Evolutionary game analysis of data sharing among large and medium-sized enterprises in the perspective of platform empowerment.

With the swift advancement of the global digital economy, data has emerged as a critical component in fostering the integration of large enterprises with small and medium-sized enterprises (SMEs). Nevertheless, due to disparities in resources and capabilities between these entities, there is a deficiency in the willingness to share data, hindering the full actualization of data's potential value. Hence, it is imperative to facilitate a novel cooperative development paradigm wherein platforms enable data sharing among large enterprises and SMEs. In this paper, we construct a tripartite evolutionary game model encompassing large enterprises, SMEs, and digital platforms, examine the evolutionary stable strategies adopted by these entities in the data sharing, and use numerical simulation to explore the system's evolutionary stability under various influencing factors. Contrasting with prior research, this study considers the heterogeneity of enterprise scale and delves into the data sharing dynamics between large enterprises and SMEs. Simultaneously, it positions the digital platform as a player in the game, examining its impact on data sharing among the enterprises. Findings indicate that: (1) SMEs exhibit greater eagerness for data sharing compared to large enterprises, which display a U-shaped influence during the process; (2) Digital platforms are particularly sensitive to costs, with the platform's initiative and the service quality will affect enterprises strategic choices; (3) Government subsidies positively encourage tripartite cooperation, and robust data security governance framework is crucial for enterprises. Finally, based on the results of the study and combining with the current situation of digital economy development, it puts forward the suggestions for promoting platforms to empower large enterprises and SMEs to realize data sharing and the prospects for future research.

Targeting c-Myc transactivation by LMNA inhibits tRNA processing essential for malate-aspartate shuttle and tumour progression.

BACKGROUND: A series of studies have demonstrated the emerging involvement of transfer RNA (tRNA) processing during the progression of tumours. Nevertheless, the roles and regulating mechanisms of tRNA processing genes in neuroblastoma (NB), the prevalent malignant tumour outside the brain in children, are yet unknown. METHODS: Analysis of multi-omics results was conducted to identify crucial regulators of downstream tRNA processing genes. Co-immunoprecipitation and mass spectrometry methods were utilised to measure interaction between proteins. The impact of transcriptional regulators on expression of downstream genes was measured by dual-luciferase reporter, chromatin immunoprecipitation, western blotting and real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) methods. Studies have been conducted to reveal impact and mechanisms of transcriptional regulators on biological processes of NB. Survival differences were analysed using the log-rank test. RESULTS: c-Myc was identified as a transcription factor driving tRNA processing gene expression and subsequent malate-aspartate shuttle (MAS) in NB cells. Mechanistically, c-Myc directly promoted the expression of glutamyl-prolyl-tRNA synthetase (EPRS) and leucyl-tRNA synthetase (LARS), resulting in translational up-regulation of glutamic-oxaloacetic transaminase 1 (GOT1) as well as malate dehydrogenase 1 (MDH1) via inhibiting general control nonrepressed 2 or activating mechanistic target of rapamycin signalling. Meanwhile, lamin A (LMNA) inhibited c-Myc transactivation via physical interaction, leading to suppression of MAS, aerobic glycolysis, tumourigenesis and aggressiveness. Pre-clinically, lobeline was discovered as a LMNA-binding compound to facilitate its interaction with c-Myc, which inhibited aminoacyl-tRNA synthetase expression, MAS and tumour progression of NB, as well as growth of organoid derived from c-Myc knock-in mice. Low levels of LMNA or elevated expression of c-Myc, EPRS, LARS, GOT1 or MDH1 were linked to a worse outcome and a shorter survival time of clinical NB patients. CONCLUSIONS: These results suggest that targeting c-Myc transactivation by LMNA inhibits tRNA processing essential for MAS and tumour progression.

Complete long-term monitoring of greenhouse gas emissions from a full-scale industrial wastewater treatment plant with different cover configurations.

