Objective To investigate the predictive value of combined radiomic features derived from chest CT scans with clinical characteristics for epidermal growth factor receptor(EGFR)gene mutations in non-small cell lung cancer(NSCLC).Methods A multi-center case-control study was conducted on the clinical data and CT images of 1 070 NSCLC patients from the radiology departments of the 3 medical institutions between January 2013 and October 2023.The 719 NSCLC patients from the First Affiliated Hospital of Army Medical University were randomly divided into a training set and an internal validation set in a ratio of 7∶3;The 173 patients in the Eastern Theatre General Hospital and the 178 patients in Army Medical Centre of PLA were assigned into the external validation set 1 and 2,respectively.Least absolute shrinkage and selection operator(LASSO)regression was employed to identify the optimal radiomic features,which were subsequently used to construct a radiomics model.Univariate and multivariate logistic regression analyses were applied to identify clinical features associated with EGFR mutation,thereby developing a clinical model.The radiomic and clinical features were subsequently combined to develop a comprehensive model.All the 3 classification models were built using random forest(RF)machine learning.The area under curve(AUC),accuracy,sensitivity and specificity were utilized to evaluate the predictive performance of the models.Calibration curve was plotted to assess the goodness of fit of the comprehensive model,while decision curve analysis was performed to assess the clinical utility of the model.Results The AUC value of the radiomics model was 0.762 4(95%CI:0.692 4～0.825 1),0.745 4(95%CI:0.671 1～0.814 3),and 0.724 7(95%CI:0.639 7～0.801 6),respectively,in the internal validation set,external validation set 1,and external validation set 2;The AUC value of the clinical prediction model was 0.691 7(95%CI:0.627 9～0.757 6),0.652 5(95%CI:0.576 7～0.729 1),and 0.779 2(95%CI:0.712 5～0.847 3),respectively in the above sets in turn;The comprehensive model constructed based on clinical features and radiomic features showed the best predictive efficacy,with an AUC value of 0.818 0(95%CI:0.757 7～0.874 3),0.782 4(95%CI:0.703 1～0.848 2),and 0.796 6(95%CI:0.718 1～0.868 6),respectively in the above sets.Calibration curve analysis indicated that the comprehensive model had a good fit,while decision curve analysis revealed that the model provided a favorable net benefit.Conclusion Our comprehensive model constructed based on chest CT radiomic features and clinical characteristics shows superior predictive performance for EGFR gene mutations in NSCLC across multiple center datasets,which may be helpful for clinical decision-making for treatment strategies.

Objective To evaluate the predictive value of deep learning features from chest CT images combined with clinical and radiomics features for epidermal growth factor receptor(EGFR)mutations in non-small cell lung cancer(NSCLC).Methods This case-control study retrospectively analyzed clinical and imaging data of 1 070 NSCLC patients from radiology departments at three hospitals(January 2013 to October 2023).Patients were divided into:a training set(n=502)and internal validation set(n=217)via 7∶3 randomization of 719 cases from the First Affiliated Hospital of Army Medical University;external validation set 1(n=173)from General Hospital of Eastern Theater Command;external validation set 2(n=178)from Daping Hospital of Army Medical University.Deep learning features were extracted using a 2.5D convolutional neural network(CNN)with ResNet101 backbone,radiomics features were derived from CT images,and clinical risk factors were identified to construct models.An integrated model combined deep learning,clinical,and radiomics features.All four models were developed using random forest(RF)classifiers.Calibration curves assessed goodness-of-fit,and decision curve analysis(DCA)evaluated clinical utility.Results The deep learning model achieved AUCs of 0.833 7(95%CI:0.770 6～0.884 7),0.815 1(0.741 6～0.882 8),and 0.810 1(0.745 2～0.873 6)in the internal and two external validation sets,respectively.Clinical models yielded AUCs of 0.731 0(0.660 2～0.802 1),0.746 0(0.666 4～0.824 9),and 0.813 4(0.743 1～0.883 6);radiomics models showed AUCs of 0.762 4(0.692 4～0.825 1),0.745 4(0.671 1～0.814 3),and 0.724 7(0.639 7～0.801 6).The integrated model demonstrated optimal performance with AUCs of 0.905 5(0.857 0～0.945 4),0.832 7(0.763 3～0.896 4),and 0.889 0(0.834 4～0.934 3).DCA indicated significant net benefit for EGFR prediction at threshold probabilities of 0.15～0.85 using the integrated model.Conclusion Deep learning features from CT images effectively predict EGFR mutation status in NSCLC.The integrated model combining deep learning,clinical,and radiomics features further enhances predictive performance.

