Chronic mucocutaneous candidiasis (CMC) is an infectious phenotype characterized by recurrent or persistent infections caused by Candida species that affect the skin, nails, oral, and genital mucosae for a duration exceeding six months. Current research suggests that CMC is an immunodeficiency disease with a complex pathogenesis. Patients with CMC have various defects in nonspecific and/or specific immunity against Candida infection, resulting in the inability of patients to defend themselves against Candida infection. CMC can be stratified into primary CMC and secondary CMC based on etiology. Primary CMC is often associated with genetic mutations leading to immunodeficiencies in T helper cell 17 and interleukin-17, whereas secondary CMC is frequently linked to factors such as human immunodeficiency virus infection, diabetes mellitus, and immunosuppressive therapy. Primary CMC typically manifests as Candida infections, with distinct genetic mutations often correlating to varied concomitant symptoms. Secondary CMC may present with not only superficial mucosal Candida infections and manifestations of the underlying primary disease but also with invasive fungal infections. Diagnosing CMC requires an integration of medical history and clinical presentation, supplemented by the outcomes of auxiliary diagnostic procedures, including microscopic examination of fungal smear, fungal culture, immunological testing, and genetic sequencing and analysis. Furthermore, confirming primary CMC requires exclusion of the aforementioned secondary factors. At present, antifungal drugs such as triazoles, echinocandins, and polyenes are the main treatment for CMC. Moreover, immunotherapy with biologics such as Janus kinase (JAK) inhibitors provides more options for the clinical treatment of patients with CMC. Gene therapy also has potential clinical application value. In this review, we discuss the etiologies, pathogenesis, clinical manifestations, diagnosis, and treatments of CMC, aiming to provide a reference for the clinical diagnosis and treatment of CMC.

BACKGROUND:β-Caryophyllene has a variety of pharmacological activities such as antioxidant,anti-inflammatory and anti-apoptotic,which may have a better therapeutic effect on osteoarthritis.OBJECTIVE:To investigate the effect and mechanism of β-caryophyllene on mouse osteoarthritis.METHODS:Forty C57BL/6J mice were randomly divided into sham group,model group,low-dose β-caryophyllene group and high-dose β-caryophyllene group,with 10 mice in each group.Hulth method was used to construct an osteoarthritis model in the latter three groups.Four weeks after modeling,70 and 140 mg/kg/d β-caryophyllene was intragastrically given in the low-and high-dose β-caryophyllene groups,respectively,and normal saline was given by gavage in the sham group and the model group,once a day,for 4 weeks.After administration,knee joint morphological changes were observed by hematoxylin-eosin staining,serum levels of inflammatory factors(tumor necrosis factor-α,interleukin-1β,interleukin-6,and interleukin-10)were detected by ELISA,and oxidative stress indexes(glutathione peroxidase,superoxide dismutase,and malondialdehyde)were detected by chemiluminescence.The expression levels of key proteins in the Sonic hedgehog(Shh)/glioma associated oncogene homolog 1(Gli1)signaling pathway were detected by immunohistochemistry and western blot.RESULTS AND CONCLUSION:(1)Compared with the sham group,a large number of inflammatory cells infiltrated in the knee joint of mice in the model group,cartilage tissue was seriously damaged,serum levels of tumor necrosis factor-α,interleukin-1β,interleukin-6,interleukin-10 and malondialdehyde were significantly increased(P＜0.01),the activities of glutathione peroxidase and superoxide dismutase were significantly decreased(P＜0.01),and the relative expression levels of Shh and Gli1 in the knee joint were significantly increased(P＜0.01).(2)Compared with the model group,in the low-and high-dose β-caryophyllene groups,inflammatory cell infiltration in the mouse knee joint was decreased,cartilage tissue injury was alleviated,serum levels of tumor necrosis factor-α,interleukin-1 β,interleukin-6 and malondialdehyde were significantly decreased(P＜0.05),the activities of glutathione peroxidase and superoxide dismutase were significantly increased(P＜0.01),and the expression levels of Shh and Gli1 in the knee joint were significantly decreased(P＜0.01).The above-mentioned improvements were more significant in the high-dose β-caryophyllene group than the low-dose β-caryophyllene group.To conclude,β-caryophyllene can improve osteoarthritis,and its mechanism may be related to reducing inflammation and oxidative stress damage by regulating the Shh/Gli1 signaling pathway.

