An Engineered Nanoplatform with Tropism toward Irradiated Glioblastoma Augments Its Radioimmunotherapy Efficacy.

Combining radiotherapy with immune checkpoint blockade therapy offers a promising approach to treat glioblastoma multiforme (GBM), yet challenges such as limited effectiveness and immune-related adverse events (irAEs) persist. These issues are largely due to the failure in targeting immunomodulators directly to the tumor microenvironment. To address this, we developed a biomimetic nanoplatform that combines a genetically modified mesenchymal stem cell (MSC) membrane with a bioactive nanoparticle core for chemokine-directed radioimmunotherapy of GBM. The CCR2-overexpressing MSC membrane acts as a tactical tentacle to achieve radiation-induced tropism toward the abundant chemokine ligand CCL2 in irradiated gliomas. The nanoparticle core, comprising diselenide-bridged mesoporous silica nanoparticles (MSNs) and PD-L1 antibodies (αPD-L1), enables X-ray-responsive drug release and radiosensitization. In two murine models with orthotopic GBM tumors, this nanoplatform reinvigorated immunogenic cell death, and augmented the efficacy and specificity of GBM radioimmunotherapy, with reduced occurrence of irAEs. This study suggests a promising radiation-induced tropism strategy for targeted drug delivery, and presents a potent nanoplatform that enhances the efficacy and safety of radio-immunotherapy. This article is protected by copyright. All rights reserved.

Exploring the crosstalk of immune cells: The impact of dysregulated RUNX family genes in kidney renal clear cell carcinoma.

Background: Abnormally expressed Runt-associated transcription factor (RUNX) family has been reported in multiple tumors. Nevertheless, the immunological role of RUNX family in kidney renal clear cell carcinoma (KIRC) remains unknown. Methods: We studied the RNA-seq data regarding tumor and healthy subjects from several public databases in detail for evaluating the prognostic and immunological functions owned by three RUNX genes in cancer patients. Quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR) and immunohistochemical (IHC) staining served for detecting their expressions in tumor and normal samples. Results: We observed that KIRC patients presented high expressions of RUNX1, RUNX2, and RUNX3. The expressions of three genes were validated by qRT-PCR, which was same as bioinformatical results. Prognostic analysis indicated that the overexpression of RUNX1 and RUNX2 negatively affects the outcomes in patients with KIRC. Related functional predictions indicated that the RUNXs and co-expression genes were significantly related to the immune response pathway. Moreover, three RUNX members were associated with immune infiltration cells and their related gene markers. The expression of RUNX family in several immune cells is positively or negatively correlated, and its dysregulation is obviously associated with the differential distribution of immune cells. RUNX family genes were abnormally expressed in KIRC patients, and were closely related to the crosstalk of immune cells. Conclusions: Our findings may help to understand the pathogenesis and immunologic roles of the RUNX family in KIRC patients from new perspectives.

Neurons upregulate PD-L1 via IFN/STAT1/IRF1 to alleviate damage by CD8+ T cells in cerebral malaria.

BACKGROUND: Cerebral malaria (CM) is the most lethal complication of malaria, and survivors usually endure neurological sequelae. Notably, the cytotoxic effect of infiltrating Plasmodium-activated CD8+ T cells on cerebral microvasculature endothelial cells is a prominent feature of the experimental CM (ECM) model with blood-brain barrier disruption. However, the damage effect of CD8+ T cells infiltrating the brain parenchyma on neurons remains unclear. Based on the immunosuppressive effect of the PD-1/PD-L1 pathway on T cells, our previous study demonstrated that the systemic upregulation of PD-L1 to inhibit CD8+ T cell function could effectively alleviate the symptoms of ECM mice. However, it has not been reported whether neurons can suppress the pathogenic effect of CD8+ T cells through the PD-1/PD-L1 negative immunomodulatory pathway. As the important inflammatory factor of CM, interferons can induce the expression of PD-L1 via different molecular mechanisms according to the neuro-immune microenvironment. Therefore, this study aimed to investigate the direct interaction between CD8+ T cells and neurons, as well as the mechanism of neurons to alleviate the pathogenic effect of CD8+ T cells through up-regulating PD-L1 induced by IFNs. METHODS: Using the ECM model of C57BL/6J mice infected with Plasmodium berghei ANKA (PbA), morphological observations were conducted in vivo by electron microscope and IF staining. The interaction between the ECM CD8+ T cells (immune magnetic bead sorting from spleen of ECM mice) and primary cultured cortical neurons in vitro was observed by IF staining and time-lapse photography. RNA-seq was performed to analyze the signaling pathway of PD-L1 upregulation in neurons induced by IFNß or IFNγ, and verified through q-PCR, WB, IF staining, and flow cytometry both in vitro and in vivo using IFNAR or IFNGR gene knockout mice. The protective effect of adenovirus-mediated PD-L1 IgGFc fusion protein expression was verified in ECM mice with brain stereotaxic injection in vivo and in primary cultured neurons via viral infection in vitro. RESULTS: In vivo, ECM mice showed infiltration of activated CD8+ T cells and neuronal injury in the brain parenchyma. In vitro, ECM CD8+ T cells were in direct contact with neurons and induced axonal damage, as an active behavior. The PD-L1 protein level was elevated in neurons of ECM mice and in primary cultured neurons induced by IFNß, IFNγ, or ECM CD8+ T cells in vitro. Furthermore, the IFNß or IFNγ induced neuronal expression of PD-L1 was mediated by increasing STAT1/IRF1 pathway via IFN receptors. The increase of PD-L1 expression in neurons during PbA infection was weakened after deleting the IFNAR or IFNGR. Increased PD-L1 expression by adenovirus partially protected neurons from CD8+ T cell-mediated damage both in vitro and in vivo. CONCLUSION: Our study demonstrates that both type I and type II IFNs can induce neurons to upregulate PD-L1 via the STAT1/IRF1 pathway mediated by IFN receptors to protect against activated CD8+ T cell-mediated damage, providing a targeted pathway to alleviate neuroinflammation during ECM.

