Triterpenes from Ganoderma lucidum inhibit hepatocellular carcinoma by regulating enhancer-associated lncRNA in vivo.

ETHNOPHARMACOLOGICAL RELEVANCE: Ganoderma lucidum (G. lucidum) has been widely used as adjuvant of anti-tumor therapy for variety tumors. The bioactive ingredients of G. lucidum mainly include triterpenes, such as Ganoderic acid A, Ganoderic acid B, Ganoderenic acid A, Ganoderenic acid B, Ganoderenic acid D, and Ganoderic acid X. However, the effects and underlying mechanisms of G. lucidum are often challenging in hepatocellular carcinoma (HCC) treatment. AIM OF THE STUDY: To explore the potential role and mechanism of enhancer-associated lncRNAs (en-lncRNAs) in G. lucidum treated HCC through the in vivo and in vitro experiments. MATERIALS AND METHODS: Hepa1-6-bearing C57 BL/6 mice model were established to evaluate the therapeutic efficacy of G. lucidum treated HCC. Ki67 and TUNEL staining were used to detect the tumor cell proliferation and apoptosis in vivo. The Mouse lncRNA 4*180K array was implemented to identify the differentially expressed (DE) lncRNAs and mRNAs of G. lucidum treated tumor mice. The constructed lncRNA-mRNA co-expression network and bioinformatics analysis were used to selected core en-lncRNAs and its neighboring genes. The UPLC-MS method was used to identify the triterpenes of G. lucidum, and the in vitro experiments were used to verify which triterpene monomers regulated en-lncRNAs in tumor cells. Finally, a stable knockdown/overexpression cell lines were used to confirm the relationship between en-lncRNA and neighboring gene. RESULTS: Ki67 and TUNEL staining demonstrated G. lucidum significantly inhibited tumor growth, suppressed cell proliferation and induced apoptosis in vivo. Transcriptomic analysis revealed the existence of 126 DE lncRNAs high correlated with 454 co-expressed mRNAs in G. lucidum treated tumor mice. Based on lncRNA-mRNA network and qRT-PCR validation, 6 core lncRNAs were selected and considered high correlated with G. lucidum treatment. Bioinformatics analysis revealed FR036820 and FR121302 might act as enhancers, and qRT-PCR results suggested FR121302 might enhance Popdc2 mRNA level in HCC. Furthermore, 6 main triterpene monomers of G. lucidum were identified by UPLC-MS method, and in vitro experiments showed FR121302 and Popdc2 were significantly suppressed by Ganoderenic acid A and Ganoderenic acid B, respectively. The knock/overexpression results demonstrated that FR121302 activating and enhancing Popdc2 expression levels, and Ganoderenic acid A and Ganoderenic acid B dramatically suppressed FR121302 and decreased Popdc2 level in Hepa1-6 cells. CONCLUSIONS: Enhancer-associated lncRNA plays a crucial role as an enhancer during hepatocarcinogenesis, and triterpenes of G. lucidum significantly inhibited tumor cell proliferation and induced apoptosis by regulating en-lncRNAs. Our study demonstrated Ganoderenic acid A and Ganoderenic acid B suppressed en-lncRNA FR121302 may be one of the critical strategies of G. lucidum inhibit hepatocellular carcinoma growth.

Valvular heart disease and cardiomyopathy in China: epidemiology and current treatments.

The Annual Report on Cardiovascular Health and Diseases in China (2022) intricate landscape of cardiovascular health in China. In connection with the previous section, this ninth section of the report offers a comprehensive analysis of valvular heart disease and cardiomyopathy. Although rheumatic valve disease is still the main cause of valvular heart disease in China, with the aging of the population and the improvement of living standards, the prevalence of degenerative valvular heart disease is on the rise. Because many patients with valvular heart disease have only mild to moderate valve stenosis or insufficiency, and no symptoms, the detection rate in the population is low and late, resulting in many patients been in the severe late stage of disease at visit, increasing the difficulty of treatment and affecting effectiveness and prognosis. Therefore, we should strengthen the examination and screening of valvular heart disease in order to find and prevent it as early as possible. In addition, compared with other diseases, the treatment of valvular heart disease needs more and higher technical support (surgery, intervention, etc). However, not all hospitals can provide relevant technologies. At present, the treatment of valvular heart disease is still mainly concentrated in the provincial hospitals. It is necessary to carry out more professional training so that more doctors and hospitals can participate in the treatment of valvular heart disease. Cardiomyopathy is a group of myocardial diseases with abnormal myocardial structure and/or function, but couldn't be explained by hypertension, coronary atherosclerosis, valvular heart disease and congenital heart disease. It includes hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), arrhythmogenic cardiomyopathy (also known as arrhythmogenic right ventricular cardiomyopathy), restrictive cardiomyopathy (RCM) and undifferentiated cardiomyopathy.

