A network meta-analysis of the effectiveness of different basic preconditioning regiments in allogeneic hematopoietic stem cell transplantation.

OBJECTIVE: To investigate and compare the effects of basic preconditioning regimens Bu/Cy, Cy/TBI and Flu/Bu for the treatment of patients in allogeneic hematopoietic stem cell transplantation. METHODS: It comprised exploring the published literature in the databases of PubMed, EMBASE, Cochrane Library, and Web of Science, using suitable keywords pertaining to various basic pretreatments Bu/Cy, Cy/TBI, and Flu/Bu, prior to allogeneic hematopoietic stem cell transplantation, and then extracting the searched outcome indicators of Overall Survival (OS) and survival (herein represented as OS and survival). Further, the results were estimated with meta-analysis using R, where the incidence of GVHD was reported in odds ratio (OR) with its 95% confidence interval (95%CI). RESULTS AND DISCUSSION: A total of 14 papers were included in this study, including 1436 cases were treated with Bu/Cy, 1816 cases with Cy/TBI, and 549 cases with Flu/Bu in the preconditioning regimen. After OS was the outcome pooled, compared with Flu/Bu in the preconditioning group, the results (Cy/TBI HR = 1.12 (95% Cl:1.04,1.61), Bu/Cy HR = 1.24 (95% Cl. 1.13,2.06)) showed that Flu/Bu preconditioning regimen significantly improved the overall survival rate of allogeneic HSCT patients. With the incidence of GVHD as the outcome summary, compared with Flu/Bu in the pretreatment group, the results (Cy/TBI HR = 1.24 (95% Cl:1.12, 1.82), Bu/Cy HR = 1.14 (95% Cl. 1.03, 2.12)) indicated that Flu/Bu in the pretreatment regimen group also significantly reduced the incidence of GVHD after allogeneic HSCT. CONCLUSION: Patients who received the basal preconditioning regimen Flu/Bu before allogeneic hematopoietic stem cell transplantation had the lowest hazard ratio for overall survival (OS) development. This indicates that the use of the basal preconditioning regimen Flu/Bu for the treatment of patients was the most effective, although the quality of the studies included needs to be confirmed by high-quality randomized controlled trials.

Preparation and application of a Cu-doped antimony electrode to improve the performance of pH measurement in seawater.

Antimony-based electrodes are widely used in various fields for pH detection due to their low cost. However, their application in the marine environment is significantly hampered by the significant potential drift observed in seawater pH measurements. This study focuses on enhancing the stability of a pure antimony electrode by doping various amounts of copper without compromising its pH response. A series of electrochemical tests demonstrated that the fabricated alloy electrodes exhibited excellent pH response characteristics, including sensitivity, ion selectivity, response time, reversibility, and temperature coefficients. Moreover, the alloy electrodes were more resistant to corrosion than the pure antimony electrode, thereby guaranteeing the stability. Notably, the alloy electrodes containing 63 at% and 70 at% antimony exhibited superior electrochemical characteristics. The surface analysis elucidated that the alloy electrode had reduced oxidation, surface cracks and antimony peeling compared to the pure antimony electrode. Furthermore, the prepared alloy electrodes exhibited excellent pH response and stability in simulated high-salinity seawater and real seawater. The above results highlight that doping cheap copper into antimony can improve the electrode stability by enhancing the corrosion resistance and slowing down the oxidation rate, thus enabling reliable long-time operation in a relatively stable state. These findings provide experimental support for developing novel pH electrodes based on non-noble metals for use in challenging environments such as seawater.

Comparative efficacy of sweated and non-sweated Salvia miltiorrhiza Bge. extracts on acute myocardial ischemia via regulating the PPARα/RXRα/NF-κB signaling pathway.

