ObjectiveTo investigate the potential mechanism of Huatan Sanjie Formula （化痰散结方， HSF） in the treatment of triple negative breast cancer （TNBC） based on the integrinβ1/focal adhesion kinase/yes-associated protein （integrinβ1/FAK/YAP） mechanotransduction signaling pathway. MethodsFifty BALB/c mice were randomly assigned to a model group， doxorubicin group， low-， medium-， and high-dose HSF groups， with 10 mice per group. An orthotopic TNBC transplantation model was established in all mice using syngeneic implantation of 4T1 cells. After successful modeling， mice in the model group received intragastric administration of normal saline 0.2 ml each day. Mice in the low-， medium-， and high-dose HSF groups received HSF by gavage at doses of 5.99， 11.97， and 23.94 g/（kg·d）， respectively. The doxorubicin group received intraperitoneal injections of doxorubicin （1.5 mg/kg） once every two days. All treatments lasted for 30 days. After the final administration， mice were sacrificed， and tumor weight and volume were measured. Hematoxylin-eosin （HE）， Masson's trichrome， and Sirius Red staining were performed to evaluate histopathological changes and collagen fiber deposition in tumor tissues. TUNEL staining was used to assess apoptosis. The Young's modulus of tumor tissues was measured using atomic force microscopy （AFM）. The nuclear-cytoplasmic localization of YAP was determined by immunofluorescence staining. Protein expression levels of integrinβ1， focal adhesion kinase （FAK）， YAP， and phosphorylated focal adhesion kinase （p-FAK） were detected by Western Blotting. The mRNA expression levels of integrinβ1， FAK， and YAP were assessed by quantitative real-time polymerase chain reaction （qRT-PCR）. Pearson correlation analysis was performed to evaluate the relationships among tumor tissue Young's modulus， apoptosis rate， and the expression levels of proteins related to the integrinβ1/FAK/YAP signaling pathway. ResultsCompared to the model group， tumor weight was significantly reduced in the doxorubicin group and the medium- and high-dose HSF groups， while tumor volume significantly decreased in the doxorubicin group and the high-dose HSF group （P＜0.01）. Tumor weight in the high-dose HSF group was significantly lower than that in the low-dose group， and tumor volume was significantly smaller than that in both the low- and medium-dose groups （P＜0.05）. Marked improvements in histopathological morphology were observed in the medium- and high-dose HSF groups and the doxorubicin group， while the proportion of collagen fiber deposition and the nuclear-to-cytoplasmic ratio of YAP were significantly reduced （P＜0.01）. Compared to the model group， all three HSF groups and the doxorubicin group exhibited significantly increased apoptosis rates， decreased Young's modulus， and reduced mRNA expression levels of integrinβ1， and YAP （P＜0.05 or P＜0.01）. Furthermore， protein expression levels of integrinβ1， p-FAK， and YAP in the high-dose HSF group were significantly lower than those in the model group （P＜0.05 or P＜0.01）. Pearson correlation analysis demonstrated a significant negative correlation between tumor tissue Young's modulus and apoptosis rate （r =-0.93， P＜0.01）. In contrast， the protein expression levels of integrinβ1， p-FAK， and YAP were positively correlated with Young's modulus （r=0.88， 0.97， and 0.98， respectively； P＜0.05） and negatively correlated with apoptosis rate （r=-0.93，-0.97， and -0.93， respectively； P＜0.05）. ConclusionHSF can significantly inhibit tumor growth in TNBC model mice. Its antitumor effect may be associated with reducing tumor tissue stiffness through suppression of the integrinβ1/FAK/YAP mechanotransduction signaling pathway.

