Liver fibrosis is a common outcome of various chronic hepatic insults, characterized by excessive extracellular matrix (ECM) deposition. The precise mechanisms, however, remain largely undefined. This study identified an elevated expression of platelet-activating factor acetylhydrolase 1B3 (Pafah1b3) in liver tissues from both carbon tetrachloride (CCl₄)-treated mice and patients with cirrhosis. Deletion of Pafah1b3 significantly attenuated CCl₄-induced fibrosis, hepatic stellate cell (HSC) activation, and activation of transforming growth factor-β (TGF-β) signaling. Mechanistically, PAFAH1B3 binds to mothers against decapentaplegic homolog 7 (SMAD7), disrupting SMAD7's interaction with TGF-β receptor 1 (TβR1), which subsequently decreases TβR1 ubiquitination and degradation. Pharmacological inhibition using 3-IN-P11, a specific Pafah1b3 inhibitor, conferred protective effects against CCl₄-induced fibrosis in mice. Furthermore, Pafah1b3 deficiency reduced hepatic inflammation. Overall, these results establish a pivotal role for Pafah1b3 in modulating TGF-β signaling and driving HSC activation.

Ferroptosis has been shown to mediate the development of fibrosis. Polyphyllin VII (PP7), a bioactive component of Paris polyphylla, exhibits potent anti-inflammatory activity and can significantly alleviate liver fibrosis. In this study, treatment with PP7 significantly inhibited the proliferation and activation of hepatic stellate cells (HSCs), which could be suppressed by a ferroptosis inhibitor. In addition, it promoted HSC ferroptosis by suppressing glutathione (GSH) peroxidase 4 (GPX4) and enhanced the expression of CX3C chemokine ligand 1 (CX3CL1). Depletion of CX3CL1 attenuated the effects of PP7 on the activation and ferroptosis of HSCs and the expression of GPX4. Notably, CX3CL1 directly interacted with GPX4, triggering HSC ferroptosis. The transcription factor hypermethylated in cancer 1 (Hic1), which binds to the Cx3cl1 promoter, increased the expression of CX3CL1. Its absence resulted in downregulation of CX3CL1, suppressing the GPX4-dependent ferroptosis of PP7-treated HSCs and promoting their activation. HIC1 was found to directly interact with PP7 at the GLY164 site. Co-culture experiments showed that PP7-induced HSC ferroptosis attenuated macrophage recruitment by regulating inflammation-related genes. HSC-specific inhibition of HIC1 counteracted PP7-induced collagen depletion and HSC ferroptosis in vivo. These findings suggest that PP7 induces HSC ferroptosis through the HIC1/CX3CL1/GPX4 axis.

AIM: To investigate the efficacy and safety of dexamethasone versus conbercept in the treatment of diabetic macular edema(DME)with different optical coherence tomography(OCT)subtypes.METHODS: A total of 160 DME patients(160 eyes)admitted to our hospital from January 2021 to March 2023 were prospectively selected, and the patients were randomly divided into dexamethasone intravitreal implant group and conbercept group, with 80 cases(80 eyes)in each group, and DME patients were divided into 51 eyes with serous retinal detachment(SRD), 55 eyes with cystoid macular edema(CME), and 54 eyes with diffuse retinal thickening(DRT)according to OCT characteristics. The best corrected visual acuity(BCVA), central macular thickness(CMT), intraocular pressure and adverse reactions were compared before treatment and at 2, 3 and 6 mo postoperatively.RESULTS: There were differences in BCVA, CMT and intraocular pressure between the two groups at 2, 3 and 6 mo compared with those before operation(all P<0.05). There were differences in BCVA, CMT and intraocular pressure between the dexamethasone intravitreal implant group and the conbercept group in the treatment of patients with different types of DME(all P<0.05). The BCVA of patients with DRT and SRD types in the dexamethasone intravitreal implant group was improved at 3 and 6 mo after treatment compared with that in the conbercept group(all P<0.05). At 6 mo after treatment, the CMT of patients with DRT type in the dexamethasone intravitreal implant group was lower than that in the conbercept group(P<0.05). During the follow-up period, none of the patients experienced adverse events such as cataract exacerbation or retinal detachment.CONCLUSION: Both dexamethasone intravitreal implant and conbercept treatment can improve visual function and macular retinal morphology in patients with different OCT subtypes of DME with good safety, but the dexamethasone intravitreal implant is better than conbercept in the treatment of DRT type.

