Pyroptosis is an identified programmed cell death that has been highly linked to endoplasmic reticulum (ER) dynamics. However, the crucial proteins for modulating dynamic ER membrane curvature change that trigger pyroptosis are currently not well understood. In this study, a biotin-labeled chemical probe of potent pyroptosis inducer α-mangostin (α-MG) was synthesized. Through protein microarray analysis, reticulon-4 (RTN4/Nogo), a crucial regulator of ER membrane curvature, was identified as a target of α-MG. We observed that chemically induced proteasome degradation of RTN4 by α-MG through recruiting E3 ligase UBR5 significantly enhances the pyroptosis phenotype in cancer cells. Interestingly, the downregulation of RTN4 expression significantly facilitated a dynamic remodeling of ER membrane curvature through a transition from tubules to sheets, consequently leading to rapid fusion of the ER with the cell plasma membrane. In particular, the ER-to-plasma membrane fusion process is supported by the observed translocation of several crucial ER markers to the "bubble" structures of pyroptotic cells. Furthermore, α-MG-induced RTN4 knockdown leads to pyruvate kinase M2 (PKM2)-dependent conventional caspase-3/gasdermin E (GSDME) cleavages for pyroptosis progression. In vivo, we observed that chemical or genetic RTN4 knockdown significantly inhibited cancer cells growth, which further exhibited an antitumor immune response with anti-programmed death-1 (anti-PD-1). In translational research, RTN4 high expression was closely correlated with the tumor metastasis and death of patients. Taken together, RTN4 plays a fundamental role in inducing pyroptosis through the modulation of ER membrane curvature remodeling, thus representing a prospective druggable target for anticancer immunotherapy.
Pyroptosis/immunology* ; Humans ; Endoplasmic Reticulum/immunology* ; Animals ; Nogo Proteins/antagonists & inhibitors* ; Mice ; Cell Line, Tumor ; Xanthones/pharmacology* ; Neoplasms/pathology* ; Mice, Nude

OBJECTIVES: To evaluate the efficacy of molecular targeted agents in children with progressive pediatric low-grade gliomas (pLGG). METHODS: A retrospective analysis was conducted on pLGG patients treated with oral targeted therapies at the Department of Pediatrics, Beijing Shijitan Hospital, Capital Medical University, from July 2021. Treatment responses and safety profiles were assessed. RESULTS: Among the 20 enrolled patients, the trametinib group (n=12, including 11 cases with BRAF fusions and 1 case with BRAF V600E mutation) demonstrated 4 partial responses (33%) and 2 minor responses (17%), with a median time to response of 3.0 months. In the vemurafenib group (n=6, all with BRAF V600E mutation), 5 patients achieved partial responses (83%), showing a median time to response of 1.0 month. Comparative analysis revealed no statistically significant difference in progression-free survival rates between the two treatment groups (P>0.05). The median duration of clinical benefit (defined as partial response + minor response + stable disease) was 11.0 months for vemurafenib and 18.0 months for trametinib. Two additional cases, one with ATM mutation treated with olaparib for 24 months and one with NF1 mutation receiving everolimus for 21 months, discontinued treatment due to sustained disease stability. No severe adverse events were observed in any treatment group. CONCLUSIONS Molecular targeted therapy demonstrates clinical efficacy with favorable tolerability in pLGG. Vemurafenib achieves high response rates and induces early tumor shrinkage in patients with BRAF V600E mutations, supporting its utility as a first-line therapy.
Humans ; Glioma/genetics* ; Male ; Female ; Child ; Child, Preschool ; Retrospective Studies ; Brain Neoplasms/genetics* ; Molecular Targeted Therapy/adverse effects* ; Adolescent ; Infant ; Proto-Oncogene Proteins B-raf/genetics* ; Pyrimidinones/therapeutic use* ; Mutation

