Impact of Aficamten on Disease and Symptom Burden in Obstructive Hypertrophic Cardiomyopathy: Results From SEQUOIA-HCM.

BACKGROUND: Aficamten is a cardiac myosin inhibitor that mitigates left ventricular outflow gradients in obstructive hypertrophic cardiomyopathy (oHCM). The clinical efficacy of aficamten across multiple outcome domains in oHCM has not been fully defined. OBJECTIVES: This responder analysis from the SEQUOIA-HCM (Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic oHCM) trial characterizes the clinical impact of aficamten. METHODS: Patients who were symptomatic of oHCM were randomized to aficamten (n = 142) or placebo (n = 140) daily for 24 weeks. Outcomes assessed included the proportion of patients with complete hemodynamic response (rest and Valsalva gradient <30 mm Hg and <50 mm Hg, respectively), relief in limiting symptoms (≥1 improvement in NYHA functional class and/or ≥10-point change in Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score), enhanced exercise capacity (≥1.5 mL/kg/min change in peak oxygen uptake), and ≥50% reduction in N-terminal pro-B-type natriuretic peptide. Eligibility for septal reduction therapy was also evaluated. RESULTS: At 24 weeks, patients treated with aficamten vs placebo showed significant improvement in limiting symptoms (71% vs 42%), were more likely to have complete hemodynamic response (68% vs 7%), demonstrated enhanced exercise capacity (47% vs 24%), and showed a decrease ≥50% in N-terminal pro-B-type natriuretic peptide (84% vs 8%) (P ≤ 0.002 for all). An improvement in ≥1 of these outcome measures was achieved in 97% of patients treated with aficamten (vs 59% placebo), including 23% on aficamten who achieved all 4 outcomes compared with none in placebo. Among 32 patients receiving aficamten and 29 patients receiving placebo who were eligible for septal reduction therapy, 28 (88%) from the aficamten group were no longer eligible at 24 weeks compared with 15 (52%) from the placebo group (P = 0.002). CONCLUSIONS: Treatment with aficamten was associated with substantial improvements across a broad range of clinically relevant efficacy measures. These results underscore the wide-ranging potential of aficamten for treatment of patients with symptomatic oHCM (Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults with oHCM [SEQUOIA-HCM]; NCT05186818).

Acceleration of brain aging after small-volume infarcts.

Introduction: Previous studies have shown that stroke patients exhibit greater neuroimaging-derived biological "brain age" than control subjects. This difference, known as the brain age gap (BAG), is calculated by comparing the chronological age with predicted brain age and is used as an indicator of brain health and aging. However, whether stroke accelerates the process of brain aging in patients with small-volume infarcts has not been established. By utilizing longitudinal data, we aimed to investigate whether small-volume infarctions can significantly increase the BAG, indicating accelerated brain aging. Methods: A total of 123 stroke patients presenting with small-volume infarcts were included in this retrospective study. The brain age model was trained via established protocols within the field of machine learning and the structural features of the brain from our previous study. We used t-tests and regression analyses to assess longitudinal brain age changes after stroke and the associations between brain age, acute stroke severity, and poststroke outcome factors. Results: Significant brain aging occurred between the initial and 6-month follow-ups, with a mean increase in brain age of 1.04 years (t = 3.066, p < 0.05). Patients under 50 years of age experienced less aging after stroke than those over 50 years of age (p = 0.245). Additionally, patients with a National Institute of Health Stroke Scale score >3 at admission presented more pronounced adverse effects on brain aging, even after adjusting for confounders such as chronological age, sex, and total intracranial volume (F 1,117 = 7.339, p = 0.008, η 2 = 0.059). There were significant differences in the proportional brain age difference at 6 months among the different functional outcome groups defined by the Barthel Index (F 2,118 = 4.637, p = 0.012, η 2 = 0.073). Conclusion: Stroke accelerates the brain aging process, even in patients with relatively small-volume infarcts. This phenomenon is particularly accentuated in elderly patients, and both stroke severity and poststroke functional outcomes are closely associated with accelerated brain aging. Further studies are needed to explore the mechanisms underlying the accelerated brain aging observed in stroke patients, with a particular focus on the structural alterations and plasticity of the brain following minor strokes.

Bootstrap each lead's latent: A novel method for self-supervised learning of multilead electrocardiograms.