Efficacy Analysis of Pneumocystoscopic Cohen Surgery for Lower Ureteral Lesions in Children.

Objective: This study aims to evaluate the clinical effects, safety, and recovery associated with minimally invasive pneumocystoscopic ureterovesical reimplantation (Cohen) compared to open surgery for treating lower ureteral lesions in children. Methods: The data of 60 sick children with lower ureteral lesions were retrospectively analyzed, who underwent ureterovesical reimplantation in our hospital from January 2017 to June 2022. All of them went through a Cohen procedure. Sixty children were divided into two groups according to surgical approaches: open surgery group (n=30) and pneumocystoscopic group (n=30). There were 26 boys and 4 girls in the open surgery group, aged from 3 months and 7 days old to 8 years and 5 months old, with 18 cases of lower ureteral stenosis and 12 cases of ureteral reflux, while there were 20 boys and 10 girls in the pneumocystoscopic group, aged from 7 months and 2 days old to 10 years and 9 months old, with 18 cases of lower ureteral stenosis and 12 cases of ureteral reflux. We retrospectively analyzed data from 60 children, comparing outcomes such as intraoperative complications, postoperative recovery, and long-term efficacy between open surgery and pneumocystoscopic approaches. Results: The pneumocystoscopic group exhibited smaller surgical incisions, reduced intraoperative bleeding, and shorter hospital stays compared to the open surgery group, although the operation duration was longer. Both groups showed similar postoperative ureter diameters and long-term recovery, with minimal occurrences of ureteral reflux relapse. Conclusion: Pneumocystoscopic ureterovesical reimplantation (Cohen) demonstrated safety, efficacy, minimal invasiveness, and faster recovery in treating lower ureteral lesions in children, with aesthetic benefits and fewer complications, making it a promising approach for pediatric urological surgeries.

The pattern of tumor progression on first-line immune checkpoint inhibitor-based systemic therapy for Chinese advanced hepatocellular carcinoma -CLEAP 004 study.

