Gut microbiota-derived cholic acid mediates neonatal brain immaturity and white matter injury under chronic hypoxia.

Chronic hypoxia, common in neonates, disrupts gut microbiota balance, which is crucial for brain development. This study utilized cyanotic congenital heart disease (CCHD) patients and a neonatal hypoxic rat model to explore the association. Both hypoxic rats and CCHD infants exhibited brain immaturity, white matter injury (WMI), brain inflammation, and motor/learning deficits. Through 16s rRNA sequencing and metabolomic analysis, a reduction in B. thetaiotaomicron and P. distasonis was identified, leading to cholic acid accumulation. This accumulation triggered M1 microglial activation and inflammation-induced WMI. Administration of these bacteria rescued cholic acid-induced WMI in hypoxic rats. These findings suggest that gut microbiota-derived cholic acid mediates neonatal WMI and brain inflammation, contributing to brain immaturity under chronic hypoxia. Therapeutic targeting of these bacteria provides a non-invasive intervention for chronic hypoxia patients.

Consolidation chemotherapy after definitive concurrent chemoradiotherapy in patients with inoperable esophageal squamous cell carcinoma: a multicenter non-inferiority phase III randomized clinical trial.

BACKGROUND: Definitive concurrent chemoradiotherapy (dCCRT) is the gold standard for the treatment of locally advanced esophageal squamous cell carcinoma (ESCC). However, the potential benefits of consolidation chemotherapy after dCCRT in patients with esophageal cancer remain debatable. Prospective randomized controlled trials comparing the outcomes of dCCRT with or without consolidation chemotherapy in patients with ESCC are lacking. In this study, we aim to generate evidence regarding consolidation chemotherapy efficacy in patients with locally advanced, inoperable ESCC. METHODS: This is a multicenter, prospective, open-label, phase-III randomized controlled trial comparing non-inferiority of dCCRT alone to consolidation chemotherapy following dCCRT. In total, 600 patients will be enrolled and randomly assigned in a 1:1 ratio to receive either consolidation chemotherapy after dCCRT (Arm A) or dCCRT alone (Arm B). Overall survival will be the primary endpoint, whereas progression-free survival, locoregional progression-free survival, distant metastasis-free survival, and treatment-related toxicity will be the secondary endpoints. DISCUSSION: This study aid in further understanding the effects of consolidation chemotherapy after dCCRT in patients with locally advanced, inoperable ESCC. TRIAL REGISTRATION: ChiCTR1800017646.

Romidepsin exhibits anti-esophageal squamous cell carcinoma activity through the DDIT4-mTORC1 pathway.

Esophageal squamous cell carcinoma (ESCC) is one of the most common human malignancies worldwide and is associated with high morbidity and mortality. Current treatment options are limited, highlighting the need for development of novel effective agents. Here, a high-throughput drug screening (HTS) was performed using ESCC cell lines in both two- and three-dimensional culture systems to screen compounds that have anti-ESCC activity. Our screen identified romidepsin, a histone deactylase inhibitor, as a potential anti-ESCC agent. Romidepsin treatment decreased cell viability, induced apoptosis and cell cycle arrest in ESCC cell lines, and these findings were confirmed in ESCC cell line-derived xenografted (CDX) mouse models. Mechanically, romidepsin induced transcriptional upregulation of DNA damage-inducible transcript 4 (DDIT4) gene by histone hyperacetylation at its promoter region, leading to the inhibition of mammalian target of rapamycin complex 1 (mTORC1) pathway. Furthermore, romidepsin exhibited better efficacy and safety compared to the conventional therapeutic drugs in ESCC patient-derived xenografted (PDX) mouse models. These data indicate that romidepsin may be a novel option for anti-ESCC therapy.

Vitamin D levels in idiopathic inflammatory myopathy patients: a meta-analysis.