BACKGROUND AND OBJECTIVE: Electrocardiogram (ECG) is one of the most important diagnostic tools for cardiovascular diseases (CVDs). Recent studies show that deep learning models can be trained using labeled ECGs to achieve automatic detection of CVDs, assisting cardiologists in diagnosis. However, the deep learning models heavily rely on labels in training, while manual labeling is costly and time-consuming. This paper proposes a new self-supervised learning (SSL) method for multilead ECGs: bootstrap each lead's latent (BELL) to reduce the reliance and boost model performance in various tasks, especially when training data are insufficient. METHOD: BELL is a variant of the well-known bootstrap your own latent (BYOL). The BELL aims to learn prior knowledge from unlabeled ECGs by pretraining, benefitting downstream tasks. It leverages the characteristics of multilead ECGs. First, BELL uses the multiple-branch skeleton, which is more effective in processing multilead ECGs. Moreover, it proposes intra-lead and inter-lead mean square error (MSE) to guide pretraining, and their fusion can result in better performances. Additionally, BELL inherits the main advantage of the BYOL: No negative pair is used in pretraining, making it more efficient. RESULTS: In most cases, BELL surpasses previous works in the experiments. More importantly, the pretraining improves model performances by 0.69% ∼ 8.89% in downstream tasks when only 10% of training data are available. Furthermore, BELL shows excellent adaptability to uncurated ECG data from a real-world hospital. Only slight performance degradation occurs (<1% in most cases) when using these data. CONCLUSION: The results suggest that the BELL can alleviate the reliance on manual ECG labels from cardiologists, a critical bottleneck of the current deep learning-based models. In this way, the BELL can also help deep learning extend its application on automatic ECG analysis, reducing the cardiologists' burden in real-world diagnosis.

Early vascular healing after neXt-generation drug-eluting stent implantation in Patients with non-ST elevation acute Coronary syndrome: a randomized optical coherence Tomography imaging study (EXPECT).

Early vascular healing after drug-eluting stent (DES) implantation is associated with better outcomes and lower incidence of in-stent thrombosis. To examine vascular healing response in patients with non-ST elevation acute coronary syndrome (NSTE-ACS) undergoing percutaneous coronary intervention (PCI) guided by optical coherence tomography (OCT) versus angiography alone. Sixty patients were randomized 1:1:1 to OCT-guided PCI with 3-month OCT follow-up (O3 group, n = 20), angiography-guided PCI with 3-month OCT follow-up (A3 group, n = 20), or angiography-guided PCI with 6-month OCT follow-up (A6 group, n = 20). The primary endpoint was the proportion of covered struts at 3- or 6-month follow-up. The proportion of covered struts in the O3 group was significantly higher than in the A3 group (95.2% vs. 92.3%, p < 0.001), but lower than in the A6 group (95.2% vs. 97.4%, p < 0.001). The O3 group had a lower proportion of incomplete strut apposition (ISA) than the A3 group (0.46% vs. 0.76%, p = 0.006), and higher than the A6 group (0.46% vs. 0.27%, p = 0.018) at follow-up. The optimal cut-off value of ISA after implantation of DES for predicting stent coverage at 3 and 6-month follow-up was 200 µm and 308 µm, respectively. Only one patient experienced target lesion revascularization in the A3 group during a 3-year clinical follow-up. In patients with NSTE-ACS undergoing PCI with DES, OCT guidance achieved higher strut coverage compared with angiography guidance at 3-month follow-up. However, the difference in the strut coverage between the OCT-guided group and the angiography-guided group at 6 months indicates that the degree of endothelialization may be more time-dependent instead of invasive device guidance.

Asundexian versus Apixaban in Patients with Atrial Fibrillation.