Objective To analyze the urban drinking water quality and its influencing factors in Anhui Province from 2014 to 2022, and to provide a scientific basis for water quality improvement and protection. Methods The data were collected, saved and monitored according to the Standard Test Method for Drinking Water (GB/T5750-2006) and evaluated according to the Hygienic Standard for Drinking Water (GB 5749-2006). Results A total of 20 941 samples were collected, and the overall qualified rate was 84.26%. The qualified rate of urban drinking water increased from 76.9% in 2014 to 93.3% in 2022, and the qualified rate of water quality was on the rise (χ²=544.43, P＜0.01). From 2014 to 2022, the qualified rate of water quality in dry season was higher than that in wet season (χ²=35.98, P<0.001), the qualified rate of surface water was higher than that of ground water (χ²=4440.8, P<0.001), and the qualified rate of peripheral tap water was higher than that of factory water (χ²=145.1, P<0.001). Among all kinds of disinfection methods, chlorination disinfection had the highest qualified rate (χ²=1483.8, P<0.001). The qualified rate of water quality increased with the increase of the scale of water plant. Among the inspected indicators, the main unqualified indicators were chlorine dioxide (7.72%), fluoride (7.41%), free residual chlorine (3.90%), and total bacterial count (2.13%). Conclusion The passing rate of urban drinking water quality in Anhui Province is on an upward trend, and the quality of urban drinking water has improved. However, it is still important to pay attention to the problem of excessive microorganism and fluoride in water, and the quality of drinking water varies from place to place.

Objective:To evaluate the detection rate, anatomical distribution, and influencing factors of bone marrow edema-like signal (BMELS) in the knees of amateur marathon runners.Methods:This was a cross-sectional study. This study publicly recruited amateur marathon runners through the Hangzhou Long-distance Running Association from January 2019 to December 2024. Based on knee magnetic resonance imaging (MRI) results, participants were divided into a BMELS-positive group (BMELS present in at least one knee) and a BMELS-negative group. General clinical information was collected from participants using a questionnaire. All participants underwent a knee MRI scan to screen for the presence of BMELS and to assess its severity. Logistic regression models were used to analyze the associated factors of BMELS in amateur marathon runners, while Spearman′s correlation analysis assessed the correlation between BMELS grade and these factors.Results:A total of 60 subjects (120 knee joints) were enrolled, including 39 males (65%), aged (40.0±8.4) years. Of these, 39 were in the BMELS-positive group, and 21 were in the BMELS-negative group. The BMELS detection rate for the 120 knee joints of these 60 subjects was 53.3% (64/120). BMELS were detected in 43.3%(52/120) of the femur, 34.2% (41/120) of tibia and 17.5% (21/120) of patella. Multivariate logistic regression analysis showed an independent positive correlation between monthly running volume and knee BMELS in amateur marathon runners ( OR=1.007, 95% CI: 1.000-1.013, P=0.035). Spearman′s correlation analysis showed a weak positive correlation between the BMELS grade of the knees and the monthly running volume of amateur marathon runners ( r s=0.360, P=0.005). Conclusions:The detection rate of knee BMELS is high in amateur marathon runners, and they are distributed in a way that is characteristic of the region, with a higher incidence in the medial femoral condyle. In this population, monthly running volume is independently associated with knee BMELS, with a higher grade associated with greater monthly running volume.

