observation and detailed investigation of these fundamental steps remain elusive owing largely to the typically slow oxidative addition rate of copper(I) complexes and the instability of the copper(III) species. We report herein a novel aryl-radical-enabled stepwise oxidative addition pathway that allows for the formation of well-defined alkyl-CuIII species from CuI complexes. The process is enabled by the SET from a CuI species to an aryl diazonium salt to form a CuII species and an aryl radical. Subsequent iodine abstraction from an alkyl iodide by the aryl radical affords an alkyl radical, which then reacts with the CuII species to form the alkyl-CuIII complex. The structure of resultant [(bpy)CuIII(CF3)2(alkyl)] complexes has been characterized by NMR spectroscopy and X-ray crystallography. Competition experiments have revealed that the rate at which different alkyl iodides undergo oxidative addition is consistent with the rate of iodine abstraction by carbon-centered radicals. The CuII intermediate formed during the SET process has been identified as a four-coordinate complex, [CuII(CH3CN)2(CF3)2], through electronic paramagnetic resonance (EPR) studies. The catalytic relevance of the high-valent organo-CuIII has been demonstrated by the C-C bond-forming reductive elimination reactivity. Finally, localized orbital bonding analysis of these formal CuIII complexes indicates inverted ligand fields in σ(Cu-CH2) bonds. These results demonstrate the stepwise oxidative addition in copper catalysis and provide a general strategy to investigate the elusive formal CuIII complexes.

Thermodynamics of Proton-Coupled Electron Transfer at Tricopper µ-Oxo/Hydroxo/Aqua Complexes.

Multicopper oxidases (MCOs) utilize a tricopper active site to reduce dioxygen to water through 4H+ 4e- proton-coupled electron transfer (PCET). Understanding the thermodynamics of PCET at a tricopper cluster is essential for elucidating how MCOs harness the oxidative power of O2 while mitigating oxidative damage. In this study, we determined the O-H bond dissociation free energies (BDFEs) and pKa values of a series of tricopper hydroxo and tricopper aqua complexes as synthetic models of the tricopper site in MCOs. Tricopper intermediates on the path of alternating electron and proton transfer (ET-PT-ET-PT-ET) have modest BDFE(O-H) values in the range of 53.0-57.1 kcal/mol. In contrast, those not on the path of ET-PT-ET-PT-ET display much higher (78.1 kcal/mol) or lower (44.7 kcal/mol) BDFE(O-H) values. Additionally, the pKa of bridging OH and OH2 motifs increase by 8-16 pKa units per oxidation state. The same oxidation state changes have a lesser impact on the pKa of N-H motif in the secondary coordination sphere, with an increase of ca. 5 pKa units per oxidation state. The steeper pKa increase of the tricopper center promotes proton transfer from the secondary coordination sphere. Overall, our study shed light on the PCET pathway least prone to decomposition, elucidating why tricopper centers are an optimal choice for promoting efficient oxygen reduction reaction.

Identification of a new class of activators of the Hippo pathway with antitumor activity in vitro and in vivo.

The Hippo pathway is a key regulator of tissue growth, organ size, and tumorigenesis. Activating the Hippo pathway by gene editing or pharmaceutical intervention has been proven to be a new therapeutic strategy for treatment of the Hippo pathway-dependent cancers. To now, a number of compounds that directly target the downstream effector proteins of Hippo pathway, including YAP and TEADs, have been disclosed, but very few Hippo pathway activators are reported. Here, we discovered a new class of Hippo pathway activator, YL-602, which inhibited CTGF expression in cells irrespective of cell density and the presence of serum. Mechanistically, YL-602 activates the Hippo pathway via MST1/2, which is different from known activators of Hippo pathway. In vitro, YL-602 significantly induced tumor cell apoptosis and inhibited colony formation of tumor cells. In vivo, oral administration of YL-602 substantially suppressed the growth of cancer cells by activation of Hippo pathway. Overall, YL-602 could be a promising lead compound, and deserves further investigation for its mechanism of action and therapeutic applications.

Posterior circulation ischemic stroke: radiomics-based machine learning approach to identify onset time from magnetic resonance imaging.

PURPOSE: Posterior circulation ischemic stroke (PCIS) possesses unique features. However, previous studies have primarily or exclusively relied on anterior circulation stroke cases to build machine learning (ML) models for predicting onset time. To date, there is no research reporting the effectiveness and stability of ML in identifying PCIS onset time. We aimed to build diffusion-weighted imaging-based ML models to identify the onset time of PCIS patients. METHODS: Consecutive PCIS patients within 24 h of definite symptom onset were included (112 in the training set and 49 in the independent test set). Images were processed as follows: volume of interest segmentation, image feature extraction, and feature selection. Five ML models, naïve Bayes, logistic regression, tree ensemble, k-nearest neighbor, and random forest, were built based on the training set to estimate the stroke onset time (binary classification: ≤ 4.5 h or > 4.5 h). Relative standard deviations (RSD), receiver operating characteristic (ROC) curves, and the calibration plot was performed to evaluate the stability and performance of the five models. RESULTS: The random forest model had the best performance in the test set, with the highest area under the curve (AUC, 0.840; 95% CI: 0.706, 0.974). This model also achieved the highest accuracy, sensitivity, specificity, positive predictive value, and negative predictive value (83.7%, 64.3%, 91.4%, 75.0%, and 86.5%, respectively). Furthermore, the model had high stability (RSD = 0.0094). CONCLUSION: The PCIS case-based ML model was effective for estimating the symptom onset time and achieved considerably high specificity and stability.

Mendelian randomization analysis identifies druggable genes and drugs repurposing for chronic obstructive pulmonary disease.

