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.

Osteoarthritis (OA), a highly prevalent degenerative joint disease worldwide, is defined by articular cartilage degradation, abnormal bone remodeling, and persistent chronic inflammation. It severely compromises patients’ quality of life, and currently, there is no radical cure. Abnormal mechanical stress is widely regarded as a core driver of OA pathogenesis, and the exploration of mechanical signal perception and transduction mechanisms has become crucial for deciphering OA’s pathophysiological processes. Piezo1, a key mechanosensitive cation channel belonging to the Piezo protein family, has recently gained significant attention due to its pivotal role in mediating cellular responses to mechanical stimuli in joint tissues. This review systematically examines Piezo1’s expression patterns, regulatory mechanisms, and pathological functions in OA, with a particular focus on its dual roles in modulating chondrocyte homeostasis and bone metabolism disorders, while also delving into the underlying molecular signaling pathways and potential therapeutic implications. Piezo1, consisting of approximately 2 500 amino acids and forming a unique trimeric propeller-like structure, is widely expressed in chondrocytes, osteocytes, mesenchymal stem cells, and synovial cells. It exhibits permeability to cations such as Ca²⁺, K⁺, and Na⁺, and directly responds to membrane tension changes induced by mechanical stimuli like fluid shear stress and mechanical overload. In OA patients and animal models, Piezo1 expression is significantly upregulated, especially in cartilage regions subjected to abnormal mechanical stress (e.g., human temporomandibular joint cartilage). This overexpression is closely associated with aggravated cartilage degeneration, increased chondrocyte apoptosis, accelerated cellular senescence, and intensified inflammatory responses. Mechanical overload and pro-inflammatory cytokines (e.g., IL-1β) are key inducers of Piezo1 upregulation: IL-1β activates the PI3K/AKT/mTOR signaling pathway to enhance Piezo1 expression, forming a pathogenic positive feedback loop that inhibits chondrocyte autophagy, promotes apoptosis, and further accelerates joint degeneration. Mechanistically, Piezo1 mediates OA progression through multiple interconnected pathways. When activated by mechanical stress, Piezo1 triggers excessive Ca²⁺ influx, leading to endoplasmic reticulum stress (ERS) and mitochondrial dysfunction, which directly induce chondrocyte apoptosis. This process involves the activation of downstream signaling cascades such as cGAS-STING and YAP-MMP13/ADAMTS5. YAP, a transcriptional regulator, upregulates the expression of matrix metalloproteinase 13 (MMP13) and aggrecanase (ADAMTS5), thereby accelerating cartilage matrix degradation. Additionally, Piezo1-driven Ca²⁺ overload promotes the accumulation of reactive oxygen species (ROS) and upregulates senescence markers (p16 and p21), accelerating chondrocyte senescence via the p38MAPK and NF-κB pathways. Senescent chondrocytes secrete senescence-associated secretory phenotype (SASP) factors (e.g., IL-6, IL-1β), further amplifying joint inflammation. In terms of bone metabolism, Piezo1 maintains joint homeostasis by promoting the differentiation of fibrocartilage stem cells into chondrocytes and balancing bone formation and resorption through regulating the FoxC1/YAP axis and RANKL/OPG ratio. Therapeutically, targeting Piezo1 shows promising potential. Preclinical studies have demonstrated that Piezo1 inhibitors (e.g., GsMTx4) can reduce joint damage and alleviate pain in OA mice. Simultaneously, siRNA-mediated co-silencing of Piezo1 and TRPV4 (another mechanosensitive channel) decreases intracellular Ca²⁺ concentration, inhibits chondrocyte apoptosis, and promotes cartilage repair. Conditional knockout of Piezo1 using Gdf5-Cre transgenic mice alleviates cartilage degeneration in post-traumatic OA models by downregulating MMP13 and ADAMTS5 expression. Despite existing challenges, such as off-target effects of inhibitors, inefficient local drug delivery, and interindividual genetic variability, strategies like developing selective Piezo1 antagonists, optimizing targeted nanocarriers, and combining Piezo1-targeted therapy with physical therapy provide viable avenues for clinical translation. The authors propose that Piezo1 serves as a critical therapeutic target for OA, and future research should focus on deciphering its context-dependent regulatory networks, developing tissue-specific intervention strategies, and validating their efficacy and safety in clinical trials to address the unmet medical needs of OA patients.