Salvia miltiorrhiza Bge. (S. miltiorrhiza) is a well-known traditional Chinese medicine for the treatment of cardiovascular diseases. The processing of S. miltiorrhiza requires the raw herbs to sweat first and then dry. The aim of this study was to investigate the anti-acute myocardial ischemia (AMI) of S. miltiorrhiza extracts (including tanshinones and phenolic acids) before and after sweating, and to further explore whether the "sweating" primary processing affected the efficacy of S. miltiorrhiza. The AMI animal model was established by subcutaneous injection of isoprenaline hydrochloride (ISO). After treatment, the cardiac function of rats was evaluated by electrocardiogram (ECG), biochemical, and histochemical analysis. Moreover, the regulation of S. miltiorrhiza extracts on the peroxisome proliferator-activated receptor α (PPARα)/retinoid X receptor α (RXRα)/nuclear transcription factor-kappa B (NF-κB) signaling pathway of rats was assessed by the Western blotting. The results showed that sweated and non-sweated S. miltiorrhiza extracts including tanshinones and phenolic acids significantly reduced ST-segment elevation in ECG and the myocardial infarction area in varying degrees. Meanwhile, sweated and non-sweated S. miltiorrhiza reversed the activities of aspartate transaminase (AST), lactic dehydrogenase (LDH), creatine kinase-MB (CK-MB), and superoxide dismutase (SOD), as well as the levels of interleukin-6 (IL-6), interleukin-10 (IL-10), and tumor necrosis factor-α (TNF-α) in AMI rats. Concurrently, the results of Western blotting revealed that S. miltiorrhiza extracts regulated the PPARα/RXRα/NF-κB signaling pathway to exert an anti-inflammatory effect. Most importantly, sweated S. miltiorrhiza tanshinones extracts are more effective than the non-sweated S. miltiorrhiza, and the anti-inflammatory efficacy of tanshinones extract was also better than that of phenolic acid extract. Although phenolic acid extracts before and after sweating were effective in anti-AMI, there was no significant difference between them. In conclusion, both tanshinones and phenolic acids extracts of sweated and non-sweated S. miltiorrhiza promote anti-oxidative stress and anti-inflammatory against AMI via regulating the PPARα/RXRα/NF-κB signaling pathway. Further, the comparations between sweated and non-sweated S. miltiorrhiza extracts indicate that sweated S. miltiorrhiza tanshinones extracts have better therapeutic effects on AMI.

Therapeutic effects of Tanshinone IIA and Tetramethylpyrazine nanoemulsions on cognitive impairment and neuronal damage in Alzheimer's disease rat models.

OBJECTIVES: The aim of this study was to investigate the therapeutic effects and related mechanisms of Tanshinone IIA and Tetramethylpyrazine O/W composite nanoemulsions on Alzheimer's disease (AD) rats. METHODS: The therapeutic effect of TSN/TMP O/W NEs on AD rats was evaluated by behavioral tests, H&E, Nissl, and Immunohistochemistry staining. ELISA and Western blot were used to analyze the mechanism. KEY FINDINGS: The results showed that TSN/TMP O/W NEs could down-regulate the expression of Bax and Caspase-3 proteins, decrease the level of MDA, increase the expression of SOD and GSH-Px, and alleviate cognitive impairment in AD rats. CONCLUSIONS: TSN/TMP O/W NEs can inhibit MAPK/ERK/CREB signaling pathway and effectively alleviate cognitive impairment, oxidative stress injury, and neuronal apoptosis in AD rats.

Associations of serum glucocorticoid levels on hypertension and blood pressure-related indicators: a nested case-control study in rural China.

BACKGROUND: The relationship between glucocorticoids and hypertension has shown inconsistent findings in previous studies. To address this, our study employed a nested case-control design in rural areas to further investigate the association between serum glucocorticoid levels and hypertension, and blood pressure-related indicators. METHODS: This study employed a nested case-control design, involving 560 pairs of hypertensive cases and matched controls. The concentrations of serum cortisol (F), cortisone (E) and 11-deoxycortisol (S) were determined using liquid chromatography-tandem mass spectrometry. We employed various methods, including generalized linear model (GLM), conditional logistic regression model, restricted cubic spline regression, subgroup analysis, interaction, and joint effects, with adjustments for multiple covariates to analyze the relationships between glucocorticoids, hypertension, and blood pressure-related indicators. RESULTS: After multivariable adjustments, ln-F, ln-F/E, and ln-S were positively associated with SBP, DBP, pulse pressure (PP), and mean arterial pressure (MAP), while ln-E was negatively associated with DBP and MAP (P < 0.05). Interestingly, ln-S showed no statistically significant association with hypertension prevalence (P > 0.05), whereas ln-F and ln-F/E were positively associated with it (P < 0.05). The adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were 1.153 (1.011-1.315) for ln-F and 2.072 (1.622-2.645) for ln-F/E, respectively. In contrast, ln-E exhibited a negative association with hypertension prevalence (adjusted OR = 0.837, 95% CI 0.714-0.982). Moreover, a significant association was observed between the combined use of high-dose F/E and high-dose S with hypertension prevalence (adjusted OR = 3.273, 95% CI 2.013-5.321). Blood pressure indicators and hypertension prevalence significantly increased with elevated serum F and F/E concentrations (P < 0.05). Interaction analysis further revealed that among women, the positive association between F/E and hypertension prevalence was more pronounced than in men (P < 0.05), and S exhibited a more significant positive association with hypertension prevalence in the overweight population (P < 0.05). CONCLUSION: Serum F/E and S levels demonstrated positive associations with hypertension and blood pressure-related indicators, and their combined influence exhibited a synergistic effect on hypertension. Notably, F, F/E, and S were associated with heightened hypertension risk, warranting particular attention in women and overweight populations.