KIF15 promotes human glioblastoma progression under the synergistic transactivation of REST and P300.

Glioblastoma (GBM) is highly invasive and lethal. The failure to cure GBM highlights the necessity of developing more effective targeted therapeutic strategies. KIF15 is a motor protein to be involved in cell mitosis promotion, cell structure assembly and cell signal transduction. The precise biological function and the potential upstream regulatory mechanisms of KIF15 in GBM remain elusive. Here, we demonstrated that KIF15 was abnormally up-regulated in GBM and predicted poor prognosis of GBM patients. KIF15 promotes GBM cell proliferation, metastasis and cell cycle progression. REST could bind to KIF15 promoter and transactivate KIF15. Furthermore, REST interacts with P300 and depends on its histone acetyltransferase (HAT) activity to co-regulate KIF15 expression. Both REST and P300 were highly expressed in GBM and predicted poor prognosis of GBM patients alone or in combination with KIF15. The tumorigenic function of KIF15 in GBM was regulated by REST in vitro and in vivo and the combinational treatment of cell cycle inhibitor Palbociclib with P300 HAT inhibitor inhibited GBM xenografts survival more significantly. Our findings indicate that KIF15 promotes GBM progression under the synergistic transactivation of REST and P300. P300/REST/KIF15 signaling axis is expected to be served as a cascade of candidate therapeutic targets in anti-GBM.

Development and validation of nomogram for predicting the cancer-specific survival among patients aged 80 and above with early-stage non-small cell lung cancer.

BACKGROUND: The use of nomograms in predicting the prognosis of early-stage non-small cell lung cancer (NSCLC), particularly in elderly patients, is not widespread. A validated prognostic model specifically for NSCLC patients over 80 years old holds promising potential for clinical application in forecasting patient outcomes. METHODS: The prognostic value of various factors for NSCLC patients aged 80 and above was evaluated using data from the Surveillance, Epidemiology, and End Results (SEER) database (2010-2017). Kaplan-Meier (KM) curves, Cox proportional hazards regression models, and nomogram were utilized to evaluate the impact of each factor on cancer-specific survival (CSS). RESULTS: A cohort comprising 7045 individuals was selected for inclusion in the analysis. Through rigorous statistical analysis, 10 independent prognostic factors were identified and incorporated into the nomogram. The nomogram's receiver operating characteristic (ROC) curve area under the curve (AUC) was higher than that of the AJCC 7th edition TNM staging system's predicted CSS (0.744 versus 0.602), establishing the superior prognostic value of the nomogram. CONCLUSIONS: We have successfully created a highly accurate and discriminative nomogram that enables oncologists to predict the survival outcome of each individual patient with I/II NSCLC who is 80 years or older.

Peripheral immunological characteristics of spontaneous pneumothorax: a Mendelian randomization study.

Background: Spontaneous pneumothorax (SP) is a common pleural disease in adolescents and adults. However, the role of immunological characteristics in the pathogenesis of SP remains unclear. This study aims to clarify the causal associations between circulating immune cells, lymphocyte subgroups, and SP susceptibility. Methods: Employing Mendelian randomization (MR), the causal association between circulating immune blood cells and lymphocyte subgroups on SP susceptibility have been assessed. Reverse MR analysis was used to further explore the causal relationship. The MR analysis ensured the reliability of the study results through the deletion of confounding single nucleotide polymorphisms (SNPs), heterogeneity testing, sensitivity analysis. Results: Seven immune cells and SP risk under stringent and lenient threshold conditions were identified. Eosinophils absolute count (AC) [odds ratio (OR) =1.0014, 95% confidence interval (CI): 1.0001-1.0014, P=0.02], memory B cell %B cell ratio (OR =1.008, 95% CI: 1.0002-1.0015, P=0.01), CD4+ T cell AC (OR =1.0014, 95% CI: 1.0003-1.0025, P=0.009), effector memory CD4+ T cell %T cell ratio (OR =1.0028, 95% CI: 1.0010-1.0046, P=0.003), and HLA-DR+CD8+ T cell %T cell ratio (OR =1.0019, 95% CI: 1.0004-1.0035, P=0.01) were identified as risk factors for increased susceptibility to SP. Conversely, CD8dim T cell AC (OR =0.9983, 95% CI: 0.9967-0.9999, P=0.03) and CD8dim natural killer T (NKT) %T cell ratio (OR =0.9982, 95% CI: 0.9965-0.9999, P=0.04) exhibited protective effects on SP. In natural killer (NK) cell subgroups and reverse MR analysis, no significance was found. Conclusions: This study establishes a close causal relationship between immune cells and SP through genetic methods, providing a new perspective for understanding the pathophysiological mechanisms of SP.

