Colorectal cancer (CRC) is the third most commonly diagnosed malignancy and the second leading cause of cancer-related mortality worldwide. Despite therapeutic advancements over recent decades, the prognosis for patients with metastatic CRC (mCRC) remains poor. Approximately 2%-4% of mCRC cases exhibit human epidermal growth factor receptor 2 (HER2) amplification or overexpression, defining a distinct molecular subtype. This HER2-positive status is strongly associated with primary resistance to anti-epidermal growth factor receptor (EGFR) therapies, which are the standard of care for patients with RAS wild-type tumors. Beyond its well-established role in breast and gastric cancers, HER2 has emerged as a pivotal biomarker and actionable therapeutic target in mCRC. However, selecting appropriate treatment strategies remains challenging due to patient heterogeneity and diverse molecular subtypes. This review systematically summarizes the molecular biology, diagnostic strategies, and advances in targeted therapies for HER2-positive mCRC. On the diagnostic front, we discuss the applications of immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), next-generation sequencing (NGS), and circulating tumor DNA (ctDNA) detection technologies. We highlight discrepancies in diagnostic criteria across key clinical trials—such as HERACLES, DESTINY, and MOUNTAINEER—underscoring the urgent need for standardized, CRC-specific definitions to ensure consistent patient selection and comparability of efficacy data across studies. Although NGS enables comprehensive genomic profiling, its cost-effectiveness relative to traditional methods must be carefully considered. Therapeutically, we summarize clinical trial data for HER2-directed agents, including tyrosine kinase inhibitors (TKIs) such as tucatinib and lapatinib, monoclonal antibodies like trastuzumab, bispecific antibodies, and antibody-drug conjugates (ADCs) such as trastuzumab deruxtecan. We review dual-targeting strategies and note recent FDA approvals that represent significant milestones in second-line treatment. Additionally, we explore the potential of combining immune checkpoint inhibitors with HER2-targeted therapies to enhance antitumor immunity through mechanisms including antibody-dependent cellular cytotoxicity (ADCC) and modulation of the tumor microenvironment. ADCs enable precise delivery of cytotoxic payloads, reducing off-target toxicity while effectively inhibiting oncogenic pathways. A substantial portion of this review is dedicated to dissecting the molecular mechanisms underlying primary and acquired resistance to HER2-targeted therapies—persistent challenges that limit clinical benefit. These mechanisms include reactivation of downstream signaling pathways such as PI3K/AKT/mTOR and MAPK, concurrent mutations in genes like KRAS or BRAF, and alterations in HER2 expression that compromise treatment efficacy. For instance, specific HER2 mutations (e.g., L755S) can reduce drug binding affinity, while ctDNA monitoring facilitates early detection of emerging resistance clones during disease progression, thereby enabling timely therapeutic adjustments. Tumor heterogeneity and dynamic interactions with the microenvironment further complicate resistance patterns observed in clinical practice. HER2-targeted therapy represents a new frontier in precision oncology for mCRC, offering renewed hope for improving patient outcomes. Realizing this potential will require continued optimization of diagnostic algorithms and treatment workflows. Future efforts must focus on overcoming resistance, validating liquid biopsy approaches for dynamic monitoring, and establishing unified clinical guidelines. HER2 has become an essential biomarker for stratifying mCRC patients beyond traditional RAS and BRAF status, underscoring the shift from empiric treatment to biomarker-driven precision medicine. International, multidisciplinary collaboration will be critical to validate emerging biomarkers and refine treatment algorithms globally.

Clinical death refers to the permanent cessation of life functions. This article reviews the definition of clinical death and the various scenarios in which it occurs, classifies the process of clinical death, and discusses the criteria for determining uncontrollable cardiac death, controllable cardiac death and the criteria and workflow for determining brain death. It elaborates on the relationship between brain death and death, and proposes the areas to note when standardizing the medical documentation of death cases. Based on this, it introduces the content of the management system and workflow construction for death determination in medical institutions, including management structure, personnel qualifications, document norms, quality control system and training mechanism. Paying attention to the construction of the management system and workflow for death determination in medical institutions is of great significance for ensuring medical quality and safety, promoting the healthy development of organ donation, and maintaining the seriousness of legal and ethical practices.

