A CT-based radiomics nomogram for predicting histologic grade and outcome in chondrosarcoma.

OBJECTIVE: The preoperative identification of tumor grade in chondrosarcoma (CS) is crucial for devising effective treatment strategies and predicting outcomes. The study aims to build and validate a CT-based radiomics nomogram (RN) for the preoperative identification of tumor grade in CS, and to evaluate the correlation between the RN-predicted tumor grade and postoperative outcome. METHODS: A total of 196 patients (139 in the training cohort and 57 in the external validation cohort) were derived from three different centers. A clinical model, radiomics signature (RS) and RN (which combines significant clinical factors and RS) were developed and validated to assess their ability to distinguish low-grade from high-grade CS with area under the curve (AUC). Additionally, Kaplan-Meier survival analysis was applied to examine the association between RN-predicted tumor grade and recurrence-free survival (RFS) of CS. The predictive accuracy of the RN was evaluated using Harrell's concordance index (C-index), hazard ratio (HR) and AUC. RESULTS: Size, endosteal scalloping and active periostitis were selected to build the clinical model. Three radiomics features, based on CT images, were selected to construct the RS. Both the RN (AUC, 0.842) and RS (AUC, 0.835) were superior to the clinical model (AUC, 0.776) in the validation set (P = 0.003, 0.040, respectively). A correlation between Nomogram score (Nomo-score, derived from RN) and RFS was observed through Kaplan-Meier survival analysis in the training and test cohorts (log-rank P < 0.050). Patients with high Nomo-score tumors were 2.669 times more likely to suffer recurrence than those with low Nomo-score tumors (HR, 2.669, P < 0.001). CONCLUSIONS: The CT-based RN performed well in predicting both the histologic grade and outcome of CS.

Modulators targeting protein-protein interactions in Mycobacterium tuberculosis.

Tuberculosis (TB) is a chronic infectious disease caused by Mycobacterium tuberculosis (M. tuberculosis), mainly transmitted through droplets to infect the lungs, and seriously affecting patients' health and quality of life. Clinically, anti-TB drugs often entail side effects and lack efficacy against resistant strains. Thus, the exploration and development of novel targeted anti-TB medications are imperative. Currently, protein-protein interactions (PPIs) offer novel avenues for anti-TB drug development, and the study of targeted modulators of PPIs in M. tuberculosis has become a prominent research focus. Furthermore, a comprehensive PPI network has been constructed using computational methods and bioinformatics tools. This network allows for a more in-depth analysis of the structural biology of PPIs and furnishes essential insights for the development of targeted small-molecule modulators. Furthermore, this article provides a detailed overview of the research progress and regulatory mechanisms of PPI modulators in M. tuberculosis, the causative agent of TB. Additionally, it summarizes potential targets for anti-TB drugs and discusses the prospects of existing PPI modulators.

Ultrafast restricted intramolecular rotation in molecules with aggregation induced emission.

In this work, the ultrafast intramolecular rotation behavior of 1,1,2,3,4,5-hexaphenylsilole has been investigated in several solutions with different viscosities using femtosecond transient absorption spectroscopy combined with density functional theory and time-dependent density functional theory calculations. It is demonstrated that the nonradiative process, which competes with radiative decay, involves two main stages, namely the restricted intramolecular rotation and internal conversion processes. The intramolecular rotation depends on viscosity and presents a significant restriction. The restricted rotational rate is determined to be dozens of picoseconds. The following nonradiative process is strongly dominated by intramolecular rotation. The nonradiative decay rate will decrease with the increase in viscosity, leading to a rise in the radiative probability and photoluminous yield. These results have borne out the mechanism of ultrafast restricted intramolecular rotation of aggregation induced emission and provided a detailed photophysical picture of nonradiative processes.

A comparison of machine learning methods for radiomics modeling in prediction of occult lymph node metastasis in clinical stage IA lung adenocarcinoma patients.