Association between lipid accumulation product and psoriasis among adults: a nationally representative cross-sectional study.

BACKGROUND: Lipid accumulation product (LAP) is an accessible and relatively comprehensive assessment of obesity that represents both anatomical and physiological lipid accumulation. Obesity and psoriasis are potentially related, according to previous research. Investigating the relationship between adult psoriasis and the LAP index was the goal of this study. METHODS: This is a cross-sectional study based on data from the National Health and Nutrition Examination Survey (NHANES) 2003-2006 and 2009-2014. The association between LAP and psoriasis was examined using multivariate logistic regression and smoothed curve fitting. To verify whether this relationship was stable across populations, subgroup analyses and interaction tests were performed. RESULTS: The LAP index showed a positive correlation with psoriasis in 9,781 adult participants who were 20 years of age or older. A 27% elevated probability of psoriasis was linked to every unit increase in ln LAP in the fully adjusted model (Model 3: OR 1.27, 95% CI 1.06-1.52). In comparison with participants in the lowest ln LAP quartile, those in the highest quartile had an 83% greater likelihood of psoriasis (Model 3: OR 1.83, 95% CI 1.08-3.11). This positive correlation was more pronounced for young males, participants who had never smoked, non-drinkers, participants who exercised little, as well as non-hypertensive and non-diabetic participants. CONCLUSIONS: This study found that the LAP index and adult psoriasis were positively correlated, especially in young males without comorbidities. Therefore, it is proposed that LAP may serve as a biomarker for early diagnosis of psoriasis and tracking the effectiveness of treatment.

Predictive value of fluid balance before extubation on its outcome in mechanically ventilated adults in the intensive care unit.

BACKGROUND: Although there are many reasons for extubation failure, maintaining negative or lower positive fluid balances 24 hours before extubation may be a key measure for successful extubation. AIM: To assess the predictive value of fluid balance before extubation and its outcome in mechanically ventilated cases in the intensive care unit (ICU). STUDY DESIGN: This retrospective cohort study involved collecting clinical data from patients undergoing mechanical ventilation in Lanzhou general adult ICU from January 2022 to December 2022. Based on extubation outcomes, the patients were divided into a successful extubation group and a failed extubation group. Their fluid balance levels 24 h before extubation were compared with analyse the predictive value of fluid balance on extubation outcomes in patients undergoing mechanical ventilation. RESULTS: In this study, clinical data from 545 patients admitted to a general adult ICU were collected. According to the inclusion and exclusion criteria, 265 (48.6%) patients were included, of which 197 (74.3%) were successfully extubated; extubation was unsuccessful in 68 (25.7%) patients. The total intake and fluid balance levels in patients in the failed extubation group 24 h before extubation were significantly higher than those in the successful extubation group, with a median of 2679.00 (2410.44-3193.50) mL versus 2435.40 (1805.04-2957.00) mL, 831.50 (26.25-1407.94) mL versus 346.00 (-163.00-941.50) mL. Receiver operating characteristic (ROC) curve analysis showed that the optimal cut-off value for predicting extubation outcomes was 497.5 mL (sensitivity 64.7%, specificity 59.4%) for fluid balance 24 h before extubation. The area under the ROC curve was 0.627 (95% confidence interval [CI] 0.547-0.707). Based on the logistic regression model, cumulative fluid balance >497.5 mL 24 h before extubation could predict its outcomes in mechanically ventilated patients in the ICU (OR = 5.591, 95% CI [2.402-13.015], p < .05). CONCLUSIONS: The fluid balance level 24 h before extubation was correlated with the outcome of extubation in mechanically ventilated patients in the ICU. The risk of extubation failure was higher when the fluid balance level was >497.5 mL. RELEVANCE TO CLINICAL PRACTICE: Tracheal intubation is a crucial life support technique for many critically ill patients, and determining the appropriate time for extubation remains a challenge for clinicians. Although there are many reasons for extubation failure, acute pulmonary oedema caused by continuous positive fluid balance and volume overload is one of the main reasons for extubation failure. Therefore, it is very important to study the relationship between fluid balance and extubation outcome to improve the prognosis of patients with invasive mechanical ventilation in ICU.