Background: For decades, stratification criteria for first-line clinical studies have been highly uniform. However, there is no principle or consensus for restratification after systemic treatment progression based on immune checkpoint inhibitors (ICIs). The aim of this study was to assess the patterns of disease progression in patients with advanced hepatocellular carcinoma (HCC) who are not eligible for surgical intervention, following the use of immune checkpoint inhibitors. Methods: This is a retrospective study that involved patients with inoperable China liver stage (CNLC) IIIa and/or IIIb. The patients were treated at eight centers across China between January 2017 and October 2022. All patients received at least two cycles of first-line treatment containing immune checkpoint inhibitors. The patterns of disease progression were assessed using RECIST criteria 1.1. Different progression modes have been identified based on the characteristics of imaging progress. The study's main outcome measures were post-progression survival (PPS) and overall survival (OS). Survival curves were plotted using the Kaplan-Meier method to compare the difference among the four groups. Subgroup analysis was conducted to compare the efficacy of different immunotherapy combinations. Variations in the efficacy of immunotherapy have also been noted across patient groups exhibiting alpha-fetoprotein (AFP) levels equal to or exceeding 400ng/mL, in contrast to those with AFP levels below 400ng/mL. Results: The study has identified four distinct patterns of progress, namely p-IIb, p-IIIa, p-IIIb, and p-IIIc. Diverse patterns of progress demonstrate notable variations in both PPS and OS. The group p-IIb had the longest PPS of 12.7m (95% 9.3-16.1) and OS 19.6m (95% 15.6-23.5), the remaining groups exhibited p-IIIb at PPS 10.5 months (95%CI: 7.9-13.1) and OS 19.2 months (95%CI 15.1-23.3). Similarly, p-IIIc at PPS 5.7 months (95%CI: 4.2-7.2) and OS 11.0 months (95%CI 9.0-12.9), while p-IIIa at PPS 3.4 months (95%CI: 2.7-4.1) and OS 8.2 months (95%CI 6.8-9.5) were also seen. Additional stratified analysis was conducted and showed there were no differences of immunotherapy alone or in combination in OS (HR= 0.92, 95%CI: 0.59-1.43, P=0.68) and PPS (HR= 0.88, 95%CI: 0.57-1.36, P=0.54); there was no significant difference in PPS (HR=0.79, 95% CI: 0.55-1.12, P=0.15) and OS (HR=0.86, 95% CI: 0.61-1.24, P=0.39) for patients with AFP levels at or over 400ng/mL. However, it was observed that patients with AFP levels above 400ng/mL experienced a shorter median progression of PPS (8.0 months vs. 5.0 months) after undergoing immunotherapy. Conclusion: In this investigation of advanced hepatocellular carcinoma among Chinese patients treated with immune checkpoint inhibitors, we identified four distinct progression patterns (p-IIb, p-IIIa, p-IIIb and p-IIIc) that showed significant differences in PPS and OS. These findings demonstrate the heterogeneity of disease progression and prognosis after immunotherapy failure. Further validation in large cohorts is necessary to develop prognostic models that integrate distinct progression patterns to guide subsequent treatment decisions. Additionally, post-immunotherapy progression in patients with AFP levels ≥400ng/mL indicates a shortened median PPS. These findings provide valuable insights for future personalized treatment decisions.

Spontaneous renal rupture caused by factor VII deficiency: A case report.

RATIONALE: Spontaneous renal rupture is an uncommon disease, it usually occurs after upper urinary calculi-related operation treatment or renal tumor. This disease caused by factor VII deficiency has rarely reported. PATIENT CONCERNS: A 49-year-old woman came to our hospital with on the left flank pain and gross hematuria that had persisted for 10 days. The patient had no recent history of waist and abdominal trauma or surgical history recently. DIAGNOSES: An outside computed tomography (CT) examination revealed left renal rupture before arriving at our hospital, but she was not treated. Further laboratory examination revealed that the patient condition was turned out to be hemophilia caused by factor VII deficiency. INTERVENTION: We have used both internal and external drainage methods, and supplemented with coagulation factor. OUTCOME: After 9 months of follow-up, it was observed that the left renal hematoma and urinary extravasation was completely absorbed. LESSONS: Spontaneous renal rupture for hemophilia is a clinical emergency. When spontaneous renal rupture is associated with abnormal coagulation function, and the coagulation function cannot be corrected by conventional treatment, the possibility of hemophilia needs to be considered, and the type of hemophilia needs to be further defined. This case indicates a successful resolution of spontaneous renal rupture, it can provide guiding value for our clinical practice.

External Validation of the Kidney Failure Risk Equation Among Urban Community-Based Chinese Patients With CKD.

Rationale & Objective: The Kidney Failure Risk Equations have been proven to perform well in multinational databases, whereas validation in Asian populations is lacking. This study sought to externally validate the equations in a community-based chronic kidney disease cohort in China. Study Design: A retrospective cohort study. Setting & Participants: Patients with and estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 dwelling in an industrialized coastal city of China. Exposure: Age, sex, eGFR, and albuminuria were included in the 4-variable model, whereas serum calcium, phosphate, bicarbonate, and albumin levels were added to the previously noted variables in the 8-variable model. Outcome: Initiation of long-term dialysis treatment. Analytical Approach: Model discrimination, calibration, and clinical utility were evaluated by Harrell's C statistic, calibration plots, and decision curve analysis, respectively. Results: A total of 4,587 participants were enrolled for validation of the 4-variable model, whereas 1,414 were enrolled for the 8-variable model. The median times of follow-up were 4.0 (interquartile range: 2.6-6.3) years for the 4-variable model and 3.4 (2.2-5.6) years for the 8-variable model. For the 4-variable model, the C statistics were 0.750 (95% CI: 0.615-0.885) for the 2-year model and 0.766 (0.625-0.907) for the 5-year model, whereas the values were 0.756 (0.629-0.883) and 0.774 (0.641-0.907), respectively, for the 8-variable model. Calibration was acceptable for both the 4-variable and 8-variable models. Decision curve analysis for the models at the 5-year scale performed better throughout different net benefit thresholds than the eGFR-based (<30 mL/min/1.73 m2) strategy. Limitations: A large proportion of patients lack albuminuria measurements, and only a subset of population could provide complete data for the 8-variable equation. Conclusions: The kidney failure risk equations showed acceptable discrimination and calibration and better clinical utility than the eGFR-based strategy for incidence of kidney failure among community-based urban Chinese patients with chronic kidney disease.