PURPOSE: This meta-analysis aimed to explore correlations between vitamin D and idiopathic inflammatory myopathy (IIM). METHODS: A comprehensive database search was conducted on 13 October 2020. Mean differences (MDs) and aggregated risk ratios (RR) with 95% confidence intervals (CIs) were used to determine the correlation between vitamin D deficiency (VDD) and IIM. Statistical analysis was performed with RevMan 5.4 and Stata15, statistical significance was set at p < 0.05. RESULTS: Search revealed five studies with 286 IIM patients and 480 healthy controls. Results with random-effects modeling indicated that serum vitamin D levels were significantly lower in IIM patients than in healthy controls (MD = -13.10 ng/mL; 95% CI: -16.51 to -9.68; p < 0.00001). No differences were found between patients with IIM and other autoimmune diseases on vitamin D levels (MD =-2.65 ng/mL; 95% CI: -11.31-6.01; p = 0.55). In two studies with 185 IIM patients, those with low vitamin D levels exhibited higher creatine kinase levels (MD = 85.20 IU/L; 95% CI: 72.67-97.73; p < 0.00001) than those with normal vitamin D levels. VDD was correlated with an increased risk of IIM (RR = 3.24, 95% CI: 1.81-5.79; p < 0.0001). CONCLUSION: This meta-analysis showed correlations between vitamin D level and IIM. The results indicated, VDD may be a risk factor for IIM, a determinant of immune dysregulation in IIM, or a consequence of IIM. Also, it implied further research to determine whether vitamin D supplementation is beneficial for patients with IIM.

Multi-omics and Multi-VOIs to predict esophageal fistula in esophageal cancer patients treated with radiotherapy.

OBJECTIVE: This study aimed to develop a prediction model for esophageal fistula (EF) in esophageal cancer (EC) patients treated with intensity-modulated radiation therapy (IMRT), by integrating multi-omics features from multiple volumes of interest (VOIs). METHODS: We retrospectively analyzed pretreatment planning computed tomographic (CT) images, three-dimensional dose distributions, and clinical factors of 287 EC patients. Nine groups of features from different combination of omics [Radiomics (R), Dosiomics (D), and RD (the combination of R and D)], and VOIs [esophagus (ESO), gross tumor volume (GTV), and EG (the combination of ESO and GTV)] were extracted and separately selected by unsupervised (analysis of variance (ANOVA) and Pearson correlation test) and supervised (Student T test) approaches. The final model performance was evaluated using five metrics: average area under the receiver-operator-characteristics curve (AUC), accuracy, precision, recall, and F1 score. RESULTS: For multi-omics using RD features, the model performance in EG model shows: AUC, 0.817 ± 0.031; 95% CI 0.805, 0.825; p < 0.001, which is better than single VOI (ESO or GTV). CONCLUSION: Integrating multi-omics features from multi-VOIs enables better prediction of EF in EC patients treated with IMRT. The incorporation of dosiomics features can enhance the model performance of the prediction.

Second haploidentical bone marrow transplantation with antithymocyte antibody-containing conditioning regimen for graft failure in eight patients with severe aplastic anemia.

The effects of a second haploidentical bone marrow transplantation with an antithymocyte antibody-containing conditioning regimen after graft failure in patients with severe aplastic anemia remain unclear. Eight severe aplastic anemia patients with graft failure with a median age of 12.5 (range, 3-22) years were retrospectively reviewed. At the second transplantation, they received a median mononuclear cell number of 15.7 (range, 11.2-20.9) × 108/kg or a median CD34+ cell number of 6.2 (range, 2.5-17.5) × 106/kg. They were all successfully engrafted, with a median time of 12.5 (range, 11-16) days for neutrophils and 24 (range, 14-50) days for platelets. Three patients developed skin acute graft-versus-host disease Grades I-II, and another 3 developed limited chronic graft-versus-host disease. All patients successfully recovered after treatment with methylprednisolone (0.5-1 mg/kg/day) and tacrolimus. One patient each died of respiratory failure caused by multidrug-resistant Klebsiella pneumoniae at 8 months and invasive fungal disease at 23 months after transplantation. Six patients survived with a 5-year estimated overall survival of 75% and a median follow-up time of 61 (range, 8-129) months. A second haploidentical bone marrow transplantation with an antithymocyte antibody-containing conditioning regimen was feasible for saving severe aplastic anemia patients with graft failure.