OBJECTIVE: To identify the underlying mechanism by which quercetin (Que) alleviates sepsis-related acute respiratory distress syndrome (ARDS). METHODS: In vivo, C57BL/6 mice were assigned to sham, cecal ligation and puncture (CLP), and CLP+Que (50 mg/kg) groups (n=15 per group) by using a random number table. The sepsisrelated ARDS mouse model was established using the CLP method. In vitro, the murine alveolar macrophages (MH-S) cells were classified into control, lipopolysaccharide (LPS), LPS+Que (10 μmol/L), and LPS+Que+acetylcysteine (NAC, 5 mmol/L) groups. The effect of Que on oxidative stress, inflammation, and apoptosis in mice lungs and MH-S cells was determined, and the mechanism with reactive oxygen species (ROS)/p38 mitogen-activated protein kinase (MAPK) pathway was also explored both in vivo and in vitro. RESULTS: Que alleviated lung injury in mice, as reflected by a reversal of pulmonary histopathologic changes as well as a reduction in lung wet/dry weight ratio and neutrophil infiltration (P<0.05 or P<0.01). Additionally, Que improved the survival rate and relieved gas exchange impairment in mice (P<0.01). Que treatment also remarkedly reduced malondialdehyde formation, superoxide dismutase and catalase depletion, and cell apoptosis both in vivo and in vitro (P<0.05 or P<0.01). Moreover, Que treatment diminished the release of inflammatory factors interleukin (IL)-1β, tumor necrosis factor-α, and IL-6 both in vivo and in vitro (P<0.05 or P<0.01). Mechanistic investigation clarifified that Que administration led to a decline in the phosphorylation of p38 MAPK in addition to the suppression of ROS expression (P<0.01). Furthermore, in LPS-induced MH-S cells, ROS inhibitor NAC further inhibited ROS/p38 MAPK pathway, as well as oxidative stress, inflammation, and cell apoptosis on the basis of Que treatment (P<0.05 or P<0.01). CONCLUSION Que was found to exert anti-oxidative, anti-inflammatory, and anti-apoptotic effects by suppressing the ROS/p38 MAPK pathway, thereby conferring protection for mice against sepsis-related ARDS.
Animals ; Sepsis/drug therapy* ; Quercetin/therapeutic use* ; Respiratory Distress Syndrome/enzymology* ; p38 Mitogen-Activated Protein Kinases/metabolism* ; Mice, Inbred C57BL ; Reactive Oxygen Species/metabolism* ; Apoptosis/drug effects* ; Male ; Oxidative Stress/drug effects* ; MAP Kinase Signaling System/drug effects* ; Lung/drug effects* ; Mice ; Lipopolysaccharides ; Macrophages, Alveolar/pathology* ; Inflammation/pathology* ; Protective Agents/therapeutic use*

Alzheimer's disease(AD)has attracted widespread attention due to its extremely complex pathogenic mechanisms,multiple pathogenic factors,and its heavy burden on patients and the society.In recent years,several studies have revealed various pathogenic mechanisms of AD,and the AD treatments based on these mechanisms become research hotspot in nanomedicine.Nanomaterials with unique physi-cochemical properties show great potential in AD treatment.Nanomaterials possess good biocompatibility.Moreover,they can regulate and release therapeutic drugs continuously and steadily to ensure the ideal concentrations of drugs reach in the target site.Meanwhile,they can bind with the therapeutic targets precisely to treat AD.Therefore,the development of novel nanodrugs has become an important research area in AD treatment.This article reviews the main pathological features and pathogenic mechanisms of AD,including β-amyloid plaque aggregation,Tau protein hyperphosphorylation,oxidative stress,and neuroinflammation.Additionally,this review mainly discusses the therapeutic strategies of nanomaterials in clearing pathological proteins(such as β-amyloid and Tau proteins),inhibiting oxidative stress,and alleviating neuroinflammation.Finally,this review prospects the risks and challenges faced on current AD treatment strategies by nanomaterials,such as low drug delivery efficiency to the brain and potential side effects after treatment.We also provide suggestions for the future directions in this research field.This review aims to promote the clinical translation of nanomaterials in AD treatment by discussing the research status of this field.