The greenhouse gas (GHG) emissions from wastewater treatment plants (WWTPs), consisting mainly of methane (CH4) and nitrous oxide (N2O), have been constantly increasing and become a non-negligible contributor towards carbon neutrality. The precise evaluation of plant-specific GHG emissions, however, remains challenging. The current assessment approach is based on the product of influent load and emission factor (EF), of which the latter is quite often a single value with huge uncertainty. In particular, the latest default Tier 1 value of N2O EF, 0.016 ± 0.012 kgN2O-N kgTN-1, is estimated based on the measurement of 30 municipal WWTPs only, without involving any industrial wastewater. Therefore, to resolve the pattern of GHG emissions from industrial WWTPs, this work conducted a 14-month monitoring campaign covering all the process units at a full-scale industrial WWTP in Shanghai, China. The total CH4 and N2O emissions from the whole plant were, on average, 447.7 ± 224.5 kgCO2-eq d-1 and 1605.3 ± 2491.0 kgCO2-eq d-1, respectively, exhibiting a 5.2- or 3.9-times more significant deviation than the influent loads of chemical oxygen demand (COD) or total nitrogen (TN). The resulting EFs, 0.00072 kgCH4 kgCOD-1 and 0.00211 kgN2O-N kgTN-1, were just 0.36% of the IPCC recommended value for CH4, and 13.2% for N2O. Besides, the parallel anoxic-oxic (A/O) lines of this industrial WWTP were covered in two configurations, allowing the comparison of GHG emissions from different odor control setup. Unit-specific analysis showed that the replacement of enclosed A/open O with enclosed A/O reduced the CH4 EF by three times, from 0.00159 to 0.00051 kgCH4 kgCOD-1, and dramatically decreased the N2O EF by an order of magnitude, from 0.00376 to 0.00032 kgN2O-N kgTN-1, which was among the lowest of all full-scale WWTPs.

A potent new-scaffold androgen receptor antagonist discovered on the basis of a MIEC-SVM model.

Prostate cancer (PCa) is the second most prevalent malignancy among men worldwide. The aberrant activation of androgen receptor (AR) signaling has been recognized as a crucial oncogenic driver for PCa and AR antagonists are widely used in PCa therapy. To develop novel AR antagonist, a machine-learning MIEC-SVM model was established for the virtual screening and 51 candidates were selected and submitted for bioactivity evaluation. To our surprise, a new-scaffold AR antagonist C2 with comparable bioactivity with Enz was identified at the initial round of screening. C2 showed pronounced inhibition on the transcriptional function (IC50 = 0.63 µM) and nuclear translocation of AR and significant antiproliferative and antimetastatic activity on PCa cell line of LNCaP. In addition, C2 exhibited a stronger ability to block the cell cycle of LNCaP than Enz at lower dose and superior AR specificity. Our study highlights the success of MIEC-SVM in discovering AR antagonists, and compound C2 presents a promising new scaffold for the development of AR-targeted therapeutics.

Leaders of Peer Groups in Chinese Early Adolescents: The Roles of Social, Academic, and Psychological Characteristics in Group Leadership.

Leadership in peer groups is an important issue in adolescent socioemotional development, yet it has received limited attention in research. This one-year longitudinal study examined peer group leadership and the roles of social, academic, and psychological characteristics in the dynamics of group leadership. Participants included 1061 Chinese students (initial mean age =11.17 years; SD = 6.98 months; 49.4% female). Data were collected from peer assessments, teacher ratings, and self-reports. The longitudinal social network analysis (SIENA) indicated that peer group leadership was fluid with leadership status evolving over time across groups in a hierarchical manner. Adolescents displaying higher social competence and aggression and lower shyness were more likely to become group leaders. Academic performance and loneliness were not significantly associated with the dynamics of peer group leadership. The results help understand peer group leadership and contributions of social behaviors to the attainment of leadership status in peer groups in early adolescence.

Mild-Temperature Supercritical Water Confined in Hydrophobic Metal-Organic Frameworks.

Fluids under extreme confinement show characteristics significantly different from those of their bulk counterpart. This work focuses on water confined within the complex cavities of highly hydrophobic metal-organic frameworks (MOFs) at high pressures. A combination of high-pressure intrusion-extrusion experiments with molecular dynamic simulations and synchrotron data reveals that supercritical transition for MOF-confined water takes place at a much lower temperature than in bulk water, ∼250 K below the reference values. This large shifting of the critical temperature (Tc) is attributed to the very large density of confined water vapor in the peculiar geometry and chemistry of the cavities of Cu2tebpz (tebpz = 3,3',5,5'-tetraethyl-4,4'-bipyrazolate) hydrophobic MOF. This is the first time the shift of Tc is investigated for water confined within highly hydrophobic nanoporous materials, which explains why such a large reduction of the critical temperature was never reported before, neither experimentally nor computationally.

Regulatory feedback loop between circ-EIF4A3 and EIF4A3 Enhances autophagy and growth in colorectal cancer cells.