Background/Aims: Regorafenib is recommended by guidelines and trials as a sequential second-line therapy following progression on first-line sorafenib or lenvatinib in hepatocellular carcinoma (HCC). However, efficacy is limited, highlighting the urgent need to screen suitable patients and develop sensitization strategies. Methods: Acquired sorafenib- or lenvatinib-resistant (SR or LR) HCC cell lines and organoids were established. Genome-wide CRISPR library screen was performed in SR or LR cell strains to identify synthetic lethal targets of regorafenib. RNA-seq and FITC-regorafenib efflux assay were used to elucidate ERBB3-driven downstream signaling. Preclinical mouse models of cell line- and patient-derived xenografts and clinical cohorts of HCC patients were employed to validate the efficacy of ERBB3-guided patient stratification. Results: Screening with CRISPR library, we showed that inhibition of ERBB3 was synthetic lethal with regorafenib in SR or LR cell strains and organoids. Mechanistically, SR or LR triggered feedback activation of ERBB3 signaling and mediated regorafenib efflux via ERBB3-HIF1A-ABCB1 cascade pathway, limiting sensitivity to regorafenib. Moreover, ERBB3-low tumors following SR or LR exhibited significant sensitivity to regorafenib, suggesting its potential as a predictive biomarker to screen optimal candidates for sequential therapy. Seribantumab, an ERBB3-targeting monoclonal antibody, inhibited ERBB3-HIF1A-ABCB1 cascade, and its combination with regorafenib exerted marked synergistic anti-tumor effects on ERBB3-high tumors resistant to sorafenib or lenvatinib both in vitro and in vivo. Conclusions This study revealed that ERBB3 was a key resistance factor driving limited efficacy to sequential regorafenib, but also an effective therapeutic target whose inhibition enhanced regorafenib sensitivity after SR or LR.

Objective:To investigate the neuroprotective effects of ginsenoside Rb1 in neonatal mice with Hypoxic Ischemia(HI)and analyze its potential molecular mechanisms.Methods:Seven-day-old C57BL/6 neonatal mice were randomly assigned to three groups:Sham group,hypoxic-ischemic(HI)model group,and HI model+ginsenoside Rb1 intervention group(HI+Rb1),with 10 mice per group.The modified Rice-Vannucci method was used to establish the HI model,and ginsenoside Rb1(20 mg/kg)was administered via intraperitoneal injection for 7 consecutive days post-surgery(once per day).Brain damage was assessed on days 7 and 14 post-surgery by evaluating cortical neurons and glial cell numbers,as well as the activation status of the ERK signaling pathway.Additionally,in utero electroporation(IUE)was used to overexpress the ERK signaling pathway in the cortical neurons,and the impact of ERK activation on glial cell development was observed.Further,IUE was used to overexpress ERK in the cortex of P0 neonatal mice,fol-lowed by the HI model on day 7 to analyze the effects of enhanced ERK signaling on oligodendrocyte development and myelin regeneration.Results:Compared to the HI group,the HI+Rb1 intervention group showed significant improve-ment in motor ability,reduction in brain injury area,less mature neuron loss,and increased newborn neurons.Addi-tionally,the number of oligodendrocytes in the cortex was increased,and the activation of the ERK signaling pathway was enhanced.In mice with overexpression of the ERK signaling pathway in the cortex,there was a significant increase in oligodendrocytes.In the HI model with ERK overexpression,an increased number of oligodendrocyte precursor cells were found around the brain injury area,consistent with the results of ginsenoside Rb1 intervention.Conclusion:Gin-senoside Rb1 exerts neuroprotective effects in neonatal mice with hypoxic-ischemic brain injury,potentially through the enhancement of ERK signaling,promoting oligodendrocyte proliferation and myelin regeneration.

Objective:To examine the near-complete genomic analysis of norovirus (NoV) subtype GⅡ.17 [P17] outbreaks in Beijing Chaoyang District from 2014 to 2024.Methods:Data and specimens related to outbreaks of the NoV aggregation in Beijing′s Chaoyang District from 2014 to 2024 were collected. The NoV was identified using real-time fluorescence reverse transcription polymerase chain reaction (RT-PCR). Specimens with positive nucleic acid were amplified by standard PCR, whole genome sequencing and evolutionary analysis. Amino acid site variations were compared.Results:In Chaoyang District, from 2014 to 2024, a total of 637 aggregated outbreaks caused by the NoV infection were reported, of which 584 were successfully typed. The epidemic caused by the GⅡ.17 [P17] subtype accounted for 8.79% (56/637), which was the dominant epidemic gene subtype in 2014-2015, sporadic in 2016-2019, reappeared in 2022, and significantly increased in 2024 (27.27%, 24/88). Outbreaks caused by the GⅡ.17 [P17] subtype occurred mainly from October to December, with the main sites of occurrence in primary schools and kindergartens. This study yielded 53 near-complete genome sequences of the GⅡ.17 [P17] subtype from 46 incidents in Chaoyang District. The GⅡ.17 [P17] subtype sequences of Chaoyang District from 2014 to 2024 were segmented into three subgroups on the evolutionary tree, with sequences from 2014 to 2019, 2022 to April 2024, and May to December 2024 clustered into the d, e, and b subgroups, respectively. In the VP1 region′s P2 area, particularly at the HBGA binding site, subgroups b and e exhibited mutations in 22 and two sites, while subgroups b and e showed mutations in four and one sites, predominantly in the RdRp region.Conclusion:The outbreak caused by the NoV GⅡ.17 [P17] subtype in Chaoyang District from 2014 to 2024 continues, with a significant increase in 2024, and it becomes the dominant gene subtype from October to December. The sequence formation of the NoV GⅡ.17 [P17] subtype in Chaoyang District from January to April 2022 and from May to December 2024 shows two different evolutions, with specific mutation sites, requiring continuous monitoring of the NoV GⅡ.17 [P17] subtype.