Turning to critical illness is a common stage of various diseases and injuries before death. Patients usually have complex health conditions, while the treatment process involves a wide range of content, along with high requirements for doctor′s professionalism and multi-specialty teamwork, as well as a great demand for time-sensitive treatments. However, this is not matched with critical care professionals and the current state of medical care in China. Telemedicine, which shortens the distance of medical professionals and the gap of disease diagnosis and treatments in various regions through electronic information, can effectively solve the current problem. Therefore, there is an urgent need to develop a standardized, high-quality visualization telemedicine round system .Therefore, experts have been organized to search domestic and foreign literature on telemedicine round for critically ill patients and to form this consensus based on clinical experiences so as to further improve the level of critical care treatments in regions.

Turning to critical illness is a common stage of various diseases and injuries before death. Patients usually have complex health conditions, while the treatment process involves a wide range of content, along with high requirements for doctor′s professionalism and multi-specialty teamwork, as well as a great demand for time-sensitive treatments. However, this is not matched with critical care professionals and the current state of medical care in China. Telemedicine, which shortens the distance of medical professionals and the gap of disease diagnosis and treatments in various regions through electronic information, can effectively solve the current problem. Therefore, there is an urgent need to develop a standardized, high-quality visualization telemedicine round system .Therefore, experts have been organized to search domestic and foreign literature on telemedicine round for critically ill patients and to form this consensus based on clinical experiences so as to further improve the level of critical care treatments in regions.

Alzheimer's disease(AD)has attracted widespread attention due to its extremely complex pathogenic mechanisms,multiple pathogenic factors,and its heavy burden on patients and the society.In recent years,several studies have revealed various pathogenic mechanisms of AD,and the AD treatments based on these mechanisms become research hotspot in nanomedicine.Nanomaterials with unique physi-cochemical properties show great potential in AD treatment.Nanomaterials possess good biocompatibility.Moreover,they can regulate and release therapeutic drugs continuously and steadily to ensure the ideal concentrations of drugs reach in the target site.Meanwhile,they can bind with the therapeutic targets precisely to treat AD.Therefore,the development of novel nanodrugs has become an important research area in AD treatment.This article reviews the main pathological features and pathogenic mechanisms of AD,including β-amyloid plaque aggregation,Tau protein hyperphosphorylation,oxidative stress,and neuroinflammation.Additionally,this review mainly discusses the therapeutic strategies of nanomaterials in clearing pathological proteins(such as β-amyloid and Tau proteins),inhibiting oxidative stress,and alleviating neuroinflammation.Finally,this review prospects the risks and challenges faced on current AD treatment strategies by nanomaterials,such as low drug delivery efficiency to the brain and potential side effects after treatment.We also provide suggestions for the future directions in this research field.This review aims to promote the clinical translation of nanomaterials in AD treatment by discussing the research status of this field.

Objective To compare the size discrepancy between ultrasonic and pathological measurement of solitary cN0M0 papillary thyroid microcarcinoma(PTMC),and to explore their correlation with lymph node metastasis.Methods From April 2021 to January 2022,234 patients with solitary cN0M0 PTMC who received thyroid lobectomy or total thyroidectomy in the Department of Thyroid and Breast Surgery of Nanjing University of Chinese Medicine,Affiliated Hospital of Integrated Traditional Chinese and Western Medicine were analyzed retrospectively.The size discrepancy between ultrasonic and pathological measurement were compared,and the risk factors of central lymph node metastasis were analyzed.Results The mean of maximum diameter of PTMC measured by ultrasound was 6.8(range 5.6 to 8.4)mm,which was significantly bigger than that measured by pathology 5.0(range 4.0 to 7.0)mm(P=0.000).Of them,37.2%of the tumor size measured by ultrasound is consistent with pathology,61.1%of the tumor size measured by ultrasound is bigger than that measured by pathology,and only 1.7%of the tumor size measured by ultrasound is smaller than that measured by pathology.There was a linear correlation between the diameter measured by ultrasound and pathology.And the regression equation can be expressed as:pathological diameter=0.799×ultrasonic diameter-0.221.In addition,28.6%patients had central lymph node metastasis.Multivariate Logistic regression analysis showed that the diameter measured by pathology is a risk factor for central lymph node metastasis in patients(OR=17.845,95%CI:2.507-127.025,P=0.004),and the cutoff value is 5.5 mm which corresponded to the diameter measured by ultrasound as 7.2 mm.Conclusions The sizes of solitary cN0M0 PTMC measured by ultrasound and pathology are different but also correlated.PMTC with pathological diameter>5.5 mm with its corresponding ultrasonic diameter as 7.2 mm indicated an increased risk of central lymph node metastasis.