Combined cryoablation and PD-1 inhibitor synergistically enhance antitumor immune responses in Lewis lung adenocarcinoma mice via the PI3K/AKT/mTOR pathway.

Cryoablation is a therapeutic modality for lung adenocarcinoma that destroys target tumors using lethal levels of cold, resulting in the release of large amounts of specific antigens that activate immune responses. However, tumor immune checkpoint escape mechanisms prevent these released self-antigens from inducing effective anti-tumor immune responses. To overcome this challenge, we propose the use of immune checkpoint inhibitors to relieve T cell inhibition by immune checkpoints and enhance the anti-tumor immune response mediated by cryoablation. We used bilateral tumor-bearing mouse models and a specific cryoablation instrument to study the efficacy of cryoablation combined with PD-1 inhibitors in Lewis lung adenocarcinoma model mice. We found that cryoablation combined with PD-1 inhibitors significantly inhibited the growth of mouse lung adenocarcinoma, prolonged mouse survival, and enhanced the anti-tumor immune response. Moreover, this combined regimen could synergistically promote the activation and proliferation of T cells via the PI3K/AKT/mTOR pathway. The present study provides a strong theoretical basis for the clinical combination of cryoablation and PD-1 inhibitors.

Current advances of chlorinated organics degradation by bioelectrochemical systems: a review.

Chlorinated organic compounds (COCs) are typical refractory organic compounds, having high biological toxicity. These compounds are a type of pervasive pollutants that can be present in polluted soil, air, and various types of waterways, such as groundwater, rivers, and lakes, posing a significant threat to the ecological environment and human health. Bioelectrochemical systems (BESs) are an effective strategy for the degradation of bio-refractory compounds. BESs improve the waste treatment efficiency through the application of weak electrical stimulation. This review discusses the processes of BESs configurations and degradation performances in different environmental media including wastewater, soil, waste gas and groundwater. In addition, the degradation mechanisms and performance-enhancing additives are summarized. The future challenges and perspectives on the development of BES for COCs removal are briefly discussed.

Components analysis of San-Bai decoction, and its pharmacodynamics and mechanism on preventing and treating melasma.