Accurate and reliable risk evaluation of chronic kidney disease (CKD) prognosis can be helpful for physicians to make decisions concerning treatment opportunity and therapeutic strategy. The kidney failure risk equation is an outstanding model for predicting risk of kidney failure among patients with CKD. However, the equation is lacking validation among Chinese populations. In the current study, we demonstrated that the equation had good discrimination among an urban community-based cohort of patients with CKD in China. The calibration was also acceptable. Decision curve analysis also showed that the equation performed better than a traditional kidney function-based strategy. The results provide the basis for using predictions derived from the kidney failure risk equation to improve the management of patients with CKD in community settings in China.

Single-center retrospective study of the diagnostic value of double-balloon enteroscopy in Meckel's diverticulum with bleeding.

BACKGROUND: The study aimed to analyze the characteristic clinical manifestations of patients with intestinal disease Meckel's diverticulum (MD) complicated by digestive tract hemorrhage. Moreover, we aimed to evaluate the value of double-balloon enteroscopy (DBE) in MD diagnosis and the prognosis after laparoscopic diverticula resection. AIM: To evaluate the value of DBE in the diagnosis and the prognosis after laparoscopic diverticula resection for MD with bleeding. METHODS: The study retrospectively analyzed relevant data from 84 MD patients treated between January 2015 and March 2022 and recorded their clinical manifestations, auxiliary examination, and follow-up after laparoscopic resection of diverticula. RESULTS: (1) Among 84 MD patients complicated with hemorrhage, 77 were male, and 7 were female with an average age of 31.31 ± 10.75 years. The incidence was higher in men than in women of different ages; (2) Among the 84 MD patients, 65 (78.40%) had defecated dark red stools, and 50 (58.80%) had no accompanying symptoms during bleeding, indicating that most MD bleeding appeared a dark red stool without accompanying symptoms; (3) The shock index of 71 patients (85.20%) was < 1, suggesting that the blood loss of most MD patients was less than 20%-30%, and only a few patients had a blood loss of > 30%; (4) The DBE-positive rate was 100% (54/54), 99mTc-pertechnetate-positive scanning rate was 78% (35/45) compared with capsule endoscopy (36%) and small intestine computed tomography (19%). These results suggest that DBE and 99mTc-pertechnetate scans had significant advantages in diagnosing MD and bleeding, especially DBE was a highly precise examination method in MD diagnosis; (5) A total of 54 MD patients with hemorrhage underwent DBE examination before surgery. DBE endoscopy revealed many mucosal manifestations including normal appearance, inflammatory changes, ulcerative changes, diverticulum inversion, and nodular hyperplasia, with ulcerative changes being the most common (53.70%). This suggests that diverticular mucosal ulcer was the main cause of MD and bleeding; and (6) Laparoscopic dissection of diverticulae was performed in 76 patients, The patients who underwent postoperative follow-up did not experience any further bleeding. Additionally, follow-up examination of the 8 cases who had declined surgery revealed that 3 of them experienced a recurrence of digestive tract bleeding. These findings indicate that laparoscopic diverticula resection in MD patients complicated by bleeding had a favorable prognosis. CONCLUSION: Bleeding associated with MD was predominantly observed in male adolescents, particularly at a young age. DBE was a highly precise examination method in MD diagnosis. Laparoscopic diverticula resection effectively prevented MD bleeding and had a good prognosis.

Weakened Mn-O bond in Mn-Ce catalysts through K doping induced oxygen activation for boosting benzene oxidation at low temperatures.

