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.

ObjectiveMigraine is a leading neurological disorder and the fourth most common cause of years lived with disability worldwide, affecting nearly 116 million individuals. Although pharmacological treatments are available, their efficacy is often limited by side effects and variable response rates. Repetitive transcranial magnetic stimulation (rTMS) over the dorsolateral prefrontal cortex (DLPFC) offers a safe, non-invasive alternative for migraine management. However, the neurophysiological mechanisms, particularly how rTMS modulates local cortical excitability and distributed pain-related circuits, remain poorly understood. Elucidating these mechanisms is essential for optimizing treatment protocols and improving clinical outcomes. MethodsThis study employed concurrent transcranial magnetic stimulation and electroencephalography (TMS-EEG) to investigate neuroplastic and neurocircuitry mechanisms of DLPFC-rTMS in migraine. Study 1 compared 30 migraineurs and 28 healthy controls to identify abnormalities in TMS-evoked potentials (TEPs) and significant current density (SCD) within sensory-discriminative regions including the primary somatosensory cortex (S1) and posterior insula (pINS), cognitive-affective regions including the anterior insula (aINS) and midcingulate cortex (MCC), and a descending modulatory region, the periaqueductal gray (PAG). Study 2 used a single-blind, crossover, sham-controlled design in 34 healthy participants. Each participant received both active (10 Hz, 80% RMT, 1 500 pulses) and sham DLPFC-rTMS in counterbalanced order. TMS-EEG and cold pain tolerance were assessed before and after each session. ResultsIn Study 1, migraineurs showed a significantly less negative N120 amplitude compared to healthy controls (P=0.027, Cohen’s d=0.60), indicating local intracortical disinhibition. No group differences were observed for N40, P60, or P180 components. At the source level, migraineurs exhibited significantly higher SCD in the S1, pINS, aINS, and MCC (allQ<0.05), but not in the ventroposterior thalamus (vpTHAL), mediodorsal thalamus (mdTHAL), or PAG. In Study 2, active rTMS significantly reduced SCD from pre- to post-stimulation in the S1, aINS, and MCC (all Q<0.05). Sham stimulation also reduced SCD in the S1 (Q<0.05) but not in the aINS or MCC. Although no significant group-level analgesic effect was observed between active and sham conditions (P=0.107), correlation analyses revealed that greater SCD reductions in the S1 and MCC were significantly associated with higher post-rTMS pain tolerance (R=-0.487 and -0.495, both Q<0.01) and larger improvements in pain tolerance(R=-0.487 and -0.451, both Q<0.05). No such correlations were found following sham stimulation, suggesting that the behavioural relevance of neural changes is specific to active rTMS. ConclusionThis study provides novel evidence that migraineurs exhibit both local neuroplastic abnormalities (reduced N120 amplitude) and hyperactivity in key pain-processing regions (S1, pINS, aINS, MCC). A single session of DLPFC-rTMS reduced hyperactivity in the aINS, MCC, and S1. Notably, greater reductions in the S1 and MCC were associated with improved pain tolerance. These findings identify distinct cortical circuitries, particularly within the cognitive-affective pain network, that may serve as potential biomarkers for optimizing rTMS treatment in migraine and other chronic pain conditions. Future studies should validate these results in patient populations experiencing spontaneous migraine attacks and explore multi-session or accelerated rTMS protocols.