Tumor microenvironment(TME)is the foundation for tumor survival,which is composed of various types of cells,tumor blood vessels,secretory factors,and extracellular matrix(ECM)within the tumor.The unique regulatory mechanism triggered by the vigorous metabolic demand of tumor plays an important role in its tumorigenesis,metastasis,invasion,and treatment resistance.A deeper understanding of the metabolic transformation and tumor-immune cell interactions in the TME will enable the development of therapeutic technologies that precisely target TME metabolism,facilitate the development of combination treatment strategies,and improve the clinical response rate of existing immunotherapies.This paper reviews the composition,metabolism and regulatory mechanisms of TME,summarizes the research progress of immunotherapy strategies targeting the physiological characteristics of TME,and discusses the prospects for clinical application of precision immunotherapy strategies targeting TME,which are expected to enhance immunotherapy drugs response and infiltration degree.

Objective:To investigate the protective effect of achyranthes bidentata(AB)on sperm quality in mice with sper-matogenic disorder through the glycolytic metabolic pathway and its action mechanism.Methods:We equally randomized 40 Kun-ming mice into a normal control,a model control,a low-dose AB(3.5 g/kg)and a high-dose AB group(7.0 g/kg),and established the model of spermatogenic disorder in the latter three groups of mice by intraperitoneal injection of doxorubicin(30 mg/kg).Two days after modeling,we collected the testis and kidney tissues and blood samples from the mice for observation of the pathological changes in the testis tissue by HE staining,detection of perm motility with the sperm quality analyzer,examination of the apoptosis of testis cells by flow cytometry,measurement of the levels of testosterone(T),malondialdehyde(MDA),superoxide dismutase(SOD)and cata-lase(CAT)in the serum and testis tissue by ELISA,and determination of expressions of the key enzymes of glycolysis hexokinase Ⅱ(HK2),pyruvate kinase M2(PKM2),platelet phosphofructokinase(PFKP),lactate dehydrogenase A(LDHA)and the meiosis pro-teins REC8 and SCP3 by Western blot,and the mRNA expressions of glycolytic phosphofructokinase 1(PFK1),phosphoglycerate ki-nase 1(PGK1),tumor necrosis factor-α(TNF-α)and interleukin-1 β(IL-1β)by fluorescence quantitative PCR(FQ-PCR).Results:Compared with the model controls,the mice in the AB groups showed significant increases in the testis coefficient,kidney in-dex,sperm concentration,sperm motility,spermatogonia,primary spermatocytes,spermatids,sperm count and the serum T level(P＜0.05 orP＜0.01),but dramatic decreases in the apoptosis of testis cells and percentage of morphologically abnormal sperm(P＜0.01).Achyranthes bidentata also significantly elevated the levels of SOD and CAT,and down-regulated the mRNA expressions of MDA,TNF-α and IL-1β(P＜0.05 or P＜0.01),and up-regulated the protein expressions of HK2,PKM2,PFKP,LDHA,REC8 and SCP3,and expressions of the glycolysis key genes Pfk1 and Pgk1(P＜0.05 orP＜0.01).Conclusion:Achyranthes bidentata ameliorates doxorubicin-induced spermatogenic disorder in mice by regulating the glycolytic pathway and reducing oxidative stress and the expressions of inflammatory factors.

Objective To examine the changing prevalence and antimicrobial resistance profiles of Burkholderia cepacia in 52 hospitals across China from 2015 to 2021.Methods A total of 9 261 strains of B.cepacia were collected from 52 hospitals between January 1,2015 and December 31,2021.Antimicrobial susceptibility of the strains was tested using Kirby-Bauer method or automated antimicrobial susceptibility testing systems according to a unified protocol.The results were interpreted according to the breakpoints released in the Clinical & Laboratory Standards Institute(CLSI)guidelines(2023 edition).Results A total of 9 261 strains of B.cepacia were isolated from all age groups,especially elderly patients.The proportion was 11.1％(1 032 strains)in children,significantly lower than the proportion in adults.About half(46.5％,4 310/9 261)of the strains were isolated from patients at least 60 years old and 42.3％(3 919/9 261)of the strains were isolated from young adults.Most isolates(71.1％)were isolated from sputum and respiratory secretions,followed by urine(10.7％)and blood samples(8.1％).B.cepacia isolates were highly susceptible to the five antimicrobial agents recommended in the CLSI M100 document(33rd edition,2023).B.cepacia isolates showed relatively higher resistance rates to meropenem and levofloxacin.However,the resistance rates to ceftazidime,trimethoprim-sulfamethoxazole,and minocycline remained below 8.1％.The percentage of B.cepacia strains resistant to levofloxacin was the highest compared to other antibiotics in any of the three age groups(from 12.4％in the patients＜18 years old to 20.6％in the patients aged 60 years or older).Conclusions B.cepacia is one of the clinically important non-fermenting gram-negative bacteria.Accurate and timely reporting of antimicrobial susceptibility test results and ongoing antimicrobial resistance surveillance are helpful for rational prescription of antimicrobial agents and proper prevention and control of nosocomial infections.