A PET/CT radiomics model for predicting distant metastasis in early-stage non-small cell lung cancer patients treated with stereotactic body radiotherapy: a multicentric study.

OBJECTIVES: Stereotactic body radiotherapy (SBRT) is a treatment option for patients with early-stage non-small cell lung cancer (NSCLC) who are unfit for surgery. Some patients may experience distant metastasis. This study aimed to develop and validate a radiomics model for predicting distant metastasis in patients with early-stage NSCLC treated with SBRT. METHODS: Patients at five institutions were enrolled in this study. Radiomics features were extracted based on the PET/CT images. After feature selection in the training set (from Tianjin), CT-based and PET-based radiomics signatures were built. Models based on CT and PET signatures were built and validated using external datasets (from Zhejiang, Zhengzhou, Shandong, and Shanghai). An integrated model that included CT and PET radiomic signatures was developed. The performance of the proposed model was evaluated in terms of its discrimination, calibration, and clinical utility. Multivariate logistic regression was used to calculate the probability of distant metastases. The cutoff value was obtained using the receiver operator characteristic curve (ROC), and the patients were divided into high- and low-risk groups. Kaplan-Meier analysis was used to evaluate the distant metastasis-free survival (DMFS) of different risk groups. RESULTS: In total, 228 patients were enrolled. The median follow-up time was 31.4 (2.0-111.4) months. The model based on CT radiomics signatures had an area under the curve (AUC) of 0.819 in the training set (n = 139) and 0.786 in the external dataset (n = 89). The PET radiomics model had an AUC of 0.763 for the training set and 0.804 for the external dataset. The model combining CT and PET radiomics had an AUC of 0.835 for the training set and 0.819 for the external dataset. The combined model showed a moderate calibration and a positive net benefit. When the probability of distant metastasis was greater than 0.19, the patient was considered to be at high risk. The DMFS of patients with high- and low-risk was significantly stratified (P < 0.001). CONCLUSIONS: The proposed PET/CT radiomics model can be used to predict distant metastasis in patients with early-stage NSCLC treated with SBRT and provide a reference for clinical decision-making. In this study, the model was established by combining CT and PET radiomics signatures in a moderate-quantity training cohort of early-stage NSCLC patients treated with SBRT and was successfully validated in independent cohorts. Physicians could use this easy-to-use model to assess the risk of distant metastasis after SBRT. Identifying subgroups of patients with different risk factors for distant metastasis is useful for guiding personalized treatment approaches.

Discovery of a potent and selective PARP1 degrader promoting cell cycle arrest via intercepting CDC25C-CDK1 axis for treating triple-negative breast cancer.

PARP1 is a multifaceted component of DNA repair and chromatin remodeling, making it an effective therapeutic target for cancer therapy. The recently reported proteolytic targeting chimera (PROTAC) could effectively degrade PARP1 through the ubiquitin-proteasome pathway, expanding the therapeutic application of PARP1 blocking. In this study, a series of nitrogen heterocyclic PROTACs were designed and synthesized through ternary complex simulation analysis based on our previous work. Our efforts have resulted in a potent PARP1 degrader D6 (DC50 = 25.23 nM) with high selectivity due to nitrogen heterocyclic linker generating multiple interactions with the PARP1-CRBN PPI surface, specifically. Moreover, D6 exhibited strong cytotoxicity to triple negative breast cancer cell line MDA-MB-231 (IC50 = 1.04 µM). And the proteomic results showed that the antitumor mechanism of D6 was found that intensifies DNA damage by intercepting the CDC25C-CDK1 axis to halt cell cycle transition in triple-negative breast cancer cells. Furthermore, in vivo study, D6 showed a promising PK property with moderate oral absorption activity. And D6 could effectively inhibit tumor growth (TGI rate = 71.4 % at 40 mg/kg) without other signs of toxicity in MDA-MB-321 tumor-bearing mice. In summary, we have identified an original scaffold and potent PARP1 PROTAC that provided a novel intervention strategy for the treatment of triple-negative breast cancer.