Objective:To analyze the pangenome, pan drug resistance genes, pan virulence genes, pan replicons, and others of the plasmids carried by hypervirulent Klebsiella pneumoniae (hvKP) in the world and their evolutionary trends over time, and provide evidence for more comprehensive understanding of the evolution of genetic diversity, drug resistance genes, and virulence genes of the plasmids. Methods:From the National Center for Biotechnology Information database, a total 1 738 plasmids were screened from 524 strains with completed genome sequences in 2 136 strains of hvKP carrying plasmids. Through pangenome, pan drug resistance gene, and pan-virulence gene composition and functional analyses, the curves of pangenome size and new gene size against plasmid isolation time were established, revealing the diversity of the plasmid pangenome and its evolutionary patterns.Results:The homologous genes, homologous drug resistance genes, homologous virulence genes, and replicons of the plasmids carried by hvKP comprised of 12 906, 149, 107 and 89 types, respectively. The fitting curves for the number of new genes, new drug resistance genes and new replicons increased with the increase of plasmids in an open state, while the curve for novel virulence genes was in a closed state. A obvious increase in new drug resistance genes was observed during 2018-2019. Among the newly added drug resistance genes during 2021-2023, beside those conferring aminoglycoside resistance, they were mainly new subtypes conferring carbapenem resistance.Conclusions:The pangenome of plasmids carried by hvKP exhibited high diversity, with the plasmid pan genes, pan drug resistance genes, and pan replicon types gradually expanding, while the pan virulence genes remains stable. The increase in novel drug resistance genes in specific years and the emergence of new carbapenem-resistant gene subtypes during 2021-2023 suggested the need for strengthened drug resistance surveillance and prevention efforts, with particular attention to carbapenem resistance.

The diagnosis rate of early breast cancer has significantly increased with the proliferation of tumor screening and heightened health awareness.Clinical research,as the evidence base for guidelines and consensus,provides optimized treatment plans for breast cancer.This article summarized and classified several pivotal clinical studies that changed the clinical practice of early breast cancer,according to updates in domestic and international guidelines and consensus from 2023 to 2024.These included the optimization of neoadjuvant and adjuvant therapies,the escalation of adjuvant endocrine therapy,the optimization of local treatment,and attention to quality of life,etc.In the optimization of neoadjuvant and adjuvant therapies,the KEYNOTE-522 study established the therapeutic role of pembrolizumab combined with chemotherapy in early high-risk triple-negative breast cancer(TNBC).The FDChina study confirmed the non-inferiority of the subcutaneous formulation of trastuzumab combined with pertuzumab(H+P)in neoadjuvant treatment of human epidermal growth factor receptor 2(HER2)-positive breast cancer,offering a more convenient administration method.The KATHERINE study clarified the adjuvant role of trastuzumab emtansine(T-DM1)in HER2-positive breast cancer patients who did not achieve a pathologic complete response(pCR)after neoadjuvant therapy.In the escalation of adjuvant endocrine therapy,the MonarchE and NATALEE studies confirmed the efficacy of abemaciclib and ribociclib combined with endocrine therapy in high-risk hormone receptor(HR)-positive HER2-negative early breast cancer patients,promoting the application of cyclin-dependent kinase(CDK)4/6 inhibitors in early breast cancer treatment.In the optimization of local treatment,the ACOSOG Z11102 study supported the feasibility of breast-conserving surgery for multicentric breast cancer,the SENOMAC study provided evidence for exempting sentinel lymph node(SLN)low-burden breast cancer patients from axillary lymph node dissection(ALND),the SOUND study supported the exemption of sentinel lymph node biopsy(SLNB)for T1 and cN0 breast cancer patients,and the ICARO study suggested the feasibility of exempting ALND for patients with isolated tumor cells(ITCs)found after neoadjuvant chemotherapy with SLNB or targeted axillary dissection(TAD).The NSABP B-51/RTOG 1304 study provided a basis for the de-escalation of regional lymph node irradiation(RNI)and local treatment in ypN0 breast cancer after neoadjuvant therapy.In terms of quality of life and chemoprevention,the POSITIVE study proposed a protocol for pausing endocrine therapy for breast cancer patients with fertility needs,and the TAM-01 and IBIS-Ⅱ studies provided strong evidence-based medical evidence for chemoprevention in high-risk breast cancer patients.These pivotal clinical studies have profoundly impacted the clinical practice of early-stage breast cancer,not only optimizing treatment plans but also focusing on the quality of life and disease prevention of breast cancer patients.This article discussed the impact of the aforementioned clinical studies on the clinical practice of early breast cancer,centered on updates to various domestic and international breast cancer diagnosis and treatment guidelines and consensus.