Intra-aortic balloon pump(IABP),as the most commonly used percutaneous mechanical circulatory assist device,is routinely implanted through the femoral artery pathway.However,when implantation through the femoral artery pathway is difficult or contraindicated,other pathways including the brachial artery pathway,axillary artery pathway,etc.can be considered.IABP assisted interventional treatment for complex high-risk and indicated patients(CHIP)can reduce the risk of intraoperative complications,stabilize hemodynamics,increase the complete revascularization rate of CHIP,and improve long-term prognosis.The reverse guidewire technique can improve the success rate of percutaneous coronary intervention(PCI)for chronic total occlusion(CTO)of coronary arteries.In clinical practice,the reverse pathway is often chosen in addition to the forward pathway,such as the contralateral radial and brachial artery pathway,femoral artery pathway,etc.This article reports a case of bilateral femoral artery occlusion,in which IABP was implanted through the left brachial artery pathway,and then with the assistance of IABP,the right coronary artery CTO lesion was successfully opened through the right radial artery in the forward direction and the right brachial artery in the reverse direction,with the aim of providing reference for clinical PCI treatment for such special cases.

Aim To explore the compatibility and po-tential mechanism of effective components of Biejia-Ezhu against triple negative breast cancer(TNBC)and verify it by experiments.Methods Effective compo-nents and targets of Biejia-Ezhu were obtained by TC-MSP and Swiss Target Prediction.Disease targets of TNBC were obtained from OMMI and GeneCards data-bases.The PPI network was constructed using STRING database.GO and KEGG path enrichment analysis was performed using DAVID database.Cytoscape3.9.1 software was used to construct the"drug-component-target-disease"network,screen key targets and compo-nents for molecular docking,and further verify the com-patibility of key components and targets in vitro.Re-sults ① A total of 71 effective components were iden-tified in the Biejia-Ezhu drug pair.There were 146 drug targets associated with the disease.A total of 113 signaling pathways were identified by KEGG analysis.The 71 potential active components of Biejia-Ezhu mainly acted on key targets such as mTORC1,ULK1,TNF,EGFR,ESR1,STAT3,HIF1A,and PTGS2.Mo-lecular docking results showed that glycine and curcu-min were the key active components of Biejia-Ezhu,and both had strong docking activity against key target proteins mTORC1 and ULK1.②The results of in vitro experiment showed that glycine combined with curcu-min significantly inhibited the proliferation and clonal formation ability of TNBC cells(P＜0.05),up-regula-ted the expression of autophagy marker LC3 Ⅱ/Ⅰ,down-regulated the expression of EGFR,down-regula-ted the expression of pathway protein mTORC1,p-mTOR,p-ULK1,and promoted the expression of path-way protein ULK1(P＜0.05).Conclusion The key component of Biejia-Ezhu against triple-negative breast cancer is glycine-curcumin,the mechanism of which may be related to the regulation of the mTORC1/ULK1 signaling pathway to promote autophagy.

Objective:This study aims to explore the job preferences of county-level Centers for Disease Control and Prevention(CDC)personnel and to provide a basis for the development of effective incentive mechanisms.Methods:This study used a combination of stratified sampling and latent class sampling to investigate 1 809 respondents from 56 county-level CDCs in Shandong Province,Hubei Province,and Guizhou Province.Data were analysed using a mixed logit model and a latent class model,and willingness to pay was calculated.Results:The results of the mixed logit model showed that,all attributes and their levels had a significant influence(P<0.05),with establishment being the most important motivating factor(β=2.249).In the latent class model,respondents were divided into three categories.The main differences between the three classes were the choice of exit options and differences in preferences for job attributes.Conclusion:County-level CDC personnel preferred jobs with higher incomes,very good benefit levels,establishment,low workload,better recognition and respect from the public,more opportunities for career advancement,and abundant training opportunities.It is recommended that the total number of establishment should be rationally controlled and dynamically adjusted to balance the differences between working conditions within and outside the establishment;that a comprehensive approach should be adopted to improve both hygiene and motivation factors;and that different incentives should be adopted for different categories of CDC staff. Those who are willing to make a change should be provided with more opportunities for training and career advancement.