ObjectivePost-ischemic acute inflammation and the subsequent persistent dysregulation of the immune microenvironment represent major pathological drivers that aggravate neuronal injury and severely restrict functional recovery following ischemic stroke. Although current reperfusion therapies partially restore blood flow, they fail to effectively modulate the secondary inflammatory cascade and oxidative stress, which remain critical barriers to neurological restoration. To address this challenge, this study aimed to engineer and systematically evaluate a biomimetic nanosystem composed of transforming growth factor-β1 (TGF-β1)-loaded platelet membrane-camouflaged lipid nanoparticles (PLP). This nanosystem was designed to achieve dual lesion-targeted delivery and immune microenvironment remodeling. By verifying its spatiotemporal accumulation, anti-inflammatory activity, and neuroprotective efficacy, we sought to establish an integrated therapeutic strategy that simultaneously enables lesion targeting, immune regulation, and functional recovery after ischemic injury. MethodsThe physicochemical properties of PLP, including hydrodynamic particle size, zeta potential, structural stability, and morphology, were characterized using dynamic light scattering, zeta potential analysis, and transmission electron microscopy. The preservation of platelet membrane-derived adhesion and immunoregulatory proteins was confirmed by SDS-PAGE through comparative analysis of protein band profiles between PLP and native platelet membranes. The in vitro biological activities of PLP were evaluated using two complementary cellular models. LPS-induced M1-polarized RAW264.7 macrophages were employed to assess inflammatory modulation, while oxygen glucose deprivation/reperfusion (OGD/R)-induced BV2 microglial cells and SH-SY5Y neuronal cells were utilized to investigate neuroinflammatory regulation and neuronal protection. For in vivo validation, a transient middle cerebral artery occlusion (tMCAO) mouse model was established to mimic ischemia-reperfusion injury. The spatiotemporal biodistribution and lesion-targeting capability of the PLP were monitored through live fluorescence imaging. Therapeutic efficacy was comprehensively evaluated by triphenyltetrazolium chloride (TTC) staining, glial fibrillary acidic protein (GFAP) immunofluorescence analysis, body weight monitoring, and neurological severity score (NSS) assessment. ResultsPLP nanoparticles displayed a uniform spherical morphology, nanoscale particle size distribution, and stable negative surface charge, indicating favorable colloidal stability and circulation potential. SDS-PAGE results confirmed the effective retention of key platelet membrane proteins associated with endothelial adhesion, immune evasion, and inflammatory regulation, demonstrating the successful biomimetic construction. Optimal therapeutic concentrations were determined in OGD/R-induced BV2 cells, where PLP exhibited excellent cytocompatibility and anti-inflammatory activity.In vitro experiments demonstrated that PLP significantly inhibited the polarization of RAW264.7 macrophages toward the pro-inflammatory M1 phenotype and markedly reduced neuronal apoptosis under ischemia-reperfusion conditions. In vivo fluorescence imaging revealed that PLP rapidly accumulated in the ischemic brain hemisphere and maintained prolonged retention for up to 7 d, suggesting enhanced lesion-specific targeting and sustained drug release. Compared with control group, PLP treatment significantly reduced cerebral infarct volume, attenuated reactive astrogliosis, improved weight recovery, and accelerated neurological functional restoration, as reflected by significantly improved NSS scores. ConclusionThis study establishes a multifunctional biomimetic nanoplatform that integrates platelet membrane-mediated active targeting with the anti-inflammatory, antioxidative, and neuroprotective properties of TGF-β1. The PLP system enables rapid lesion homing and long-term retention while synergistically regulating the post-stroke inflammatory microenvironment by suppressing pro-inflammatory immune activation, reducing neuronal apoptosis, and limiting excessive astrocyte reactivity. Importantly, this study proposes a conceptually therapeutic paradigm that combines targeted delivery with immune microenvironment remodeling to achieve comprehensive neurovascular protection. These findings provide strong experimental evidence supporting the translational potential of biomimetic nanotherapeutics as next-generation precision interventions for ischemic stroke.