Recent studies indicate that circular RNAs (circRNAs) are crucial in the progression of colorectal cancer (CRC). Eukaryotic translation initiation factor 4A3 (EIF4A3) has been identified as a promoter of circRNA production. The biological roles and mechanisms of EIF4A3-derived circRNA (circEIF4A3) in CRC cell autophagy remain poorly understood. This study explores the effects of circEIF4A3 on CRC cell growth and autophagy, aiming to elucidate the underlying molecular mechanisms. We discovered that EIF4A3 and circEIF4A3 synergistically enhance CRC cell growth. CircEIF4A3 sequesters miR-3126-5p, consequently upregulating EIF4A3. Further, circEIF4A3 increases EIF4A3 expression, which promotes autophagy by stabilizing ATG5 mRNA and enhances ATG7 protein stability through the stabilization of USP14 mRNA, a deubiquitinating enzyme. Upregulation of ATG5 and ATG7 counteracts the growth-inhibitory effects of EIF4A3 knockdown on CRC cells. Moreover, our findings demonstrate that EIF4A3 induces the formation of circEIF4A3 in CRC cells. In conclusion, a positive feedback loop between circEIF4A3 and EIF4A3 supports CRC cell growth by facilitating autophagy.

Subcutaneous administration of Stattic alleviates neuropathic pain by relieving inflammation in a mouse model of postherpetic neuralgia.

Stattic, a commercial inhibitor of STAT3, can drive the development of neuropathic pain. Exploring the connection between Stattic and JAK1/STAT3 signaling may facilitate the understanding of neuropathic pain caused by postherpetic neuralgia (PHN). In the current study, as crucial regulators of inflammation, STAT3 and its associated JAK1/STAT3 pathway were found to be upregulated and activated in the L4-L6 dorsal root ganglion (DRG) of mice in response to resiniferatoxin (RTX)-induced PHN, while subcutaneous administration of Stattic was found to downregulate STAT3 expression and phosphorylation in a PHN model. Stattic administration further attenuated hypersensitivity to mechanical and thermal stimuli in PHN mice, and alleviated inflammation and cell death in the L4-L6 DRG of mice. Overexpression of STAT3 via microinjection of a lentiviral-STAT3 overexpression vector reversed the abnormal decrease of STAT3 at both the mRNA and protein levels in the L4-6 DRGs of PHN mice and significantly promoted hypersensitivity to mechanical stimuli in the mice. Collectively, we found that subcutaneous static administration alleviated RTX-induced neuropathic pain by deactivating JAK1/STAT3 in mice.

Five undescribed meroterpenoids from Ganoderma lucidum and their inhibitory activities against renal fibrosis.

Five undescribed meroterpenoids, baosglucidnes A - E (1-5), were isolated from the fruiting bodies of Ganoderma lucidum. Among them, baosglucidne B (2) as a racemic mixture was obtained. Chiral HPLC was employed to separate a pair of enantiomers (+)-2 and (-)-2. The structures and stereochemical features of these substances were characterized by utilizing spectroscopic data and ECD calculations. Finally, the results of anti-renal fibrosis activity evaluation showed that baosglucidne E (5) could inhibit the expression of collagen I in TGF-ß1-induced rat kidney proximal tubular cells at 20 µM.

Association between ambient air pollution and dry eye symptoms among Chinese individuals during the COVID-19 pandemic: A national-based study.

PURPOSE: To examine the association between ambient air pollution and dry eye symptoms (DES) during the COVID-19 pandemic and explore whether air pollution had increased the risk of DES to a greater extent than other risk factors. METHODS: A nationwide cross-sectional survey was conducted from June 20, 2022 to August 31, 2022. The Ocular Surface Disease Index-6 (OSDI-6) questionnaire was used to assess the presence of DES. Logistic regression models were employed to analyze the associations between DES and air pollution variables, including air quality index (AQI), fine particulate matter (PM2.5), PM10, sulfur dioxide (SO2), carbon monoxide (CO), nitrogen dioxide (NO2), ozone (O3) and residing near industrial zones. We explored the interactions of air pollutants and other risk factors in the additive models by calculating the synergy index (SI). Standardized regression coefficients were calculated to compare the relative importance of risk factors for DES. RESULTS: A total of 21,909 participants were included in the analysis. Residing near industrial zones was significantly correlated with a higher risk of DES (Odds ratio (OR): 1.57, 95 % confidence interval (CI): 1.38-1.79). No significant associations were found between DES and air pollutants except SO2 (OR: 1.05, 95 % CI: 1.02-1.09, per standard deviation increment in SO2 concentration). The restricted cubic spline analyses revealed a linear concentration-response relationship between SO2 and DES. The interaction analyses suggested synergetic interactions of SO2 with depression and problematic internet use. Among the risk factors, depression, anxiety and problematic Internet use contributed more to the increased risk of DES. CONCLUSION: The association between ambient air pollutants and DES may have been mitigated during the pandemic due to increased time spent indoors. Despite this, our findings support the deleterious health impact of air pollutants. Future urban planning should plan industrial zones further away from residential areas.

