BACKGROUND: To evaluate the efficacy and safety of the first cohort of people in China treated with a responsive neurostimulation system (Epilcure TM , GenLight MedTech, Hangzhou, China) for focal drug-resistant epilepsy in this study. METHODS: This multicenter, before-and-after self-controlled study was conducted across 8 centers from March 2022 to June 2023, involving patients with drug-resistant epilepsy who were undergoing responsive neurostimulation (RNS). The study was based on an ongoing multi-center, single-blind, randomized controlled study. Efficacy was assessed through metrics including median seizure count, seizure frequency reduction (SFR), and response rate. Multivariable linear regression analysis was conducted to explore the relationships of basic clinical factors and intracranial electrophysiological characteristics with SFR. The postoperative quality of life, cognitive function, depression, and anxiety were evaluated as well. RESULTS: The follow-up period for the 19 participants was 10.7 ± 3.4 months. Seizure counts decreased significantly 6 months after device activation, with median SFR of 48% at the 6th month (M6) and 58% at M12 ( P  <0.05). The average response rate after 13 months of treatment was 42%, with 21% ( n  = 4) of the participants achieving seizure freedom. Patients who have previously undergone resective surgery appear to achieve better therapeutic outcomes at M11, M12 and M13 ( β  <0, P  <0.05). No statistically significant differences were observed in patients' scores of quality of life, cognition, depression and anxiety following stimulation when compared to baseline measurements. No serious adverse events related to the devices were observed. CONCLUSIONS: The preliminary findings suggest that Epilcure TM exhibits promising therapeutic potential in reducing the frequency of epileptic seizures. However, to further validate its efficacy, larger-scale randomized controlled trials are required. REGISTRATION Chinese Clinical Trial Registry (No. ChiCTR2200055247).
Humans ; Female ; Male ; Drug Resistant Epilepsy/therapy* ; Adult ; Young Adult ; Middle Aged ; China ; Adolescent ; Treatment Outcome ; Quality of Life ; Single-Blind Method ; Seizures ; Electric Stimulation Therapy/methods*

Background: Nasopharyngeal carcinoma (NPC) is characterized by high programmed death-ligand 1 (PD-L1) expression and abundant infiltration of non-malignant lymphocytes, which renders patients potentially suitable candidates for immune checkpoint blockade therapies. Palate, lung, and nasal epithelium clone (PLUNC) inhibit the growth of NPC cells and enhance cellular apoptosis and differentiation. Currently, the relationship between PLUNC (as a tumor-suppressor) and PD-L1 in NPC is unclear. Methods: We collected clinical samples of NPC to verify the relationship between PLUNC and PD-L1. PLUNC plasmid was transfected into NPC cells, and the variation of PD-L1 was verified by western blot and immunofluorescence. In NPC cells, we verified the relationship of PD-L1, activating transcription factor 3 (ATF3), and β-catenin by western blot and immunofluorescence. Later, we further verified that PLUNC regulates PD-L1 through β-catenin. Finally, the effect of PLUNC on β-catenin was verified by co-immunoprecipitation (Co-IP). Results: We found that PLUNC expression was lower in NPC tissues than in paracancer tissues. PD-L1 expression was opposite to that of PLUNC. Western blot and immunofluorescence showed that β-catenin could upregulate ATF3 and PD-L1, while PLUNC could downregulate ATF3/PD-L1 by inhibiting the expression of β-catenin. PLUNC inhibits the entry of β-catenin into the nucleus. Co-IP experiments demonstrated that PLUNC inhibited the interaction of DEAD-box helicase 17 (DDX17) and β-catenin. Conclusions PLUNC downregulates the expression of PD-L1 by inhibiting the interaction of DDX17/β-catenin in NPC.