ObjectiveTo explore the clinical efficacy of Juanbitang hot compress pack combined with intensive rehabilitation training in stroke patients with hemiplegia. MethodsA total of 80 stroke patients with hemiplegia were selected and assigned into a control group （40 cases） and an observation group （40 cases） according to the random number table method. The control group received conventional rehabilitation training and nursing intervention，while the observation group was additionally treated with Juanbitang hot compress pack. The two groups were compared in terms of the neurological function （national institute of health stroke scale score，NIHSS score），muscle strength，motor function （fugl-meyer assessment scale score，FMA score），daily living activity （modified barthel index，MBI），balance ability （berg balance scale score，BBS score），trunk control ability （Sheikh Trunk Control Test score，Sheikh TCT score），and homocysteine （Hcy） level before and after treatment. ResultsAfter treatment，the observation group had lower NIHSS score and Hcy level than the control group （P<0.05）. The total response rate of the observation group （97.50%） was higher than that of the control group （77.50%）. The scores of upper limb and lower limb FMA，MBI，BBS，and Sheikh TCT in the observation group were all higher than those in the control group （P<0.05）. ConclusionThe application of Juanbitang hot compress pack combined with rehabilitation training can effectively improve the neurological function，muscle strength，motor function，daily living ability，balance ability，and trunk control ability and reduce the Hcy level in stroke patients with hemiplegia，demonstrating enhanced clinical efficacy.

Aging is characterized by a gradual deterioration of the physiological integrity of cells,tissues,and or-gans,resulting in a decrease in the body's physiological functions and an acceleration of the onset of age-related diseases,ultimately leading to death.The aging of the liver,which is a critical metabolic organ,is closely linked to various chronic liver diseases,such as hepatitis,liver fibrosis,and cirrhosis,and it ex-acerbates their prognosis and is a primary risk factor for their development at all stages.Therefore,a comprehensive understanding of the causes,mechanisms,and potential therapeutic targets associated with liver aging holds significant clinical importance for delaying or potentially reversing liver aging and for treating chronic liver diseases.Stem cells,which are potential anti-aging agents,present a promising and effective alternative for managing liver aging.In this review,we systematically assess the driving factors,characteristics,and underlying mechanisms of liver aging.We then discuss the current status of the use of stem cells to mitigate liver senescence and address related liver diseases.The review reveals that a stem cell-based approach represents a promising therapeutic strategy for combating liver aging and associated diseases.

Objective To evaluate the application of shear wave elastography(SWE)in the diagnosis of peripheral neuropathy in patients with diabetes.Methods Totally 85 patients with type 2 diabetes(T2DM)were selected from the Chengdu Office Hospital of People's Government of Tibetan Autonomous Region,including 46 patients with peripheral neuropathy(DPN)and 39 patients without peripheral neuropathy(NDPN).Compared for clinical data(gender,age,disease duration),cross-sectional area of the median nerve measured by high-frequency ultra-sound(CSA)and shear wave elastography(SWE)parameters(mean Young's modulus value,Emean)and shear wave velocity(SWV)between two groups of patients.Multifactor Logistic regression analysis was carried out on the indicators between the above groups to screen independent predictors in the diagnosis of peripheral neuropathy in diabetes patients,and a combined model was constructed.The area under the operating characteristic curve(AUC),sensitivity and specificity of the subjects were used to evaluate the diagnostic efficacy of the single model and com?bined model of the quantitative parameters(CSA,Emean,SWV)measured by clinical data,high?frequency ultra?sound and SWE in the diagnosis of peripheral neuropathy in diabetes patients.Results Age,course of disease,Emean,SWV and CSA were statistically significant in the diagnosis of peripheral neuropathy in diabetes patients(all P<0.05).AUC was 0.658,0.754,0.839,0.822 and 0.736,respectively.The combination model based on disease course,CSA and SWV showed the highest diagnostic efficiency,with AUC,sensitivity,and specificity of 0.887(0.800-0.946),80.43％,and 84.62％,respectively.Conclusions The combined model based on the course of disease,CSA and SWV have a high diagnostic efficiency in peripheral neuropathy of diabetes patients,and has good clinical application value.

