Elemene is widely recognized as an effective anti-cancer compound and is routinely administered in Chinese clinical settings for the management of several solid tumors,including non-small cell lung cancer(NSCLC).However,its detailed molecular mechanism has not been adequately demonstrated.In this research,it was demonstrated that elemene effectively curtailed NSCLC growth in the patient-derived xenograft(PDX)model.Mechanistically,employing high-throughput screening techniques and subsequent biochemical validations such as microscale thermophoresis(MST),microRNA-145-5p(miR-145-5p)was pinpointed as a critical target through which elemene exerts its anti-tumor effects.Inter-estingly,elemene serves as a binding stabilizer for miR-145-5p,demonstrating a strong binding affinity(dissociation constant(KD)=0.39±0.17 μg/mL)and preventing its degradation both in vitro and in vivo,while not interfering with the synthesis of the primary microRNA transcripts(pri-miRNAs)and precursor miRNAs(pre-miRNAs).The stabilization of miR-145-5p by elemene resulted in an increased level of this miRNA,subsequently suppressing NSCLC progression through the miR-145-5p/mitogen-activated pro-tein kinase kinase kinase 3(MAP3K3)/nuclear factor kappaB(NF-κB)pathway.Our findings provide a new perspective on revealing the interaction patterns between clinical anti-tumor drugs and miRNAs.

Objective:To construct a realistic surface model of human glioma T98G cells, aiming to enhance the accuracy of dose assessment at the cellular level in radiotherapy.Methods:Three-dimensional tomographic images of T98G cells were acquired using a laser confocal microscope. Subsequently, after cropping via MATLAB software and conversion to the DICOM format, the Amira and Meshmixer softwares were employed to repair and reconstruct the authentic curved - surface models of the cell nucleus and cytoplasm. The GATE Monte Carlo simulation platform was utilized to construct the 160 kV X ray energy spectrum of the RS - 2000 Pro irradiator. In a vacuum environment, the energy deposition processes of single cells and cell populations were simulated, and the dose distributions of the cell nucleus and cytoplasm were computed.Results:In the single cell simulation, the absorbed dose of the cell nucleus was 0.07 Gy, and 0.23 Gy for the cytoplasm. Under the same irradiation duration, the dose of the cell nucleus accounted for approximately 70% of the external irradiation dose. The calculated standard deviations of absorbed dose were 3.03×10?? and 5.73×10?? Gy, respectively, indicating a notable randomness in dose deposition. Since 2 Gy is a widely-adopted dose in radiotherapy fractionation regimens, cell populations were irradiated with 2 Gy. The findings revealed that the internal dose distribution of cell populations exhibited a non-Gaussian distribution, demonstrating the randomness of dose deposition. Specifically, the dose of the cell nucleus was concentrated in the range of 0.6-1.8 Gy, and the dose of the cytoplasm was concentrated in the range of 0.9-2.7 Gy.Conclusions:A curved- surface model of human glioma cells is successfully constructed, which can lay a foundation for improving the accuracy of microscopic dosimetry simulation.

Objective:Drug safety assessments based on real-world data are often challenged by both treatment switching and rare events. In this study, we used statistical simulations to investigate the effects of switching rates and treatment effects on the statistical performance of commonly used analytical strategies and methods under overlapping scenarios of treatment switching and rare events.Methods:The simulation scenario was set up as a bidirectional treatment switching (allowing the control group to switch to the treatment group and the treatment group to switch to the control group), and the event rates were set at approximately 2%, 5%, and 20%. Different simulation scenarios were generated with sufficient sample size to consider switching rate and relative treatment effect. The simulated datasets were analyzed using three types of analysis strategy, i.e. intention to treat (ITT), per protocol (PP), and as treated (AT). The performance of five indicators, namely percentage bias, mean square error, empirical standard error, coverage, and rejection rate, were compared among the different methods in different scenarios, and recommendations for method selection were given.Results:In terms of analytical strategies and methods, AT analysis were relatively optimal in terms of percentage bias and accuracy, followed by PP analysis and ITT analysis. When the relative treatment effects converged (e.g. HR=1.0), both the ITT analysis and the time-dependent AT approaches (marginal structural model, time-dependent Cox regression model or time-dependent propensity score matching) performed well; when the relative treatment effects were small (e.g. HR=0.8), the marginal structural model was the most optimal; when the relative treatment effects were large (e.g. HR=0.6 or 0.4), the approaches of using a censored treatment for switchers in the AT analysis were more accurate. In addition, the time-dependent AT approaches had the highest rejection rate when there was a difference in treatment effect between the two groups, and the ITT analysis had the lowest rejection rate. Conclusions:For the dual challenges of bidirectional switching and rare events in real-world drug safety evaluations, adequate sample size is a prerequisite for accurate estimation of treatment effects, while switching rates and effect sizes of switched drugs might also affect estimation accuracy. Appropriate strategies and methods should be selected for the analysis. It is necessary to consider whether the event is rare or not, the switching rate and the expected treatment effect size of the two types of treatment to select appropriate analysis strategies and methods.