BACKGROUND:β-Caryophyllene has a variety of pharmacological activities such as antioxidant,anti-inflammatory and anti-apoptotic,which may have a better therapeutic effect on osteoarthritis.OBJECTIVE:To investigate the effect and mechanism of β-caryophyllene on mouse osteoarthritis.METHODS:Forty C57BL/6J mice were randomly divided into sham group,model group,low-dose β-caryophyllene group and high-dose β-caryophyllene group,with 10 mice in each group.Hulth method was used to construct an osteoarthritis model in the latter three groups.Four weeks after modeling,70 and 140 mg/kg/d β-caryophyllene was intragastrically given in the low-and high-dose β-caryophyllene groups,respectively,and normal saline was given by gavage in the sham group and the model group,once a day,for 4 weeks.After administration,knee joint morphological changes were observed by hematoxylin-eosin staining,serum levels of inflammatory factors(tumor necrosis factor-α,interleukin-1β,interleukin-6,and interleukin-10)were detected by ELISA,and oxidative stress indexes(glutathione peroxidase,superoxide dismutase,and malondialdehyde)were detected by chemiluminescence.The expression levels of key proteins in the Sonic hedgehog(Shh)/glioma associated oncogene homolog 1(Gli1)signaling pathway were detected by immunohistochemistry and western blot.RESULTS AND CONCLUSION:(1)Compared with the sham group,a large number of inflammatory cells infiltrated in the knee joint of mice in the model group,cartilage tissue was seriously damaged,serum levels of tumor necrosis factor-α,interleukin-1β,interleukin-6,interleukin-10 and malondialdehyde were significantly increased(P＜0.01),the activities of glutathione peroxidase and superoxide dismutase were significantly decreased(P＜0.01),and the relative expression levels of Shh and Gli1 in the knee joint were significantly increased(P＜0.01).(2)Compared with the model group,in the low-and high-dose β-caryophyllene groups,inflammatory cell infiltration in the mouse knee joint was decreased,cartilage tissue injury was alleviated,serum levels of tumor necrosis factor-α,interleukin-1 β,interleukin-6 and malondialdehyde were significantly decreased(P＜0.05),the activities of glutathione peroxidase and superoxide dismutase were significantly increased(P＜0.01),and the expression levels of Shh and Gli1 in the knee joint were significantly decreased(P＜0.01).The above-mentioned improvements were more significant in the high-dose β-caryophyllene group than the low-dose β-caryophyllene group.To conclude,β-caryophyllene can improve osteoarthritis,and its mechanism may be related to reducing inflammation and oxidative stress damage by regulating the Shh/Gli1 signaling pathway.

ObjectiveDiscriminating atypical hepatocellular carcinoma (HCC) from other malignancies in liver nodules classified as Liver Imaging Reporting and Data System category M (LR-M) remains a significant diagnostic challenge on conventional ultrasound examination. The LR-M category, originally intended to capture non-HCC malignancies, paradoxically contains up to 63% of atypical HCCs that deviate from classic enhancement patterns, leading to potential misdiagnosis and suboptimal treatment planning. While deep learning has shown promise in HCC diagnosis, most existing models rely exclusively on single-modality ultrasound, overlooking the diagnostic benefits of integrating complementary information from multiple imaging sources. To address this gap, we propose a novel attention-weighted tri-modal ultrasound network (TUS-Net) that integrates contrast-enhanced ultrasound (CEUS), B-mode ultrasound (BUS), and time-intensity curves (TICs) to improve diagnostic accuracy for these clinically challenging lesions. MethodsOur framework incorporates a three-dimensional convolutional neural network (C3D) backbone to extract spatiotemporal features from CEUS videos, capturing dynamic vascular patterns critical for lesion characterization. To effectively fuse complementary modalities, we introduce a dual-channel feature fusion module (DCFFM) that adaptively combines features from CEUS and BUS through channel-wise attention mechanisms, allowing the model to dynamically weigh the contribution of each modality based on diagnostic relevance. Additionally, we propose a temporal intensity feature fusion module (TIFFM) that leverages quantitative hemodynamic information from TICs to guide the model’s attention toward diagnostically critical temporal phases, such as arterial wash-in and portal venous washout. The model is further enhanced by automated lesion localization using YOLOX and class activation mapping for interpretability, ensuring that predictions align with clinically meaningful imaging features. ResultsEvaluated on a tri-modal ultrasound dataset comprising 161 patients with pathologically confirmed LR-M nodules (131 atypical HCC and 30 non-HCC malignancies), our model achieved an accuracy of 86.83%, a sensitivity of 92.50%, a specificity of 75.50%, and an AUC of 89.32% in screening atypical HCC. Compared to single-modality baselines, TUS-Net demonstrated superior specificity, a clinically critical metric given the higher risk associated with misclassifying non-HCC malignancies. Ablation studies confirmed the contribution of each module, with the full model outperforming both standard C3D and 3D ResNet backbones integrated with attention mechanisms. A reader study involving junior and senior radiologists further validated the clinical utility of AI assistance, showing consistent improvements in specificity and inter-reader consistency, particularly for less experienced clinicians. ConclusionThese results surpass existing benchmark models and demonstrate the potential of our approach to enhance diagnostic precision in clinically specific cases. By intelligently fusing multi-modal ultrasound data with attention-guided mechanisms, TUS-Net offers a reliable and interpretable tool that holds promise for improving the non-invasive diagnosis of atypical HCC in challenging LR-M liver nodules.