A novel CT-responsive hydrogel for the construction of an organ simulation phantom for the repeatability and stability study of radiomic features.

Radiomic features have demonstrated reliable outcomes in tumor grading and detecting precancerous lesions in medical imaging analysis. However, the repeatability and stability of these features have faced criticism. In this study, we aim to enhance the repeatability and stability of radiomic features by introducing a novel CT-responsive hydrogel material. The newly developed CT-responsive hydrogel, mineralized by in situ metal ions, exhibits exceptional repeatability, stability, and uniformity. Moreover, by adjusting the concentration of metal ions, it achieves remarkable CT similarity comparable to that of human organs on CT scans. To create a phantom, the hydrogel was molded into a universal model, displaying controllable CT values ranging from 53 HU to 58 HU, akin to human liver tissue. Subsequently, 1218 radiomic features were extracted from the CT-responsive hydrogel organ simulation phantom. Impressively, 85-97.2% of the extracted features exhibited good repeatability and stability during coefficient of variability analysis. This finding emphasizes the potential of CT-responsive hydrogel in consistently extracting the same features, providing a novel approach to address the issue of repeatability in radiomic features.

Porphyrin-based Bi-MOFs with Enriched Surface Bi Active Sites for Boosting Photocatalytic CO2 Reduction.

The inherent challenges in using metal-organic frameworks (MOFs) for photocatalytic CO2 reduction are the combination of wide-range light harvesting, efficient charge separation and transfer as well as highly exposed catalytic active sites for CO2 activation and reduction. We present here a promising solution to satisfy these requirements together by modulating the crystal facet and surface atomic structure of a porphyrin-based bismuth-MOF (Bi-PMOF). The series of structural and photo-electronic characterizations together with photocatalytic CO2 reduction experiment collectively establish that the enriched Bi active sites on the (010) surface prefer to promote efficient charge separation and transfer as well as the activation and reduction of CO2 . Specifically, the Bi-PMOFs-120-F with enriched surface Bi active sites exhibits optimal photocatalytic CO2 reduction performance to CO (28.61 µmol h-1 g-1 ) and CH4 (8.81 µmol h-1 g-1 ). This work provides new insights to synthesize highly efficient main group p-block metal Bi-MOF photocatalysts for CO2 reduction through a facet-regulation strategy and sheds light on the surface structure-activity relationships of the MOFs.

Serological Biomarker-Based Machine Learning Models for Predicting the Relapse of Ulcerative Colitis.

Purpose: To explore whether machine learning models using serological markers can predict the relapse of Ulcerative colitis (UC). Patients and Methods: This clinical cohort study included 292 UC patients, and serological markers were obtained when patients were discharged from the hospital. Subsequently, four machine learning models including the random forest (RF) model, the logistic regression model, the decision tree, and the neural network were compared to predict the relapse of UC. A nomogram was constructed, and the performance of these models was evaluated by accuracy, sensitivity, specificity, and the area under the receiver operating characteristic curve (AUC). Results: Based on the patients' characteristics and serological markers, we selected the relevant variables associated with relapse and developed a LR model. The novel model including gender, white blood cell count, percentage of leukomonocyte, percentage of monocyte, absolute value of neutrophilic granulocyte, and erythrocyte sedimentation rate was established for predicting the relapse. In addition, the average AUC of the four machine learning models was 0.828, of which the RF model was the best. The AUC of the test group was 0.889, the accuracy was 76.4%, the sensitivity was 78.5%, and the specificity was 76.4%. There were 45 variables in the RF models, and the relative weight coefficients of these variables were determined. Age has the greatest impact on classification results, followed by hemoglobin concentration, white blood cell count, and platelet distribution width. Conclusion: Machine learning models based on serological markers had high accuracy in predicting the relapse of UC. The model can be used to noninvasively predict patient outcomes and can be an effective tool for determining personalized treatment plans.