Elemene is widely recognized as an effective anti-cancer compound and is routinely administered in Chinese clinical settings for the management of several solid tumors, including non-small cell lung cancer (NSCLC). However, its detailed molecular mechanism has not been adequately demonstrated. In this research, it was demonstrated that elemene effectively curtailed NSCLC growth in the patient-derived xenograft (PDX) model. Mechanistically, employing high-throughput screening techniques and subsequent biochemical validations such as microscale thermophoresis (MST), microRNA-145-5p (miR-145-5p) was pinpointed as a critical target through which elemene exerts its anti-tumor effects. Interestingly, elemene serves as a binding stabilizer for miR-145-5p, demonstrating a strong binding affinity (dissociation constant (K _D) = 0.39 ± 0.17 μg/mL) and preventing its degradation both in vitro and in vivo, while not interfering with the synthesis of the primary microRNA transcripts (pri-miRNAs) and precursor miRNAs (pre-miRNAs). The stabilization of miR-145-5p by elemene resulted in an increased level of this miRNA, subsequently suppressing NSCLC progression through the miR-145-5p/mitogen-activated protein kinase kinase kinase 3 (MAP3K3)/nuclear factor kappaB (NF-κB) pathway. Our findings provide a new perspective on revealing the interaction patterns between clinical anti-tumor drugs and miRNAs.

Objective: To explore the brain-predicted age difference (Brain-PAD) in patients with type 2 diabetes mellitus (T2DM) by a machine learning prediction model based on structural magnetic resonance ( sMRI) in the Southwest University Adult Lifespan Dataset (SALD) , and to reveal the relationship between Brain-PAD and dura- tion of T2DM and cognition . Methods: Group comparisons about demographic variables and cognitive function were conducted respectively in local database of 104 T2DM patients and 83 healthy controls (HC) . The prediction model via Gaussian process regression (GPR) was constructed by training sMRI data of 329 healthy volunteers in SALD , then its performance was validated and evaluated . Furthermore , Brain-PAD ( predicted age-chronological age) in the local database was calculated . Group comparisons of Brain-PAD between T2DM patients and HCs were conducted by Mann-Whitney U test. Finally , Pearson correlation coefficient (r) was calculated between Brain-PAD and duration of disease and cognition . Results: Poor performance in auditory verbal learning test (AVLT)-delayed recall , AVLT-recognition , symbol digital modalities test (SDMT) (P < 0. 05) , and increased Brain-PAD were ob- served in T2DM patients , compared with HCs [1 . 619 ( - 4. 001 , 8. 272) years vs - 1 . 289 ( - 4. 128 , 4. 134) years , Z = 2. 056 , P = 0. 034] . Notably , the median of Brain-PAD in T2DM group was positive , indicating that the brain of T2DM patient maybe relatively “older”than his chronological age . Brain-PAD in T2DM group was as- sociated with performance in AVLT-immediate recall ( r = 0. 291 , P = 0. 003) , AVLT-delayed recall ( r = 0. 248 , P = 0. 011) , SDMT( r = 0. 376 , P = 0. 001) and trail making test (TMT)-A ( r = - 0. 206 , P = 0. 036) . However , the relationships between Brain-PAD and duration of T2DM were not explored . Conclusion Decreased cognitive function in patients with T2DM is demonstrated in this study . The machine learning prediction model based on sMRI supports the identification of brain aging objectively in patients with T2DM .

Sodium glucose cotransporter(SGLT)2 inhibitors,initially developed as antihyperglycemic agents,have demonstrated remarkable cardioprotective effects in numerous clinical trials and are now utilized in the treat-ment of heart failure across a range of ejection fractions.SGLT2 is predominantly expressed in the renal proximal tubules,brain,and epicardial adipose tissue within the human body.Research indicates that the protective effects of SGLT2 inhibi-tors in heart failure are linked to their direct modulation of SGLT2 receptors in both the kidneys and epicardial adipose tis-sue.Furthermore,SGLT is also present in the brain,and recent studies have revealed that SGLT2 inhibitors can enhance sympathetic activity in patients with metabolic syndrome,suggesting a potential neuroregulatory role.Given that excessive activation of the sympathetic nervous system can contribute to the onset and progression of heart failure,this paper reviews the neural regulatory mechanisms of SGLT2 inhibitors to provide insights for a deeper understanding of heart failure and to optimize their clinical application.