Background: Accurate prediction of occult lymph node metastasis (ONM) is an important basis for determining whether lymph node (LN) dissection is necessary in clinical stage IA lung adenocarcinoma patients. The aim of this study is to determine the best machine learning algorithm for radiomics modeling and to compare the performances of the radiomics model, the clinical-radilogical model and the combined model incorporate both radiomics features and clinical-radilogical features in preoperatively predicting ONM in clinical stage IA lung adenocarcinoma patients. Methods: Patients with clinical stage IA lung adenocarcinoma undergoing curative surgery from one institution were retrospectively recruited and assigned to training and test cohorts. Radiomics features were extracted from the preoperative computed tomography (CT) images of the primary tumor. Seven machine learning algorithms were used to construct radiomics models, and the model with the best performance, evaluated using the area under the curve (AUC), was selected. Univariate and multivariate logistic regression analyses were performed on the clinical-radiological features to identify statistically significant features and to develop a clinical model. The optimal radiomics and clinical models were integrated to build a combined model, and its predictive performance was assessed using receiver operating characteristic curves, Brier score, and decision curve analysis (DCA). Results: This study included 258 patients who underwent resection (training cohort, n=182; test cohort, n=76). Six radiomics features were identified. Among the seven machine learning algorithms, extreme gradient boosting (XGB) demonstrated the highest performance for radiomics modeling, with an AUC of 0.917. The combined model improved the AUC to 0.933 and achieved a Brier score of 0.092. DCA revealed that the combined model had optimal clinical efficacy. Conclusions: The superior performance of the combined model, based on XGB algorithm in predicting ONM in patients with clinical stage IA lung adenocarcinoma, might aid surgeons in deciding whether to conduct mediastinal LN dissection and contribute to improve patients' prognosis.

Planar Cell Polarity in the Multiciliated Epithelial Lining of the Mouse Eustachian Tube.

OBJECTIVES: Planar cell polarity (PCP) signaling, essential for uniform alignment and directional beating of motile cilia, has been investigated in multiciliated epithelia. As a complex structure connecting the middle ear to the nasopharynx, the eustachian tube (ET) is important in the onset of ear-nose-throat diseases. However, PCP signaling, including the orientation that is important for ciliary motility and clearance function in the ET, has not been studied. We evaluated PCP in the ET epithelium. STUDY DESIGN: Morphometric examination of the mouse ET. METHODS: We performed electron microscopy to assess ciliary polarity in the mouse ET, along with immunohistochemical analysis of PCP protein localization in the ET epithelium. RESULTS: We discovered PCP in the ET epithelium. Motile cilia were aligned in the same direction in individual and neighboring cells; this alignment manifested as ciliary polarity in multiciliated cells. Additionally, PCP proteins were asymmetrically localized between adjacent cells in the plane of the ET. CONCLUSIONS: The multiciliated ET epithelium exhibits polarization, suggesting novel structural features that may be critical for ET function. LEVEL OF EVIDENCE: NA Laryngoscope, 2024.

Pharmacokinetics, pharmacodynamics, and safety of frunexian in healthy Chinese volunteer adults: A randomized dose-escalation phase I study.

The purpose of this study was to evaluate the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of frunexian (formerly known as EP-7041 and HSK36273) injection, a small molecule inhibitor of activated coagulation factor XI (FXIa), in healthy Chinese adult volunteers. This study was a randomized, placebo- and positive-controlled, sequential, ascending-dose (0.3/0.6/1.0/1.5/2.25 mg/kg/h) study of 5-day continuous intravenous infusions of frunexian. Frunexian administration exhibited an acceptable safety profile with no bleeding events. Steady state was rapidly reached with a median time ranging from 1.02 to 1.50 h. The mean half-life ranged from 1.15 to 1.43 h. Frunexian plasma concentration at a steady state and area under the concentration-time curve exhibited dose-proportional increases. The dose-escalation study of frunexian demonstrated its progressively enhanced capacities to prolong activated partial thromboplastin time (aPTT) and inhibit FXIa activity. The correlations between PK and PD biomarkers (aPTT/baseline and FXI clotting activity/baseline) were described by the two Emax models, with the EC50 values of 8940 and 1300 ng/mL, respectively. Frunexian exhibits good safety and PK/PD properties, suggesting it is a promising candidate for anticoagulant drug.

Can Perceivers Differentiate Intense Facial Expressions? Eye Movement Patterns.