Protein tyrosine phosphatase nonreceptor type 2 (PTPN2) is a promising target for sensitizing solid tumors to immune checkpoint blockades. However, the highly polar active sites of PTPN2 hinder drug discovery efforts. Leveraging small interfering RNA (siRNA) technology, we developed a novel glutathione-responsive nano-platform HPssPT (HA/PEIss@siPtpn2) to silence PTPN2 and enhance immunotherapy efficacy in hepatocellular carcinoma (HCC). HPssPT showed potent transfection and favorable safety profiles. PTPN2 deficiency induced by HPssPT amplified the interferon γ signaling in HCC cells by increasing the phosphorylation of Janus-activated kinase 1 and signal transducer and activator of transcription 1, resulting in enhanced antigen presentation and T cell activation. The nano-platform was also able to promote the M1-like polarization of macrophages in vitro. The unique tropism of HPssPT towards tumor-associated macrophages, facilitated by hyaluronic acid coating and CD44 receptor targeting, allowed for simultaneous reprogramming of both tumor cells and tumor-associated macrophages, thereby synergistically reshaping tumor microenvironment to an immunostimulatory state. In HCC, colorectal cancer, and melanoma animal models, HPssPT monotherapy provoked robust antitumor immunity, thereby sensitizing tumors to PD-1 blockade, which provided new inspiration for siRNA-based drug discovery and tumor immunotherapy.

The nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome plays a crucial role in the prognosis of subarachnoid hemorrhage (SAH). WNK1 kinase negatively regulates NLRP3 in various inflammatory conditions, but its role in early brain injury (EBI) after SAH remains unclear. In this study, we used an in vivo SAH model in rats/mice and AAV-WNK1 intraventricular injection to investigate its neuroprotective mechanisms. WNK1 expression was significantly reduced in SAH patient blood and SAH model brain tissue, correlating negatively with microglial activation. AAV-WNK1 alleviated brain edema, neuronal necrosis, behavioral deficits, and inflammation by inhibiting NLRP3 inflammasome activation. In hemin-stimulated BV-2 cells, WNK1 overexpression reduced NLRP3 activation and inflammatory cytokines. Chloride counteracted WNK1's inhibitory effects, and WNK1 suppressed P2X7R-induced NLRP3 activation. Mechanistically, WNK1 functioned via the OXSR1/STK39 pathway. These findings highlight WNK1 as a key regulator of intracellular chloride balance and neuroinflammation, presenting a potential therapeutic target for SAH treatment.
Animals ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism* ; Subarachnoid Hemorrhage/complications* ; Inflammasomes/metabolism* ; Rats ; Mice ; Neuroinflammatory Diseases/metabolism* ; WNK Lysine-Deficient Protein Kinase 1/genetics* ; Male ; Humans ; Chlorides/metabolism* ; Mice, Inbred C57BL ; Rats, Sprague-Dawley ; Brain Injuries/metabolism* ; Microglia/metabolism* ; Protein Serine-Threonine Kinases

Ivonescimab is a humanized bispecific antibody targeting human vascular endothelial growth factor-A(VEGF-A)and programmed death protein-1(PD-1).It was approved by National Medi-cal Products Administration on May 24th,2024,and can be used in combination with pemetrexed and carboplatin for locally advanced or positive EG-FR gene mutation after treatment with epidermal growth factor receptor(EGFR)tyrosine kinase inhib-itor.This paper mainly introduces the research progress of the world's first PD-1/VEGF bispecific antibody ivonescimab,and summarizes the mecha-nism of action,pharmacokinetics,phase Ⅰ-Ⅲ clinical trials and drug safety.