A Meta-analysis of Randomized Controlled Trials Comparing Breast-Conserving Surgery and Mastectomy in Terms of Patient Survival Rate and Quality of Life in Breast Cancer.

BACKGROUND: The study aimed to assess the effects of breast-conserving surgery (BCS) versus mastectomy on survival and quality of life in stages I, II and III breast cancer, providing solid evidence for clinical decisions. METHODS: We conducted a meta-analysis of randomised controlled trials on breast cancer treatments, searching databases such as PubMed and the Cochrane Library to compare BCS and mastectomy's effects on survival and quality of life. A combined total of 16,734 patients in the control group and 17,435 patients in the experimental group were included in this analysis. This meta-analysis used RevMan 5.3 (Cochrane Collaboration, Copenhagen, Denmark) software for analysis. RESULTS: Our meta-analysis of 34,169 patients from 11 studies showed that BCS significantly reduced the overall recurrence rate at a median follow-up of 29 months, with a mean difference of 1.27 and a 95% confidence interval (CI) of 1.19-1.36, strongly supporting its effectiveness (p<0.00001). Furthermore, our analysis found no significant increase in 5-year local recurrence rates for BCS versus mastectomy, indicating its long-term effectiveness with a mean difference of 1.13 (95% CI: [1.03, 1.24], p = 0.01). Additionally, there was a notable decrease in tissue ischemic necrosis among patients who had received BCS, with a mean difference of 0.37 (95% CI: [0.33, 0.42], p<0.00001), underscoring its benefits and long-term viability. CONCLUSION: Breast-conserving surgery resulted in fewer cases of tissue ischemic necrosis and higher body image scores compared with mastectomy, suggesting it is a preferable option for better cosmetic outcomes and potentially favourable effects on prognosis and quality of life.

A Fruit-Expressed MYB Transcription Factor Regulates Anthocyanin Biosynthesis in Atropa belladonna.

Anthocyanins are water-soluble flavonoid pigments that play a crucial role in plant growth and metabolism. They serve as attractants for animals by providing plants with red, blue, and purple pigments, facilitating pollination and seed dispersal. The fruits of solanaceous plants, tomato (Solanum lycopersicum) and eggplant (Solanum melongena), primarily accumulate anthocyanins in the fruit peels, while the ripe fruits of Atropa belladonna (Ab) have a dark purple flesh due to anthocyanin accumulation. In this study, an R2R3-MYB transcription factor (TF), AbMYB1, was identified through association analysis of gene expression and anthocyanin accumulation in different tissues of A. belladonna. Its role in regulating anthocyanin biosynthesis was investigated through gene overexpression and RNA interference (RNAi). Overexpression of AbMYB1 significantly enhanced the expression of anthocyanin biosynthesis genes, such as AbF3H, AbF3'5'H, AbDFR, AbANS, and Ab3GT, leading to increased anthocyanin production. Conversely, RNAi-mediated suppression of AbMYB1 resulted in decreased expression of most anthocyanin biosynthesis genes, as well as reduced anthocyanin contents in A. belladonna. Overall, AbMYB1 was identified as a fruit-expressed R2R3-MYB TF that positively regulated anthocyanin biosynthesis in A. belladonna. This study provides valuable insights into the regulation of anthocyanin biosynthesis in Solanaceae plants, laying the foundation for understanding anthocyanin accumulation especially in the whole fruits of solanaceous plants.

Phase 1 Study of MK-5475, an Inhaled Soluble Guanylate Cyclase Stimulator, in Participants with Pulmonary Hypertension Associated with Chronic Obstructive Pulmonary Disease.