Potent covalent irreversible inhibitor of KRAS G12C IBI351 in patients with advanced solid tumors: First-in-human phase I study.

BACKGROUND: IBI351 is an irreversible and covalent inhibitor of KRAS G12C. Despite FDA approval of two KRAS G12C inhibitors, there are still significant unmet clinical needs in Chinese patients and ongoing concerns about the optimal dosage. Herein, we presented the phase Ia/Ib study of IBI351 monotherapy in Chinese patients with advanced solid tumors harboring KRAS G12C mutation. METHODS: In phase Ia dose escalation, IBI351 at 250/450/700/900 mg once daily and 450/600/750 mg twice daily (BID) were evaluated. Potentially efficacious doses and optimal recommended phase 2 dose (RP2D) were further evaluated in patients with advanced non-small cell lung cancer (NSCLC) in phase Ia dose expansion and phase Ib. Safety, pharmacokinetics, and investigator-assessed tumor response were evaluated. RESULTS: As of June 13, 2023, 176 patients were enrolled. IBI351 was well tolerated with no dose-limiting toxicity reported across all evaluated doses. The RP2D was determined as 600 mg BID by considering safety, efficacy and pharmacokinetics. A total of 168 patients (95.5 %) had at least one treatment-related adverse event (TRAE), and 64 patients (36.4 %) had grade 3 or higher TRAEs, most commonly gamma-glutamyl transferase increased (10.2 %) and anemia (6.8 %). For patients with NSCLC, the confirmed objective response rate (ORR) was 45.5 % across all doses. At 600 mg BID, the confirmed ORR was 46.8 % and median progression-free survival was 9.6 months with a median follow-up of 6.9 months. CONCLUSIONS: IBI351 was well tolerated in patients with advanced solid tumors and showed promising antitumor activity in advanced NSCLC patients with KRAS G12C mutation.

Structural lesions and transcriptomic specializations shape gradient perturbations in Wilson disease.

Functional dysregulations in multiple regions are caused by excessive copper deposition in the brain in Wilson disease (WD) patients. The genetic mechanism of WD is thought to involve the abnormal expression of ATP7B in the liver, whereas the biological and molecular processes involved in functional dysregulation within the brain remain unexplored. The objective of this study was to unravel the underpinnings of functional gradient perturbations underlying structural lesions and transcriptomic specializations in WD. In this study, we included 105 WD patients and 93 healthy controls who underwent structural and functional MRI assessments. We used the diffusion mapping embedding model to derive the functional connectome gradient and further employed gray matter volume to uncover structure-function decoupling for WD. Then, we used Neurosynth, clinical data, and whole-brain gene expression data to examine the meta-analytic cognitive function, clinical phenotypes, and transcriptomic specializations related to WD gradient alterations. Compared with controls, WD patients exhibited global topographic changes in the principal pramary-to-transmodal gradient. Meta-analytic terms and clinical characteristics were correlated with these gradient alterations in motor-related processing, higher-order cognition, neurological symptoms, and age. Spatial correlations revealed structure-function decoupling in multiple networks, especially in subcortical and visual networks. Within the cortex, the spatial association between gradient alterations and gene expression profiles has revealed transcriptomic specilizations in WD that display properties indicative of ion homeostasis, neural development, and motor control. Furthermore, for the first time, we characterized the role of the ATP7B gene in impacting subcortical function. The transcriptomic specializations of WD were also associated with other neurological and psychiatric disorders. Finally, we revealed that structural lesions and gradient perturbations may share similar transcriptomic specializations in WD. In conclusion, these findings bridged functional gradient perturbations to structural lesions and gene expression profiles in WD patients, possibly promoting our understanding of the neurobiological mechanisms underlying the emergence of complex neurological and psychiatric phenotypes.