Recent research on intense real-life faces has shown that although there was an objective difference in facial activities between intense winning faces and losing faces, viewers failed to differentiate the valence of such expressions. In the present study, we explored whether participants could perceive the difference between intense positive facial expressions and intense negative facial expressions in a forced-choice response task using eye-tracking techniques. Behavioral results showed that the recognition accuracy rate for intense facial expressions was significantly above the chance level. For eye-movement patterns, the results indicated that participants gazed more and longer toward the upper facial region (eyes) than the lower region (mouth) for intense losing faces. However, the gaze patterns were reversed for intense winning faces. The eye movement pattern for successful differentiation trials did not differ from failed differentiation trials. These findings provided preliminary evidence that viewers can utilize intense facial expression information and perceive the difference between intense winning faces and intense losing faces produced by tennis players in a forced-choice response task.

Serum high mobility group box 1 as a potential biomarker for the progression of kidney disease in patients with type 2 diabetes.

Background: As a damage-associated molecular pattern protein, high mobility group box 1 (HMGB1) is associated with kidney and systemic inflammation. The predictive and therapeutic value of HMGB1 as a biomarker has been confirmed in various diseases. However, its value in diabetic kidney disease (DKD) remains unclear. Therefore, this study aimed to investigate the correlation between serum and urine HMGB1 levels and DKD progression. Methods: We recruited 196 patients with type 2 diabetes mellitus (T2DM), including 109 with DKD and 87 T2DM patients without DKD. Additionally, 60 healthy participants without T2DM were also recruited as controls. Serum and urine samples were collected for HMGB1 analysis. Simultaneously, tumor necrosis factor receptor superfamily member 1A (TNFR-1) in serum and kidney injury molecule (KIM-1) in urine samples were evaluated for comparison. Results: Serum and urine HMGB1 levels were significantly higher in patients with DKD than in patients with T2DM and healthy controls. Additionally, serum HMGB1 levels significantly and positively correlated with serum TNFR-1 (R 2 = 0.567, p<0.001) and urine KIM-1 levels (R 2 = 0.440, p<0.001), and urine HMGB1 has a similar correlation. In the population with T2DM, the risk of DKD progression increased with an increase in serum HMGB1 levels. Multivariate logistic regression analysis showed that elevated serum HMGB1 level was an independent risk factor for renal function progression in patients with DKD, and regression analysis did not change in the model corrected for multiple variables. The restricted cubic spline depicted a nonlinear relationship between serum HMGB1 and renal function progression in patients with DKD (p-nonlinear=0.007, p<0.001), and this positive effect remained consistent across subgroups. Conclusion: Serum HMGB1 was significantly correlated with DKD and disease severity. When the HMGB1 level was ≥27 ng/ml, the risk of renal progression increased sharply, indicating that serum HMGB1 can be used as a potential biomarker for the diagnosis of DKD progression.

Epstein-Barr virus gp42 antibodies reveal sites of vulnerability for receptor binding and fusion to B cells.

Epstein-Barr virus (EBV) causes infectious mononucleosis and is associated with B cell lymphomas. EBV glycoprotein 42 (gp42) binds HLA class II and activates membrane fusion with B cells. We isolated gp42-specific monoclonal antibodies (mAbs), A10 and 4C12, which use distinct mechanisms to neutralize virus infection. mAb A10 was more potent than the only known neutralizing gp42 mAb, F-2-1, in neutralizing EBV infection and blocking binding to HLA class II. mAb 4C12 was similar to mAb A10 in inhibiting glycoprotein-mediated B cell fusion but did not block receptor binding, and it was less effective in neutralizing infection. Crystallographic structures of gH/gL/gp42/A10 and gp42/4C12 complexes revealed two distinct sites of vulnerability on gp42 for receptor binding and B cell fusion. Passive transfer of mAb A10 into humanized mice conferred nearly 100% protection from viremia and EBV lymphomas after EBV challenge. These findings identify vulnerable sites on EBV that may facilitate therapeutics and vaccines.

A novel intronic TCOF1 pathogenic variant in a Chinese family with Treacher Collins syndrome.