DMU-212 against EGFR-mutant non-small cell lung cancer via AMPK/PI3K/Erk signaling pathway.

Although some important advances have been achieved in clinical and diagnosis in the past few years, the management of non-small cell lung cancer (NSCLC) is ultimately dissatisfactory due to the low overall cure and survival rates. Epidermal growth factor (EGFR) has been recognized as a carcinogenic driver and is a crucial pharmacological target for NSCLC. DMU-212, an analog of resveratrol, has been reported to have significant inhibitory effects on several types of cancer. However, the effect of DMU-212 on lung cancer remains unclear. Therefore, this study aims to determine the effects and underlying mechanism of DMU-212 on EGFR-mutant NSCLC cells. The data found that the cytotoxicity of DMU-212 on three EGFR-mutant NSCLC cell lines was significantly higher than that of normal lung epithelial cell. Further study showed that DMU-212 can regulate the expression of cell cycle-related proteins including p21 and cyclin B1 to induce G2/M phase arrest in both H1975 and PC9 cells. Moreover, treatment with DMU-212 significantly promoted the activation of AMPK and simultaneously down-regulated the expression of EGFR and the phosphorylation of PI3K, Akt and ERK. In conclusion, our study suggested that DMU-212 inhibited the growth of NSCLCs via targeting of AMPK and EGFR.

The first suspected disseminated Hormographiella aspergillata infection in China, diagnosed using metagenomic next-generation sequencing: a case report and literature review.

Hormographiella aspergillata is a rare and emerging cause of invasive mould infections in patients with haematological malignancies, with a mortality rate of approximately 70%. Here, we present the first reported case of suspected disseminated H. aspergillata infection in China. The patient experienced a second relapse of acute myeloid leukaemia and developed neutropenia, fever, discrepant blood pressure between limbs, and cutaneous lesions limited to the left upper extremity. Since lung tissue biopsy was not feasible, metagenomic next-generation sequencing (mNGS) and panfungal polymerase chain reaction (PCR) analysis of bronchoalveolar lavage fluid and blood samples were performed, which indicated probable H. aspergillata pulmonary infection. Histopathology of cutaneous lesions revealed numerous fungal hyphae within dermal blood vessels. mNGS of a skin biopsy sample identified H. aspergillata sequences, and the fungi was subsequently recovered from fungal culture, proving cutaneous H. aspergillata infection. Despite combined antifungal therapy, the patient died owing to disease progression. Additionally, 22 previously reported cases of invasive H. aspergillata infection were reviewed in patients with haematological malignancies. Thus, mNGS is a powerful diagnostic tool for the early and effective detection of invasive H. aspergillata infections, with the advantage of sequencing all potential pathogens, and providing results within 24 h.

Supercritical CO2 Directional-Assisted Synthesis of Low-Dimensional Materials for Functional Applications.

Supercritical CO2 (SC CO2 ), as one of the unique fluids that possess fascinating properties of gas and liquid, holds great promise in chemical reactions and fabrication of materials. Building special nanostructures via SC CO2 for functional applications has been the focus of intense research for the past two decades, with facile regulated reaction conditions and a particular reaction field to operate compared to the more widely used solvent systems. In this review, the significance of SC CO2 on fabricating various functional materials including modification of 1D carbon nanotubes, 2D materials, and 2D heterostructures is stated. The fundamental aspects involving building special nanostructures via SC CO2 are explored: how their structure, morphology, and chemical composition be affected by the SC CO2 . Various optimization strategies are outlined to improve their performances, and recent advances are combined to present a coherent understanding of the mechanism of SC CO2 acting on these functional nanostructures. The wide applications of these special nanostructures in catalysis, biosensing, optoelectronics, microelectronics, and energy transformation are discussed. Moreover, the current status of SC CO2 research, the existing scientific issues, and application challenges, as well as the possible future directions to advance this fertile field are proposed in this review.