[Investigation of Coupling Effect for Adjacent Orthopedic Implants on MRI Radio-Frequency Heating].

This paper investigates the mechanism of radio-frequency (RF) heating that occurs when two adjacent orthopedic implants are present together under magnetic resonance imaging (MRI) at 1.5 Tesla and 3.0 Tesla. When a patient has multiple implants close to each other, interactions between the implants may increase RF heating. Typical generic interlocking plate and antibiotic nail implants are adopted as examples. To analyze the effect of adjacent implants, the amplitude and direction of incident and scattering vector electric fields at the hot spot position are calculated and extracted using numerical simulation based on Huygens principle. It is shown that a strong coupling effect occurs due to the existence of both the incident field and a strong scattering field. Huygens principle can be used to obtain the first and second order scattering fields generated between implants. If the first- and second-order electric field terms are summed within a certain region, the RF-induced heating of this dual-implant system increases.

[Discussion on Magnetic Resonance Compatibility of Implantable Brain-Computer Interface Devices].

Brain-computer interface (BCI) devices are crucial tools for neural stimulation and recording, offering broad prospects in the diagnosis and treatment of neurological disorders. Furthermore, magnetic resonance imaging (MRI) is an effective and non-invasive technique for capturing whole-brain signals, providing detailed information on brain structures and activation patterns. Integrating the neural stimulation/recording capabilities of BCI devices with the non-invasive detection function of MRI is considered highly significant for brain function analysis. However, this combination imposes specific requirements on the magnetic and electronic performance of neural interface devices. The interaction between BCI devices and MRI is initially explored. Subsequently, potential safety risks arising from their combination are summarized and organized. Starting from the source of these hazards, such as the metallic electrodes and wires of BCI devices, the issues are analyzed, and current research countermeasures are summarized. In conclusion, the regulatory oversight of BCI's magnetic resonance safety is briefly discussed, and suggestions for enhancing the magnetic resonance compatibility of related BCI devices are proposed.

Quantitative Prediction of Acid Value of Camellia Seed Oil Based on Hyperspectral Imaging Technology Fusing Spectral and Image Features.

Acid value (AV) serves as an important indicator to assess the quality of oil, which can be used to judge the deterioration of edible oil. In order to realize the quantitative prediction of the AV of camellia seed oil, which was made from camellia oleifolia, hyperspectral data of 168 camellia seed oil samples were collected using a hyperspectral imaging system, which were related to their AV content measured via classical chemical titration. On the basis of hyperspectral full wavelengths, characteristic wavelengths, and fusing spectral and image features, the quantitative prediction AV models for camellia seed oil were established. The results demonstrating the 2Der-SPA-GLCM-PLSR model fusing spectral and image features stood out as the optimal choices for the AV prediction of camellia seed oil, with the correlation coefficient of calibration set (Rc2) and the correlation coefficient of prediction set (Rp2) at 0.9698 and 0.9581, respectively. Compared with those of 2Der-SPA-PLSR, the Rc2 and Rp2 were improved by 2.11% and 2.57%, respectively. Compared with those of 2Der-PLSR, the Rc2 and Rp2 were improved by 5.02% and 5.31%, respectively. Compared with the model based on original spectrum, the Rc2 and Rp2 were improved by 32.63% and 40.11%, respectively. After spectral preprocessing, characteristic wavelength selection, and fusing spectral and image features, the correlation coefficient of the optimal AV prediction model was continuously improved, while the root mean square error was continuously decreased. The research demonstrated that hyperspectral imaging technology could precisely and quantitatively predict the AV of camellia seed oil and also provide a new environmental method for detecting the AV of other edible oils, which is conducive to sustainable development.

Grade Classification of Camellia Seed Oil Based on Hyperspectral Imaging Technology.