Ivonescimab is a humanized bispecific antibody targeting human vascular endothelial growth factor-A(VEGF-A)and programmed death protein-1(PD-1).It was approved by National Medi-cal Products Administration on May 24th,2024,and can be used in combination with pemetrexed and carboplatin for locally advanced or positive EG-FR gene mutation after treatment with epidermal growth factor receptor(EGFR)tyrosine kinase inhib-itor.This paper mainly introduces the research progress of the world's first PD-1/VEGF bispecific antibody ivonescimab,and summarizes the mecha-nism of action,pharmacokinetics,phase Ⅰ-Ⅲ clinical trials and drug safety.

The flow diverter provides a new treatment strategy for intracranial aneurysms which are difficult to treat due to its ability to reconstruct blood vessels and protect branch blood vessels. Among them, the Surpass Evolve flow diverter is particularly suitable for the treatment of large, wide-necked, and fusiform intracranial aneurysms. The Surpass Evolve flow diverter has significant advantages in promoting aneurysm sac thrombosis, improving hemodynamics, and reducing recurrence in intracranial aneurysms. This article reviews the safety and efficacy of the Surpass Evolve flow diverter in the treatment of intracranial aneurysms.

Purpose: Cavernous nerve injury induced erectile dysfunction (ED) is a refractory complication with high incidence in person under radical prostatectomy. Studies have shown that relaxin-2 (RLX-2) plays a vital role of endothelial protection, vasodilation, anti-fibrosis and neuroprotection in a variety of diseases. However, whether penile cavernous erection can benefit from RLX-2 remains unknown. The purpose of the experiment was to explore the effects of RLX-2 on ED in the rat suffering with bilateral cavernous nerve injury (BCNI). Materials and Methods: The rats were divided into three groups: Sham group was underwent sham operation, BCNI+RLX group or BCNI group was underwent bilateral cavernous nerve crush and then randomly treated with RLX-2 (0.4 mg/kg/d) or saline by continuous administration using a subcutaneously implanted micro pump for 4 weeks respectively. Then, erectile function was evaluated by electrical stimulation of cavernous nerves. Cavernous nerves and penile tissues and were collected for histological evaluation. Results: Erectile function of rats with BCNI was partially improved after RLX-2 treatment. The BCNI group had lower expression of relaxin family peptide receptor (RXFP) 1, p-AKT/AKT, p-eNOS/eNOS ratios than sham operation rats, but RLX-2 could partially reversed these changes. Histologically, the BCNI+RLX group had a significant effect on preservation of neurofilament, neuronal glial antigen 2 of penile tissue and nNOS of cavernous nerves when compared with BCNI group. RLX-2 could inhibited the lever of BCNI induced corporal fibrosis and apoptosis via regulating TGFβ1-Smad2/3-CTGF pathway and the expression of Bax/Bcl-2 ratio, caspase3. Conclusions RLX-2 could improve erectile function of BCNI rats by protecting cavernous nerve and endothelial function and suppressing corporal fibrosis and apoptosis via RXFP1 and AKT/eNOS pathway. Our findings may provide a promising treatment for refractory BCNI induced ED.