BACKGROUND: Stroke prevention with direct-acting oral anticoagulant agents in patients with atrial fibrillation confers a risk of bleeding and limits their use. Asundexian, an activated factor XI (XIa) inhibitor, is an oral anticoagulant that may prevent strokes with less bleeding. METHODS: In a phase 3, international, double-blind trial, we randomly assigned high-risk patients with atrial fibrillation in a 1:1 ratio to receive asundexian at a dose of 50 mg once daily or standard-dose apixaban. The primary efficacy objective was to determine whether asundexian is at least noninferior to apixaban for the prevention of stroke or systemic embolism. The primary safety objective was to determine whether asundexian is superior to apixaban with respect to major bleeding events. RESULTS: A total of 14,810 randomly assigned patients were included in the intention-to-treat population. The mean (±SD) age of the patients was 73.9±7.7 years, 35.2% were women, 18.6% had chronic kidney disease, 18.2% had a previous stroke or transient ischemic attack, 16.8% had received oral anticoagulants for no more than 6 weeks, and the mean CHA2DS2-VASc score (range, 0 to 9, with higher scores indicating a greater risk of stroke) was 4.3±1.3. The trial was stopped prematurely at the recommendation of the independent data monitoring committee. Stroke or systemic embolism occurred in 98 patients (1.3%) assigned to receive asundexian and in 26 (0.4%) assigned to receive apixaban (hazard ratio, 3.79; 95% confidence interval [CI], 2.46 to 5.83). Major bleeding occurred in 17 patients (0.2%) who received asundexian and in 53 (0.7%) who received apixaban (hazard ratio, 0.32; 95% CI, 0.18 to 0.55). The incidence of any adverse event appeared to be similar in the two groups. CONCLUSIONS: Among patients with atrial fibrillation at risk for stroke, treatment with asundexian at a dose of 50 mg once daily was associated with a higher incidence of stroke or systemic embolism than treatment with apixaban in the period before the trial was stopped prematurely. There were fewer major bleeding events with asundexian than with apixaban during this time. (Funded by Bayer; OCEANIC-AF ClinicalTrials.gov number, NCT05643573; EudraCT number, 2022-000758-28.).

Finerenone in Heart Failure with Mildly Reduced or Preserved Ejection Fraction.

BACKGROUND: Steroidal mineralocorticoid receptor antagonists reduce morbidity and mortality among patients with heart failure and reduced ejection fraction, but their efficacy in those with heart failure and mildly reduced or preserved ejection fraction has not been established. Data regarding the efficacy and safety of the nonsteroidal mineralocorticoid receptor antagonist finerenone in patients with heart failure and mildly reduced or preserved ejection fraction are needed. METHODS: In this international, double-blind trial, we randomly assigned patients with heart failure and a left ventricular ejection fraction of 40% or greater, in a 1:1 ratio, to receive finerenone (at a maximum dose of 20 mg or 40 mg once daily) or matching placebo, in addition to usual therapy. The primary outcome was a composite of total worsening heart failure events (with an event defined as a first or recurrent unplanned hospitalization or urgent visit for heart failure) and death from cardiovascular causes. The components of the primary outcome and safety were also assessed. RESULTS: Over a median follow-up of 32 months, 1083 primary-outcome events occurred in 624 of 3003 patients in the finerenone group, and 1283 primary-outcome events occurred in 719 of 2998 patients in the placebo group (rate ratio, 0.84; 95% confidence interval [CI], 0.74 to 0.95; P = 0.007). The total number of worsening heart failure events was 842 in the finerenone group and 1024 in the placebo group (rate ratio, 0.82; 95% CI, 0.71 to 0.94; P = 0.006). The percentage of patients who died from cardiovascular causes was 8.1% and 8.7%, respectively (hazard ratio, 0.93; 95% CI, 0.78 to 1.11). Finerenone was associated with an increased risk of hyperkalemia and a reduced risk of hypokalemia. CONCLUSIONS: In patients with heart failure and mildly reduced or preserved ejection fraction, finerenone resulted in a significantly lower rate of a composite of total worsening heart failure events and death from cardiovascular causes than placebo. (Funded by Bayer; FINEARTS-HF ClinicalTrials.gov number, NCT04435626.).

Apelin-13-Loaded Macrophage Membrane-Encapsulated Nanoparticles for Targeted Ischemic Stroke Therapy via Inhibiting NLRP3 Inflammasome-Mediated Pyroptosis.

