Background/Aims: Lenvatinib resistance remains a critical barrier in advanced hepatocellular carcinoma (HCC) therapy. However, the underlying mechanisms and strategies for reversing resistance remain incompletely understood. Methods: Integrated transcriptomics of lenvatinib-resistant patient tumors and an acquired-resistance murine model identified a novel macrophage subpopulation. Functional validation employed CRISPR-SAM screening, conditioned medium (CM) assays, subcutaneous/orthotopic xenografts, patient-derived organoids (PDOs), and patient-derived xenografts (PDXs). Mechanistic studies included ChIP-qPCR, co-immunoprecipitation, and pharmacologic targeting. Clinical relevance was assessed in a retrospective cohort. Results: Resistant HCC exhibited significant enrichment of a COLEC12high TAM subset , which correlated with poor survival and treatment response. These TAMs secreted neuregulin-1 (NRG1) , activating HER2/HER3-AKT signaling in tumor cells to drive cancer stemness and lenvatinib resistance. Mechanistically, in TAMs COLEC12 sequestered STAT1 in the cytoplasm, preventing its phosphorylation, and thereby derepressing STAT3-mediated NRG1 transcription. Depletion of NRG1 reversed the stemness phenotypes and resensitized tumors to lenvatinib both in vitro and in vivo. Clinically, high NRG1 expression predicted an inferior lenvatinib response and shorter survival. Crucially, the bispecific anti-HER2/HER3 antibody zenocutuzumab restored lenvatinib efficacy in PDOs, PDXs, and murine models. Conclusions Our work establishes the COLEC12high TAM/NRG1 axis as a master regulator of therapeutic resistance and identifies NRG1 as a predictive biomarker, providing a clinically actionable strategy to overcome lenvatinib resistance in HCC.

Background: and Purpose Limited evidence exists on the effectiveness of endovascular treatment (EVT) for acute posterior circulation tandem lesion (PCTL). This study aimed to explore the role of extracranial vertebral artery (VA) stenting in patients with PCTL stroke undergoing EVT. Methods: Individual patient data were pooled from the BASILAR (EVT for Acute Basilar Artery Occlusion Study) and PERSIST (Posterior Circulation Ischemic Stroke) registries. Patients with PCTLs who underwent EVT were included in the present cohort and divided into the stenting and nonstenting groups based on the placement of extracranial VA stents. The primary efficacy outcome was the modified Rankin Scale (mRS) scores at 90 days and 1 year. Safety outcomes included 24-hour symptomatic intracranial hemorrhage (sICH) and all-cause mortality at 90 days and 1 year post-surgery. Results: A combined dataset of 1,320 patients with posterior circulation artery occlusion, including 263 (19.9%) with tandem lesions, of whom 217 (median age, 65 years; 82.9% male) met the inclusion criteria for the analysis. The stenting group had 84 (38.7%) patients, while the non-stenting group had 133 (61.3%). After adjustment for the potential confounders, extracranial VA stenting was associated with favorable shifts in mRS scores at both 90 days (adjusted common odds ratio [OR], 2.30; 95% confidence interval [CI], 1.23–4.28; P<0.01) and 1 year (adjusted OR [aOR], 2.04; 95% CI [1.05–3.97]; P=0.04), along with lower rate of mortality at both 90 days (aOR, 0.45; 95% CI [0.21–0.93]; P=0.01) and 1 year (aOR, 0.36; 95% CI [0.16–0.79]; P=0.01), with no significant difference in sICH incidence (aOR, 0.35; 95% CI [0.06–1.98]; P=0.24). Conclusion Extracranial VA stenting during EVT may improve functional outcomes and reduce mortality in patients with PCTL strokes.