K-doped Mn-Ce solid solution catalysts were synthesized using a combination of coprecipitation and hydrothermal methods, demonstrating excellent performance in benzene oxidation. The catalyst K1Ce5Mn5 exhibited comparable activity to noble metal catalysts, achieving a 90 % benzene conversion at approximately 194 ℃. Durable tests under dry and moist conditions revealed that the catalyst could maintain its activity for 50 h at 218 ℃ and 236 ℃, respectively. Characterization results indicated that the catalyst's enhanced activity resulted from the weakened Mn-O bonding caused by the introduction of K+, facilitating the activation of oxygen and its involvement in the reaction. CeOx, the main crystalline phase of Mn-Ce solid solutions, provided abundant oxygen vacancies for capturing and activating oxygen molecules for the weakened Mn-O structures. This conclusion was further supported by partial density of state analysis from density functional theory computations, revealing that the introduction of K+ weakened the orbital hybridization of Mn3d and O2p. Finally, in situ diffuse reflectance infrared Fourier-transform spectroscopy (in situ DRIFTS) studies on Ce5Mn5 and K1Ce5Mn5 catalysts suggested that the introduction of K+ promoted the conversion of adsorbed benzene. Furthermore, intermediate products were transformed more rapidly for K1Ce5Mn5 compared to Ce5Mn5.

Spatiotemporal distribution of mediastinal neoplasms: A comprehensive multi-center study.

OBJECTIVES: Mediastinal neoplasms are typical but uncommon thoracic diseases with increasing incidence and unfavorable prognoses. A comprehensive understanding of their spatiotemporal distribution is essential for accurate diagnosis and timely treatment. However, previous studies are limited in scale and data coverage. Therefore, this study aims to elucidate the distribution of mediastinal lesions, offering valuable insights into this disease. MATERIALS AND METHODS: This multi-center, hospital-based observational study included 20 nationwide institutions. A retrospective search of electronic medical records from January 1st, 2009, to December 31st, 2020, was conducted, collecting sociodemographic data, computed tomography images, and pathologic diagnoses. Analysis focused on age, sex, time, location, and geographical region. Comparative assessments were made with global data from a multi-center database. RESULTS: Among 7,765 cases, thymomas (30.7%), benign mediastinal cysts (23.4%), and neurogenic tumors (10.0%) were predominant. Distribution varied across mediastinal compartments, with thymomas (39.6%), benign cysts (28.1%), and neurogenic tumors (51.9%) most prevalent in the prevascular, visceral, and paravertebral mediastinum, respectively. Age-specific variations were notable, with germ cell tumors prominent in patients under 18 and aged 18-29, while thymomas were more common in patients over 30. The composition of mediastinal lesions across different regions of China remained relatively consistent, but it differs from that of the global population. CONCLUSION: This study revealed significant heterogeneity in the spatiotemporal distribution of mediastinal neoplasms. These findings provide useful demographic data when considering the differential diagnosis of mediastinal lesions, and would be beneficial for tailoring disease prevention and control strategies.

Design, synthesis, and biological evaluation of 3-phenyl substituted pyridine derivatives as potential dual inhibitors of XOR and URAT1.

Xanthine oxidoreductase (XOR) and uric acid transporter 1 (URAT1) are two most widely studied targets involved in production and reabsorption of uric acid, respectively. Marketed drugs almost target XOR or URAT1, but sometimes, single agents might not achieve aim of lowering uric acid to ideal value in clinic. Thus, therapeutic strategies of combining XOR inhibitors with uricosuric drugs were proposed and implemented. Based on our initial work of virtual screening, A and B were potential hits for dual-targeted inhibitors on XOR/URAT1. By docking A/B with XOR/URAT1 respectively, compounds I1-7 were designed to get different degree of inhibition effect on XOR and URAT1, and I7 showed the best inhibitory effect on XOR (IC50 = 0.037 ± 0.001 µM) and URAT1 (IC50 = 546.70 ± 32.60 µM). Further docking research on I7 with XOR/URAT1 led to the design of compounds II with the significantly improved inhibitory activity on XOR and URAT1, such as II11 and II15. Especially, for II15, the IC50 of XOR is 0.006 ± 0.000 µM, superior to that of febuxostat (IC50 = 0.008 ± 0.000 µM), IC50 of URAT1 is 12.90 ± 2.30 µM, superior to that of benzbromarone (IC50 = 27.04 ± 2.55 µM). In acute hyperuricemia mouse model, II15 showed significant uric acid lowering effect. The results suggest that II15 had good inhibitory effect on XOR/URAT1, with the possibility for further investigation in in-vivo models of hyperuricemia.

A new gene signature associated with disulfidptosis that forecasts myasthenia gravis and suggests infiltration of immune microenvironment in thymoma patients.