Purpose: Ischemic stroke is a refractory disease wherein the reperfusion injury caused by sudden restoration of blood supply is the main cause of increased mortality and disability. However, current therapeutic strategies for the inflammatory response induced by cerebral ischemia-reperfusion (I/R) injury are unsatisfactory. This study aimed to develop a functional nanoparticle (MM/ANPs) comprising apelin-13 (APNs) encapsulated in macrophage membranes (MM) modified with distearoyl phosphatidylethanolamine-polyethylene glycol-RVG29 (DSPE-PEG-RVG29) to achieve targeted therapy against ischemic stroke. Methods: MM were extracted from RAW264.7. PLGA was dissolved in dichloromethane, while Apelin-13 was dissolved in water, and CY5.5 was dissolved in dichloromethane. The precipitate was washed twice with ultrapure water and then resuspended in 10 mL to obtain an aqueous solution of PLGA nanoparticles. Subsequently, the cell membrane was evenly dispersed homogeneously and mixed with PLGA-COOH at a mass ratio of 1:1 for the hybrid ultrasound. DSPE-PEG-RVG29 was added and incubated for 1 h to obtain MM/ANPs. Results: In this study, we developed a functional nanoparticle delivery system (MM/ANPs) that utilizes macrophage membranes coated with DSPE-PEG-RVG29 peptide to efficiently deliver Apelin-13 to inflammatory areas using ischemic stroke therapy. MM/ANPs effectively cross the blood-brain barrier and selectively accumulate in ischemic and inflamed areas. In a mouse I/R injury model, these nanoparticles significantly improved neurological scores and reduced infarct volume. Apelin-13 is gradually released from the MM/ANPs, inhibiting NLRP3 inflammasome assembly by enhancing sirtuin 3 (SIRT3) activity, which suppresses the inflammatory response and pyroptosis. The positive regulation of SIRT3 further inhibits the NLRP3-mediated inflammation, showing the clinical potential of these nanoparticles for ischemic stroke treatment. The biocompatibility and safety of MM/ANPs were confirmed through in vitro cytotoxicity tests, blood-brain barrier permeability tests, biosafety evaluations, and blood compatibility studies. Conclusion: MM/ANPs offer a highly promising approach to achieve ischemic stroke-targeted therapy inhibiting NLRP3 inflammasome-mediated pyroptosis.

Unattended versus conventional blood pressure measurements in hospitalized hypertensive patients.

BACKGROUND: This study aims to compare the differences between unattended and conventional blood pressure measurements in hospitalized hypertensive patients. METHODS: In fall of 2019, hypertensive patients at Ruijin Hospital underwent two rounds of unattended and conventional (nurse-monitored) blood pressure measurement. Both rounds used the same electronic blood pressure monitor with measurements taken three times, 30 s apart. Comparison was made using intra-class correlation coefficients, Bland-Altman plots, paired t-tests, etc. RESULTS: Among the 92 subjects in the study, the median age was 50 years old, with women accounting for 33.7%. Among the subjects, the median duration of hypertension was 8.0 years. The prevalence of diabetes, coronary heart disease, and stroke were 26.1%, 5.4%, and 6.5%, respectively. Whether unattended or conventional measurements were taken first, the average blood pressure measured first was slightly higher than the one measured later, but the difference was within 1-2 mmHg. Except that the average DBP during the round of conventional blood pressure measurements was significantly reduced by 1.6 mmHg compared to the conventional DBP, there were no other significant differences. Subgroup analysis by age, gender, BMI, and diabetes showed no significant difference in blood pressure measurement results between unattended and conventional methods. CONCLUSION: No significant difference was observed between unattended and conventional methods of blood pressure measurement in hospitalized hypertensive patients. Unattended blood pressure measurement can be adopted as the current standard for blood pressure management in hospitalized patients.

Concentrations, probabilistic human and ecological risks assessment attribute to antibiotics residues in river water in China: Systematic review and meta-analysis.

Antibiotics residues even low concentrations increases human health risk and ecological risk. The current study was conducted with the aims of meta-analysis concentrations of antibiotics in river water including amoxicillin (AMX), tetracyclines (TCN), sulfamethoxazole (SMX), ciprofloxacin (CIP), trimethoprim (TMP), azithromycin (AZM) and amoxicillin (AMX) and estimates human health and ecological risks. Search was performed in databases including Scopus, PubMed, Web of Science, Embase, Science direct, Cochrane, Science Direct, Google Scholar were used to retrieve scientific papers from January 1, 2004 to June 15, 2024. The concentration of antibiotics residues was meta-analyzed using random effects model in water river water based on type of antibiotics subgroups. Human health risk assessment from ingestion and dermal contact routs was estimated using target hazard quotient (THQ), total target hazard quotient (TTHQ), carcinogenic (CR) and ecological hazard quotient (EHQ) of antibiotics in river water was estimated using monte carlo simulations (MCS) model. Sixty-two papers on antibiotics in river water with 272 data-reports (n = 28,522) were included. The rank order of antibiotics residues in river water based on pooled concentration was SMX (66.086 ng/L) > CIP (26.005 ng/L) > TCN (17.888 ng/L) > TMP (6.591 ng/L) > AZM (2.077 ng/L) > AMX (0.029 ng/L). The overall pooled concentration of antibiotics residues in river water was 24.262 ng/L, 95 %CI (23.110-25.413 ng/L). TTHQ for adults and children due to antibiotics in water was 2.41E-3 and 2.36E-3, respectively. The sort of antibiotics based on their quota in TTHQ for adults and children was AMX > CIP > TMP > AZM > TCN > SMX. Total CR in adults and children was 2.41E-03 and 2.36E-03, respectively. The sort of antibiotics based on percentile 95 % EHQ was SMX (7.70E+03) > TCN (7.63E+01) > TMP (7.03E-03) > CIP (2.86E-03) > AMX (5.71E-04) and TEHQ values due to antibiotics in river water in China was equal to 7.78E+03. Current study suggests that conduct effective monitoring and water quality control plans to reduce concentration of antibiotics especially SMX, TCN, and CIP in river water of China.