Objective: To investigate the distribution characteristics of CD36 antigen in healthy individuals in Xinjiang, China and analyze the molecular mechanisms underlying CD36 deficiency. Methods: Flow cytometry was used to assess CD36 antigen expression on platelets from 881 healthy individuals who underwent physical examinations between June and August 2023. Differences in CD36 antigen distribution among ethnic groups were compared, and genotyping and third-generation sequencing were conducted on samples with CD36 deficiency. Results: Among the 881 samples, 4 cases (0.5%) of CD36 type Ⅱ deficiency were identified. The deficiency frequency was 0.7% (3/430) in Han individuals and 0.3% (1/363) in Uygur individuals, with no statistically significant difference between the two groups (P>0.05). No mutations were detected in the coding regions of the deficient samples. Two samples exhibited a (TG)11 in intron 3. Among the 12 linked mutation sites, g. 55589 G>A was mutated to g. 55589G Del, while g. 55593 A del did not occur; however, g. 55591A>T was observed nearby. Additionally, 52742insGAAAA was present in 100% of the (TG)11 haplotypes, potentially representing a novel linked mutation. Conclusion: This study indicates that the positive frequency of CD36 antigen in Xinjiang is relatively high, suggesting a low risk of alloimmune diseases in clinical practice. The (TG)11 in intron 3 is not universally present in all CD36 type Ⅱ deficiency cases, and the number of linked mutation sites extends beyond the previously reported 12.

The mutual transformation and intertweaving of qi stagnation and blood stasis exist through the development and progression of pediatric pneumonia.Based on the pathogenic mechanism of qi stagnation and blood stasis obstructing the lungs and by analyzing the progression of pneumonia,this paper proposed that the traditional Chinese medicine(TCM)pathogenesis of pediatric pneumonia can be divided into three stages:early,middle,and late.In the early stage,external pathogens invade and then lead to lung qi stagnation and blockage.In the middle stage,qi stagnation and blood stasis block the lungs and then cause blood vessel stagnation.In the late stage,qi stagnation and blood stasis linger,and then result into the residual pathogens lurking in the lungs.Accordingly,the principles of treating pediatric pneumonia are proposed,i.e.,ventilating the lungs and dispelling pathogens,activating blood circulation and resolving stasis,relieving qi stagnation and unblocking blockage.The strategies for treating pediatric pneumonia in three stages are also introduced:for the early stage of pneumonia characterized by lung qi stagnation and blockage,the formula Yinqiao San combined with Wuhu Erchen Decoction are used for clearing lung-heat,resolving phlegm,and relieving wheezing;for the middle stage of pneumonia characterized by the intertweaving of qi stagnation and blood stasis,the formula Xuefu Zhuyu Decoction combined with Xuanfei Baidu Prescription are used for activating blood circulation and resolving stasis,ventilating the lungs and removing toxins,relieving qi stagnation and unblocking blockage;for the late stage of pneumonia characterized by qi stagnation and blood stasis lingering in the lungs,Qinghao Biejia Decoction and Qingfei Touxie Prescription are used by modification for clearing heat and nourishing yin,resolving blood stasis and relieving qi stagnation,nourishing yin and subduing yang.The approach to treating pediatric pneumonia from the pathogenic mechanism of qi stagnation and blood stasis obstructing the lung show significant efficacy on improving clinical symptoms in children with pediatric pneumonia and preventing the progression of pneumonia,and will provide reference to the clinical prevention and treatment of pediatric pneumonia.

BACKGROUND: Disease-modifying therapies have been approved for the treatment of relapsing multiple sclerosis (RMS). The present study aims to examine the safety of teriflunomide in Chinese patients with RMS. METHODS: This non-randomized, multi-center, 24-week, prospective study enrolled RMS patients with variant (c.421C>A) or wild type ABCG2 who received once-daily oral teriflunomide 14 mg. The primary endpoint was the relationship between ABCG2 polymorphisms and teriflunomide exposure over 24 weeks. Safety was assessed over the 24-week treatment with teriflunomide. RESULTS: Eighty-two patients were assigned to variant ( n  = 42) and wild type groups ( n  = 40), respectively. Geometric mean and geometric standard deviation (SD) of pre-dose concentration (variant, 54.9 [38.0] μg/mL; wild type, 49.1 [32.0] μg/mL) and area under plasma concentration-time curve over a dosing interval (AUC tau ) (variant, 1731.3 [769.0] μg∙h/mL; wild type, 1564.5 [1053.0] μg∙h/mL) values at steady state were approximately similar between the two groups. Safety profile was similar and well tolerated across variant and wild type groups in terms of rates of treatment emergent adverse events (TEAE), treatment-related TEAE, grade ≥3 TEAE, and serious adverse events (AEs). No new specific safety concerns or deaths were reported in the study. CONCLUSION: ABCG2 polymorphisms did not affect the steady-state exposure of teriflunomide, suggesting a similar efficacy and safety profile between variant and wild type RMS patients. REGISTRATION NCT04410965, https://clinicaltrials.gov .
Humans ; Crotonates/adverse effects* ; Toluidines/adverse effects* ; Nitriles ; Hydroxybutyrates ; Female ; Male ; Adult ; ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics* ; Middle Aged ; Multiple Sclerosis, Relapsing-Remitting/genetics* ; Prospective Studies ; Young Adult ; Neoplasm Proteins/genetics* ; East Asian People