A 36-year-old male developed unconsciousness and no response to voice stimuli after taking approximately 2 050 mg felodipine (the specific time was unknown). Two hours later, he was sent to the department of emergency by his family and admitted to the hospital. His vital signs showed body temperature 35.1 ℃, pulse 148 times/min, respiration 32 times/min, and blood pressure 65/34 mmHg. Acute drug poisoning, acute toxic cardiomyopathy, acute toxic shock, acute type Ⅱ respiratory failure, acute toxic encephalopathy, and acute renal failure were diagnosed based on the patient′s clinical manifestations combined with laboratory tests results, cardiac ultrasound, chest and abdominal CT scans. Endotracheal intubation connected to a ventilator for invasive assisted ventilation, pressure boosting, and fluid resuscitation were given. At the same time, repeated gastric lavage and enema were performed to remove toxins. Blood perfusion was intermittently and repeatedly administered, and continuous renal replacement therapy was used. The blood concentration of felodipine was 1 298 μg/L at 2 hours after admission, and cardiac arrest occurred at 4 hours. Venous-arterial extracorporeal membrane oxygenation (V-A ECMO) treatment was administered immediately. After 48 hours of ECMO operation, sedatives were discontinued and the patient′s consciousness was improved after 4 hours. On the 5th day of ECMO treatment, his heart rate was 72 beats per minute, and blood pressure was 127/65 mmHg. The blood concentration of felodipine decreased to 2 μg/L. The patient′s vital signs were significantly improved and ECMO supportive treatment was withdrawn. After 26 days of hospitalization, the patient recovered and was discharged.

Objective:To explore the current status and influencing factors of fatigue in patients with Cushing syndrome in China, so as to provide a basis for clinical interventions.Methods:Convenience sampling was used to select 260 inpatients with Cushing syndrome who met the inclusion and exclusion criteria in 9 ClassⅢ Grade A hospitals within the 7 geographic subregions of China from February to April 2023 for the study. General Information Questionnaire, the Chinese version of the Multidimensional Fatigue Inventory-20, Barthel Index, and Self-Rating Depression Scale were used for the survey.Results:A total of 260 questionnaires were distributed and 241 valid questionnaires were recovered, with an effective recovery rate of 92.7% (241/260). The MFI-20 score of 241 patients with Cushing syndrome was 58.00 (46.00, 64.00). 65.1% (157/241) of patients with Cushing syndrome suffered from fatigue, and 73.2% (115/157) of patients with fatigue exhibited multidimensional fatigue. Univariate analysis showed that there were statistically significant differences in fatigue scores among patients with Cushing syndrome with different cultural levels, recurrence frequency, activity of daily living, hypertension, and depression ( P<0.05). Multiple linear regression analysis showed that depression was a risk factor for fatigue in patients with Cushing syndrome, and the difference was statistically significant ( P<0.05) . Conclusions:Fatigue in patients with Cushing syndrome needs attention. Medical and nursing staff should pay close attention to the psychological status of patients with Cushing syndrome, encourage them to actively cope, alleviate their depression, in order to improve their fatigue.