BACKGROUND: Treacher Collins syndrome (TCS; OMIM 154500) is a craniofacial developmental disorder. METHODS: To investigate the genetic features of a four-generation Chinese family with TCS, clinical examinations, hearing tests, computed tomography, whole-exome sequencing (WES), Sanger sequencing, reverse transcription (RT)-PCR, and the Minigene assay were performed. RESULTS: The probands, an 11-year-old male and his cousin exhibited typical clinical manifestations of TCS including conductive hearing loss, downward slanting palpebral fissures, and mandibular hypoplasia. Computed tomography revealed bilateral fusion of the anterior and posterior stapedial crura and malformation of the long crura of the incus. WES of both patients revealed a novel heterozygous intronic variant, i.e., c.4342 + 5_4342 + 8delGTGA (NM_001371623.1) in TCOF1. Minigene expression analysis revealed that the c.4342 + 5_4342 + 8delGTGA variant in TCOF1 caused a partial deletion of exon 24 (c.4115_4342del: p.Gly1373_Arg1448del), which was predicted to yield a truncated protein. The deletion was further confirmed via RT-PCR and sequencing of DNA from proband blood cells. A heterozygous variant in the POLR1C gene (NM_203290; exon6; c.525delG) was found almost co-segregated with the TCOF1 pathogenic variant. CONCLUSIONS: In conclusion, we identified a heterozygous TCOF1 splicing variant c.4342 + 5_4342 + 8delGTGA (splicing) in a Chinese TSC family with ossicular chain malformations and facial anomalies. Our findings broadened the spectrum of TCS variants and will facilitate diagnostics and prognostic predictions.

Ct-based intratumoral and peritumoral radiomics for predicting prognosis in osteosarcoma: A multicenter study.

PURPOSE: To evaluate the performance of CT-based intratumoral, peritumoral and combined radiomics signatures in predicting prognosis in patients with osteosarcoma. METHODS: The data of 202 patients (training cohort:102, testing cohort:100) with osteosarcoma admitted to the two hospitals from August 2008 to February 2022 were retrospectively analyzed. Progression free survival (PFS) and overall survival (OS) were used as the end points. The radiomics features were extracted from CT images, three radiomics signatures（RSintratumoral, RSperitumoral, RScombined）were constructed based on intratumoral, peritumoral and combined radiomics features, respectively, and the radiomics score (Rad-score) were calculated. Kaplan-Meier survival analysis was used to evaluate the relationship between the Rad-score with PFS and OS, the Harrell's concordance index (C-index) was used to evaluate the predictive performance of the radiomics signatures. RESULTS: Finally, 8, 6, and 21 features were selected for the establishment of RSintratumoral, RSperitumoral, and RScombined, respectively. Kaplan-Meier survival analysis confirmed that the Rad-scores of the three RSs were significantly correlated with the PFS and OS of patients with osteosarcoma. Among the three radiomics signatures, RScombined had better predictive performance, the C-index of PSF prediction was 0.833 in the training cohort and 0.814 in the testing cohort, the C-index of OS prediction was 0.796 in the training cohort and 0.764 in the testing cohort. CONCLUSIONS: CT-based intratumoral, peritumoral and combined radiomics signatures can predict the prognosis of patients with osteosarcoma, which may assist in individualized treatment and improving the prognosis of osteosarcoma patients.

Co-catalpol alleviates fluoxetine-induced main toxicity: Involvement of ATF3/FSP1 signaling-mediated inhibition of ferroptosis.