BACKGROUND: While emotional distress, encompassing anxiety and depression, has been associated with negative clinical outcomes, its impact across various clinical departments and general hospitals has been less explored. Previous studies with limited sample sizes have examined the effectiveness of specific treatments (e.g., antidepressants) rather than a systemic management strategy for outcome improvement in non-psychiatric inpatients. To enhance the understanding of the importance of addressing mental health care needs among non-psychiatric patients in general hospitals, this study retrospectively investigated the impacts of emotional distress and the effects of early detection and management of depression and anxiety on hospital length of stay (LOS) and rate of long LOS (LLOS, i.e., LOS >30 days) in a large sample of non-psychiatric inpatients. METHODS: This retrospective cohort study included 487,871 inpatients from 20 non-psychiatric departments of a general hospital. They were divided, according to whether they underwent a novel strategy to manage emotional distress which deployed the Huaxi Emotional Distress Index (HEI) for brief screening with grading psychological services (BS-GPS), into BS-GPS ( n = 178,883) and non-BS-GPS ( n = 308,988) cohorts. The LOS and rate of LLOS between the BS-GPS and non-BS-GPS cohorts and between subcohorts with and without clinically significant anxiety and/or depression (CSAD, i.e., HEI score ≥11 on admission to the hospital) in the BS-GPS cohort were compared using univariable analyses, multilevel analyses, and/or propensity score-matched analyses, respectively. RESULTS: The detection rate of CSAD in the BS-GPS cohort varied from 2.64% (95% confidence interval [CI]: 2.49%-2.81%) to 20.50% (95% CI: 19.43%-21.62%) across the 20 departments, with a average rate of 5.36%. Significant differences were observed in both the LOS and LLOS rates between the subcohorts with CSAD (12.7 days, 535/9590) and without CSAD (9.5 days, 3800/169,293) and between the BS-GPS (9.6 days, 4335/178,883) and non-BS-GPS (10.8 days, 11,483/308,988) cohorts. These differences remained significant after controlling for confounders using propensity score-matched comparisons. A multilevel analysis indicated that BS-GPS was negatively associated with both LOS and LLOS after controlling for sociodemographics and the departments of patient discharge and remained negatively associated with LLOS after controlling additionally for the year of patient discharge. CONCLUSION Emotional distress significantly prolonged the LOS and increased the LLOS of non-psychiatric inpatients across most departments and general hospitals. These impacts were moderated by the implementation of BS-GPS. Thus, BS-GPS has the potential as an effective, resource-saving strategy for enhancing mental health care and optimizing medical resources in general hospitals.
Humans ; Retrospective Studies ; Male ; Length of Stay/statistics & numerical data* ; Female ; Middle Aged ; Adult ; Psychological Distress ; Inpatients/psychology* ; Aged ; Anxiety/diagnosis* ; Depression/diagnosis*