Purpose: This phase 1 study (NCT04370873) evaluated safety and pharmacokinetics/pharmacodynamics (PK/PD) of MK-5475 in participants with pulmonary hypertension associated with COPD (PH-COPD). Methods: Eligible participants were 40-80 years old with COPD (FEV1/FVC <0.7; FEV1 >30% predicted) and PH (mean pulmonary arterial pressure ≥25 mmHg). Participants were randomized 2:1 to MK-5475 or placebo via dry-powder inhaler once daily for 7 days in Part 1 (360 µg) or 28 days in Part 2 (380 µg). Safety was assessed by adverse events (AEs) and arterial blood oxygenation. Part-2 participants had pulmonary vascular resistance (PVR; primary PD endpoint) and pulmonary blood volume (PBV; secondary PD endpoint) measured at baseline and Day 28. A non-informative prior was used to calculate posterior probability (PP) that the between-group difference (MK-5475 - placebo) in mean percent reduction from baseline in PVR was less than -15%. Results: Nine participants were randomized in Part 1, and 14 participants in Part 2. Median age of participants (86.4% male) was 68.5 years (41-77 years); 95.5% had moderate-to-severe COPD. Incidences of AEs were comparable between MK-5475 and placebo: overall (5/14 [36%] versus 5/8 [63%]), drug-related (1/14 [7%] versus 2/8 [25%]), and serious (1/14 [7%] versus 1/8 [13%]). MK-5475 caused no meaningful changes in arterial blood oxygenation or PBV. MK-5475 versus placebo led to numerical improvements from baseline in PVR (-21.2% [95% CI: -35.4, -7.0] versus -5.4% [95% CI: -83.7, 72.9]), with between-group difference in PVR less than -15% and calculated PP of 51%. Conclusion: The favorable safety profile and numerical reductions in PVR observed support further clinical development of inhaled MK-5475 for PH-COPD treatment.

Post-marketing risk analysis of bendamustine: a real-world approach based on the FAERS database.

Objective: Bendamustine was approved for treating chronic lymphocytic leukemia and indolent B-cell non-Hodgkin lymphoma. Despite its therapeutic benefits, the long-term safety of bendamustine in a large population remains inadequately understood. This study evaluates the adverse events (AEs) associated with bendamustine, using a real-world pharmacovigilance database to support its clinical application. Methods: We conducted a post-marketing risk analysis to assess the association between bendamustine and its AEs. Data were extracted from the US FDA's Adverse Event Reporting System (FAERS), covering the period from January 2017 to September 2023. The characteristics of bendamustine-associated AEs and the onset time were further analyzed. Statistical analysis was performed using MYSQL 8.0, Navicat Premium 15, Microsoft EXCEL 2016, and Minitab 21.0. Results: 9,461,874 reports were collected from the FAERS database, 9,131 identified bendamustine as the "primary suspected" drug. We identified 331 significant disproportionality preferred terms (PTs). Common AEs included pyrexia, neutropenia, infusion site reaction, progressive multifocal leukoencephalopathy (PML), injection site vasculitis, and pneumonia-all documented on bendamustine's label. Notably, 16 unexpected and significant AEs were discovered, including hypogammaglobulinemia, which is concerning due to its potential to increase infection susceptibility following bendamustine treatment. Other significant findings were anaphylactic reactions, PML, and cutaneous malignancies, suggesting updates to the drug's label may be necessary. Physicians should monitor for neurological and skin changes in patients and discontinue treatment if PML is suspected. Moreover, the median onset time for bendamustine-associated AEs was 13 days, with an interquartile range [IQR] of 0-59 days, predominantly occurring on the first day post-initiation. The ß of bendamustine-related AEs suggested risk reduction over time. Conclusion: Our study uncovered some potential pharmacovigilance signals for bendamustine, providing important insights for its safe and effective clinical use.

Genomic landscape and tumor mutational features of resected preinvasive to invasive lung adenocarcinoma.