Objective To explore the physical function indicators of elderly women with fall experiences,so as to provide more data reference for fall prevention,risk assessment,and solving of aging-related health problems in elderly women.Methods The fall history of 167 elderly women in communities in Tianjin was investigated by a questionnaire.The participants were assigned into a fall group(more than 2 falls in the last 1 year)and a non-fall group according to the number of falls.Body composition was tested by an Inbody 770 Body Composition Analyzer,and the calcaneus bone mineral density was measured by a UBD2002A Ultrasound Bone Densitometer.The muscle strength and proprioception of knee and ankle joints of lower limbs were measured by a PRIMUS BTE Isokinetic Tester.The muscle strength of lower limbs was evaluated by the number of 30-second sitting-rising.The visual sensitivity was examined by two-contrast near point reading cards(with a small number of strokes).The dynamic and static balance abilities were determined by a Korebalance Tester,and the static balance ability was tested by one-leg standing with eyes closed.The dynamic and static balance was assessed based on the Berg balance scale,and walking gait characteristics were studied by a BTS three-dimensional motion capture system.Results The skeletal muscle content(P<0.001),strength of non-dominant knee flexor muscle(P=0.002),number of 30-second sitting-rising(P=0.006),and average walking speed(P=0.013)in the fall group were lower than those in the non-fall group.The visual acuity at 10% grayscale(P=0.001),active knee joint position sense(P<0.001),strength of non-dominant ankle flexor muscle(P<0.001),and one-leg standing time with eyes closed(P<0.001)in the fall group were lower than those in the non-fall group.The fall group outperformed the non-fall group in right-left balance rate(P=0.031)and forward-backward balance rate(P=0.028)during static and dynamic balance tests.Conclusion The ankle angle,proprioception,muscle strength,and skeletal muscle content of lower limbs,visual sensitivity,dynamic and static balance abilities,and walking ability of elderly women with fall experiences were lower than those without fall experiences.
Humans ; Accidental Falls ; Aged ; Female ; Postural Balance ; Muscle Strength ; Body Composition ; Bone Density ; Surveys and Questionnaires ; Gait

Objective To explore the acceptability of routine biochemical test results for serum samples with varying degrees of chylous high triglyceride(TG).Methods Blood samples of 69 patients with different degrees of lipids were collected,including 33 patients with mild to moderate lipids(1.7 mmol/L≤TG<5.6 mmol/L)and 36 patients with severe lipids(TG≥5.6 mmol/L).Twenty-nine biochemical tests were detected before and after high-speed centrifugation.The result acceptability before high speed centrifugation of serum was compared with the results after high speed centrifugation as the gold standard[TG and total cholesterol(TC)before centrifugation].The acceptable criteria were subject to the following three conditions at the same time.Firstly,correlation coefficient(R2)was greater than or equal to 0.95.Secondly,the slope of linear re-gression equation was 1.00±0.05.Thirdly,for the same index,the number of samples whose result bias be-fore and after centrifugation was less than 1/2 total allowable error(TEa)in more than 90%of the total sam-ple numbers.Results Firstly,in the mild to moderate lipemia group,22 tests met the criteria,7 tests did not,including total protein(TP),albumin(ALB),TG,aspartate aminotransferase(AST),carbon dioxide(CO2),α-L-fucosidase(AFU),lactate dehydrogenase(LDH)(bias<10%),and the coincidence rate was 75.9%.In the severe lipemia group,12 tests met the criteria,17 tests did not,including pre-albumin(PA),AFU,γ-glu-tamyltransferase(γ-GT),LDH,AST,TC,direct bilirubin(DBIL),CO2,5'-nucleotidase(5'-NT),small and low-density lipoprotein cholesterol(sd-LDL-C),high density lipoprotein cholesterol(HDL-C),low-density lipoprotein cholesterol(LDL-C),adenosine deaminase(ADA),cystatin C(CysC),glycosylated albumin(GA),total bilirubin(TBIL)(bias>10%),the coincidence rate was 41.4%,and there was a statistically sig-nificant difference in the coincidence rate between the two groups(P<0.05).Secondly,there was no statisti-cally significant difference in the acceptability of results between continuous monitoring method and endpoint method detection methods(P>0.05).Conclusion Most test results of direct determination with mild or moderate lipemia samples are acceptable,and the bias of unacceptable tests is small(<10%),so it is recom-mended to issue a test report without further sample treatment.However,due to the large number of unacceptable tests and larger bias(>10%),severe lipemia samples should be determined after high-speed centrifugation.