BACKGROUND: Fluoxetine is often used as a well-known first-line antidepressant. However, it is accompanied with hepatogenic injury as its main organ toxicity, thereby limiting its application despite its superior efficacy. Fluoxetine is commonly traditionally used combined with some Chinese antidepressant prescriptions containing Rehmannia glutinosa (Dihuang) for depression therapy and hepatoprotection. Our previous experiments showed that co-Dihuang can alleviate fluoxetine-induced liver injury while efficiencies, and catalpol may be the key ingredient to characterize the toxicity-reducing and synergistic effects. However, whether co-catalpol can alleviate fluoxetine-induced liver injury and its toxicity-reducing mechanism remain unclear. PURPOSE: On the basis of the first recognition of the dose and duration at which pre-fluoxetine caused hepatic injury, co-catalpol's alleviation of fluoxetine-induced hepatic injury and its pathway was comprehensively elucidated. METHOD AND RESULTS: The hepatoprotection of co-catalpol was evaluated by serum biochemical indexes sensitive to hepatic injury and multiple staining techniques for hepatic pathologic analysis. Subsequently, the pathway by which catalpol alleviated fluoxetine-induced hepatic injury was predicted by network pharmacology to be predominantly the inhibition of ferroptosis. These were validated and confirmed in subsequent experiments with key technologies and diagnostic reagents related to ferroptosis. Further molecular docking showed that activating transcription factor 3 (ATF3) and ferroptosis suppressor protein 1 (FSP1) were the the most prospective molecules for catalpol and fluoxetine among many ferroptosis-related molecules. The critical role of ATF3/FSP1 signaling was further observed by surface plasmon resonance, diagnostic reagents, transmission electron microscopy, Western blot, real-time PCR, immunofluorescence, and immunohistochemistry. Results showed that fluoxetine directly bound to ATF3 and FSP1; agonisting ATF3 or blocking FSP1 abolished the alleviation of catalpol on fluoxetine-induced liver injury, and both exacerbated ferroptosis. Moreover, co-catalpol significantly enhanced the antidepressant efficacy of fluoxetine against depressive behaviours in mice. CONCLUSION: The hepatic impairment properties of fluoxetine were largely dependent on ATF3/FSP1 target-mediated ferroptosis. Co-catalpol alleviated fluoxetine-induced hepatic injury while enhancing its antidepressant efficacy, and that ATF3/FSP1 signaling-mediated inhibition of ferroptosis was involved in its co-administration detoxification mechanism. This study was the first to reveal the hepatotoxicity characteristics, targets, and mechanisms of fluoxetine; provide a detoxification and efficiency regimen by co-catalpol; and elucidate the detoxification mechanism.

Dual-energy CT-based radiomics in predicting EGFR mutation status non-invasively in lung adenocarcinoma.

Objectives: Patients with epidermal growth factor receptor (EGFR) mutations in lung adenocarcinoma (LUAD) can benefit from individualized targeted therapy. This study aims to develop, compare, analyse prediction models based on dual-energy spectral computed tomography (DESCT) and CT-based radiomic features to non-invasively predict EGFR mutation status in LUAD. Materials and methods: Patients with LUAD (n = 175), including 111 patients with and 64 patients without EGFR mutations, were enrolled in the current study. All patients were randomly divided into a training dataset (122 cases) and validation dataset (53 cases) at a ratio of 7:3. After extracting CT-based radiomic, DESCT and clinical features, we built seven prediction models and a nomogram of the best prediction. Receiver operating characteristic (ROC) curves and the mean area under the curve (AUC) values were used for comparisons among the models to obtain the best prediction model for predicting EGFR mutations. Results: The best distinguishing ability is the combined model incorporating radiomic, DESCT and clinical features for predicting the EGFR mutation status with an AUC of 0.86 (95 % CI: 0.79-0.92) in the training group and an AUC value of 0.83 (95 % CI: 0.73, 0.96) in the validation group. Conclusions: Our study provides a predictive nomogram non-invasively with a combination of CT-based radiomic, DESCT and clinical features, which can provide image-based biological information for targeted therapy of LUAD with EGFR mutations.

Acupuncture for primary insomnia: Effectiveness, safety, mechanisms and recommendations for clinical practice.