This study identified 8 members including NjBIN2 of the GSK3 family in Nardostachys jatamansi by bioinformatics analysis. Moreover, the phylogenetic tree revealed that the GKS3 family members of N. jatamansi had a close relationship with those of Arabidopsis. RT-qPCR results showed that NjBIN2 presented a tissue-specific expression pattern with the highest expression in roots, suggesting that NjBIN2 played a role in root growth and development. In addition, the application of epibrassinolide or the brassinosteroid(BR) synthesis inhibitor(brassinazole) altered the expression pattern of NjBIN2 and influenced the photomorphogenesis(cotyledon opening) and root development of N. jatamansi, which provided direct evidence about the functions of NjBIN2. In conclusion, this study highlights the roles of BIN2 in regulating the growth and development of N. jatamansi by analyzing the expression pattern and biological function of NjBIN2. It not only enriches the understanding about the regulatory mechanism of the growth and development of N. jatamansi but also provides a theoretical basis and potential gene targets for molecular breeding of N. jatamansi with improved quality in the future.
Brassinosteroids/metabolism* ; Steroids, Heterocyclic/metabolism* ; Gene Expression Regulation, Plant/drug effects* ; Plant Proteins/metabolism* ; Phylogeny ; Nardostachys/metabolism* ; Plant Growth Regulators/pharmacology* ; Plant Roots/drug effects*

Traditional Chinese medicine(TCM) capable of clearing heat and removing toxin is most commonly used in clinical practice and has the effect of removing fire-heat and toxin. Studies have shown that most of the Ilex plants have the effect of clearing heat and removing toxin, among which the varieties of I. cornuta, I. pubescens, I. rotunda, I. latifolia, and I. chinensis are most widely used. These plants generally contain triterpenoids and their glycosides, alkaloids, flavonoids, phenylpropanoids, and other chemical components, especially pentacyclic triterpenoids. According to their skeletons, pentacyclic triterpenoids can be divided into the oleanane type, the ursane type, the lupinane type, etc. Among them, ursane-type components are the most abundant, and 136 species have been found so far. These components have been proved to have pharmacological effects such as anti-inflammatory, anti-tumor, hypolipidemic, anti-thrombosis, cardiomyocyte-protective, antibacterial, and hepatoprotective effects. Therefore, this paper systematically reviews the domestic and foreign literature on Ilex plants with a focus on the research progress on pentacyclic triterpenoids and their pharmacological activities, aiming to provide reference for the development of TCM resources with the effect of clearing heat and removing toxin.
Ilex/chemistry* ; Plants, Medicinal/chemistry* ; Pentacyclic Triterpenes/pharmacology* ; Medicine, Chinese Traditional ; Drugs, Chinese Herbal/pharmacology* ; Humans ; Animals

Based on the interleukin-17(IL-17) signaling pathway, this study explores the effect and mechanism of Bufei Decoction on Klebsiella pneumoniae pneumonia in rats. SD rats were randomly divided into the control group, model group, Bufei Decoction low-dose group(6.68 g·kg~(-1)·d~(-1)), Bufei Decoction high-dose group(13.36 g·kg~(-1)·d~(-1)), and dexamethasone group(1.04 mg·kg~(-1)·d~(-1)), with 10 rats in each group. A pneumonia model was established by tracheal drip injection of K. pneumoniae. After successful model establishment, the improvement in lung tissue damage was observed following drug administration. Core targets and signaling pathways were screened using transcriptomics techniques. Real-time fluorescence quantitative polymerase chain reaction was used to detect the mRNA expression of core targets interleukin-6(IL-6), interleukin-1β(IL-1β), tumor necrosis factor-α(TNF-α), and chemokine CXC ligand 6(CXCL6). Western blot was used to assess key proteins in the IL-17 signaling pathway, including interleukin-17A(IL-17A), nuclear transcription factor-κB activator 1(Act1), tumor necrosis factor receptor-associated factor 6(TRAF6), and downstream phosphorylated p38 mitogen-activated protein kinase(p-p38 MAPK), and phosphorylated nuclear factor-κB p65(p-NF-κB p65). Apoptosis of lung tissue cells was detected by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling(TUNEL). The results showed that, compared with the control group, the model group exhibited significant pathological damage in lung tissue. The mRNA expression of IL-6, IL-1β, TNF-α, and CXCL6, as well as the protein levels of IL-17A, Act1, TRAF6, p-p38 MAPK/p38 MAPK, and p-NF-κB p65/NF-κB p65, were significantly increased, and the number of apoptotic cells was notably higher, indicating successful model establishment. Compared with the model group, both low-and high-dose groups of Bufei Decoction showed reduced pathological damage in lung tissue. The mRNA expression levels of IL-6, IL-1β, TNF-α, and CXCL6, and the protein levels of IL-17A, Act1, TRAF6, p-p38 MAPK/p38 MAPK, and p-NF-κB p65/NF-κB p65, were significantly decreased, with a significant reduction in apoptotic cells in the high-dose group. In conclusion, Bufei Decoction can effectively improve lung tissue damage and reduce inflammation in rats with K. pneumoniae. The mechanism may involve the regulation of the IL-17 signaling pathway and the reduction of apoptosis.
Animals ; Interleukin-17/metabolism* ; Drugs, Chinese Herbal/administration & dosage* ; Rats, Sprague-Dawley ; Signal Transduction/drug effects* ; Rats ; Male ; Klebsiella pneumoniae/physiology* ; Klebsiella Infections/immunology* ; Humans ; Lung/drug effects*