Zanthoxylum bungeanum seed oil inhibits tumorigenesis of human melanoma A375 by regulating CDC25A/CyclinB1/CDK1 signaling pathways in vitro and in vivo.

Background: Zanthoxylum bungeanum seed oil (ZBSO) is extracted from the seeds of the traditional Chinese medicine Z. bungeanum Maxim, which has been shown to have anti-melanoma effects. However, the specific mechanisms are not illustrated adequately. Aims: To further investigate the mechanism by which ZBSO inhibits melanoma and to provide scientific evidence to support ZBSO as a potential melanoma therapeutic candidate. Methods: CCK-8 assays were used to detect the function of ZBSO on A375 cells. Based on transcriptomics analyses, Western blot analysis was applied to determine whether an association existed in ZBSO with the CDC25A/CyclinB1/CDK1 signaling pathway. In addition, RT-qPCR and immunohistochemistry analysis validated that ZBSO has the anti-melanoma effect in a nude mouse xenograft model of human melanoma. Then, 16S rRNA sequencing was used to detect the regulation of gut microbes. Results: Cellular assays revealed that ZBSO could inhibit A375 cell viability by regulating the cell cycle pathway. Further studies presented that ZBSO could constrain CDC25A/CyclinB1/CDK1 signaling pathway in vitro and in vivo models of melanoma. ZBSO did not produce toxicity in mice, and significantly reduced tumor volume in xenotransplants of A375 cells. Genome analysis indicated that ZBSO successfully altered specific gut microbes. Conclusion: ZBSO inhibited the growth of A375 cells by regulating CDC25A/cyclinB1/CDK1 signaling pathway both in vitro and in vivo, suggesting that ZBSO may be a novel potential therapeutic agent.

Multi-omics to predict acute radiation esophagitis in patients with lung cancer treated with intensity-modulated radiation therapy.

PURPOSE: The study aimed to predict acute radiation esophagitis (ARE) with grade ≥ 2 for patients with locally advanced lung cancer (LALC) treated with intensity-modulated radiation therapy (IMRT) using multi-omics features, including radiomics and dosiomics. METHODS: 161 patients with stage IIIA-IIIB LALC who received chemoradiotherapy (CRT) or radiotherapy by IMRT with a prescribed dose from 45 to 70 Gy from 2015 to 2019 were enrolled retrospectively. All the toxicity gradings were given following the Common Terminology Criteria for Adverse Events V4.0. Multi-omics features, including radiomics, dosiomics (including dose-volume histogram dosimetric parameters), were extracted based on the planning CT image and three-dimensional dose distribution. All data were randomly divided into training cohorts (N = 107) and testing cohorts (N = 54). In the training cohorts, features with reliably high outcome relevance and low redundancy were selected under random patient subsampling. Four classification models (using clinical factors (CF) only, using radiomics features (RFs) only, dosiomics features (DFs) only, and the hybrid features (HFs) containing clinical factors, radiomics and dosiomics) were constructed employing the Ridge classifier using two-thirds of randomly selected patients as the training cohort. The remaining patient was treated as the testing cohort. A series of models were built with 30 times training-testing splits. Their performances were assessed using the area under the ROC curve (AUC) and accuracy. RESULTS: Among all patients, 51 developed ARE grade ≥ 2, with an incidence of 31.7%. Next, 8990 radiomics and 213 dosiomics features were extracted, and 3, 6, 12, and 13 features remained after feature selection in the CF, DF, RF and DF models, respectively. The RF and HF models achieved similar classification performance, with the training and testing AUCs of 0.796 ± 0.023 (95% confidence interval (CI [0.79, 0.80])/0.744 ± 0.044 (95% CI [0.73, 0.76]) and 0.801 ± 0.022 (95% CI [0.79, 0.81]) (p = 0.74), respectively. The model performances using CF and DF features were poorer, with training and testing AUCs of 0.573 ± 0.026 (95% CI [0.56, 0.58])/ 0.509 ± 0.072 (95% CI [0.48, 0.53]) and 0.679 ± 0.027 (95% CI [0.67, 0.69])/0.604 ± 0.041 (95% CI [0.53, 0.63]) compared with the above two models (p < 0.001), respectively. CONCLUSIONS: In LALC patients treated with CRT IMRT, the ARE grade ≥ 2 can be predicted using the pretreatment radiotherapy image features. To predict ARE, the multi-omics features had similar predictability with radiomics features; however, the dosiomics features and clinical factors had a limited classification performance.