Objective To investigate the types and mechanisms of microglial cell death induced by interaction between palmitic acid(PA)and lipopolysaccharide(LPS).Methods BV-2 microglial cells were divided into three groups for apoptosis research,BSA group,PA treatment group,and staurosporine(STA)group.They were further divided into four groups for necrosis research,BSA group,BSA+inhibitor group,PA group,and PA+inhibitor group.Western blotting was conducted to assess the expression levels of key proteins involved in apoptosis and necrosis pathways.The effect of PA on microglial cells was validated through feeding a high-fat diet to Institute of Cancer Research(ICR)mice.Results Apoptotic microglia were observed in both BSA group and PA group,PA significantly induced the activation of caspase-3,caspase-7,and poly ADP-ribose polymerase(PARP).However,compared to the BSA group,the level of activated Caspase-7 in the STA group did not change significantly.Inhibition of ferroptosis,necroptosis,or autophagy did not protect against PA-induced cell damage,while the Caspase-11 inhibitor,wedelolactone(WE),significantly improved PA induced cell damage.This study also found that PA could promote LPS entry into microglial cells and induce pyroptosis.This phenomenon and the protective effect of WE were further confirmed in a high-fat diet mouse model through immunofluorescent staining and Western blotting.Conclusion PA induces apoptosis and pyroptosis in microglial cells,while simultaneously promoting LPS entry into microglial cells and inducing pyroptosis.

Objective In this preliminary survey,we sought to determine the composition of mosquito species inhabiting the Emeifeng Nature Reserve,Fujian Province,China.Methods Mosquito larvae were collected by straw and spoon trapping,and adult mosquitoes were collected by lamp trapping at selected breeding sites in the reserve.The specimens were initially identified based on morphology,with subsequent verification using molecular biology methods.Results A total of 34 mosquito species in 13 genera were collected,among which,there were 4 species of Anopheles(Genus Anopheles Meigen,1818),2 species of Lutzia(Genus Lutzia Theobald,1903),15 species of Culex(Genus Culex Linnaeus,1758),4 species of Stegomyia(Genus Stegomyia Theobald,1901),and single species of Hulecoeteomyia(Genus Hulecoeteomyia Theobald,1904),Luius(Genus Luius Reinert,Harbach et Kitching,2008),Aedes(Genus Aedes Meigen,1818),Downsiomyia(Genus Downsiomyia Vargas,1950),Collessius(Genus Collessius Reinert,Harbach et kitching,2006),Uranotaenia(Genus Uranotaenia Lynch 1891),Armigeres(Genus Armigeres Theobald,1901),Toxorhynchites(Genus Toxorhynchites Theobald,1901),and pestle mosquito(Genus Tripteroides Giles,1904).Conclusions The species composition of mosquitoes sampled in the Emeifeng Nature Reserve will provide a basis for further research on mosquito vectors and contribute to measures for local mosquito control.

Objective:To explore the demographic composition of type 2 diabetes mellitus (T2DM) with metabolic associated fatty liver disease (MAFLD) and the role of energy metabolism in the progression of MAFLD in order to provide theoretical support for improving the prognosis of MAFLD.Methods:A cross-sectional study was conducted. Ninety-four cases with T2DM combined with MAFLD admitted to the Endocrinology Department of Tianjin Third Central Hospital from July 2014 to July 2019 were selected. Patients were divided into three groups: non-metabolic associated steatohepatitis (MASH) group (25 cases), borderline MASH group (49 cases), and MASH group (20 cases) according to the non-alcoholic fatty liver disease activity score (NAS). Patients were further divided into two groups: non/mild fibrosis (F0-1) group (74 cases) and the significant fibrosis (F2-4) group (20 cases) in accordance with liver fibrosis scores. The differences in general clinical and biochemical indicators, body composition, and energy metabolism indicators among the groups were compared. Binary logistic regression analysis was conducted to explore factors affecting liver inflammation and fibrosis severity degree in patients with MAFLD.Results:The visceral fat area (VFA) and body fat percentage (PBF) were significantly higher in the MASH group than in the non-MASH group ( P<0.05), while the skeletal muscle mass index and body mass index (SMI-BMI) were significantly lower in the MASH group than in the marginal MASH group ( P<0.05) during the comparison of body composition and substrate metabolism at different stages of MASH. Alanine aminotransferase (ALT) and homeostasis model assessment of insulin resistance (HOMA-IR) were significantly higher in the fibrotic group than in those in the no/mild fibrosis group ( P<0.05) when comparing clinical and biochemical indicators, body composition, and substrate metabolism at different stages of fibrosis. The skeletal muscle mass (SMM), SMI-BMI, SMM-Weight, resting energy expenditure (REE), and fat oxidation rate (FAT OXR) were significantly lower in the fibrotic group than those in the no/mild fibrosis group ( P<0.05). The respiratory quotient and carbohydrate functional ratio (%CHO) were significantly higher in the fibrotic group than in the no/mild fibrosis group ( P<0.05). Correlation analysis indicated a positive correlation between the NAS score, reflecting the severity of liver inflammatory lesions, with VFA and PBF ( r=0.258 and 0.323, P<0.05); while the F score was positively correlated with the respiratory quotient, %CHO, and VFA ( r=0.292, 0.303, and 0.239, P<0.05), and negatively correlated with REE, the energy ratio from fat, FAT OXR, SMM, SMI-Weight, and SMI-BMI ( r=-0.209, -0.214, -0.333, -0.240, -0.250, and -0.305, P<0.05). Logistic regression analysis indicated that SMI-Weight and FAT OXR were independent factors affecting the progression of liver fibrosis. Conclusion:The reduction of skeletal muscle, particularly because of energy metabolism, is a factor affecting the progression of fibrosis in MAFLD.