Primary insomnia (PI) is an increasing concern in modern society. Cognitive-behavioral therapy for insomnia is the first-line recommendation, yet limited availability and cost impede its widespread use. While hypnotics are frequently used, balancing their benefits against the risk of adverse events poses challenges. This review summarizes the clinical and preclinical evidence of acupuncture as a treatment for PI, discussing its potential mechanisms and role in reliving insomnia. Clinical trials show that acupuncture improves subjective sleep quality, fatigue, cognitive impairments, and emotional symptoms with minimal adverse events. It also positively impacts objective sleep processes, including prolonging total sleep time, improving sleep efficiency, reducing sleep onset latency and wake after sleep onset, and enhancing sleep architecture/structure, including increasing N3% and REM%, and decreasing N1%. However, methodological shortcomings in some trials diminish the overall quality of evidence. Animal studies suggest that acupuncture restores circadian rhythms in sleep-deprived rodents and improves their performance in behavioral tests, possibly mediated by various clinical variables and pathways. These may involve neurotransmitters, brain-derived neurotrophic factors, inflammatory cytokines, the hypothalamic-pituitary-adrenal axis, gut microbiota, and other cellular events. While the existing findings support acupuncture as a promising therapeutic strategy for PI, additional high-quality trials are required to validate its benefits.

Intratumoral and peritumoral CT radiomics in predicting prognosis in patients with chondrosarcoma: a multicenter study.

OBJECTIVE: To evaluate the efficacy of the CT-based intratumoral, peritumoral, and combined radiomics signatures in predicting progression-free survival (PFS) of patients with chondrosarcoma (CS). METHODS: In this study, patients diagnosed with CS between January 2009 and January 2022 were retrospectively screened, and 214 patients with CS from two centers were respectively enrolled into the training cohorts (institution 1, n = 113) and test cohorts (institution 2, n = 101). The intratumoral and peritumoral radiomics features were extracted from CT images. The intratumoral, peritumoral, and combined radiomics signatures were constructed respectively, and their radiomics scores (Rad-score) were calculated. The performance of intratumoral, peritumoral, and combined radiomics signatures in PFS prediction in patients with CS was evaluated by C-index, time-dependent area under the receiver operating characteristics curve (time-AUC), and time-dependent C-index (time C-index). RESULTS: Eleven, 7, and 16 features were used to construct the intratumoral, peritumoral, and combined radiomics signatures, respectively. The combined radiomics signature showed the best prediction ability in the training cohort (C-index, 0.835; 95%; confidence interval [CI], 0.764-0.905) and the test cohort (C-index, 0.800; 95% CI, 0.681-0.920). Time-AUC and time C-index showed that the combined signature outperformed the intratumoral and peritumoral radiomics signatures in the prediction of PFS. CONCLUSION: The CT-based combined signature incorporating intratumoral and peritumoral radiomics features can predict PFS in patients with CS, which might assist clinicians in selecting individualized surveillance and treatment plans for CS patients. CRITICAL RELEVANCE STATEMENT: Develop and validate CT-based intratumoral, peritumoral, and combined radiomics signatures to evaluate the efficacy in predicting prognosis of patients with CS. KEY POINTS: • Reliable prognostic models for preoperative chondrosarcoma are lacking. • Combined radiomics signature incorporating intratumoral and peritumoral features can predict progression-free survival in patients with chondrosarcoma. • Combined radiomics signature may facilitate individualized stratification and management of patients with chondrosarcoma.

Emotion contagion and physiological synchrony: The more intimate relationships, the more contagion of positive emotions.

The study aimed to explore how interpersonal closeness (friends vs. strangers) and emotion type (positive vs. negative) influenced emotion contagion and physiological synchrony between interacting partners. Twenty-eight friend dyads (n = 56) and 29 stranger dyads (n = 58) participated in an emotion contagion laboratory task. In each dyad, one participant, the 'sender', was randomly asked to watch a film clip (neutral, positive, or negative), while their partner, the 'observer' passively observed the sender's facial expressions. Participants' electrocardiograms (ECG) and facial electromyography (EMG) signals were recorded using the BIOPAC system. Results revealed that observing the sender's facial expressions led to the observer's spontaneous mimicry and emotional contagion, accompanied by enhanced physiological synchrony between interacting partners. In the positive emotion condition, the observers reported more positive emotions and displayed stronger zygomaticus major activity in friend dyads than in stranger dyads. Greater physiological synchrony (heart rate and heart rate variability) between interacting partners was also observed in friend dyads than in stranger dyads in the positive emotion condition. These results indicate that positive emotion contagion is more likely to occur between close partners than negative emotion contagion.

Investigation of the principle of concoction by using the processing excipient Glycyrrhiza uralensis Fisch. juice to reduce the main toxicity of Dioscorea bulbifera L. and enhance its main efficacy as expectorant and cough suppressant.