Nursing Care of an Older Patient With Severe COVID-19 Receiving Prolonged Prone Ventilation: A Case Report.

INTRODUCTION: Prone positioning has been shown to improve ventilation status for patients with severe COVID-19 who are receiving mechanical ventilation. This case report describes the nursing care of a patient with severe COVID-19 who underwent prone ventilation for 72 hours. Relevant nursing management and operational considerations are also discussed. CLINICAL FINDINGS: An 83-year-old woman was admitted to the hospital with fatigue, dizziness, and positive tests for SARS-CoV-2 on nasopharyngeal swab specimens. The patient was intubated. DIAGNOSIS: The patient's positive tests for SARS-CoV-2, chest computed tomography findings, and clinical symptoms were consistent with a diagnosis of severe COVID-19. INTERVENTIONS: When the patient's condition did not improve with mechanical ventilation and intermittent prone positioning, she was placed in the prone position for 72 hours. She received sedation, analgesics, anti-infective medications, and enteral nutrition support in the intensive care unit. Nurses performed dynamic monitoring based on blood gas analysis results to guide lung rehabilitation. OUTCOMES: The patient was weaned from the ventilator on day 20 and successfully discharged home on day 28 of hospitalization. CONCLUSION: During prolonged prone ventilation of a patient with severe COVID-19, nursing strategies included airway management, early lung rehabilitation training guided by pulmonary ultrasonography, skin care, hierarchical management of nurses, hemodynamic support, and enteral nutrition. This report may assist critical care nurses caring for similar patients.

Interactions of glial cells with neuronal synapses, from astrocytes to microglia and oligodendrocyte lineage cells.

The mammalian brain is a complex organ comprising neurons, glia, and more than 1 × 1014 synapses. Neurons are a heterogeneous group of electrically active cells, which form the framework of the complex circuitry of the brain. However, glial cells, which are primarily divided into astrocytes, microglia, oligodendrocytes (OLs), and oligodendrocyte precursor cells (OPCs), constitute approximately half of all neural cells in the mammalian central nervous system (CNS) and mainly provide nutrition and tropic support to neurons in the brain. In the last two decades, the concept of "tripartite synapses" has drawn great attention, which emphasizes that astrocytes are an integral part of the synapse and regulate neuronal activity in a feedback manner after receiving neuronal signals. Since then, synaptic modulation by glial cells has been extensively studied and substantially revised. In this review, we summarize the latest significant findings on how glial cells, in particular, microglia and OL lineage cells, impact and remodel the structure and function of synapses in the brain. Our review highlights the cellular and molecular aspects of neuron-glia crosstalk and provides additional information on how aberrant synaptic communication between neurons and glia may contribute to neural pathologies.

Targeting the STAT5A/IDO1 axis overcomes radioresistance and reverses the immunosuppressive tumor microenvironment in NSCLC.