Objective:To explore the optimal cut-off value of aldosterone-to-renin ratio (ARR) for primary aldosteronism screening in hypertensive populations stratified by sex and age.Methods:This study was a cross-sectional study. Patients who were diagnosed with hypertension from November 2016 to December 2023 at the First Affiliated Hospital of Dalian Medical University were included. Upright direct renin concentration (DRC) and plasma aldosterone concentration (PAC) were measured using chemiluminescence, and the ARR was calculated as PAC/DRC. Patients were divided into primary aldosteronism and primary hypertension groups based on the results of comprehensive screening tests and confirmatory tests (saline infusion test and/or captopril challenge test). Spearman correlation analysis was used to explore the correlation between ARR and age. Patients were stratified by age (≤40, >40 to 50, >50 to 60, and >60 years) and sex. The efficacy of ARR for primary aldosteronism screening was assessed by drawing the receiver operating characteristic curve and calculating the area under curve ( AUC), and to explore the optimal cut-off values for different ages and sexes. Results:A total of 1 282 hypertensive patients were enrolled, aged 46.0 (37.0, 56.0) years with 746 males. ARR showed a positive correlation with age in both primary aldosteronism ( r=0.168, P=0.007) and primary hypertension patients ( r=0.327, P<0.001). In the general population, male patients, and female patients, the AUC values of ARR screening for primary aldosteronism were 0.975 (95% CI 0.967-0.982), 0.989 (95% CI 0.983-0.995), 0.957 (95% CI 0.942-0.972), respectively. In the four groups of patients ≤40, >40 to 50, >50 to 60, and >60 years, the AUC values of ARR screening for primary aldosteronism were 0.990 (95% CI 0.983-0.997), 0.973 (95% CI 0.958-0.988), 0.965 (95% CI 0.947-0.982), 0.958 (95% CI 0.933-0.984), respectively. In the four groups of patients aged ≤40, >40 to 50, >50 to 60, and >60 years, the optimal ARR cut-off values for primary aldosteronism screening were 2.31, 2.67, 2.94, and 3.68 (ng·dl -1)/(mU·L -1)(1 ng/dl=27.7 pmol/L), respectively. The optimal ARR cut-off values for primary aldosteronism screening were 2.37 and 2.94 (ng·dl -1)/(mU·L -1) in male and female patients, respectively. Conclusion:The optimal cut-off value of ARR in the screening of primary aldosteronism increases with age, and the optimal cut-off value of ARR in female patients is higher than that in male patients. The ARR cut-off value should be selected individually based on the patient′s characteristics in clinical practice.