ETHNOPHARMACOLOGICAL RELEVANCE: San-Bai Decoction (SBD) is a classic whitening prescription originally recorded in the 'Introduction to Medicine' of the Ming Dynasty. SBD has been known for invigorating Qi and blood, promoting spleen and stomach, whitening skin, and fading melasma. However, its pharmacodynamic material basis and specific mechanism remain unclear. AIM OF THE STUDY: The aim of this study is to clarify the pharmacodynamic material basis of SBD and its mechanism of removing melasma. MATERIALS AND METHODS: The positive and negative ion mass spectrum data of SBD extract were collected by UHPLC-Q-Exactive Orbitrap MS/MS, imported into Compound Discoverer (CD) 3.1 software, matched through the online database, and manually checked. Finally, the in vitro chemical components of SBD were classified. Similarly, the mass spectrum data of SBD in the serum of normal rats and melasma model rats were also analyzed by CD 3.1 software. The in vitro identified Compound file of SBD was imported into the Expected Compounds and the Generate Expected Compounds project was selected. The SBD compounds were then chosen under the Compound Section. All phase I and II reaction types related to SBD components were selected, and the metabolic platform of CD 3.1 software was utilized to process the results and obtain possible metabolites. The metabolites were scored and products with high scores were subsequently screened. According to literature comparison, the final metabolites of SBD in both normal rats and melasma model rats were determined and comprehensively analyzed. The Melasma model rats were constructed through intramuscular injection of progesterone and ultraviolet radiation B (UVB) irradiation. The preventing and treating effect of SBD on melasma were evaluated by regulating inflammation, epidermal collagen content, and oxidative stress. Additionally, the effect of SBD on the Phosphatidylinositol 3-kinase (PI3K)/Protein kinase B (Akt)/Glycogen synthase kinase 3ß (GSK3ß) pathway was investigated through Western blot (WB) to explore its underlying mechanism on whitening and removing melasma efficacy. RESULTS: Ultimately, 94 components were identified in SBD, including 41 flavonoids, 27 organic acids, and 9 glycosides, 3 terpenoids, 2 amides, 2 aldehydes, 1 phenylpropanoid and 9 other compounds. In the blood of normal rat group, a total of 24 prototype components and 61 metabolites were identified. Similarly, there were19 prototype components and 44 metabolites identified from the blood of melasma model rats. Pharmacodynamic experiment results indicated that SBD effectively reduced the incidence of melasma, prevent the loss of epidermal collagen, and elevate the activity of superoxide dismutase and decrease the malondialdehyde content in both liver and skin. Interestingly, the WB results demonstrated that SBD effectively activated PI3K/Akt/GSK3ß pathway, and down-regulated the expression of melanin-related proteins. CONCLUSIONS: For the first time, the components of SBD extracts, and its prototype components and metabolites in the blood of normal rats and melasma model rats were successfully identified by high-resolution liquid chromatography-mass spectrometry with CD software. Additionally, the differences of in vivo components of SBD between normal rats and melasma model rats were analyzed. The preventive and therapeutic effect of SBD on melasma was verified in the melasma model rats induced by progesterone and UVB irradiation, and its mechanism was related to activating PI3K/Akt/GSK3ß pathway and downregulating the expression of melanin-related proteins. These results provide an experimental foundation for further research on the pharmacodynamic substance basis and pharmacodynamic mechanism of SBD, as well as developing new anti-melasma formula with SBD.

Engineered endolysin of Klebsiella pneumoniae phage is a potent and broad-spectrum bactericidal agent against "ESKAPEE" pathogens.

The rise of antimicrobial resistance in ESKAPEE pathogens poses significant clinical challenges, especially in polymicrobial infections. Bacteriophage-derived endolysins offer promise in combating this crisis, but face practical hurdles. Our study focuses on engineering endolysins from a Klebsiella pneumoniae phage, fusing them with ApoE23 and COG133 peptides. We assessed the resulting chimeric proteins' bactericidal activity against ESKAPEE pathogens in vitro. ApoE23-Kp84B (CHU-1) reduced over 3 log units of CFU for A. baumannii, E. faecalis, K. pneumoniae within 1 h, while COG133-Kp84B (CHU-2) showed significant efficacy against S. aureus. COG133-L1-Kp84B, with a GS linker insertion in CHU-2, exhibited outstanding bactericidal activity against E. cloacae and P. aeruginosa. Scanning electron microscopy revealed alterations in bacterial morphology after treatment with engineered endolysins. Notably, CHU-1 demonstrated promising anti-biofilm and anti-persister cell activity against A. baumannii and E. faecalis but had limited efficacy in a bacteremia mouse model of their coinfection. Our findings advance the field of endolysin engineering, facilitating the customization of these proteins to target specific bacterial pathogens. This approach holds promise for the development of personalized therapies tailored to combat ESKAPEE infections effectively.

Hydrogen Bonds Induced Ultralong Stability of Conductive π-d Conjugated FeCo3(DDA)2 with High OER Activity.

Conductive π-d conjugated metal-organic frameworks (MOFs) have attracted wide concerns in electrocatalysis due to their intrinsic high conductivity. However, the poor electrocatalytic stability is still a major problem that hinders the practical application of MOFs. Herein, a novel approach to enhancing the stability of MOF-based electrocatalyst, namely, the introduction of hydrogen bonds (H-bonds), is reported. Impressively, the π-d conjugated MOF FeCo3(DDA)2 (DDA = 1,5-diamino-4,8-dihydroxy-9,10-anthraceneedione) exhibits ultrahigh oxygen evolution reaction (OER) stability (up to 2000 h). The experimental studies demonstrate that the presence of H-bonds in FeCo3(DDA)2 is responsible for its ultrahigh OER stability. Besides that, FeCo3(DDA)2 also displays a prominent OER activity (an overpotential of 260 mV vs reversible hydrogen electrode (RHE) at a current density of 10 mA cm-2 and a Tafel slope of 46.86 mV dec-1). Density functional theory (DFT) calculations further indicate that the synergistic effect of the Fe and Co sites in FeCo3(DDA)2 contributes to its prominent OER performance. This work provides a new avenue of boosting the electrocatalytic stability of conductive π-d conjugated MOFs.