ObjectiveDiscriminating atypical hepatocellular carcinoma (HCC) from other malignancies in liver nodules classified as Liver Imaging Reporting and Data System category M (LR-M) remains a significant diagnostic challenge on conventional ultrasound examination. The LR-M category, originally intended to capture non-HCC malignancies, paradoxically contains up to 63% of atypical HCCs that deviate from classic enhancement patterns, leading to potential misdiagnosis and suboptimal treatment planning. While deep learning has shown promise in HCC diagnosis, most existing models rely exclusively on single-modality ultrasound, overlooking the diagnostic benefits of integrating complementary information from multiple imaging sources. To address this gap, we propose a novel attention-weighted tri-modal ultrasound network (TUS-Net) that integrates contrast-enhanced ultrasound (CEUS), B-mode ultrasound (BUS), and time-intensity curves (TICs) to improve diagnostic accuracy for these clinically challenging lesions. MethodsOur framework incorporates a three-dimensional convolutional neural network (C3D) backbone to extract spatiotemporal features from CEUS videos, capturing dynamic vascular patterns critical for lesion characterization. To effectively fuse complementary modalities, we introduce a dual-channel feature fusion module (DCFFM) that adaptively combines features from CEUS and BUS through channel-wise attention mechanisms, allowing the model to dynamically weigh the contribution of each modality based on diagnostic relevance. Additionally, we propose a temporal intensity feature fusion module (TIFFM) that leverages quantitative hemodynamic information from TICs to guide the model’s attention toward diagnostically critical temporal phases, such as arterial wash-in and portal venous washout. The model is further enhanced by automated lesion localization using YOLOX and class activation mapping for interpretability, ensuring that predictions align with clinically meaningful imaging features. ResultsEvaluated on a tri-modal ultrasound dataset comprising 161 patients with pathologically confirmed LR-M nodules (131 atypical HCC and 30 non-HCC malignancies), our model achieved an accuracy of 86.83%, a sensitivity of 92.50%, a specificity of 75.50%, and an AUC of 89.32% in screening atypical HCC. Compared to single-modality baselines, TUS-Net demonstrated superior specificity, a clinically critical metric given the higher risk associated with misclassifying non-HCC malignancies. Ablation studies confirmed the contribution of each module, with the full model outperforming both standard C3D and 3D ResNet backbones integrated with attention mechanisms. A reader study involving junior and senior radiologists further validated the clinical utility of AI assistance, showing consistent improvements in specificity and inter-reader consistency, particularly for less experienced clinicians. ConclusionThese results surpass existing benchmark models and demonstrate the potential of our approach to enhance diagnostic precision in clinically specific cases. By intelligently fusing multi-modal ultrasound data with attention-guided mechanisms, TUS-Net offers a reliable and interpretable tool that holds promise for improving the non-invasive diagnosis of atypical HCC in challenging LR-M liver nodules.

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.