Introduction: Adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) are considered pre-invasive forms of lung adenocarcinoma (LUAD) with a 5-year recurrence-free survival of 100%. We investigated genomic profiles in early tumorigenesis and distinguished mutational features of preinvasive to invasive adenocarcinoma (IAC) for early diagnosis. Methods: Molecular information was obtained from a 689-gene panel in the 90 early-stage LUAD Chinese patients using next-generation sequencing. Gene signatures were identified between pathology subtypes, including AIS/MIA (n=31) and IAC (n=59) in this cohort. Mutational and clinicopathological information was also obtained from the Cancer Genome Atlas (TCGA) as a comparison cohort. Results: A higher mutation frequency of TP53, RBM10, MUC1, CSMD, MED1, LRP1B, GLI1, MAP3K, and RYR2 was observed in the IAC than in the AIS/MIA group. The AIS/MIA group showed higher mutation frequencies of ERBB2, BRAF, GRIN2A, and RB1. Comparable mutation rates for mutually exclusive genes (EGFR and KRAS) across cohorts highlight the critical transition to invasive LUAD. Compared with the TCGA cohort, EGFR, KRAS, TP53, and RBM10 were frequently mutated in both cohorts. Despite limited gene mutation overlap between cohorts, we observed variant mutation types in invasive LUAD. Additionally, the tumor mutation burden (TMB) values were significantly lower in the AIS/MIA group than in the IAC group in both the Chinese cohort (P=0.0053) and TCGA cohort (P<0.01). Conclusion: These findings highlight the importance of distinguishing preinvasive from invasive LUAD in the early stages of LUAD and both pathology and molecular features in clinical practice, revealing genomic tumor heterogeneity and population differences.

Healthcare-seeking behavior and spatial variation of internal migrants with chronic diseases: a nationwide empirical study in China.

Individuals migrating with chronic diseases often face substantial health risks, and their patterns of healthcare-seeking behavior are commonly influenced by mobility. However, to our knowledge, no research has used spatial statistics to verify this phenomenon. Utilizing data from the China Migrant Dynamic Survey of 2017, we conducted a geostatistical analysis to identify clusters of chronic disease patients among China's internal migrants. Geographically weighted regressions were utilized to examine the driving factors behind the reasons why treatment was not sought by 711 individuals among a population sample of 9272 migrant people with chronic diseases. The results indicate that there is a spatial correlation in the clustering of internal migrants with chronic diseases in China. The prevalence is highly clustered in Zhejiang and Xinjiang in north-eastern China. Hotspots were found in the northeast (Jilin and Liaoning), the north (Hebei, Beijing, and Tianjin), and the east (Shandong) and also spread into surrounding provinces. The factors that affect the migrants with no treatment were found to be the number of hospital beds per thousand population, the per capita disposable income of medical care, and the number of participants receiving health education per 1000 Chinese population. To rectify this situation, the local government should "adapt measures to local conditions." Popularizing health education and coordinating the deployment of high-quality medical facilities and medical workers are effective measures to encourage migrants to seek reasonable medical treatment.

Glutathione-responsive Aggregation-induced Emission Photosensitizers for Enhanced Photodynamic Therapy of Lung Cancer.

Lung cancer, a highly prevalent and lethal form of cancer, is often associated with oxidative stress. Photodynamic therapy (PDT) has emerged as a promising alternative therapeutic tool in cancer treatments, but its efficacy is closely correlated to the photosensitizers generating reactive oxygen species (ROS) and the antioxidant capacity of tumor cells. In particular, glutathione (GSH) can reduce the ROS and thus compromise PDT efficacy. In this study, a GSH-responsive near-infrared photosensitizer (TBPPN) based on aggregation-induced emission for real-time monitoring of GSH levels and enhanced PDT for lung cancer treatment is developed. The strategic design of TBPPN, consisting of a donor-acceptor structure and incorporation of dinitrobenzene, enables dual functionality by not only the fluorescence being activated by GSH but also depleting GSH to enhance the cytotoxic effect of PDT. TBPPN demonstrates synergistic PDT efficacy in vitro against A549 lung cancer cells by specifically targeting different cellular compartments and depleting intracellular GSH. In vivo studies further confirm that TBPPN can effectively inhibit tumor growth in a mouse model with lung cancer, highlighting its potential as an integrated agent for the diagnosis and treatment of lung cancer. This approach enhances the effectiveness of PDT for lung cancer and deserves further exploration of its potential for clinical application.

Bimetallic Cu@Ru Core-Shell Structures with Ligand Effects for Endo-Exogenous Stimulation-Mediated Dynamic Oncotherapy.