Introduction: The mechanism of thymoma-associated myasthenia gravis (TAMG) is currently unknown, although patients with TAMG experience more severe myasthenic symptoms and have worse prognoses compared to regular thymoma patients. The objective of this research is to create a transcriptome map of TAMG using genes linked to disulfidptosis, detect possible biomarkers, and examine the disparities in the tumor immune microenvironment (TIME) among different thymoma patients. The findings will offer valuable knowledge for personalized treatment alternatives. Methods: Thymoma samples' RNA-seq data, along with their corresponding clinical data, were acquired from the TCGA database using methods. Next, genes and disulfidptosis-related lncRNAs(DRLs) were chosen through correlation analysis. Then, a prediction model of TAMG was established by LASSO regression. Subsequent to that, an analysis of the mutation data, the tumor mutational burden (TMB), and the assessment of immune and stromal elements within the tumor microenvironment were conducted. Results: A total of 87 patients diagnosed with thymoma were included in the study, with 29 of them having TAMG. We discovered a group of 325 lncRNAs in this sample that showed significant associations with genes related to disulfidptosis, with 25 of them displaying significantly altered expression. Moreover, utilizing LASSO regression, we constructed a predictive model incorporating 11 DRLs. The analysis revealed an area under the curve (AUC) of 0.934 (CI 0.879-0.989), a cut-off value of 0.797, along with a sensitivity of 82.8 % and specificity of 93.1 %. Furthermore, we examined the TIME in both the high-risk and low-risk groups, and observed noteworthy disparities in B cells, T cells, and APC among the two groups (p < 0.05). Conclusion: This research offers the initial examination of genes associated with disulfidptosis and TAMG through genomic and transcriptomic analysis. Furthermore, a strong risk forecasting model was created and the significance of TIME in TAMG was also clarified. The discoveries offer significant understanding into the molecular processes of TAMG and present possible indicators for categorizing risk.

Heparin-free veno-arterial extracorporeal membrane oxygenation in lung transplantation: a retrospective cohort study.

BACKGROUND: In lung transplantation (LTx) surgery, veno-arterial extracorporeal membrane oxygenation (VA-ECMO) can provide mechanical circulatory support to patients with cardiopulmonary failure. However, the use of heparin in the administration of ECMO can increase blood loss during LTx. This study aimed to evaluate the safety of heparin-free V-A ECMO strategies. METHODS: From September 2019 to April 2022, patients who underwent lung transplantation at the First Affiliated Hospital of Guangzhou Medical University were retrospectively reviewed. A total of 229 patients were included, including 117 patients in the ECMO group and 112 in the non-ECMO group. RESULT: There was no significant difference in the incidence of thrombus events and bleeding requiring reoperation between the two groups. The in-hospital survival rate after single lung transplantation (SLTx) was 81.08%in the ECMO group and 85.14% in the Non-ECMO group, (P = 0.585). The in-hospital survival rate after double lung transplantation (DLTx) was 80.00% in the ECMO group and 92.11% in the Non-ECMO groups (P = 0.095). CONCLUSIONS: In conclusion, the findings of this study suggest that the heparin-free V-A ECMO strategy in lung transplantation is a safe approach that does not increase the incidence of perioperative thrombotic events or bleeding requiring reoperation.

A bibliometric analysis of the research landscape on vascular normalization in cancer.

Tumor vascular normalization profoundly affects the advancement of cancer therapy. Currently, with the rapid increase in research on tumor vascular normalization, few analytical and descriptive studies have investigated the trends in its development, key research power, present research hotspots, and future outlooks. In this study, articles and reviews published between January 1, 2003, and October 29, 2022 were retrieved from Web of Science database. Subsequently, published research trends, countries/regions, institutions, authors, journals, references, and keywords were analyzed based on traditional bibliometric laws (such as Price's exponential growth, Bradford's, Lotka's, and Zipf's). Our results showed that the last two decades have seen an increase in tumor vascular normalization research. USA emerged as the preeminent contributor to the field, boasting the highest H-index and accruing the greatest quantity of publications and citations. Among institutions, Massachusetts General Hospital and Harvard University made significant contributions, and Professor RK Jain was identified as a key leader in this field. Out of 583 academic journals, Cancer Research and Clinical Cancer Research published the most articles on vascular normalization. The research focal points in the field primarily include immunotherapy, tumor microenvironments, nanomedicine, and emerging frontier themes such as metabolism and mechanomedicine. Concurrently, the challenges of vascular normalization in cancer are discussed as well. In conclusion, the study presented a thorough analysis of the literature covering the past 20 years on vascular normalization in cancer, highlighting leading countries, institutions, authors, journals, and the emerging research focal points in this field. Future studies will advance the ongoing efforts in the field of tumor vascular normalization, aiming to enhance our ability to effectively manage and treat cancer.