ETHNOPHARMACOLOGICAL RELEVANCE: Dioscorea bulbifera L. (Rhizoma Dioscoreae Bulbiferae; RDB) is commonly used as an expectorant and cough suppressant herb but is accompanied by severe hepatotoxicity. Using the juice of auxiliary herbs (such as Glycyrrhiza uralensis Fisch. (Glycyrrhizae Radix et Rhizoma; GRR) juice) in concocting poisonous Chinese medicine is a conventional method to reduce toxicity or increase effects. Our previous study found that concoction with GRR juice provided a detoxifying effect against the major toxic hepatotoxicity induced by RDB, but the principle for the detoxification of the concoction is unknown to date. AIM OF THE STUDY: The principle of concoction was investigated by using the processing excipient GRR juice to reduce the major toxic hepatotoxicity of RDB, and the efficacy of RDB as an expectorant and cough suppressant was enhanced. MATERIALS AND METHODS: In this study, common factors (RDB:GRR ratio, concocted temperature, and concocted time) in the concoction process were used for the preparation of each RDB concocted with GRR juice by using an orthogonal experimental design. We measured the content of the main toxic compound diosbulbin B (DB) and serum biochemical indicators and performed pathological analysis in liver tissues of mice to determine the best detoxification process of RDB concocted with GRR juice. On this basis, the biological mechanisms of target organs were detected by Western blot and enzyme-linked immunosorbent assay at the inflammation and apoptosis levels. Further, the effects of RDB on expectorant and cough suppressant with GRR juice were evaluated by the conventional tests of phenol red expectorant and concentrated ammonia-induced cough. Lastly, the major compounds in the GRR juice introduced to RDB concoction were determined. RESULTS: RDB concocted with GRR juice significantly alleviated DB content, serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase levels, and improved liver pathological damages. The best detoxification process was achieved by using an RDB:GRR ratio of 100:20 at 120 °C for 20 min. Further, RDB concocted with GRR juice down-regulated the protein levels of nuclear factor kappa B (NF-κB), cyclooxygenase 2 (COX-2), and Bcl-2 related X protein (Bax) in the liver and enhanced the expectorant and cough suppressant effects of RDB. Finally, liquiritin (LQ) and glycyrrhizic acid (GA) in the GRR juice were introduced to the RDB concoction. CONCLUSION: Concoction with GRR juice not only effectively reduced the major toxic hepatotoxicity of RDB but also enhanced its main efficacy as an expectorant and cough suppressant, and that the rationale for the detoxification and/or potentiation of RDB was related to the reduction in the content of the main hepatotoxic compound, DB, the introduction of the hepatoprotective active compounds, LQ and GA, in the auxiliary GRR juice, as well as the inhibition of NF-κB/COX-2/Bax signaling-mediated inflammation and apoptosis.

Suppression of alpha-tubulin acetylation potentiates therapeutic efficacy of Eribulin in liver cancer.

Hepatocellular carcinoma (HCC) is a prevalent cancer with limited effective treatments. Eribulin mesylate is a novel chemotherapy drug that inhibits microtubule elongation and may impact the tumor microenvironment and immune pathway. This study aims to investigate the impact of changes in microtubule acetylation levels on HCC development and treatment outcomes. Clinical and molecular data were aggregated from databases, with survival analysis conducted to evaluate the relevance of microtubule acetylation. In vitro experiments using HCC cell lines and a tumor cell transplantation model in C57BL/c mice were performed to investigate the effects of microtubule acetylation on Eribulin treatment. A significant correlation was found between the level of lysine 40 acetylation of α-tubulin (acetyl-α-tubulin-lys40) and overall survival of HCC patients, with a better prognosis associated with a lower level of acetyl-α-tubulin-lys40. Knocking down ATAT1 or overexpressing HDAC6 reduced the level of acetyl-α-tubulin-lys40 and sensitized Eribulin treatment both in vitro and in vivo. In summary, acetyl-α-tubulin-lys40 was increased in HCC and was associated with a shorter overall survival of HCC patients. Reducing the level of acetyl-α-tubulin-lys40 can enhance sensitivity to Eribulin treatment both in vitro and in vivo, thereby establishing acetyl-α-tubulin-lys40 as a potential prognostic marker and predictive indicator for Eribulin treatment in HCC patients.