Objective:To explore the potential categories and influencing factors of medication compliance in patients with cardiometabolic multimorbidity, and provide a reference for formulating targeted intervention measures.Methods:A cross-sectional study design was adopted. From March to October 2024, the patients with cardiometabolic multimorbidity in the First Hospital Affiliated with Hunan Normal University (Hunan Provincial People′s Hospital) were selected by convenience sampling method as research objects. Data were collected using a general information questionnaire, Medication Adherence Rating Scale (MARS), Perceived Social Support Scale (PSSS), and Medication Literacy Questionnaire. The latent class analysis was used to explore the characteristics and classifications of medication compliance in cardiometabolic multimorbidity, and unordered multivariate Logistic regression was used to analyze the influencing factors of different latent classes.Results:A total of 421 subjects were included, consisting of 291 males and 130 females, aged (64.28±9.74) years old. The overall medication adherence score was 6.00 (5.00, 8.00) points, which could be divided into four categories: overall good adherence group (24.47%, 103/421), subjective perception-poor adherence group (15.91%, 67/421), forgetfulness-poor adherence group (37.53%, 158/421), and overall poor adherence group (22.09%, 93/421). The results showed that when taking the overall good adherence group as a reference, the inability to obtain pharmaceutical information from social media, medication literacy scores, social support scores were the influencing factors for the subjective perception-poor adherence group ( OR=4.210, 0.516, 0.733, all P<0.05). Occupational characteristics (employees in public institutions or government-affiliated institutions), age, social support scores were the influencing factors for the forgetfulness-poor adherence group( OR=0.173, 1.155, 0.781, all P<0.05). Occupational characteristics (employees in public institutions or government-affiliated institutions), failure to receive medication guidance from medical staff, medication literacy scores and social support scores were the influencing factors for the overall poor adherence group( OR values were 0.136-5.275, all P<0.05). When taking the overall poor adherence group as a reference, failure to receive medication guidance from medical staff and medication literacy scores were the influencing factors for the subjective perception-poor adherence group ( OR=0.310, 1.752, both P<0.05). Failure to receive medication guidance from medical staff, age, medication literacy scores and social support scores were the influencing factors for the forgetfulness-poor adherence group ( OR values were 0.315-2.554, all P<0.05). Conclusions:There is significant heterogeneity in medication adherence among patients with cardiometabolic multimorbidity. Healthcare professionals should consider individual characteristics in clinical practice and provide targeted, precise interventions to improve adherence in different patient categories.

Objective Pharmacovigilance,as an essential component of post-marketing drug regulation,plays a crucial role in ensuring the safety of public medication use.In recent years,Artificial intelligence(AI)technology,with its powerful data processing and analysis capabilities,has shown tremendous potential in the field of Pharmacovigilance.This article introduced and analyzed the application background of AI technology in Pharmacovigilance,its exploration and current status both internationally and within China,highlighted its application in the country,as well as the associated problems and challenges from the perspective of post-marketing regulation.It aims to provide reference for post-marketing regulation in China.Currently,China's exploration and application of AI in pharmacovigilance have just begun,and efforts should be intensified and the pace accelerated.Regulatory agencies should actively develop and implement regulatory standards or relevant guidelines for AI technologies throughout the product lifecycle,strengthen personnel training,talent cultivation,and introduction,actively promote close cooperation among regulatory agencies,pharmaceutical companies,research institutes,and universities,and jointly promote the innovative application of AI technology in the field of drug regulation.