Integration of Transcriptomics and Metabolomics Reveals the Antitumor Mechanism of Protopanaxadiol Triphenylphosphate Derivative in Non-Small-Cell Lung Cancer.

The objective of this study was to enhance the membrane permeability and anticancer effectiveness of (20S)-protopanaxadiol (PPD) by introducing triphenylphosphonium into the OH group at the C-3 site. This study shows that the anti-proliferation activity of CTPPPPD, with an IC50 value of 1.65 ± 0.10 µmol/L, was 33-times better than that of PPD (with an IC50 value of 54.56 ± 4.56 µmol/L) and superior to that of cisplatin (with an IC50 value of 1.82 ± 0.25 µmol/L) against A549 cells. Biological examinations suggested that CTPPPPD treatment reduced the growth rate of A549 cells, increased the permeability of cell membranes, and changed the structure of chromosomal DNA in a concentration-dependent manner. Annexin V/PI assay and flow cytometry were employed to detect the effect of CTPPPPD on the apoptosis of A549 cells. The results showed that CTPPPPD could induce the apoptosis of A549 cells, and the apoptosis rate of A549 cells treated with 0, 1.0, 2.0, and 4.0 µM of CTPPPPD for 24 h was 0%, 4.9%, 12.7%, and 31.0%, respectively. The integration of transcriptomics and metabolomics provided a systematic and detailed perspective on the induced antitumor mechanisms. A combined analysis of DEGs and DAMs suggested that they were primarily involved in the central carbon metabolism pathway in cancer, as well as the metabolism of aminoacyl-tRNA biosynthesis, alanine, aspartate, and glutamate. Central carbon metabolism in cancer-related genes, i.e., SLC16A3, FGFR3, LDHA, PGAM1, and SLC2A1, significantly reduced after treatment with CTPPPPD. In particular, the dominant mechanism responsible for total antitumor activity may be attributed to perturbations in the PI3K-AKT, MAPK, and P53 pathways. The findings derived from transcriptomics and metabolomics were empirically confirmed through q-PCR and molecular docking. Further analyses revealed that CTPPPPD could be a promising lead for the development of protopanaxadiol for non-small-cell lung cancer (NSCLC) drugs.

Biological methane potentials of food waste of different components: Methane yields, production kinetics, and element balance.

This study assessed the methane production from food waste (FW) with dominant components of Meat (MFW), Fruit &Veg (VFW), Grain (GFW), Dairy (DFW), and the mixed feed of these components (MixFW). The high protein and lipid content FW (HPLFW) of MFW, DFW, and MixFW showed the methane yields of 337.0 ± 3.0, 307.4 ± 0.8, and 297.1 ± 1.2 ml-CH4/gCOD, respectively, while those for the high carbohydrate content FW (HCFW) of VFW and GFW were 238.3 ± 1.2 and 171.2 ± 0.3 ml-CH4/gCOD, respectively. A modified two-component kinetic (MTK) model was demonstrated to be the best to describe the methane production kinetics of both HPLFW and HCFW types of feeds. The element balance analysis revealed the element formula of the FW feeds and the methane-conversion organic content. The results obtained from this study showed that the high lipid and animal protein content increased the methane yield and biogas methane composition.

The role of KLF5 in gut microbiota and lung adenocarcinoma: unveiling programmed cell death pathways and prognostic biomarkers.