Objective:To explore the value of current indications for fetal pulmonary valvuloplasty (FPV) by summarizing the postnatal diagnosis, treatment, and prognosis of fetuses with pulmonary atresia with intact ventricular septum (PA/IVS) and right ventricular hypoplasia (RVH).Methods:This prospective study was conducted at the Heart Center of Women and Children's Hospital, Qingdao University from September 2018 to March 2021, which included pregnant women who were (1) with fetal PA/IVS and RVH; (2) unable to receive FPV due to fetal position or gestational age despite the indications; (3) given integrated pre- and postnatal management. Prenatal fetal echocardiography assessment, postnatal diagnosis, treatment, and follow-up were summarized using Wilcoxon matched-pair signed-rank test.Results:A total of 35 singleton pregnant women were diagnosed with fetal PA/IVS and RVH by ultrasonic cardiogram and admitted during the study period. Among the 28 fetuses meeting the FPV indications, 18 underwent FPV, while the other 10 did not due to inappropriate fetal position or gestational age. After excluding four terminated pregnancies, the rest six cases were enrolled. The median gestational age at the initial prenatal fetal echocardiography diagnosis was 28.9 weeks (28.3-30.4 weeks). Compared with the initial evaluation, the fetal right ventricular to left ventricular length/diameter ratio [0.8 (0.6-0.9) vs 0.6 (0.5-0.8)] and tricuspid regurgitation velocity [4.7 m/s (3.2-5.1 m/s) vs 4.1 m/s (3.3-4.8 m/s)] were increased, while tricuspid valve Z value [－0.8(－1.6-0.8) vs 0.4 (－0.3-1.9)] and single-ventricular predictive score [0.5 (0.0-2.0) vs 2.0 (1.0-3.0)] were decreased when re-evaluated six weeks later ( T were－2.21, 2.00,－2.20, and 2.00; all P<0.05). All of the six fetuses were born alive with a median gestational age of 38.9 weeks (37.3-40.1 weeks). The median weight was 3 425 g (3 100-4 160) g after being transferred to cardiac intensive care unit. The median age was 12.5 d (0.0-20.0 d) at the first surgical intervention. The median follow-up duration was 15 months (11.8-18.5 months). At initial diagnosis, the single-ventricular predictive score was 1-2 points in four fetuses, and =3 points in two fetuses. There was no death during follow-up. Four patients achieved anatomical biventricular circulation, one achieved clinical biventricular circulation, and one still needed further follow-up, with single-ventricular predictive score at initial diagnosis of 1-3, 3, and 2 points, respectively. Conclusions:The prognosis is good in fetuses with PA/IVS and RVH who have FPV indications but do not receive intrauterine intervention, which suggests that the current FPV indications may be too broad, and a more suitable FPV indication need to be further explored given the difficulty of implementing FPV.

Objective:To summarize the interim outcome and right heart development of pulmonary atresia with intact ventricular septum (PA-IVS) in children after fetal cardiac intervention (FCI).Methods:The clinical data of 5 live births underwent FCI from October 2018 to April 2019 in Women and Children′s Hospital, Qingdao University were analyzed retrospectively. The development of right ventricle (RV) and tricuspid valve (TV) in uterus after FCI, at birth, the age of 6 months, 1 year and 2 years, and the final outcome were assessed.Results:Five PA-IVS fetuses were included in this study. The first evaluation was performed at 24-26 weeks of gestational age, and the FCI was performed at 26-28 weeks of gestational age. During the follow-up of 6 weeks after FCI, the minimum diameter of tricuspid annulus increased from 0.85 cm to 0.92 cm, and the minimum Z-score of tricuspid annulus decreased from -0.03 to -1.62. The minimum values of TV/mitral valve annular diameter and RV/left ventricular length ratios of all fetuses increased from 0.57, 0.52 to 0.88, 0.82, respectively. The maximum tricuspid regurgitation velocity decreased from 4.60 m/s to 3.64 m/s. No severe hemodynamic change was found in any of the fetuses. All 5 fetuses were born alive. Three cases underwent percutaneous balloon pulmonary valvuloplasty (PBPV) and stent implantation for ductus arteriosus. Two cases received PBPV alone. At follow-up (26 to 32 months), obvious development of TV was observed 6 months to 1 year after birth in 5 cases with the growth rate ranging from 19.64% to 40.00%. Meanwhile, the RV development was relatively slow at 6 months with the growth rate ranging from 9.41% to 21.42%. There were individual differences in RV development at 2 years. The growth and development of all children were equal to healthy children of the same age with the body mass index less than 18.4 kg/m 2. At the last follow-up, all children had a transcutaneous oxygen saturation of greater than 0.95, three became biventricular circulation and two had circulation approximation to biventricular circulation with almost closed stent. Conclusions:The findings support the potential of development of right ventricular and tricuspid valve for fetuses with PA-IVS underwent FCI. All fetuses underwent FCI received intervention after birth, and biventricular circulation can be realized finally. The development of right ventricular and tricuspid valve is not proportional. In utero, the right ventricle develops rapidly, and the development of tricuspid valve is more advantageous after birth.