Objective To establish a method for quantitative analysis of tiny amounts of tritium in hydrogen below the detection limit of isotope ratio mass spectrometer. Methods Hydrogen was oxidized to produce water in a self-developed catalytic oxidation device filled with platinum hydrophobic catalyst. The effects of different experimental conditions on hydrogen conversion rate were investigated. The tritium concentration in the synthetic water was measured using a liquid scintillation counter. The tritium concentration in hydrogen was calculated according to the measurement of the synthetic water. Results When the flow rate of hydrogen was fixed, the conversion rate of hydrogen increased with the increase of the reaction temperature but increased and then decreased with the increase of the flow rate of oxygen. Hydrogen could be completely converted under optimal experimental conditions. The hydrogen samples with volumetric tritium concentrations in the range of 1 × 10⁻⁷ to 2 × 10⁻¹⁴ were converted to water at the reaction temperature of 110 ℃ and hydrogen/oxygen flow rate of 100 mL/min. The resulting water was measured using a liquid scintillation counter. The measurement accuracy was better than 2%. Conclusion This method can be used to measure hydrogen samples with tiny amounts of tritium below the detection limit of isotope ratio mass spectrometer. Our results provide data support for the calculation of the separation capacity of cryogenic distillation process.

Objective To explore the value of dynamic nomogram constructed by multi spiral computed tomography(MSCT)features combined with inflammatory indicators in predicting the status of microvascular invasion(MVI)of hepatocellular carcinoma(HCC)before surgery.Methods The clinical and imaging data of 137 patients with postoperative pathologically confirmed HCC were analyzed retrospectively.According to the status of the MVI,they were divided into positive group(44 cases)and negative group(93 cases).Multivariate logistic regression analysis was used to screen independent risk factors for predicting the MVI status of HCC patients,and a joint prediction model was constructed,which was displayed in the form of a dynamic nomogram.The receiver operating characteristic(ROC)curve,calibration curve and Hosmer-Lemeshow test were used to evaluate the diagnostic efficiency,calibration and goodness of fit of the model,Akaike information criterion(AIC)and Bayesian information criterion(BIC)were used for comparison between the models,and a 5-fold cross-validation and decision curve analysis(DCA)were also used to evaluate the stability and clinical applicability of the model.Results Multivariate logistic regression analysis showed that necrosis and delayed-phase enhancement(DEd),and alkaline phosphatase to lymphocyte ratio(ALR)were independent risk factors for predicting MVI status in HCC patients.The area under the curve(AUC)of the dynamic nomogram was 0.721,with the sensitivity of 0.705 and the specificity of 0.656.The AIC and BIC values were 152.372 and 158.212,respectively.The calibration curve and the Hosmer-Lemeshow test showed that the model had a high degree of calibration and goodness of fit(χ2=2.372,P=0.967),the average AUC of the 5-fold cross-validation was 0.787,and the DCA showed that the nomogram model had a good clinical applicability.Conclusion The dynamic nomogram model constructed by MSCT features combined with inflammatory indicators is feasible to predict the MVI status of HCC patients before surgery,and the dynamic nomogram can directly generate the prediction results of different individuals.