Objective In view of the potential threat of adverse drug reaction(ADR)to patients'health and the limitations of traditional monitoring methods,this study investigates the construction method of an ADR knowledge graph based on a knowledge-driven technology path to promote the intelligent upgrading of pharmacovigilance field.Methods In this study,an adverse drug reaction knowledge base was established,and the data within the knowledge base were preprocessed.The BERT-CRF model was utilized to identify and extract the relevant entities,relationships and attribute information,and knowledge alignment was carried out by combining the rule method and statistical method.The knowledge fusion data was stored in the Neo4j graph database to construct the knowledge graph.Results Based on the established knowledge base,this study explored the method of constructing knowledge graph of adverse drug reaction by knowledge-driven technology,laying the groundwork for data mining and the development of intelligent auxiliary system tools based on knowledge graph.Conclusions The study on the construction method of an ADR knowledge graph based on a knowledge-driven technology path provides a new perspective and technical path for the intelligent upgrading of pharmacovigilance field.It holds important theoretical and practical significance for improving drug safety,protecting patients'health,and promoting the healthy development of pharmaceutical industry.

Hypothermia is a clinical syndrome characterized by core body temperature<35℃,caused by significant heat loss from body surface in cold environment.As a systemic cold injury,it can be lethal if treatment is delayed.Emergent diagnosis and treatment of hypothermia are expected to improve the prognosis of patients.In 2005,the U.S.Army Research Institute of Environmental Medicine(USARIEM)issued guidelines for the prevention and management of cold injuries,but there has been no corresponding standard in China.Therefore,Emergency Branch of Chinese Medical Rescue Association,Emergency Medical Equipment Society of China Association of Medical Equipment,Integrated Rehabilitation Medical Branch of Chinese Medical Rescue Association,and Pre-Hospital Emergency Care Working Committee of Chinese Aging Well Association jointly developed the Chinese Expert Consensus on Emergent Treatment of Hypothermia(2025 edition).The consensus covers the pathophysiology,etiology and epidemiology,diagnosis and severity grading,prehospital treatment,and in-hospital treatment of hypothermia,including 15 recommendations in total,aiming to provide guidance for the relevant clinical rescue work.

Purpose To analyze the expression of SNAP23 in esophageal squamous cell carcinoma(ESCC)and its influence on invasion of ESCC cells.Methods A total of 41 cases of ESCC and paired normal adjacent tissue(NAT)were collected.The expression and localization of SNAP23 were detected by immunohistochemical EnVision method.The differences of SNAP23 expression levels between ESCC tissues and NAT tissues were compared to analyze the relationship between SNAP23 expression and clinicopathological characteristics.The expression level of SNAP23 in human immortalized esophageal epithelial cells SHEE and ESCC cell lines TE-1,TE-13 and KYSE150 were detected by Western blot.Lentiviral vector transfection technique was used to construct stable transfection cell lines with knock-down and overexpression of SNAP23 gene.The effect of SNAP23 on invasion of ESCC cell line TE-13 was evaluated by cell invasion experiment.Results The expression of SNAP23 in ESCC was significantly higher(53.7％,22/41)than that in the NAT group(19.5％,8/41),the difference was statistically significant(x2=10.303,P＜0.01).The expression level of SNAP23 in ESCC tissues was significantly correlated with maximum tumor diameter(x2=4.193,P＜0.05)and invasion depth(x2=7.264,P＜0.05),but was not correlated with patient gender,age,tumor site,tumor type,pathologic grade,vascular embolus,nerve invasion and lymph node metastasis(P＞0.05).Compared with human immortalized esophageal epithelial cells SHEE,SNAP23 was highly expressed in ESCC cell lines(P＜0.000 1).Compared with the sh-NT group,the invasion of ESCC cell line TE-13 was inhibited when SNAP23 expression was knocked down(P＜0.000 1);compared with the Vector group,the invasion of ESCC cell line TE-13 was enhanced after overexpression of SNAP23(P＜0.000 1).Conclusion SNAP23 is highly expressed in ESCC tis-sue and cell lines,and its expression level in ESCC tissues is positively correlated with tumor maximum diameter and invasion depth;SNAP23 promotes the invasion of ESCC cells.