Lung adenocarcinoma (LUAD) is the most important subtype of lung cancer. It is well known that the gut microbiome plays an important role in the pathophysiology of various diseases, including cancer, but little research has been done on the intestinal microbiome associated with LUAD. Utilizing bioinformatics tools and data analysis, we identified novel potential prognostic biomarkers for LUAD. To integrate differentially expressed genes and clinical significance modules, we used a weighted correlation network analysis system. According to the Peryton database and the gutMGene database, the composition and structure of gut microbiota in LUAD patients differed from those in healthy individuals. LUAD was associated with 150 gut microbiota and 767 gut microbiota targets, with Krüppel-like factor 5 (KLF5) being the most closely related. KLF5 was associated with immune status and correlated well with the prognosis of LUAD patients. The identification of KLF5 as a potential prognostic biomarker suggests its utility in improving risk stratification and guiding personalized treatment strategies for LUAD patients. Altogether, KLF5 could be a potential prognostic biomarker in LUAD.

Dual inhibitory potential of ganoderic acid A on GLUT1/3: computational and in vitro insights into targeting glucose metabolism in human lung cancer.

Human glucose transporters (GLUTs) facilitate the uptake of hexoses into cells. In cancer, the increased proliferation necessitates higher expression of GLUTs, with particular emphasis on GLUT1 and GLUT3. Thus, inhibiting GLUTs holds promise as an anticancer therapy by starving these cells of fuel. Ganoderic acid A (GAA), a triterpene found in Ganoderma lucidum, has anticancer and antidiabetic properties. Recent studies show that GAA reduces glucose uptake in cancer cells, which indicates that GAA may affect GLUT1/GLUT3 by inhibiting glucose uptake. Therefore, this study aimed to inspect whether GAA could target GLUT1/GLUT3 and play an inhibitory role in changing their endofacial and exofacial conformations. To this end, AlphaFold2 was employed to model the endofacial and exofacial conformations of GLUT3 and GLUT1, respectively. Molecular docking, molecular dynamics simulation, cell viability, cellular thermal shift assays (CETSA), glucose uptake, qPCR, and western blotting were harnessed. In comparison to the endofacial (cytochalasin B) and exofacial (phloretin) GLUT1/3 inhibitors, the computational findings unveiled GAA's capacity to bind and stabilize GLUT1/3 in their two conformational states, with a preference for binding the endofacial conformation. A low, non-cytotoxic dose of GAA thermally stabilized both transporters and inhibited glucose uptake in human lung cancer cells, similar to cytochalasin B and phloretin. In conclusion, this study has unearthed novel functionalities of GAA, suggesting its potential utility in cancer therapy by targeting glucose metabolism.

Elucidating the protective mechanism of ganoderic acid DM on breast cancer based on network pharmacology and in vitro experimental validation.

Ganoderma lucidum, a popular medicinal fungus, has been utilized to treat a variety of diseases. It possesses a unique therapeutic and pharmacological reputation in suppressing cancer/tumor progression, especially breast cancer, due to its embedded rich bioactive chemical constituents, mainly triterpenoids (ganoderic acids). The most prevalent malignant tumor in women with a high mortality and morbidity rate is breast cancer. Ganoderic acids A, D, DM, F, and H are evidenced in previous research to have breast cancer-preventive properties by exhibiting autophagic and apoptosis, anti-proliferative, and anti-angiogenesis effects. However, the anti-breast cancer mechanism remains unclear. The putative targets of the ganoderic acids were further determined using bioinformatics techniques and molecular docking calculation. Finally, the key targets were verified in vitro. A total of 53 potential target proteins associated with 202 pathways were predicted to be related to breast cancer. The potential targets were narrowed down to six key targets (AKT1, PIK3CA, epidermal growth factor receptor [EGFR], STAT1, ESR1, and CTNNB1), using different algorithms of the CytoHubba plugin, which were further validated using molecular docking analysis. The ganoderic acid DM (GADM) and the targets (PIK3CA and EGFR) with the strongest interactions were validated via MDA-MB-231 and MCF7 cells. The expression level of PIK3CA in both MDA-MB-231 and MCF7 cells was dose-dependently suppressed by GADM, whereas EGFR expression was unexpectedly increased, which warrants further investigation. These data indicated that the network pharmacology-based prediction of GADM targets for treating human breast cancer could be reliable.

A discovery in traditional Chinese medicine compatibility: Cinnabaris suppresses the Strychni Semen-induced neurotoxicity in Shang-Ke-Jie-Gu tablet.