Background: Chronic obstructive pulmonary disease (COPD) is a prevalent condition that significantly impacts public health. Unfortunately, there are few effective treatment options available. Mendelian randomization (MR) has been utilized to repurpose existing drugs and identify new therapeutic targets. The objective of this study is to identify novel therapeutic targets for COPD. Methods: Cis-expression quantitative trait loci (cis-eQTL) were extracted for 4,317 identified druggable genes from genomics and proteomics data of whole blood (eQTLGen) and lung tissue (GTEx Consortium). Genome-wide association studies (GWAS) data for doctor-diagnosed COPD, spirometry-defined COPD (Forced Expiratory Volume in one second [FEV1]/Forced Vital Capacity [FVC] <0.7), and FEV1 were obtained from the cohort of FinnGen, UK Biobank and SpiroMeta consortium. We employed Summary-data-based Mendelian Randomization (SMR), HEIDI test, and colocalization analysis to assess the causal effects of druggable gene expression on COPD and lung function. The reliability of these druggable genes was confirmed by eQTL two-sample MR and protein quantitative trait loci (pQTL) SMR, respectively. The potential effects of druggable genes were assessed through the phenome-wide association study (PheWAS). Information on drug repurposing for COPD was collected from multiple databases. Results: A total of 31 potential druggable genes associated with doctor-diagnosed COPD, spirometry-defined COPD, and FEV1 were identified through SMR, HEIDI test, and colocalization analysis. Among them, 22 genes (e.g., MMP15, PSMA4, ERBB3, and LMCD1) were further confirmed by eQTL two-sample MR and protein SMR analyses. Gene-level PheWAS revealed that ERBB3 expression might reduce inflammation, while GP9 and MRC2 were associated with other traits. The drugs Montelukast (targeting the MMP15 gene) and MARIZOMIB (targeting the PSMA4 gene) may reduce the risk of spirometry-defined COPD. Additionally, an existing small molecule inhibitor of the APH1A gene has the potential to increase FEV1. Conclusions: Our findings identified 22 potential drug targets for COPD and lung function. Prioritizing clinical trials that target these identified druggable genes with existing drugs or novel medications will be beneficial for the development of COPD treatments.

The efficacy and safety of stereotactic body radiotherapy combined with systematic therapy for metastatic renal cell carcinoma: a systematic review and meta-analysis.

There is considerable interest in the potential of stereotactic body radiation therapy (SBRT) combined with systemic therapy such as tyrosine kinase inhibitors (TKIs) or immune checkpoint inhibitors (ICIs). However, its efficacy and safety remain unclear. The purpose of this study was to evaluate the efficacy and safety of conducting SBRT during ICI or TKI treatment in different disease settings for patients with metastatic renal cell carcinoma (mRCC). A total of 16 studies were ultimately included. Under the random effects model, the pooled 1-year local control rate (1-yr LCR) and objective response rate (ORR) were 90% (95% confidence interval [CI]: 80%-95%, I 2 = 67%) and 52% (95% CI: 37%-67%, I 2 = 90%), respectively. SBRT concomitant with different systemic therapy yield significant different 1-yr LCR (p < 0.01) and ORR (p = 0.02). Regarding survival benefits, the pooled 1-year progression-free survival (1-yr PFS) and 1-year overall survival (1-yr OS) rates were 45% (95% CI: 29%-62%, I 2 = 91%) and 85% (95% CI: 76%-91%, I 2 = 66%), respectively. 1-yr PFS and 1-yr OS in different disease settings demonstrated significant difference (p < 0.01). As for toxicity, the pooled incidence of grade 3-4 adverse events was 14% (95% CI: 5%-26%, I 2 = 90%). This study highlights the feasibility of utilizing these strategies in mRCC patients, especially those with a low metastatic tumor burden.

Investigating Sea-Level Brain Predictors for Acute Mountain Sickness: A Multimodal MRI Study before and after High-Altitude Exposure.

BACKGROUND AND PURPOSE: Acute mountain sickness is a series of brain-centered symptoms that occur when rapidly ascending to high altitude. Predicting acute mountain sickness before high-altitude exposure is crucial for protecting susceptible individuals. The present study aimed to evaluate the feasibility of predicting acute mountain sickness after high-altitude exposure by using multimodal brain MR imaging features measured at sea level. MATERIALS AND METHODS: We recruited 45 healthy sea-level residents who flew to the Qinghai-Tibet Plateau (3650 m). We conducted T1-weighted structural MR imaging, resting-state fMRI, and arterial spin-labeling perfusion MR imaging both at sea level and high altitude. Acute mountain sickness was diagnosed for 5 days using Lake Louise Scoring. Logistic regression with Least Absolute Shrinkage and Selection Operator logistic regression was performed for predicting acute mountain sickness using sea-level MR imaging features. We also validated the predictors by using MR images obtained at high altitude. RESULTS: The incidence rate of acute mountain sickness was 80.0%. The model achieved an area under the receiver operating characteristic curve of 86.4% (sensitivity = 77.8%, specificity = 100.0%, and P < .001) in predicting acute mountain sickness At sea level, valid predictors included fractional amplitude of low-frequency fluctuations (fALFF) and degree centrality from resting-state fMRI, mainly distributed in the somatomotor network. We further learned that the acute mountain sickness group had lower levels of fALFF in the somatomotor network at high altitude, associated with smaller changes in CSF volume and higher Lake Louise Scoring, specifically relating to fatigue and clinical function. CONCLUSIONS: Our study found that the somatomotor network function detected by sea-level resting-state fMRI was a crucial predictor for acute mountain sickness and further validated its pathophysiologic impact at high altitude. These findings show promise for pre-exposure prediction, particularly for individuals in need of rapid ascent, and they offer insight into the potential mechanism of acute mountain sickness.