[Objective] To establish a new scoring system to predict the perioperative outcomes (operation time, intraoperative blood loss, and trifecta achievement) in patients undergoing robot-assisted partial nephrectomy (RAPN) by integrating the RENAL and Mayo adhesive probability (MAP) scores. [Methods] Clinical data of 178 patients with renal cell carcinoma who underwent RAPN performed by the same surgeon in our hospital during Jan.2015 and Jan.2022 were retrospectively analyzed.The RENAL and MAP scores of all patients were calculated.Linear regression and logistic regression were used to evaluate the associations between the components of the RENAL and MAP scores (a total of 6 variables) and perioperative outcomes.The factors with significant associations were then included into logistic regression analysis to identify independent predictors for constructing an assessment system for perioperative outcomes, and the receiver operating characteristic (ROC) curve was plotted to calculate the area under the curve (AUC) to predict its efficacy. [Results] Multivariate linear regression analysis showed that tumor size (β=6.14, 95%CI: 1.93—10.34, P=0.004), exophytic rate (β=10.60, 95%CI: 3.44—17.76, P=0.004), and perinephric fat thickness (β=16.48, 95%CI: 8.52—24.45, P<0.001) were significantly associated with operation time.Tumor size (β=10.55 95%CI: 5.60—15.49, P<0.001) was associated with both intraoperative blood loss and trifecta achievement (OR=1.73, 95%CI: 1.26—2.36, P=0.001). Multivariate logistic regression analysis of these 3 factors identified tumor size (OR=9.07, 95% CI: 1.18—69.45, P=0.03) and perinephric fat thickness (OR=2.28, 95%CI: 1.86—6.04, P=0.01) as independent predictors of perioperative outcomes.Based on these findings, the tumor size and perinephric fat thickness (RP) scoring was constructed, which demonstrated better predictive ability than RENAL score or MAP score alone (RP vs.RENAL vs.MAP: 0.766 vs.0.548 vs.0.684). [Conclusion] The RP score includes fewer variables than the RENAL and MAP scores but outperforms them.

Objective To evaluate the clinical efficacy of Long's spinal manipulation therapy combined with four postures of rotational tendon-releasing maneuver in treating lumbar disc herniation(LDH).Methods Sixty-eight patients diagnosed with LDH were enrolled from the Department of Acupuncture and Rehabilitation at Guangdong Second Traditional Chinese Medicine Hospital between July 2024 and December 2024.Patients were randomly divided into an observation group and a control group using a random number table,with 34 cases in each group.The control group received Long's spinal manipulation therapy,while the observation group received additional training in four postures of rotational tendon-releasing maneuver.Both groups were treated for 2 weeks,with a 1-month follow-up.Clinical efficacy was evaluated after treatment by comparing Visual Analogue Scale(VAS)scores,Oswestry Disability Index(ODI)scores,and Japanese Orthopaedic Association(JOA)scores before and after intervention.Spinal parameters including maximum lumbar curvature angle,pelvic tilt angle,and maximum vertebral rotation angle were assessed using the DIERS formetric 3D evaluation system.Results(1)The total effective rate was 94.12%(32/34)in the observation group and 91.18%(31/34)in the control group,and both groups achieved ideal therapeutic efficacy,but the difference was not statistically significant(P＞0.05).(2)After treatment,the VAS scores of patients in the two groups significantly improved(P＜0.05),and the observation group was significantly superior to the control group in improving VAS scores,with statistically significant differences(P＜0.05).At the 1-month follow-up after treatment,the VAS score of the observation group significantly improved(P＜0.05),and the observation group was significantly superior to the control group,and the difference was statistically significant(P＜0.05).(3)After treatment,the JOA and ODI scores of the patients in the two groups significantly improved(P＜0.05),and the observation group was significantly superior to the control group in improving the JOA and ODI scores,and the difference was statistically significant(P＜0.05).At 1-month follow-up after treatment,JOA and ODI scores of the observation group significantly improved(P＜0.05),and the observation group was significantly superior to the control group,with statistically significant differences(P＜0.05).(4)After treatment,the maximum angle of lumbar flexion,pelvic torsion angle,and maximum rotation angle of the vertebral body of the two groups of patients were significantly improved(P＜0.05),and the observation group was significantly better than the control group,and the difference was statistically significant(P＜0.05).At the 1-month follow-up after treatment,the maximum angle of lumbar flexion,pelvic torsion angle,and maximum vertebral rotation angle of the observation group were significantly improved(P＜0.05),and the observation group was significantly superior to the control group,and the difference was statistically significant(P＜0.05).Conclusion The combination of Long's spinal manipulation therapy and four postures of rotational tendon-releasing maneuve significantly improves spinal alignment,reduces pain and disability,and enhances quality of life in patients with LDH,demonstrating notable clinical efficacy.