Liver fibrosis is a common outcome of various chronic hepatic insults,characterized by excessive extracellular matrix(ECM)deposition.The precise mechanisms,however,remain largely undefined.This study identified an elevated expression of platelet-activating factor acetylhydrolase 1B3(Pafah1b3)in liver tissues from both carbon tetrachloride(CCl4)-treated mice and patients with cirrhosis.Deletion of Pafah 1b3 significantly attenuated CCl4-induced fibrosis,hepatic stellate cell(HSC)activation,and acti-vation of transforming growth factor-β(TGF-β)signaling.Mechanistically,PAFAH1B3 binds to mothers against decapentaplegic homolog 7(SMAD7),disrupting SMAD7's interaction with TGF-β receptor 1(TβR1),which subsequently decreases TβR1 ubiquitination and degradation.Pharmacological inhibition using 3-IN-P11,a specific Pafah1b3 inhibitor,conferred protective effects against CCl4-induced fibrosis in mice.Furthermore,Pafah 1b3 deficiency reduced hepatic inflammation.Overall,these results establish a pivotal role for Pafahl b3 in modulating TGF-β signaling and driving HSC activation.

Ferroptosis has been shown to mediate the development of fibrosis.Polyphyllin Ⅶ(PP7),a bioactive component of Paris polyphylla,exhibits potent anti-inflammatory activity and can significantly alleviate liver fibrosis.In this study,treatment with PP7 significantly inhibited the proliferation and activation of hepatic stellate cells(HSCs),which could be suppressed by a ferroptosis inhibitor.In addition,it promoted HSC ferroptosis by suppressing glutathione(GSH)peroxidase 4(GPX4)and enhanced the expression of CX3C chemokine ligand 1(CX3CL1).Depletion of CX3CL1 attenuated the effects of PP7 on the activation and ferroptosis of HSCs and the expression of GPX4.Notably,CX3CL1 directly interacted with GPX4,triggering HSC ferroptosis.The transcription factor hypermethylated in cancer 1(Hic1),which binds to the Cx3cl1 promoter,increased the expression of CX3CL1.Its absence resulted in downregulation of CX3CL1,sup-pressing the GPX4-dependent ferroptosis of PP7-treated HSCs and promoting their activation.HIC1 was found to directly interact with PP7 at the GLY164 site.Co-culture experiments showed that PP7-induced HSC ferroptosis attenuated macrophage recruitment by regulating inflammation-related genes.HSC-specific inhibition of HIC1 counteracted PP7-induced collagen depletion and HSC ferroptosis in vivo.These findings suggest that PP7 induces HSC ferroptosis through the HIC1/CX3CL1/GPX4 axis.

It is believed that the occurrence and development of squamous cell carcinoma （SCC） is closely associated with inflammatory responses. The theory of fire and heat， advocated by LIU Wansu， provides significant clinical guidance for understanding the pathogenesis and treatment of SCC. Based on this theory， the pathological mechanisms and clinical characteristics of SCC at different stages were analyzed. In the precancerous and early stages， the primary pathogenesis is qi stagnation leading to internal generation of constrained heat； in post-surgery， the condition shifts to qi deficiency with latent yin fire； during the treatment phase， the pathogenesis involves accumulation of pathogenic factors， excess toxins， and severe heat toxicity； in the late stage， the main pathology is yin deficiency with toxic heat， and phlegm-stasis obstruction of the internal organs. Corresponding stage-based treatment strategies are proposed. In the early stage， regulating qi movement to dissipate constrained heat； for post-surgery， tonifying qi and raising yang to dispel latent fire； during treatment stage， clearing heat and detoxifying to eliminate cancerous toxins； and in the late stage， nourishing yin and unblocking the bowels to clear deficiency heat.