It has been not been updated for nearly 5 years since the Pharmacoepidemiology Professional Committee of the Chinese Pharmaceutical Association released the Guide on Methodological Standards in Pharmacoepidemiology in China(1st edition)in 2019,and an update is urgently needed.This study adopts a systematic review approach to comprehensively search for global pharmacoepidemiology methodological guidelines and analyze their development status.By extracting the frameworks and key elements of the guidelines,the China's guide was compared with other included guidelines,its shortcomings were analysed,and pragmatic and feasible suggestions for improvement in line with China's national conditions,were proposed in order to provide references for updating China's guide.A systematic search was conducted by searching PubMed,Embase,CNKI,WanFang Data and 17 official websites of international academic organizations for pharmacoepidemiology and regulatory agencies from countries or regions including Europe,the United States,Japan,and China,etc.,and relevant guidelines or standards were screened based on predefined inclusion and exclusion criteria,resulting in the inclusion of 33 methodological guidelines or standards for pharmacoepidemiological studies.A qualitative synthesis approach was then employed to extract core elements from the guidelines through thematic categorization and content summarization,followed by a descriptive comparative analysis.The results indicate that the 1st edition of the China's guide provides relatively comprehensive guidance on adverse drug reaction reporting and publication of research findings.However,there are gaps in study protocol development,data analysis during study implementation,study reporting,and specific study scenarios.By integrating and drawing upon the latest international pharmacoepidemiology methodology guidelines while balancing comprehensiveness,practicality,and user-friendliness,this study provides recommendations for updating the China's guide.

Objective:To investigate the effect of PD-1/PD-L1 inhibitor BMS-1 on LPS-induced inflammation in mouse microg-lia cells(BV-2 cells).Methods:Bv-2 cells were divided into Control group,LPS group and LPS+BMS-1 group.Bv-2 cells in Control group were cultured in DMEM medium for 78 hours,cells in LPS group were stimulated with 100 ng/ml LPS for 6 hours after 72 hours of normal culture,Bv-2 cells in LPS+BMS-1 group were treated with 50 nmol/ml BMS-1 for 72 hours and then stimulated with 100 ng/ml LPS for 6 hours.Expressions of PD-1 and iNOS mRNA in each group were detected by RT-qPCR,and expressions of PD-1 and iNOS protein in microglia were detected by Western blot.Flow cytometry was used to detect cell apoptosis in each group.Levels of inflamma-tory cytokines IL-1β,IL-6,TNF-α and IL-10 were detected by ELISA.Results:RT-qPCR and Western blot results showed that com-pared with Control group,LPS group had significantly increased expression of PD-1 and iNOS(P<0.05).Compared with LPS group,LPS+BMS-1 group had significantly decreased expression of PD-1(P<0.05)and significantly increased expression of iNOS(P<0.05).Flow cytometry showed that compared with Control group,LPS group had a significantly increased in apoptosis of microglia(P<0.000 1).Compared with LPS group,LPS+BMS-1 group had a significantly increased in apoptosis of microglia(P<0.000 1).ELISA results showed that compared with Control group,LPS group had no significantly increased in pro-inflammatory factors IL-1β and IL-6(P>0.05),while significantly increased in TNF-α(P<0.000 1)and anti-inflammatory factor IL-10(P<0.000 1).Pro-inflammatory cyto-kine IL-1β in LPS+BMS-1 group was significantly higher than that in LPS group(P=0.000 1),IL-6 and TNF-α were also significantly higher than those in LPS group(P<0.000 1),while anti-inflammatory cytokine IL-10 in LPS+BMS-1 group was significantly lower than that in LPS group(P<0.000 1).Conclusion:BMS-1 can promote LPS-induced inflammatory response or impede the recovery of inflammation,and increase apoptosis of microglia.PD-1/PD-L1 pathway may be a potential therapeutic target for neuroinflammation.