Kai-Xin-San ameliorates Alzheimer's disease-related neuropathology and cognitive impairment in APP/PS1 mice via the mitochondrial autophagy-NLRP3 inflammasome pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Kai-Xin-San (KXS) is a classic famous prescription that has been utilized for centuries to address dementia. New investigations have shown that the anti-dementia effect of KXS is connected with improved neuroinflammation. Nevertheless, the underlying mechanism is not well elucidated. AIM OF THE STUDY: We propose to discover the ameliorative impact of KXS on Alzheimer's disease (AD) and its regulatory role on the mitochondrial autophagy-nod-like receptor protein 3 (NLRP3) inflammasome pathway. MATERIALS AND METHODS: The Y maze, Morris water maze, and new objection recognition tests were applied to ascertain the spatial learning and memory capacities of amyloid precursor protein/presenilin 1 (APP/PS1) mice after KXS-treatment. Meanwhile, the biochemical indexes of the hippocampus were detected by reagent kits. The pathological alterations and mitochondrial autophagy in the mice' hippocampus were detected utilizing hematoxylin and eosin (H&E), immunohistochemistry, immunofluorescence staining, and transmission electron microscopy. Besides, the PTEN-induced putative kinase 1 (PINK1)/Parkin and NLRP3 inflammasome pathways protein expressions were determined employing the immunoblot analysis. RESULTS: The results of behavioral tests showed that KXS significantly enhanced the AD mice' spatial learning and memory capacities. Furthermore, KXS reversed the biochemical index levels and reduced amyloid-ß protein deposition in AD mice brains. Besides, H&E staining showed that KXS remarkably ameliorated the neuronal damage in AD mice. Concurrently, the results of transmission electron microscopy suggest that KXS ameliorated the mitochondrial damage in microglia and promoted mitochondrial autophagy. Moreover, the immunofluorescence outcomes exhibited that KXS promoted the expression of protein 1 light chain 3B (LC3B) associated with microtubule and the generation of autophagic flux. Notably, the immunofluorescence co-localization results confirmed the presence of mitochondrial autophagy in microglia. Finally, KXS promoted the protein expressions of the PINK1/Parkin pathway and reduced the activation of NLRP3 inflammasome. Most importantly, these beneficial effects of KXS were attenuated by the mitochondrial autophagy inhibitor chloroquine. CONCLUSION: KXS ameliorates AD-related neuropathology and cognitive impairment in APP/PS1 mice by enhancing the mitochondrial autophagy and suppressing the NLRP3 inflammasome pathway.

Prognostic factors of adrenocortical carcinoma in children and adolescents: a population-based study.

PURPOSE: Adrenocortical carcinoma (ACC) is an uncommon adrenal gland endocrine tumor that has a poor prognosis in children. We aimed to conduct a population-based cohort study to predict overall survival (OS) in pediatric patients with ACC. METHODS: We used the Surveillance, Epidemiology, and End Results (SEER) database to conduct a retrospective cohort research on pediatric patients diagnosed with ACC between 1975 and 2018. We examined demographic characteristics, tumor stage and size, treatment options, and survival results. Kaplane-Meier estimations were used to generate survival curves based on several parameters. To compare survival curves, the log-rank test was applied.Cox proportional-hazards regression was used to determine the variables related with OS. In addition, we created a nomogram to predict overall survival in pediatric ACC patients. RESULTS: A total of 143 pediatric ACC patients were identified. Females were the most impacted (60.8%). Overall 1 year, 3 year, and 5 year survival rates were 75.0%, 57.6%, and 53.7% for all patients, respectively. In comparison to older patients (5-19 years), younger patients (≤ 4 years) were shown to have more positive characteristics, including a higher likelihood of local disease (29.4% vs. 14%, P < 0.001), tumors less than 10 cm (23.1% vs. 14.7%, P < 0.001), and improved overall survival (5 year OS 89.6% vs. 27.7%, P < 0.001). Age at diagnosis, SEER stage, and surgery were significant independent predictors of OS in this model, according to the results of Cox proportional hazard regression. After that, we developed a nomogram for predicting OS in children with ACC. Patients older than 4 years old had a higher chance of dying. Furthermore, the higher the SEER stage, the higher the risk of death. Patients who do not have surgery have a worse survival rate than those who do. CONCLUSIONS: Our study revealed that age at diagnosis, SEER stage, and surgery were found to be the most important predictors of the overall survival of pediatric ACC. These findings contribute to the existing body of knowledge and emphasize the importance of continued research to advance our understanding of pediatric ACC and improve patient care.