Background: Nasopharyngeal carcinoma (NPC) is characterized by high programmed death-ligand 1 (PD-L1) expression and abundant infiltration of non-malignant lymphocytes, which renders patients potentially suitable candidates for immune checkpoint blockade therapies. Palate, lung, and nasal epithelium clone (PLUNC) inhibit the growth of NPC cells and enhance cellular apoptosis and differentiation. Currently, the relationship between PLUNC (as a tumor-suppressor) and PD-L1 in NPC is unclear. Methods: We collected clinical samples of NPC to verify the relationship between PLUNC and PD-L1. PLUNC plasmid was transfected into NPC cells, and the variation of PD-L1 was verified by western blot and immunofluorescence. In NPC cells, we verified the relationship of PD-L1, activating transcription factor 3 (ATF3), and β-catenin by western blot and immunofluorescence. Later, we further verified that PLUNC regulates PD-L1 through β-catenin. Finally, the effect of PLUNC on β-catenin was verified by co-immunoprecipitation (Co-IP). Results: We found that PLUNC expression was lower in NPC tissues than in paracancer tissues. PD-L1 expression was opposite to that of PLUNC. Western blot and immunofluorescence showed that β-catenin could upregulate ATF3 and PD-L1, while PLUNC could downregulate ATF3/PD-L1 by inhibiting the expression of β-catenin. PLUNC inhibits the entry of β-catenin into the nucleus. Co-IP experiments demonstrated that PLUNC inhibited the interaction of DEAD-box helicase 17 (DDX17) and β-catenin. Conclusions PLUNC downregulates the expression of PD-L1 by inhibiting the interaction of DDX17/β-catenin in NPC.

Background: Nasopharyngeal carcinoma (NPC) is characterized by high programmed death-ligand 1 (PD-L1) expression and abundant infiltration of non-malignant lymphocytes, which renders patients potentially suitable candidates for immune checkpoint blockade therapies. Palate, lung, and nasal epithelium clone (PLUNC) inhibit the growth of NPC cells and enhance cellular apoptosis and differentiation. Currently, the relationship between PLUNC (as a tumor-suppressor) and PD-L1 in NPC is unclear. Methods: We collected clinical samples of NPC to verify the relationship between PLUNC and PD-L1. PLUNC plasmid was transfected into NPC cells, and the variation of PD-L1 was verified by western blot and immunofluorescence. In NPC cells, we verified the relationship of PD-L1, activating transcription factor 3 (ATF3), and β-catenin by western blot and immunofluorescence. Later, we further verified that PLUNC regulates PD-L1 through β-catenin. Finally, the effect of PLUNC on β-catenin was verified by co-immunoprecipitation (Co-IP). Results: We found that PLUNC expression was lower in NPC tissues than in paracancer tissues. PD-L1 expression was opposite to that of PLUNC. Western blot and immunofluorescence showed that β-catenin could upregulate ATF3 and PD-L1, while PLUNC could downregulate ATF3/PD-L1 by inhibiting the expression of β-catenin. PLUNC inhibits the entry of β-catenin into the nucleus. Co-IP experiments demonstrated that PLUNC inhibited the interaction of DEAD-box helicase 17 (DDX17) and β-catenin. Conclusions PLUNC downregulates the expression of PD-L1 by inhibiting the interaction of DDX17/β-catenin in NPC.

ObjectiveTo investigate the dynamic trajectories of prognostic scores and key clinical indicators in hepatitis B virus-related acute-on-chronic liver failure （HBV-ACLF） patients without liver cirrhosis， to clarify their association with outcomes， and to provide new evidence for individualized prognostic assessment. MethodsA prospective study was conducted for the data of 154 non-cirrhotic HBV-ACLF patients who attended Beijing YouAn Hospital of Capital Medical University from January 2016 to December 2023， including prognostic scores and key biochemical indicators on Days 3， 7， 14， 21， and 28 of the disease course. According to the outcome of patients at 1 year， they were divided into death/liver transplantation group with 43 patients， liver cirrhosis group with 23 patients， and non-liver cirrhosis group with 88 patients， and the trajectory heterogeneity of different outcome subgroups was analyzed. A one-way analysis of variance was used for comparison of normally distributed continuous data among the three groups； the Kruskal-Wallis H test was used for comparison of non-normally distributed continuous data among the three groups； the Wilcoxon test was used between two groups. the chi-square test was used for comparison of categorical data between groups. The mean and its 95% confidence interval （CI） were calculated for each indicator at difference time points； the linear interpolation method was used to connect the means at adjacent time points and construct the group-specific longitudinal trend curve； the 95%CI was visualized using the semi-transparent ribbon area， with the transparency parameter （α=0.2） optimized to enhance the visual discrimination of overlapping intervals across multiple groups. A linear mixed-effects model was used to compare the longitudinal changing trend of each indicator between the patients with different outcomes； likelihood ratio was used to evaluate the significance of the interaction effect between time and group， and in case of the significant interaction effect， the slope based on the estimated marginal mean was used for comparison between two groups. ResultsThere were significant differences between the three groups in the incidence rates of ascites and grade Ⅲ — Ⅳ hepatic encephalopathy， MELD score， MELD-Na score， CLIF-C ACLF score， COSSH-ACLF Ⅱ score， total bilirubin （TBil）， international normalized ratio （INR）， alpha-fetoprotein， blood sodium， alanine aminotransferase， and procalcitonin at the baseline（all P0.05）. The analysis of dynamic trajectories showed that the death/liver transplantation group had high levels of prognostic scores and the biochemical parameters of TBil and INR （TBil400 μmol/L， INR2.5）， as well as a low level of platelet count （PLT） （100×10⁹/L）. The non-liver cirrhosis group had rapid improvements in indicators， with TBil200 μmol/L， INR1.5， and PLT100×10⁹/L by day 28， while the liver cirrhosis group showed a trend of recovery， with TBil200 μmol/L， INR2.0， and PLT 100×10⁹/L on day 28， with significant global heterogeneity in the temporal trends of the above indicators across the three groups （all P0.01）. ConclusionDynamic monitoring of prognostic scores and key clinical indicators can effectively stratify the 1-year outcomes of non-cirrhotic patients with HBV-ACLF. Patients with poor prognosis were typically characterized by INR 2.5 and TBil 400 μmol/L. Among those who survived beyond 1 year， individuals who subsequently progressed to cirrhosis were frequently identified by the presence of INR 1.5， TBil 200 μmol/L， and PLT 100×10⁹/L at day 28.