Identifying complementary and alternative medicine recommendations for anxiety treatment and care: a systematic review and critical assessment of comprehensive clinical practice guidelines.

Background: Clinical practice guidelines (CPGs) are used to guide decision-making, especially regarding complementary and alternative medicine (CAM) therapies that are unfamiliar to orthodox healthcare providers. This systematic review aimed to critically review and summarise CAM recommendations associated with anxiety management included in the existing CPGs. Methods: Seven databases, websites of six international guidelines developing institutions, and the National Centre for Complementary and Integrative Health website were systematically searched. Their reporting and methodological quality were evaluated using the Reporting Items for practice Guidelines in Healthcare checklist and the Appraisal of Guidelines for Research and Evaluation (2nd version) instrument, respectively. Results: Ten CPGs were included, with reporting rates between 51.4 and 88.6%. Seven of these were of moderate to high methodological quality. Seventeen CAM modalities were implicated, involving phytotherapeutics, mind-body practice, art therapy, and homeopathy. Applied relaxation was included in 70% CPGs, which varied in degree of support for its use in the treatment of generalised anxiety disorder. There were few recommendations for other therapies/products. Light therapy was not recommended for use in generalised anxiety disorder, and St John's wort and mindfulness were not recommended for use in social anxiety disorder in individual guidelines. Recommendations for the applicability of other therapies/products for treating a specific anxiety disorder were commonly graded as "unclear, unambiguous, or uncertain". No CAM recommendations were provided for separation anxiety disorder, specific phobia or selective mutism. Conclusion: Available guidelines are limited in providing logically explained graded CAM recommendations for anxiety treatment and care. A lack of high-quality evidence and multidisciplinary consultation during the guideline development are two major reasons. High quality and reliable clinical evidence and the engagement of a range of interdisciplinary stakeholders are needed for future CPG development and updating. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022373694, identifier CRD42022373694.

Targeting the ZNF-148/miR-335/SOD2 signaling cascade triggers oxidative stress-mediated pyroptosis and suppresses breast cancer progression.

BACKGROUND: The implication of zinc finger protein 148 (ZNF-148) in pathophysiology of most human cancers has been reported; however, the biological functions of ZNF-148 in breast cancer remain unclear. This study sought to elucidate the potential molecular mechanism of ZNF-148 on breast cancer pathology. METHODS: ZNF148 expression was tested in breast cancer tissues and cells. Then, cells were transfected with ZNF-148 overexpression or downregulation vector, and the cell proliferation, pyroptosis, apoptosis, and reactive oxygen species (ROS) production were analyzed by MTT, western blot, flow cytometry, and immunofluorescence staining, respectively. Tumor-bearing nude mouse was used to evaluate tumorigenesis of ZNF-148. Mechanisms underpinning ZNF-148 were examined using bioinformatics and luciferase assays. RESULTS: We found that ZNF-148 was upregulated in breast cancer tissues and cell lines. Knockdown of ZNF-148 suppressed malignant phenotypes, including cell proliferation, epithelial-mesenchymal transition, and tumorigenesis in vitro and in vivo, while ZNF-148 overexpression had the opposite effects. Further experiments showed that ZNF-148 deficiency promoted ROS production and triggered both apoptotic and pyroptotic cell death, which were restored by cotreating cells with ROS scavengers. A luciferase reporter assay revealed that miR-335 was the downstream target of ZNF-148 and that overexpressed ZNF-148 increased superoxide dismutase 2 (SOD2) expression by sponging miR-335. In parallel, both miR-335 downregulation and SOD2 overexpression abrogated the antitumor effects of ZNF-148 deficiency on proliferation and pyroptosis in breast cancer cells. CONCLUSIONS: Our findings indicated that ZNF-148 promotes breast cancer progression by triggering miR-335/SOD2/ROS-mediated pyroptotic cell death and aid the identification of potential therapeutic targets for breast cancer.