Objectives:To systemically evaluate the efficacy and safety of His-Purkinje conduction system pacing(HPCSP,including His bundle pacing[HBP]and left bundle branch area pacing[LBBAP])combined with atrioventricular node ablation for the treatment of atrial fibrillation combined with heart failure.Methods:The PubMed,Cochrane Library,Web of Science,Embase,China National Knowledge Infrastructure(CNKI),Wanfang Data,VIP,and Yiigle were searched for studies on HPCSP combined with atrioventricular node ablation for the treatment of atrial fibrillation combined with heart failure since the established until July 31,2024.Meta-analysis was performed using RevMan 5.4 and Stata 15.1.Results:A total of 13 studies were included with 1 071 patients,the success rate of HPCSP combined with atrioventricular node ablation was 93.1%.The meta-analysis results revealed that,in terms of effectiveness outcomes,compared with baseline,left ventricular end-diastolic diameter(mean difference[MD]=-3.11,95%CI:-4.16 to-2.06,P<0.000 01)was significantly reduced,New York Heart Association(NYHA)cardiac function classification(MD=-1.36,95%CI:-1.48 to-1.24,P<0.000 01)was significantly decreased,and left ventricular ejection fraction(MD=9.86,95%CI:7.02 to 12.69,P<0.000 01)was significantly increased during follow-up.The pacing QRS duration was prolonged from baseline after atrioventricular node ablation(MD=7.83,95%CI:2.79 to 12.87,P=0.002);In terms of safety outcomes,HPCSP pacing thresholds remained stable(MD=0.07,95%CI:-0.01 to 0.15,P=0.11)and impedance was decreased(MD=-78.84,95%CI:-120.21 to-37.47,P=0.000 2)during operation and follow-up.The complication rate was 7.9%,the heart failure rehospitalization rate was 4.5%and the mortality rate was 5.8%.Compared with biventricular pacing(BVP),HPCSP was correlated with shorter pacing QRS duration(MD=-39.08,95%CI:-62.35 to-15.80,P=0.001)and higher left ventricular ejection fraction(MD=4.38,95%CI:0.37 to 8.40,P=0.03),there was no significant difference in left ventricular end-diastolic diameter(MD=-9.11,95%CI:-19.93 to 1.72,P=0.100).During follow-up,LBBAP exhibited a lower pacing threshold than HBP(MD=0.61,95%CI:0.23 to 1.00,P=0.002);Endpoint event rates were similar between HBP and LBBP(RR=1.47,95%CI:0.83 to 2.60,P=0.190).Conclusions:Results of this meta-analysis demonstrate that HPCSP combined with atrioventricular node ablation for the treatment of atrial fibrillation combined with heart failure is effective and safe.HPCSP is associated with better ventricular electro-mechanical synchronization and cardiac function compared with BVP,and LBBAP pacing parameters are superior to HBP.

Objective:Drug safety assessments based on real-world data are often challenged by both treatment switching and rare events. In this study, we used statistical simulations to investigate the effects of switching rates and treatment effects on the statistical performance of commonly used analytical strategies and methods under overlapping scenarios of treatment switching and rare events.Methods:The simulation scenario was set up as a bidirectional treatment switching (allowing the control group to switch to the treatment group and the treatment group to switch to the control group), and the event rates were set at approximately 2%, 5%, and 20%. Different simulation scenarios were generated with sufficient sample size to consider switching rate and relative treatment effect. The simulated datasets were analyzed using three types of analysis strategy, i.e. intention to treat (ITT), per protocol (PP), and as treated (AT). The performance of five indicators, namely percentage bias, mean square error, empirical standard error, coverage, and rejection rate, were compared among the different methods in different scenarios, and recommendations for method selection were given.Results:In terms of analytical strategies and methods, AT analysis were relatively optimal in terms of percentage bias and accuracy, followed by PP analysis and ITT analysis. When the relative treatment effects converged (e.g. HR=1.0), both the ITT analysis and the time-dependent AT approaches (marginal structural model, time-dependent Cox regression model or time-dependent propensity score matching) performed well; when the relative treatment effects were small (e.g. HR=0.8), the marginal structural model was the most optimal; when the relative treatment effects were large (e.g. HR=0.6 or 0.4), the approaches of using a censored treatment for switchers in the AT analysis were more accurate. In addition, the time-dependent AT approaches had the highest rejection rate when there was a difference in treatment effect between the two groups, and the ITT analysis had the lowest rejection rate. Conclusions:For the dual challenges of bidirectional switching and rare events in real-world drug safety evaluations, adequate sample size is a prerequisite for accurate estimation of treatment effects, while switching rates and effect sizes of switched drugs might also affect estimation accuracy. Appropriate strategies and methods should be selected for the analysis. It is necessary to consider whether the event is rare or not, the switching rate and the expected treatment effect size of the two types of treatment to select appropriate analysis strategies and methods.