OBJECTIVE: To evaluate early effectiveness of posterior 180-degree decompression via unilateral biportal endoscopy (UBE) in the treatment of lumbar spinal stenosis (LSS) combined with Michigan State University (MSU)-1 lumbar disc herniation (LDH). METHODS: A retrospective analysis was conducted on clinical data from 33 patients with LSS combined with MSU-1 LDH, who met selection criteria and were treated between March 2022 and January 2024. All patients underwent UBE-assisted 180-degree spinal canal decompression. The cohort comprised 17 males and 16 females, aged 37-82 years (mean, 67.1 years). Preoperative presentations included bilateral lower limbs intermittent claudication and radiating pain, with disease duration ranging from 5 to 13 months (mean, 8.5 months). Affected segments included L _{3, 4} in 4 cases, L _{4, 5} in 28 cases, and L ₅, S ₁ in 1 case. LSS was rated as Schizas grade A in 4 cases, grade B in 5 cases, grade C in 13 cases, and grade D in 11 cases. LDH was categorized as MSU-1A in 24 cases, MSU-1B in 2 cases, and MSU-1AB in 7 cases. Intraoperative parameters (operation time, blood loss) and postoperative hospitalization length were recorded. The visual analogue scale (VAS) score and Oswestry Disability Index (ODI) were used to assess the lower limb pain and functional outcomes after operation. Clinical efficacy was evaluated at last follow-up via modified MacNab criteria. Quantitative radiological assessments included dural sac cross-sectional area (DSCA) measurements and spinal stenosis grading on lumbar MRI. Morphological classification of lumbar canal stenosis was determined according to the Schizas grading, categorized into four grades. RESULTS: The operation time was 60.4-90.8 minutes (mean, 80.3 minutes) and intraoperative blood loss was 13-47 mL (mean, 29.9 mL). The postoperative hospitalization length was 3-5 days (mean, 3.8 days). All patients were followed up 12-16 months (mean, 13.8 months). The VAS score and ODI improved at immediate and 3, 6, and 12 months after operation compared to before operation, and the differences between different time points were significant ( P<0.05). At last follow-up, the clinical efficacy assessed by the modified MacNab criteria were graded as excellent in 23 cases, good in 9 cases, and poor in 1 case, with an excellent and good rate of 96.97%. Postoperative lumbar MRI revealed the significant decompression of the dural sac in 32 cases, with 1 case showing inadequate dural expansion. DSCA measurements confirmed progressive enlargement and stenosis reduction over time. The differences were significant ( P<0.05) before operation, immediately after operation, and at 6 months after operation. At 6 months after operation, Schizas grading of spinal stenosis improved to grade A in 27 cases and grade B in 6 cases. CONCLUSION Posterior 180-degree decompression via UBE is a safe and feasible strategy for treating LSS combined with MSU-1 LDH, achieving effective neural decompression while preserving intervertebral disc integrity.
Humans ; Spinal Stenosis/diagnostic imaging* ; Male ; Female ; Aged ; Lumbar Vertebrae/surgery* ; Middle Aged ; Intervertebral Disc Displacement/complications* ; Decompression, Surgical/methods* ; Retrospective Studies ; Endoscopy/methods* ; Adult ; Aged, 80 and over ; Treatment Outcome