To achieve the rapid grade classification of camellia seed oil, hyperspectral imaging technology was used to acquire hyperspectral images of three distinct grades of camellia seed oil. The spectral and image information collected by the hyperspectral imaging technology was preprocessed by different methods. The characteristic wavelength selection in this study included the continuous projections algorithm (SPA) and competitive adaptive reweighted sampling (CARS), and the gray-level co-occurrence matrix (GLCM) algorithm was used to extract the texture features of camellia seed oil at the characteristic wavelength. Combined with genetic algorithm (GA) and support vector machine algorithm (SVM), different grade classification models for camellia seed oil were developed using full wavelengths (GA-SVM), characteristic wavelengths (CARS-GA-SVM), and fusing spectral and image features (CARS-GLCM-GA-SVM). The results show that the CARS-GLCM-GA-SVM model, which combined spectral and image information, had the best classification effect, and the accuracy of the calibration set and prediction set of the CARS-GLCM-GA-SVM model were 98.30% and 96.61%, respectively. Compared with the CARS-GA-SVM model, the accuracy of the calibration set and prediction set were improved by 10.75% and 12.04%, respectively. Compared with the GA-SVM model, the accuracy of the calibration set and prediction set were improved by 18.28% and 18.15%, respectively. The research showed that hyperspectral imaging technology can rapidly classify camellia seed oil grades.

The prognostic value and immunological role of calcium/calmodulin dependent protein kinase kinase 2 (CAMKK2) in pan-cancer study.

A thorough assessment of calcium/calmodulin dependent protein kinase kinase 2 (CAMKK2) in pan-cancer studies is currently absent. We integrate multi-omics and clinical data to conduct a molecular landscape of CAMKK2. Gene variation results revealed abnormal high frequency mutations of CAMKK2 in uterine corpus endometrial carcinoma, while expression level analysis demonstrated relatively high expression of CAMKK2 in prostate adenocarcinoma. The aberrant expression of CAMKK2 was found to be predictive of survival outcomes in several cancer types. Additionally, we identified potential regulators of CAMKK2 expression, including miRNAs such as miR.129.1.3p, as well as small-molecule drugs such as EPZ004777, which significantly correlated with CAMKK2 expression. Single-cell transcriptome analysis of kidney renal clear cell carcinoma further revealed a significantly higher expression of CAMKK2 in and monocyte and macrophage M1. Furthermore, in the kidney renal clear cell carcinoma IMvigor210 cohort, patients ongoing immunotherapy with higher CAMKK2 expression experienced a significantly longer median overall survival, but it was observed that in bladder urothelial carcinoma GSE176307 and skin cutaneous melanoma GSE78220 cohorts, CAMKK2 might significantly prolong overall survival. Briefly, CAMKK2 emerges as a promising molecular biomarker that holds potential implications for prognostic evaluation and predicting the effectiveness of immunotherapy across cancers.

Seasonal mouse cadaver microbial study: rupture time and postmortem interval estimation model construction.

The estimation of postmortem interval (PMI) has long been a focal point in the field of forensic science. Following the death of an organism, microorganisms exhibit a clock-like proliferation pattern during the course of cadaver decomposition, forming the foundation for utilizing microbiology in PMI estimation. The establishment of PMI estimation models based on datasets from different seasons is of great practical significance. In this experiment, we conducted microbiota sequencing and analysis on gravesoil and mouse intestinal contents collected during both the winter and summer seasons and constructed a PMI estimation model using the Random Forest algorithm. The results showed that the MAE of the gut microbiota model in summer was 0.47 ± 0.26 d, R2 = 0.991, and the MAE of the gravesoil model in winter was 1.04 ± 0.22 d, R2 = 0.998. We propose that, in practical applications, it is advantageous to selectively build PMI estimation models based on seasonal variations. Additionally, through a combination of morphological observations, gravesoil microbiota sequencing results, and soil physicochemical data, we identified the time of cadaveric rupture for mouse cadavers, occurring at around days 24-27 in winter and days 6-9 in summer. This study not only confirms previous research findings but also introduces novel insights, contributing to the foundational knowledge necessary to advance the utilization of microbiota for PMI estimation.

Boosting Oxygen Evolution Reaction Performance on NiFe-Based Catalysts Through d-Orbital Hybridization.