FU Qingzhu Nyuke·Zhongzi is a concentrated manifestation of Fu′s academic thoughts of promoting conception (Zhongzi), which affects the treatment of infertility in later generations. However, the Zhongzi chapter is named after "symptoms" and is not divided into chapters according to "syndromes, "limiting the clinical application of Fu′s thoughts of Zhongzi. The "qi circle in round" theory is the crystallization of HUANG Yuanyu′s academic thinking, advocating for qi transformation, emphasizing middle qi, and considering the four phenomena. This theory highlights the role of middle qi in the rise, fall, and circulation of disease development. The "qi cycle in round" theory, a comprehensive view of Fu′s Zhongzi chapter, reveals that FU Qingzhu emphasizes the transformation of visceral qi in diagnosing and treating infertility, focusing on the spleen, liver, and kidneys. His prescription aims to restore the overall qi mechanism of the body, highlighting the circulation of middle earth and the dredging of meridians, aligning perfectly with the theory of the "qi cycle in round." Therefore, this article argues from the perspective of the "qi cycle in round, "deconstructing the pathogenesis of Fu′s infertility based on the dereliction of spleen earth, stagnation of liver wood, and kidney yin and yang deficiency. It reorganizes Fu′s formula system of Zhongzi by mediating middle earth, soothing liver depression, and regulating kidney function, summarizing the characteristics of Fu′s thoughts of Zhongzi with the aid of qi around the waist and navel, simultaneous treatment of conqenital and acquired essence, and restriction and generation of five phases. Based on the "qi cycle in round" theory, this study explores Fu′s academic thoughts of Zhongzi to strengthen the organic integration of Fu′s academic thoughts of Zhongzi with the theory of "qi cycle in round, "providing new perspectives for the study and inheritance of Fu′s academic thoughts of Zhongzi.

Cholangiocarcinoma has an extremely poor prognosis, and the efficacy of existing treatment methods is limited. In the highly desmoplastic tumor microenvironment of cholangiocarcinoma, cancer-associated fibroblasts (CAFs) are the core regulators. Their significant heterogeneity and complex intercellular crosstalk network are not only key factors driving cholangiocarcinoma progression and drug resistance, but also highly promising therapeutic targets. This review focuses on the characteristics of CAFs in cholangiocarcinoma and the key crosstalk mechanisms between CAFs and tumor cells as well as immune cells, and summarizes the research progress and limitations of current therapeutic strategies targeting CAFs.

Saliva is an important body fluid in the oral cavity containing lots of biomarkers, whose inherent micro-ecosystem holds significant value for early diagnosis and monitoring of oral diseases. Simultaneously, saliva has particular advantages, such as ease of sampling, painless and non-invasive collection, and suitability for repeated sampling, making it highly appropriate for surveillance and follow-up of diseases. In a series of studies conducted by the research group for preventive dentistry in Peking University School and Hospital of Stomatology, we compared different segments of saliva and those samples collected via different sampling methods using proteomic/peptidomic and microbiomic technologies to explore the stability of saliva samples. Besides, the significance of applying representative salivary biomarkers in early prevention and control of representative oral diseases (e.g. dental caries, periodontal diseases) and systemic conditions (e.g. type 2 diabetes mellitus, chronic kidney disease) was confirmed as well.
Humans ; Saliva/chemistry* ; Dental Caries/diagnosis* ; Biomarkers/analysis* ; Periodontal Diseases/diagnosis* ; Mouth Diseases/diagnosis* ; Proteomics/methods* ; Diabetes Mellitus, Type 2/diagnosis* ; Microbiota ; Renal Insufficiency, Chronic/prevention & control*

Glioma represents the most prevalent malignant tumor of the central nervous system, with chemotherapy serving as an essential adjunctive treatment. However, most chemotherapeutic agents exhibit limited ability to penetrate the blood-brain barrier (BBB). This study introduced a novel dual-targeting strategy for glioma therapy by modulating the formation of nanobody-driven protein coronas to enhance the brain and tumor-targeting efficiency of hydrophobic cisplatin prodrug-loaded lipid nanoparticles (C8Pt-Ls). Specifically, nanobodies (Nbs) with fibrinogen-binding capabilities were conjugated to the surface of C8Pt-Ls, resulting in the generation of Nb-C8Pt-Ls. Within the bloodstream, Nb-C8Pt-Ls could bound more fibrinogen, forming the protein corona that specifically interacted with LRP-1, a receptor highly expressed on the BBB. This interaction enabled a "Hitchhiking Effect" mechanism, facilitating efficient trans-BBB transport and promoting effective brain targeting. Additionally, the protein corona interacted with LRP-1, which is also overexpressed in glioma cells, achieving precise tumor targeting. Computational simulations and SPR detection clarified the molecular interaction mechanism of the Nb-fibrinogen-(LRP-1) complex, confirming its binding specificity and stability. Our results demonstrated that this strategy significantly enhanced C8Pt accumulation in brain tissues and tumors, induced apoptosis in glioma cells, and improved therapeutic efficacy. This study provides a novel framework for glioma therapy and underscores the potential of protein corona modulation-based dual-targeting strategies in advancing treatments for brain tumors.