Evaluation of Secondary Alveolar Bone Grafting for Unilateral Complete Cleft Alveolus: A Retrospective Cone Beam Computed Tomography-Based Study.

Background: In patients with cleft lip and palate (CLP), secondary alveolar bone grafting (SABG) with particulate cancellous bone marrow (PCBM) is recommended. Objective: To compare bone graft outcomes in patients with unilateral CLP, when SABG is completed before or after canine tooth eruption (ACE or BCE), as measured by cone beam computed tomography (CBCT). Methods: Patients were allocated into two cohorts, ACE and BCE. The outcomes were evaluated using CBCT, followed by univariate and multifactorial analyses. Results: A total of 468 patients (age 11.61 ± 4.03 years; male/female 288/180) were analyzed, including 282 in the BCE group (9.41 ± 1.59 years, 175/107) and 186 in the ACE group (14.95 ± 4.31 years, 113/73). Although 5-level assessment revealed no significant difference in clinical success rate (>4 points) between the BCE and ACE groups (53.90% vs. 47.85%, p = 0.20), BCE group showed significantly higher rate of bone bridges formation (73.05% vs. 62.90%, p = 0.02), which can be attributed to variations in orthodontic participation and follow-up time. Independent predictors of graft failure were wide cleft, severe oronasal fistula, no palatal bone wall, and insufficient PCBM filling (p < 0.01). Conclusions: SABG should be performed before canine eruption with more aggressive PCBM filling and oral fistula management.

FOXO3 Inhibits the Cisplatin Resistance and Progression of Melanoma Cells by Promoting CDKN1C Transcription.

BACKGROUND: Forkhead box O3 (FOXO3) and cyclin dependent kinase inhibitor 1 C Gene (CDKN1C) have been shown to be involved in the melanoma process, but their roles in the cisplatin (DDP) resistance of melanoma remain unclear. METHODS: The mRNA levels of CDKN1C and FOXO3 were measured using quantitative real-time PCR. The protein levels of CDKN1C, FOXO3 and mitochondrial oxidative phosphorylation (mtOXPHOS)-related markers were determinant by western blot analysis. The DDP resistance, proliferation, and apoptosis of melanoma cells were assessed by cell counting kit 8 assay, colony formation assay and flow cytometry. Glucose consumption, lactate production and ATP level were detected to assess glycolysis. The regulation of FOXO3 on CDKN1C was confirmed by ChIP assay and dual-luciferase reporter assay. In vivo experiments were performed to evaluate the effect of FOXO3 on DDP sensitivity in melanoma tumor tissues. RESULTS: CDKN1C and FOXO3 were downregulated in chemoresistant melanoma tissues, and their low expression levels were related to the poor prognosis of melanoma patients. Overexpression of CDKN1C and FOXO3 repressed DDP resistance, proliferation, and glycolysis, while promoted apoptosis and mtOXPHOS in DDP-resistant melanoma cells. Further analysis suggested that FOXO3 could bind to CDKN1C promoter region to enhance its transcription. Besides, CDKN1C knockdown reversed the regulation of FOXO3 on melanoma cell DDP resistance and progression. Moreover, FOXO3 overexpression enhanced the DDP sensitivity of melanoma tumor tissues in vivo. CONCLUSION: FOXO3 promoted the transcription of CDKN1C, thereby inhibiting the DDP resistance and progression of melanoma cells.

Outcome of Tocilizumab Treatment in Febrile Neutropenic Children with Severe Sepsis/Septic Shock in a Single-Center Retrospective Case Series.

PURPOSE: To assess the efficacy of an IL-6 blockade with tocilizumab on treatment outcome of severe sepsis/septic shock in children with febrile neutropenia. METHODS: We performed a retrospective study of febrile neutropenic patients younger than 18 years old who developed severe sepsis/septic shock at a single medical center between November 2022 and October 2023. RESULTS: Seven patients with febrile neutropenia complicated with severe sepsis/septic shock were identified. Four of seven patients received tocilizumab in addition to standard of care. The median IL-6 level before administration of tocilizumab was 14,147 pg/mL (range: 672-30,509 pg/mL). All four patients successfully recovered from severe sepsis/septic shock. Three of seven patients received standard of care without tocilizumab. IL-6 levels were checked intwo2 patients, with a median of 1514.5 (range: 838-2191). Only one of three (33%) patients without tocilizumab therapy made a full recovery from severe sepsis/septic shock. The mortality rate was higher in patients without tocilizumab therapy compared to patients with tocilizumab therapy (67% vs. 0%). CONCLUSIONS: Administration of tocilizumab reduced mortality of severe sepsis/septic shock in children with febrile neutropenia. However, it warrants confirmation with a larger number of patients and a longer follow-up.