Anion-exchange membrane water electrolyzers (AEMWEs) for green hydrogen production have received intensive attention due to their feasibility of using earth-abundant NiFe-based catalysts. By introducing a third metal into NiFe-based catalysts to construct asymmetrical M-NiFe units, the d-orbital and electronic structures can be adjusted, which is an important strategy to achieve sufficient oxygen evolution reaction (OER) performance in AEMWEs. Herein, the ternary NiFeM (M: La, Mo) catalysts featured with distinct M-NiFe units and varying d-orbitals are reported in this work. Experimental and theoretical calculation results reveal that the doping of La leads to optimized hybridization between d orbital in NiFeM and 2p in oxygen, resulting in enhanced adsorption strength of oxygen intermediates, and reduced rate-determining step energy barrier, which is responsible for the enhanced OER performance. More critically, the obtained NiFeLa catalyst only requires 1.58 V to reach 1 A cm-2 in an anion exchange membrane electrolyzer and demonstrates excellent long-term stability of up to 600 h.

An aberrant immune-epithelial progenitor niche drives viral lung sequelae.

The long-term physiological consequences of respiratory viral infections, particularly in the aftermath of the COVID-19 pandemic-termed post-acute sequelae of SARS-CoV-2 (PASC)-are rapidly evolving into a major public health concern1-3. While the cellular and molecular aetiologies of these sequelae are poorly defined, increasing evidence implicates abnormal immune responses3-6 and/or impaired organ recovery7-9 after infection. However, the precise mechanisms that link these processes in the context of PASC remain unclear. Here, with insights from three cohorts of patients with respiratory PASC, we established a mouse model of post-viral lung disease and identified an aberrant immune-epithelial progenitor niche unique to fibroproliferation in respiratory PASC. Using spatial transcriptomics and imaging, we found a central role for lung-resident CD8+ T cell-macrophage interactions in impairing alveolar regeneration and driving fibrotic sequelae after acute viral pneumonia. Specifically, IFNγ and TNF derived from CD8+ T cells stimulated local macrophages to chronically release IL-1ß, resulting in the long-term maintenance of dysplastic epithelial progenitors and lung fibrosis. Notably, therapeutic neutralization of IFNγ + TNF or IL-1ß markedly improved alveolar regeneration and pulmonary function. In contrast to other approaches, which require early intervention10, we highlight therapeutic strategies to rescue fibrotic disease after the resolution of acute disease, addressing a current unmet need in the clinical management of PASC and post-viral disease.

Pulmonary embolism and deep venous thrombosis in China.

The Annual Report on Cardiovascular Health and Diseases in China (2022) intricate landscape of cardiovascular health in China. In connection with the previous section, this eighth section of the report offers a comprehensive analysis of pulmonary embolism and deep venous thrombosis. In recent years, research in the field of pulmonary vessel in China has made great progress. A number of nationwide multi-center registry research results have filled the gaps in the epidemiology, diagnosis and treatment of pulmonary hypertension and venous thromboembolism. Different types of pulmonary hypertension still need attention to the identification of risk factors and/or risk stratification, and venous thromboembolism needs attention in the prevention and the overall management inside and outside hospital. In the future, we look forward to the publication of more high-quality research in China, which could be able to improve relevant guidelines for pulmonary vascular diseases both domestically and internationally.

A simple HPLC-MS/MS method for the determination of polymyxin B in human plasma and its application in the pharmacokinetic study in elderly patients infected with multidrug-resistant Gram-negative bacteria.

Introduction: Polymyxin B is widely used to treat infections caused by multidrug-resistant Gram-negative bacteria. However, the pharmacokinetic study data of PB in the elderly are scarce. Herein, a simple method to measure the concentration of PB in human plasma was developed and validated by high performance liquid chromatography-tandem mass spectrometry, and it was applied to a PK study in the elderly. Methods: PB was extracted from human plasma by a rapid protein-precipitation method using 0.1% formic acid in methanol and then separated on an ultimate AQ-C18 column using linear gradient elution with a 0.5-mL/min flow rate. Subsequently, PB was detected using a mass spectrometer operated in positive-ion and multiple-reaction-monitoring modes. Results: The lower limits of quantification of the method for Polymyxin B1 and Polymyxin B2 were 1.00 and 0.10 µg/mL, respectively. The linear ranges for PB1 and PB2 were 1.00-20.02 and 0.10-2.04 µg/mL, respectively. Patients receiving a 75-mg maintenance dose every 12h had AUCss, 24 h, and Css, av values of 117.70 ± 37.03 µg h/mL and 4.14 ± 1.74 µg/mL, respectively. For patients receiving a 100 mg maintenance dose, these values were 152.73 ± 70.09 µg h/mL and 5.43 ± 2.85 µg/mL, respectively. Conclusion: The validated HPLC-MS/MS method was successfully applied to a study on the pharmacokinetics of PB in elderly patients infected with multidrug-resistant Gram-negative bacteria. Both two dose strategies in this study would have a excessive PB exposure in the elderly patients then the therapeutic window recommended by guidelines.