As a metabolic mediator of antitumor immunity, indoleamine­2,3­dioxygenase 1 (IDO1) is upregulated in various types of cancer; however, the regulatory mechanism and clinical significance of IDO1 in non­small cell lung cancer (NSCLC) radiotherapy (RT) remain unclear. The present study investigated the role of IDO1 in the NSCLC microenvironment. MTT assay, immunofluorescence, apoptosis analysis, cell cycle analysis, and C57BL/6 and BALB/c nude mouse tumor models were utilized to evaluate the roles of the STAT5A/IDO1/kynurenine axis in radioresistance and in the immune microenvironment of NSCLC. Protein expression levels were evaluated by western blotting, immunofluorescence and immunohistochemistry. Flow cytometry was performed to assess the status of CD8+ T lymphocytes, regulatory T cells (Tregs) and immune­related inflammatory factors in C57BL/6 mice. Notably, IDO1 and STAT5A were positively associated with the immune microenvironment. RT treatment significantly promoted the expression levels of IDO1. IDO1 knockdown markedly enhanced the radiosensitivity of lung tumor cells and the anti­apoptotic properties of T lymphocytes. It was demonstrated that STAT5A knockdown suppressed T­cell apoptosis by inhibiting IDO1 enzyme function. Finally, in vivo experiments showed that STAT5A knockdown combined with RT was associated with greater numbers of CD8+ T cells and fewer Tregs. Results from the present study indicated that targeting the STAT5A/IDO1 axis may reshape the immune microenvironment and promote the efficacy of RT in NSCLC treatment. The present study may provide a theoretical foundation for more efficient use of immunotherapy regimens in NSCLC treatment.

Kir4.1 channel activation in NG2 glia contributes to remyelination in ischemic stroke.

BACKGROUND: Stroke is one of the most common neurological diseases in the world and is clinically manifested by transient or permanent brain dysfunction. It has a high mortality and disability rate, which severely affects people's health and diminishes the quality of life. However, there is no efficient treatment that can be considered curative and there are other less well-known theories of pathogenesis. Therefore, it is imperative to gain a full understanding of the pathophysiology of ischemia and to seek new therapeutic strategies. METHODS: We first examined Kir4.1 channel and myelin based protein (MBP) expression in brain tissues from acute ischemic patients by Western blotting. We then established a transient ischemic mouse model (tMCAO) to conduct molecular, cell biological, transmission electron microscopy and pharmacokinetic studies, as well as in Kir4.1 cKO mice. Finally, neuroimaging and behavioral analyses were used to examine whether activation of Kir4.1 channel by luteolin could contribute to neuronal functional recovery in ischemic stroke. FINDINGS: In acute ischemic stroke patients, we first demonstrated that Kir4.1 ion channels were greatly impaired and a severe demyelination of axons occurred in ischemic infarction area of cerebral cortex in these patients. Further evidence showed that the deficits of Kir4.1 channels in NG2 glia led to the myelin loss of axons in a transient ischemic mouse model (tMCAO). Treating ischemic mice with a natural botanical extract, luteolin augmented Kir4.1 channel currents in NG2 glia and consequently promoted remyelination of axons, alleviated the infarction area and ultimately improved motor function in a series of behavioral tests. INTERPRETATION: Targeting Kir4.1 ion channels expressed in NG2 glial cells by luteolin treatment highlights an effective therapeutic strategy for a prompt brain functional recovery in ischemic stroke. FUNDING: This work was supported by grants from the Ministry of Science and Technology China Brain Initiative (2022ZD0204702, to X.T.), the National Natural Science Foundation of China (82271466, 82171279, 31970904 and 31571063), the Program for Professor of Special Appointment (Eastern Scholar for Dr. X.T.) at Shanghai Institutions for Higher Learning (1510000084), Shanghai Pujiang Talent Award (15PJ1404600), Shanghai Municipal Science and Technology Major Project (2018SHZDZX05) and Shanghai Science and Technology Project (17411954000).