Sodium glucose cotransporter(SGLT)2 inhibitors,initially developed as antihyperglycemic agents,have demonstrated remarkable cardioprotective effects in numerous clinical trials and are now utilized in the treat-ment of heart failure across a range of ejection fractions.SGLT2 is predominantly expressed in the renal proximal tubules,brain,and epicardial adipose tissue within the human body.Research indicates that the protective effects of SGLT2 inhibi-tors in heart failure are linked to their direct modulation of SGLT2 receptors in both the kidneys and epicardial adipose tis-sue.Furthermore,SGLT is also present in the brain,and recent studies have revealed that SGLT2 inhibitors can enhance sympathetic activity in patients with metabolic syndrome,suggesting a potential neuroregulatory role.Given that excessive activation of the sympathetic nervous system can contribute to the onset and progression of heart failure,this paper reviews the neural regulatory mechanisms of SGLT2 inhibitors to provide insights for a deeper understanding of heart failure and to optimize their clinical application.

Objectives:To systemically evaluate the efficacy and safety of His-Purkinje conduction system pacing(HPCSP,including His bundle pacing[HBP]and left bundle branch area pacing[LBBAP])combined with atrioventricular node ablation for the treatment of atrial fibrillation combined with heart failure.Methods:The PubMed,Cochrane Library,Web of Science,Embase,China National Knowledge Infrastructure(CNKI),Wanfang Data,VIP,and Yiigle were searched for studies on HPCSP combined with atrioventricular node ablation for the treatment of atrial fibrillation combined with heart failure since the established until July 31,2024.Meta-analysis was performed using RevMan 5.4 and Stata 15.1.Results:A total of 13 studies were included with 1 071 patients,the success rate of HPCSP combined with atrioventricular node ablation was 93.1%.The meta-analysis results revealed that,in terms of effectiveness outcomes,compared with baseline,left ventricular end-diastolic diameter(mean difference[MD]=-3.11,95%CI:-4.16 to-2.06,P<0.000 01)was significantly reduced,New York Heart Association(NYHA)cardiac function classification(MD=-1.36,95%CI:-1.48 to-1.24,P<0.000 01)was significantly decreased,and left ventricular ejection fraction(MD=9.86,95%CI:7.02 to 12.69,P<0.000 01)was significantly increased during follow-up.The pacing QRS duration was prolonged from baseline after atrioventricular node ablation(MD=7.83,95%CI:2.79 to 12.87,P=0.002);In terms of safety outcomes,HPCSP pacing thresholds remained stable(MD=0.07,95%CI:-0.01 to 0.15,P=0.11)and impedance was decreased(MD=-78.84,95%CI:-120.21 to-37.47,P=0.000 2)during operation and follow-up.The complication rate was 7.9%,the heart failure rehospitalization rate was 4.5%and the mortality rate was 5.8%.Compared with biventricular pacing(BVP),HPCSP was correlated with shorter pacing QRS duration(MD=-39.08,95%CI:-62.35 to-15.80,P=0.001)and higher left ventricular ejection fraction(MD=4.38,95%CI:0.37 to 8.40,P=0.03),there was no significant difference in left ventricular end-diastolic diameter(MD=-9.11,95%CI:-19.93 to 1.72,P=0.100).During follow-up,LBBAP exhibited a lower pacing threshold than HBP(MD=0.61,95%CI:0.23 to 1.00,P=0.002);Endpoint event rates were similar between HBP and LBBP(RR=1.47,95%CI:0.83 to 2.60,P=0.190).Conclusions:Results of this meta-analysis demonstrate that HPCSP combined with atrioventricular node ablation for the treatment of atrial fibrillation combined with heart failure is effective and safe.HPCSP is associated with better ventricular electro-mechanical synchronization and cardiac function compared with BVP,and LBBAP pacing parameters are superior to HBP.