ApoE Mimetic Peptide COG1410 Kills Mycobacterium smegmatis via Directly Interfering ClpC's ATPase Activity.

Antimicrobial peptides (AMPs) hold promise as alternatives to combat bacterial infections, addressing the urgent global threat of antibiotic resistance. COG1410, a synthetic peptide derived from apolipoprotein E, has exhibited potent antimicrobial properties against various bacterial strains, including Mycobacterium smegmatis. However, our study reveals a previously unknown resistance mechanism developed by M. smegmatis against COG1410 involving ClpC. Upon subjecting M. smegmatis to serial passages in the presence of sub-MIC COG1410, resistance emerged. The comparative genomic analysis identified a point mutation in ClpC (S437P), situated within its middle domain, which led to high resistance to COG1410 without compromising bacterial fitness. Complementation of ClpC in mutant restored bacterial sensitivity. In-depth analyses, including transcriptomic profiling and in vitro assays, uncovered that COG1410 interferes with ClpC at both transcriptional and functional levels. COG1410 not only stimulated the ATPase activity of ClpC but also enhanced the proteolytic activity of Clp protease. SPR analysis confirmed that COG1410 directly binds with ClpC. Surprisingly, the identified S437P mutation did not impact their binding affinity. This study sheds light on a unique resistance mechanism against AMPs in mycobacteria, highlighting the pivotal role of ClpC in this process. Unraveling the interplay between COG1410 and ClpC enriches our understanding of AMP-bacterial interactions, offering potential insights for developing innovative strategies to combat antibiotic resistance.

Metabolomics in cirrhosis: Recent advances and opportunities.

Liver cirrhosis (LC) represents a significant hepatic disorder that persistently commands the attention of the scientific community, especially concerning its pathogenesis and therapeutic approaches. Metabolomics, the comprehensive profiling of an organism's metabolome, has been increasingly applied in the research of cirrhosis over the past decade. This review summarizes the recent advancements and applications of metabolomics within the context of LC research, in recent five years. It highlights the role of metabolomics in the diagnosis of LC, the assessment of prognostic markers, and the evaluation of therapeutic outcomes. The discussion focuses on the potential and challenges of metabolomics in LC research, including the evolution of analytical technologies, advancements in bioinformatics, and the challenges impeding clinical implementation. Additionally, the review anticipates the forthcoming developments in metabolomics related to LC research, with the objective of facilitating innovative approaches for early detection and intervention in LC.

Accurate network pharmacology and novel ingredients formula of herbal targeting estrogen signaling for psoriasis intervention.

ETHNOPHARMACOLOGICAL RELEVANCE: As a common chronic inflammatory skin disease, psoriasis is incompletely understood and brings a lot of distress to patients. The estrogen signaling pathway has been implicated in its pathogenesis, making it a potential therapeutic target. Si Cao Formula (SCF) has demonstrated promise in treating psoriasis clinically. However, its molecular mechanisms concerning psoriasis remain largely unexplored. AIM OF THE STUDY: To elucidate the underlying mechanisms of the action of SCF on psoriasis. MATERIALS AND METHODS: Active ingredients were identified by LC-MS/MS. After the treatment with SCF, the exploration of differentially expressed proteins (DEPs) were conducted using tandem mass tag (TMT)-based quantitative proteomics analysis. By GO/KEGG, WikiPathways and network pharmacology, core signaling pathway and protein targets were explored. Consequently, major signaling pathway and protein targets were validated by RT-qPCR, immunoblotting and immunofluorescence. Based on Lipinski's Rule of Five rules and molecular docking, 8 active compounds were identified that acted on the core targets. RESULTS: 41 compounds of SCF and 848 specific targets of these compounds were identified. There were 570 DEPs between IMQ (Imiquimod) and IMQ + SCF group, including 279 up-regulated and 304 down-regulated proteins. GO/KEGG, WikiPathways and network pharmacology revealed estrogen signaling pathway as the paramount pathways, through which SCF functioned on psoriasis. We further show novel ingredients formula of SCF contributes to estrogen signaling intervention, including liquiritin, parvisoflavone B, glycycoumarin, 8-prenylluteone, licochalcone A, licochalcone B, oxymatrine, and 13-Hydroxylupanine, where targeting MAP2K1, ILK, HDAC1 and PRKACA, respectively. Molecular docking proves that they have good binding properties. CONCLUSION: Our results provide an in-depth view of psoriasis pathogenesis and herbal intervention, which expands our understanding of the systemic pharmacology to reveal the multiple ingredients and multiple targets of SCF and focus on one pathway (estrogen signaling pathway) may be a novel therapeutic strategy for psoriasis treatment of herbal medicine.