Dynamic therapies, which induce reactive oxygen species (ROS) production in situ through endogenous and exogenous stimulation, are emerging as attractive options for tumor treatment. However, the complexity of the tumor substantially limits the efficacy of individual stimulus-triggered dynamic therapy. Herein, bimetallic copper and ruthenium (Cu@Ru) core-shell nanoparticles are applied for endo-exogenous stimulation-triggered dynamic therapy. The electronic structure of Cu@Ru is regulated through the ligand effects to improve the adsorption level for small molecules, such as water and oxygen. The core-shell heterojunction interface can rapidly separate electron-hole pairs generated by ultrasound and light stimulation, which initiate reactions with adsorbed small molecules, thus enhancing ROS generation. This synergistically complements tumor treatment together with ROS from endogenous stimulation. In vitro and in vivo experiments demonstrate that Cu@Ru nanoparticles can induce tumor cell apoptosis and ferroptosis through generated ROS. This study provides a new paradigm for endo-exogenous stimulation-based synergistic tumor treatment.

Pharmacokinetics and tissue distribution of Yigong San in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: In traditional Chinese medicine (TCM), Yigong San (YGS) is mainly used to treat dyspepsia caused by deficiency of spleen and stomach qi. Although the chemical composition and bioactivity of YGS has been well studied, the main in vivo compounds and their distribution in tissues still need to be made clearer. AIM OF THE STUDY: To elucidate the pharmacokinetic profiles and tissue distribution of eight main compounds of YGS in rats, and provide a reference for clinical application and new drug development. MATERIALS AND METHODS: UPLC-Q-Exactive-Orbitrap-MS was used to qualitatively characterize the parent compounds and their metabolites in the plasma of rats after oral administration of YGS. A sensitive, reliable, and accurate ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method using UPLC-AB Sciex QTRAP 5500 MS was established to quantitatively determine eight main compounds of YGS in rat plasma and tissues, including liquiritin, isoliquiritin, hesperidin, ginsenosides Rb1, Re and Rg1, atractylenolides I and II. RESULTS: The mean area under the concentration-time curve (AUC) values of ginsenoside Rb1, hesperidin, and liquiritin at low, medium, and high doses were greater than 150 ng h/mL. The elimination half-life (t1/2) values of ginsenoside Rb1, atractylenolides I and II (low and medium doses) were longer than 10 h. Peak time (Tmax) values of all compounds were shorter than 10 h. Except for atractylenolides, the maximum concentration (Cmax) values of the compounds were greater than 10 ng/mL. The eight compounds were detected in the heart, brain, liver, spleen and kidney at 0.25 h after oral administration. Liquiritin and isoliquiritin had higher exposure in the liver and heart. Hesperidin and ginsenosides Rb1, Re, and Rg1 are mainly distributed in the spleen and kidney. Atractylenolides I and II are mainly distributed in spleen, liver and kidney. CONCLUSIONS: All main compounds of YGS, i.e., liquiritin, isoliquiritin, hesperidin, ginsenosides Rb1, Re, and Rg1, and atractylenolides I and II are absorbed into plasma and widely distributed in various tissues. Among them, hesperidin, ginsenoside Rb1, and atractylenolide I are main in vivo compounds. They are mainly distributed in spleen, liver and kidney. The results of this study provide a basis for further in-depth development and application of YGS.

Dichotomous transactivation domains contribute to growth inhibitory and promotion functions of TAp73.

The transcription factor p73, a member of the p53 tumor-suppressor family, regulates cell death and also supports tumorigenesis, although the mechanistic basis for the dichotomous functions is poorly understood. We report here the identification of an alternate transactivation domain (TAD) located at the extreme carboxyl (C) terminus of TAp73ß, a commonly expressed p73 isoform. Mutational disruption of this TAD significantly reduced TAp73ß's transactivation activity, to a level observed when the amino (N)-TAD that is similar to p53's TAD, is mutated. Mutation of both TADs almost completely abolished TAp73ß's transactivation activity. Expression profiling highlighted a unique set of targets involved in extracellular matrix-receptor interaction and focal adhesion regulated by the C-TAD, resulting in FAK phosphorylation, distinct from the N-TAD targets that are common to p53 and are involved in growth inhibition. Interestingly, the C-TAD targets are also regulated by the oncogenic, amino-terminal-deficient DNp73ß isoform. Consistently, mutation of C-TAD reduces cellular migration and proliferation. Mechanistically, selective binding of TAp73ß to DNAJA1 is required for the transactivation of C-TAD target genes, and silencing DNAJA1 expression abrogated all C-TAD-mediated effects. Taken together, our results provide a mechanistic basis for the dichotomous functions of TAp73 in the regulation of cellular growth through its distinct TADs.