BACKGROUND: Cinnabaris, as a commonly used mineral drugs, is a classic sedative medicine. Shang-Ke-Jie-Gu tablet is a famous Chinese patent medicine with Cinnabaris, However, the function of Cin in the prescription hasn't been clarified. PURPOSE: Our study evaluated the toxicity of Shang-Ke-Jie-Gu tablet (SK) with or without Cinnabaris, and illuminate the related mechanisms that why cinnabaris is necessary. METHODS: The toxicity of SK and Cin free Shang-Ke-Jie-Gu tablet (CFSK) was evaluated by physical and behavioral tests and histological examinations. The detoxificaion mechanism of Cin on Strychni Semen (SS)-induced neurotoxicity in SK was performed based on the analysis of intestinal absorption, liver metabolism, serum metabolomics, and gut microbiota. The mercury accumulation of SK was assayed using human hair by ICP-MS. RESULTS: Cin was found to inhibit the neurotoxicity of SS in SK. Our study shows that Cin could inhibit SS's absorption in small intestine and promote its metabolism in the liver. A serum metabolomics study showed that taurine and hypotaurine metabolism and retrograde endocannabinoid signaling pathway were associated with Cin attenuation. Association analysis with gut microbiota suggested that Cin could downregulate four key metabolites, including 12­hydroxy arachidonic acid, GM4(d18:1/18:0), C16 sphinganine, and LysoPC(18:1(11Z)/0:0), by downregulating Lachnospiraceae_NK4A136 and upregulating Prevotella to inhibit the toxic effects of SS. In addition, the danger of mercury poisoning in a longer time administration of SK was evaluated using human hair, and no visible increase in mercury was observed. CONCLUSION: As a new discovery in compatibility, Cin was proved to be capable of inhibiting the neurotoxicity not only in SK but also in Cin-SS combination, displaying vital roles in Traditional Chinese Medicines.

Preoperative protective stenting of the carotid artery in severe complex head and neck cancer resection.

OBJECTIVE: To investigate effects of preoperative protective carotid artery (CA) stenting in complex head and neck cancer (HNC) resection. MATERIAL AND METHODS: HNC that encases the CA is complex. Fifty-five patients diagnosed with complex HNC from 2018 to 2021 were enrolled, and were divided into Control group (general complex cases) and carotid artery stent (CAS) group (severe complex cases). All patients underwent standard tumor resection, while patients in the CAS group also underwent preoperative covered CA stenting. Medical information was retrospectively analyzed. RESULTS: CA stenting and tumor resection were successfully performed. Baseline demographics were recorded. CAS and Control groups had similar results for complete tumor resection rate, operation time, and intraoperative blood loss, although the CA was obviously more involved in CAS group than in Control group. However, recurrence rate in the CAS group was significantly lower than Control group, indicating that preoperative CA stent implantation facilitates complete tumor removal. Furthermore, perioperative CA-associated complications including common/internal CA ligation were more frequent in Control group. Overall survival and disease-free survival rate in CAS group and Control group was 87.5% and 69.2%, respectively. Disease-free survival rate in CAS group and Control group was 87.5% and 42.3%, respectively. No postoperative cerebral infarction was observed in either group. Overall hospitalization cost was recorded. CONCLUSIONS: Preoperative protective CA stenting facilitates more thorough tumor removal while better preserving the CA during complex HNC resection, reducing the surgical difficulty. Preoperative CA stenting may be a safe and effective therapeutic option for resection of HNC encasing the CA.

Real-world large sample assessment of drug-related dry eye risk: Based on the FDA adverse event reporting system database.

PURPOSE AND DESIGN: This study aimed to evaluate the risk of drug-related dry eye using real-world data, underscoring the significance of tracing pharmacological etiology for distinct clinical types of dry eye. METHODS: Analyzing adverse event reports in the Food and Drug Administration Adverse Event Reporting System (FAERS) from January 2004 to September 2023, we employed disproportionality analysis and the Bayesian confidence propagation neural network algorithm. The analysis involved categorizing drugs causing dry eye, assessing risk levels, and conducting segmental assessments based on the time of onset of drug-related dry eye adverse reactions. RESULTS: In the FAERS database, adverse reactions related to dry eye were linked to 1160 drugs. Disproportionality analysis identified 33 drugs with significant risk, notably in ophthalmic (brimonidine, bimatoprost), oncology (tisotumab vedotin, erdafitinib), and other medications (isotretinoin, oxymetazoline). The top three drugs with the highest risk of drug-related dry eye are isotretinoin (Bayesian confidence propagation neural network (BCPNN) = 6.88), tisotumab vedotin (BCPNN = 6.88), and brimonidine (BCPNN = 6.77). Among different categories of drugs, respiratory medications have the shortest mean onset time for drug-related dry eye, averaging 50.99 days. The prevalence skewed towards females (69.9 %), particularly in menopausal and elderly individuals (45-70 years old, mean age 54.7 ± 18.2). Reports of drug-related dry eye adverse reactions showed an annual increase. CONCLUSION: Informed clinical decision-making is crucial for preventing drug-related dry eye. Assessing the risk of dry eyes associated with both local and systemic medications helps optimize treatment and provide necessary cautionary information.