Objective To establish a human luminal breast cancer stem cell(BCSC)model and investigate the inhibitory effects of astragaloside Ⅳ(AS-Ⅳ)on BCSC growth.Methods MCF-7 breast cancer cells were cultured in stem cell-specific medium to induce BCSC formation.The BCSCs were then divided into a blank control group and an AS-Ⅳ treatment group,both groups were given PBS or AS-Ⅳ treatment.Morphological changes were observed after intervention.The therapeutic efficacy of AS-Ⅳ was evaluated using 3D spheroid formation and cell viability assays.Transcriptomic profiling and gene expression analysis were performed to elucidate the underlying mechanisms.Results Compared with the MCF7 breast cancer cells,MCF7 breast cancer stem cell mammospheres exhibited accelerated growth(P＜0.01)and significantly increased expression of the stemness marker ALDH1A1(P＜0.01).Further comparison with the blank control group revealed that astragaloside Ⅳ(AS-Ⅳ)treatment significantly inhibited MCF7 breast cancer stem cell proliferation(P＜0.001)and slowed mammosphere growth(P＜0.01).Transcriptomic analysis demonstrated that differentially expressed genes(DEGs)induced by stem cell modeling and AS-Ⅳ intervention were enriched in the cellular senescence signaling pathway.AS-Ⅳ intervention substantially increased the number of SA-β-gal-positive cells(P＜0.01).RT-PCR analysis confirmed that AS-Ⅳsignificantly upregulated mRNA expression of IL-1α(P＜0.01),P21(P＜0.001),and P53(P＜0.05)in MCF7 breast cancer stem cells.Conclusion Astragaloside Ⅳ suppresses the growth of human luminal breast cancer stem cells by inducing cellular senescence.

Objective To evaluate the clinical efficacy of tendon-regulating and bone-setting manipulation combined with subtalar joint arthroereisis in the treatment of adolescent flexible flatfoot.Methods A retrospective analysis was conducted on the clinical data of 86 children with flexible flatfoot treated at Dongguan Hospital of Guangzhou University of Chinese Medicine(Dongguan Traditional Chinese Medicine Hospital)between December 2022 and February 2024.Based on pre-treatment physician-patient communication,the children were divided into an trial group(44 cases)and a control group(42 cases).The control group received subtalar joint arthroereisis alone,while the trial group received additional tendon-regulating and bone-setting manipulation just once one day before surgery and once weekly postoperatively for one month,with a follow-up period of no less than 6 months.The Visual Analogue Scale(VAS)pain score,American Orthopaedic Foot & Ankle Society(AOFAS)ankle-hindfoot score,Tegner activity score,radiographic parameters,and static plantar pressure parameters of the two groups were observed before and after surgery.Results(1)Regarding clinical data,all surgeries were successfully completed in both groups.There were no statistically significant differences in perioperative general data,including operative time,hospital stays,and complication rates(P＞0.05).All children were followed up for no less than 6 months.The results showed that at the final follow-up,the VAS pain score,AOFAS ankle-hindfoot score,and Tegner activity score were significantly improved in both groups compared to preoperative values(P＜0.05),and the improvement in the trial group was significantly greater than that in the control group(P＜0.05 or P＜0.01).(2)Regarding radiographic parameters,at the final follow-up,the talonavicular coverage angle(TNCA),talus-first metatarsal angle(T1MT),talus-second metatarsal angle(T2MT)on weight-bearing anteroposterior radiographs,and the Meary angle between the talus and the first metatarsal as well as calcaneal Pitch angle(Pitch angle)on weight-bearing lateral radiographs were significantly improved in both groups compared to preoperative values(P＜0.05).The improvement in Meary angle,T1MT angle,and T2MT angle in the trial group was significantly greater than that in the control group(P＜0.01).However,there were no statistically significant differences in TNCA and Pitch angle between the two groups at the final follow-up(P＞0.05).(3)Regarding plantar pressure testing,at the 1-month postoperative follow-up,the forefoot load increased significantly in both groups compared to preoperative values(P＜0.05),while the midfoot load significantly decreased(P＜0.05).The increase in forefoot load and decrease in midfoot load in the trial group were significantly greater than those in the control group(P＜0.05 or P＜0.01).However,there were no statistically significant differences in hindfoot load between preoperative and postoperative values or between the two groups at the 1-month follow-up(P＞0.05).Conclusion For adolescent flexible flatfoot,tendon-regulating and bone-setting manipulation combined with subtalar joint arthroereisis can effectively restore the arch,improve foot mechanical imbalance,thereby correcting flatfoot deformity and enhancing joint motor function.