Traditional development of small protein scaffolds has relied on display technologies and mutation-based engineering, which limit sequence and functional diversity, thereby constraining their therapeutic and application potential. Protein design tools have significantly advanced the creation of novel protein sequences, structures, and functions. However, further improvements in design strategies are still needed to more efficiently optimize the functional performance of protein-based drugs and enhance their druggability. Here, we extended an evolution-based design protocol to create a novel minibinder, BindHer, against the human epidermal growth factor receptor 2 (HER2). It not only exhibits super stability and binding selectivity but also demonstrates remarkable properties in tissue specificity. Radiolabeling experiments with ^99mTc, ⁶⁸Ga, and ¹⁸F revealed that BindHer efficiently targets tumors in HER2-positive breast cancer mouse models, with minimal nonspecific liver absorption, outperforming scaffolds designed through traditional engineering. These findings highlight a new rational approach to automated protein design, offering significant potential for large-scale applications in therapeutic mini-protein development.

Objective To investigate the influence of metabolism-related factors(overweight and/or obesity,hyperglycemia,hypertension and dyslipidemia)on the 90-day prognosis of patients with hepatitis B virus-related acute-on-chronic liver failure(HBV-ACLF),and to establish a predictive model.Methods A retrospective analysis was performed for the clinical data of 365 patients with HBV-ACLF who were hospitalized in Department of Infectious Diseases,The Affiliated Hospital of Southwest Medical University,from June 2018 to June 2022,and according to the 90-day follow-up results,they were divided into survival group with 273 patients and death group with 92 patients.General information and related laboratory markers were collected from all patients.The t-test was used for comparison of normally distributed continuous data between groups,and the Mann-Whitney U test was used for comparison of non-normally distribution continuous data between groups;the chi-square test was used for comparison of categorical data between groups.A Logistic regression analysis was used to determine whether metabolism-related factors were independent risk factors for the 90-day prognosis of HBV-ACLF patients,and the Kaplan-Meier analysis was used to investigate the correlation between metabolism-related factors and the 90-day survival rate of HBV-ALCF patients.The area under the ROC curve(AUC)was used to compare the value of different scoring models in predicting the 90-day prognosis of HBV-ACLF patients.Results The multivariate Logistic regression analysis showed that hypertension(odds ratio[OR]=4.698,95%confidence interval[CI]:1.904-11.593,P=0.001),alanine aminotransferase(OR=0.999,95%CI:0.999-1.000,P=0.010),triglyceride(TG)(OR=4.979,95%CI:2.433-10.189,P＜0.001),high-density lipoprotein cholesterol(OR=0.258,95%CI:0.087-0.762,P=0.012),apolipoprotein B(OR=0.118,95%CI:0.026-0.547,P=0.006),and CLIF-C OF score(OR=2.275,95%CI:1.150-4.502,P＜0.001)were independent influencing factors for the short-term prognosis of HBV-ACLF.The combined predictive model of metabolism-related factors had a larger AUC than the predictive model of a single factor,among which the predictive model of hypertension+TG+CLIF-C OF score had the largest AUC of 0.886.The patients with metabolism-related factors tended to have higher incidence rate of liver complications and 30-and 90-day mortality rates.Conclusion The presence of the metabolism-related factors such as hypertension and dyslipidemia can increase the severity of HBV-ACLF and the risk of short-term mortality,and the hypertension+TG+CLIF-C OF score predictive model has a good value in predicting the short-term prognosis of HBV-ACLF patients.