A meta analysis of the lateral decubitus position and prone position percutaneous nephrolithotomy.

Objective To analyzed the safety and efficacy of percutaneous nephrolithotomy (PCNL) in lateral decubitus position and prone position for upper ureteral calculi. Methods Databases including PubMed, Springer, ScienceDirect, Wiley Online Library, CNKI, CSPD and VIP were searched for clinical controlled studies involved with lateral decubitus position and prone position PCNL from their establishment to November 2023.Studies were enrolled according to inclusion and exclusion criteria. the dates were compared by Review Manager 5.4 software. Results seven studies were eligible, including 807 cases. The Meta-analysis showed that, blood loss and perioperative complication rate of lateral decubitus position PCNL group were significantly different from those of the prone position PCNL group (P < 0.05). There was no significant difference between the two groups regarding hospital time, operative time, channel establishment time and stone-free rate (P>0.05).Conclusions The lateral decubitus position can reduce blood loss and perioperative complication rate. The lateral decubitus position PCNL is safe and effective for upper ureteral calculi which was deserved clinical popularizing use.

Dative Bonding Activation Enables Precise Functionalization of the Remote B-H Bond of nido-Carborane Clusters.

The innovation of synthetic strategies for selective B-H functionalization is a pivotal objective in the realm of boron cluster chemistry. However, the precise, efficient, and rapid functionalization of a B-H bond of carboranes that is distant from the existing functional groups remains intractable owing to the limited approaches for site-selective control from the established methods. Herein, we report a dative bonding activation strategy for the selective functionalization of a nonclassical remote B-H site of nido-carboranes. By leveraging the electronic effects brought by the exopolyhedral B(9)-dative bond, a cross-nucleophile B-H/S-H coupling protocol of the distal B(5)-H bond has been established. The dative bond not only amplifies the subtle reactivity difference among B-H bonds but also significantly changes the reactive sites, further infusing nido-carboranes with additional structural diversity. This reaction paradigm features mild conditions, rapid conversion, efficient production, broad scope, and excellent group tolerance, thus enabling the applicability to an array of complex bioactive molecules. The efficient and scalable reaction platform is amenable to the modular construction of photofunctional molecules and boron delivery agents for boron neutron capture therapy. This work not only provides an unprecedented solution for the selective diversification of distal B-H sites in nido-carboranes but also holds the potential for expediting the discovery of novel carborane-based functional molecules.

Fluoride Alters Gene Expression via Histone H3K27 Acetylation in Ameloblast-like LS8 Cells.

Excessive fluoride ingestion during tooth development can cause dental fluorosis. Previously, we reported that fluoride activates histone acetyltransferase (HAT) to acetylate p53, promoting fluoride toxicity in mouse ameloblast-like LS8 cells. However, the roles of HAT and histone acetylation status in fluoride-mediated gene expression remain unidentified. Here, we demonstrate that fluoride-mediated histone modification causes gene expression alterations in LS8 cells. LS8 cells were treated with or without fluoride followed by ChIP-Seq analysis of H3K27ac. Genes were identified by differential H3K27ac peaks within ±1 kb from transcription start sites. The levels of mRNA of identified genes were assessed using rea-time PCR (qPCR). Fluoride increased H3K27ac peaks associated with Bax, p21, and Mdm2 genes and upregulated their mRNA levels. Fluoride decreased H3K27ac peaks and p53, Bad, and Bcl2 had suppressed transcription. HAT inhibitors (Anacardic acid or MG149) suppressed fluoride-induced mRNA of p21 and Mdm2, while fluoride and the histone deacetylase (HDAC) inhibitor sodium butyrate increased Bad and Bcl2 expression above that of fluoride treatment alone. To our knowledge, this is the first study that demonstrates epigenetic regulation via fluoride treatment via H3 acetylation. Further investigation is required to elucidate epigenetic mechanisms of fluoride toxicity in enamel development.