Circulating tumor DNA-based stratification strategy for chemotherapy plus PD-1 inhibitor in advanced non-small-cell lung cancer.

Stratification strategies for chemotherapy plus PD-1 inhibitors in advanced non-small-cell lung cancer (NSCLC) are critically demanded. We performed high-throughput panel-based deep next-generation sequencing and low-pass whole genome sequencing on prospectively collected circulating tumor DNA (ctDNA) specimens from 460 patients in the phase 3 CHOICE-01 study at different time points. We identified predictive markers for chemotherapy plus PD-1 inhibitor, including ctDNA status and genomic features such as blood-based tumor mutational burden, intratumor heterogeneity, and chromosomal instability. Furthermore, we established an integrated ctDNA-based stratification strategy, blood-based genomic immune subtypes (bGIS) scheme, to distinguish patients who benefit from the addition of PD-1 inhibitor to first-line chemotherapy. Moreover, we demonstrated potential applications for the dynamic monitoring of ctDNA. Overall, we proposed a potential therapeutic algorithm based on the ctDNA-based stratification strategy, shedding light on the individualized management of immune-chemotherapies for patients with advanced NSCLC.

Disorders of cardiac rhythm in China.

The Annual Report on Cardiovascular Health and Diseases in China (2022) intricate landscape of cardiovascular health in China. In connection with the previous section, this seventh section of the report offers a comprehensive analysis of disorders of heart rhythm in China. In 2021, China has achieved significant development and gratifying results in many aspects of the field of arrhythmia. Left bundle branch pacing (LBBP), as an emerging pacing technique originating from China, has received widespread attention. New research results have emerged on its indications, surgical procedures, clinical evaluation, and comparison with other pacing techniques. Its feasibility, effectiveness, and safety have been basically verified, but its long-term prognosis still needs further confirmation from larger samples and longer follow-up time research results. Leadless pacemakers have begun to be used in a wider range of clinical applications, and related large sample cohort studies have been reported. In addition, there are also noteworthy new achievements in the fields of pacemaker remote programming, anticoagulation and radiofrequency catheter ablation (RFCA) therapy for atrial fibrillation, and implantable cardioverter defibrillator prevention of sudden cardiac death. In terms of clinical practice, due to COVID-19 pandemic, the number of RFCA procedures and other device implantations in China has fluctuated, but it has gradually recovered since 2020.

Tumor cavitation in patients with non-small-cell lung cancer receiving anti-angiogenic therapy with apatinib.

Background: Cavities have been reported in approximately 20% of lung cancer after anti-angiogenesis treatments. However, the effect of which on treatment outcomes remains unclear. This study sought to investigate the incidence and radiographic patterns of tumor cavitation in patients with non-small cell lung cancer (NSCLC) treated with apatinib, and its associations with patients' clinical characteristics and outcomes. Methods: A total of 300 patients with NSCLC treated with apatinib were retrospectively identified. Baseline and follow-up chest computed tomography scans were reviewed to identify tumor cavitation, and the subsequent filling-in of the cavitation. A multivariate logistic regression analysis was conducted to identify the factors associated with tumor cavitation. Survival curves were constructed using the Kaplan-Meier method and compared using the log-rank test. Results: Of the 300 patients, 51 (17.0%) developed lung cavitation after initiating apatinib therapy. The results of the multivariate analysis showed that apatinib combination therapy (vs. apatinib monotherapy, odds ratio: 0.593, 95% confidence interval: 0.412-0.854, P=0.005) was significantly associated with tumor cavitation. Patients with tumor cavitation had significantly longer progression-free survival (PFS) than those without cavitation (8.2 vs. 5.2 months, P<0.01). Of the patients, 18 had cavity filling after progression, while 13 had persistent cavities after progression. The corresponding median PFS times were 11.9 and 3.2 months in patients with filled and persistent cavities after disease progression, respectively (P<0.001). Conclusions: Tumor cavitation occurred in 17% of the NSCLC patients treated with apatinib and was associated with better PFS. Patients who had cavities filled after progression had a better prognosis than those with persistent cavities.