Total Synthesis of the Racemate of Laurolitsine.

The total synthesis of laurolitsine was achieved for the first time. This reaction was accomplished in 14 steps with a 2.3% yield (this was calculated using 3-hydroxy-4-methoxybenzaldehyde as the starting material) starting from two simple materials, 3-hydroxy-4-methoxybenzaldehyde and 2-(3-hydroxy-4-methoxyphenyl)acetic acid, and the longest linear sequence consisted of 11 steps. The key steps included an electrophilic addition reaction in which a nitro group was reduced to an amino group using lithium tetrahydroaluminum and a Pd-catalyzed direct biaryl coupling reaction. In this paper, many of the experimental steps were optimized, and an innovative postprocessing method in which 2-(3-(benzyloxy)-4-methoxyphenyl)ethanamine is salted with oxalic acid was proposed.

SCUBE3 Exerts a Tumor-Promoting Effect in Tongue Squamous Cell Carcinoma by Promoting CEBPA Binding to the CCL2 Promoter.

Tongue squamous cell carcinoma (TSCC) is the main pathologic subtype of oral cancer, and the current therapeutic effect is far from satisfactory. The signal peptide-CUB-EGF domain-containing protein 3 (SCUBE3) has been shown to be a tumor-promoting factor in several malignancies. However, little is known about the role of SCUBE3 in TSCC. In this study, we identified that SCUBE3 was highly expressed in TSCC. Clinically, high expression of SCUBE3 was positively associated with tumor stage and T stage of TSCC. Functionally, SCUBE3 silence remarkably restrained cell proliferation, migration, and invasion, induced apoptosis as well as cell cycle arrest in G2-phase, and weakened the tumorigenicity of TSCC cells in vivo. Mechanistically, SCUBE3 promoted the direct binding of CCAAT enhancer binding protein alpha (CEBPA) to C-C motif chemokine ligand 2 (CCL2) promoter in TSCC cells. Interestingly, CCL2 overexpression partially reversed the inhibitory effect of SCUBE3 deficiency on TSCC cell viability and migration. Moreover, STAT3 signaling contributed to CCL2-mediated phenotypes in TSCC cells. IMPLICATIONS: Our data revealed a tumor-promoting role for SCUBE3 in TSCC via the CEBPA/CCL2/STAT3 axis, which provided new insight into novel potential therapeutic target for TSCC.

CSN6-SPOP-HMGCS1 Axis Promotes Hepatocellular Carcinoma Progression via YAP1 Activation.

Cholesterol metabolism has important roles in maintaining membrane integrity and countering the development of diseases such as obesity and cancers. Cancer cells sustain cholesterol biogenesis for their proliferation and microenvironment reprograming even when sterols are abundant. However, efficacy of targeting cholesterol metabolism for cancer treatment is always compromised. Here it is shown that CSN6 is elevated in HCC and is a positive regulator of hydroxymethylglutaryl-CoA synthase 1 (HMGCS1) of mevalonate (MVA) pathway to promote tumorigenesis. Mechanistically, CSN6 antagonizes speckle-type POZ protein (SPOP) ubiquitin ligase to stabilize HMGCS1, which in turn activates YAP1 to promote tumor growth. In orthotopic liver cancer models, targeting CSN6 and HMGCS1 hinders tumor growth in both normal and high fat diet. Significantly, HMGCS1 depletion improves YAP inhibitor efficacy in patient derived xenograft models. The results identify a CSN6-HMGCS1-YAP1 axis mediating tumor outgrowth in HCC and propose a therapeutic strategy of targeting non-alcoholic fatty liver diseases- associated HCC.