Objective To observe the reliability of regional 4D flow and whole heart 4D flow cardiac MRI(CMRI)for measuring hemodynamic parameters of left ventricle.Methods Heart ultrasonography and CMRI were prospectively obtained in 31 healthy subjects.Hemodynamic parameters of left ventricle were measured using heart ultrasound,3-chamber 4D flow CMRI(based on inflow and outflow channel of left ventricle)and whole heart 4D flow CMRI,respectively.Intra-class correlation coefficient(ICC)was performed to evaluate the consistencies of the measured left ventricle hemodynamic parameters among the above 3 methods.Results Good consistencies of peak systolic velocity in aortic supravalvular/subvalvular,E peak diastolic velocity of mitral valve,supravalvular/subvalvular aortic pressure and aortic valve pressure gradient(all ICC＞0.75),while moderate consistency of A peak diastolic velocity of mitral valve(ICC=0.718)were found between heart ultrasound and 3-chamber 4D flow CMRI.Good consistencies of peak systolic velocity in aortic supravalvular/subvalvular,A peak diastolic velocity of mitral valve and supravalvular/subvalvular aortic pressure(all ICC＞0.75),while moderate consistencies of E peak diastolic velocity of mitral valve and aortic valve pressure gradient(ICC=0.600,0.628)were found between heart ultrasound and whole heart 4D flow CMRI.Meanwhile,good consistencies of the above parameters were found between 3-chamber 4D flow CMRI and whole heart 4D flow CMRI(all ICC＞0.75).Conclusion Measuring left ventricular hemodynamic parameters using local regional 4D flow and whole heart 4D flow CMRI were reliable,with good consistency with cardiac ultrasound.

Objective:To investigate the impacts of ionizing radiation on protein expression profiles in esophageal tissues of rats using quantitative proteomics, in order to reveal the molecular mechanisms underlying the onset and development of radiation-induced esophagitis (RIE).Methods:A total of twenty-four male SD rats were divided by simple randomization into three groups: the control, 25 Gy irradiation, and 35 Gy irradiation groups, and their esophageal tissues were collected at 7 d post-irradiation to extract total protein. Then, changes in the protein expression profiles of the esophageal tissues in irradiated rats were investigated using tandem mass tag (TMT)-labeled quantitative proteomics and bioinformatics analysis. Additionally, the expressions of two key proteins, Hp and Ndufs4, were validated using immunohistochemistry and Western blot.Results:A comparison with the control group revealed a total of 847 differentially expressed proteins (DEPs; 483 up-regulated and 364 down-regulated) following 25 Gy irradiation and 699 DEPs (443 up-regulated and 256 down-regulated) following 35 Gy irradiation. Different radiation doses led to common 326 up-regulated proteins, which were mainly involved in biological processes and signaling pathways related to immune and inflammatory responses, and 210 down-regulated proteins, which were primarily involved in biological processes and signaling pathways related to energy production and metabolism. Furthermore, a total of 155 proteins were screened using a constructed protein protein interaction(PPI) network. Of these proteins, the up-regulated ones were most associated with three functional pathways, namely innate immune responses, complement and coagulation cascades, and innate immune system, while the down-regulated ones were most associated with energy acquisition via oxidizing organic compounds, oxidative phosphorylation, and the tricarboxylic acid (TCA) cycle and respiratory electron transfer. These functions were enriched with nine complement-related up-regulated and five mitochondria-related down-regulated proteins, respectively. Ionizing radiation significantly up-regulated Hp ( t = 27.94, 10.96, P<0.001) and down-regulated Ndufs4 ( t = 59.27, 54.07, P<0.001), consistent with the protein sequencing result. Conclusions:Ionizing radiation can change the protein expression profiles in the esophageal tissues of rats, and these DEPs are involved in multiple radiobiology-related functional pathways such as immune processes, inflammatory responses, and abnormal energy metabolism. Screening and validation of key proteins are helpful for identifying potential biomarkers of radiation-induced esophagitis.