Artemisinin Confers Cytoprotection toward Hydrogen Peroxide-Induced Cell Apoptosis in Retinal Pigment Epithelial Cells in Correlation with the Increased Acetylation of Histone H4 at Lysine 8.

Increased oxidative stress is one of the critical pathologies inducing age-related macular degeneration (AMD), characterized by retinal pigment epithelial (RPE) cell damage and death. The unbalanced acetylation and deacetylation of histones have been implicated in AMD pathogenesis or hydrogen peroxide (H2O2)-induced cell damage. Therefore, strategies aimed at controlling the balance between acetylation and deacetylation may effectively protect RPE cells from oxidative damage. Artemisinin is an antimalarial lactone drug derived from Artemisia annua, with antioxidant activity known to modulate histone acetylation in the brain, but its effect on the retina is unknown. In this study, we aimed to investigate whether Artemisinin exerts a cytoprotective effect on oxidative stress-induced apoptosis in RPE cells by regulating histone acetylation. We hypothesized that Artemisinin confers cytoprotection toward H2O2-induced apoptosis in RPE cells through this mechanism. In the present study, we found that Artemisinin at a sub-clinic dosage of 20 µM inhibited the H2O2-induced cell viability decrease and B-cell lymphoma 2 (Bcl-2) protein level decrease and attenuated the H2O2-induced decrease in the histone H4 lysine (Lys) 8 acetylation [Acetyl-H4 (Lys 8)] level in the retinal RPE cell line D407. As expected, histone deacetylase inhibitor Trichostatin A at the concentration of 250 nM increased the Acetyl-H4 (Lys 8) level in D407 cells and attenuated the H2O2-induced cell viability decrease and apoptosis. Similar findings were obtained using adult RPE (ARPE)19 cells, another human RPE cell line, and primary human RPE cell cultures. In conclusion, these results confirmed our hypothesis and indicated that Artemisinin attenuated H2O2-induced apoptosis in apparent correlation with the increase in the Acetyl-H4 (Lys 8) level, which is associated with gene transcription and cell survival. By modulating histone acetylation, Artemisinin may restore the balance between acetylation and deacetylation and enhance the resistance and survival of RPE cells under oxidative stress. Our study provides novel mechanistic insights into the effect of Artemisinin on histone acetylation and apoptosis in RPE cells and supports the potential application of Artemisinin in the prevention and/or treatment of AMD.

Treatment of metastatic TFE3 microphthalmia transcription factor translocation renal cell carcinoma: a case report.

Background: Microphthalmia-associated transcription factor/transcription factor E (MiTF/TFE) translocation renal cell carcinoma (RCC) is a rare type of non-clear cell RCC (nccRCC), which is more common in females. Currently, there is no standardized treatment for advanced metastatic microphthalmia translocation RCC (MiT-RCC). The main treatment modalities include surgery, chemotherapy, immunotherapy, anti-vascular endothelial growth factor or vascular endothelial growth factor receptor (VEGFR) inhibitors, mammalian target of rapamycin (mTOR) inhibitors, and targeted therapy against the mesenchymal-epithelial transition (MET) factor signaling pathway. Case Description: We present the case of an 8-year-old male patient with hematuria and paroxysmal urinary pain. Based on tumor genetic testing results and targeted drug matching analysis, the patient underwent tumor biopsy, tumor radical surgery with vascular osteotomy, and cervicothoracic lymph node dissection. The patient was then treated with a combination of immunotherapy [sintilimab, a drug directed against programmed cell death receptor-1 (PD-1)] and VEGFR tyrosine kinase inhibitor (TKI) (from pazopanib to sunitinib). Throughout the 10 cycles of conventional chemotherapy (seven courses of sintilimab since the start of the third chemotherapy treatment), the patient's condition remained stable, with no tumor recurrence at the primary site. However, in the later stages, the patient developed a large amount of ascites, and the family requested discontinuation of treatment, ultimately leading to the patient's death. Conclusions: In this case report, we summarize the therapeutic strategy of a young patient with metastatic transcription factor E3 (TFE3) MiT-RCC. For this disease, early immunotherapy and the use of precision-targeted drugs may have a favorable impact on the survival prognosis of the patient but may still be of less benefit in children with advanced multiple metastases. Therefore, further research on tumor driver genes, among other treatment components, is urgently needed to improve precision therapy.