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.

Objective To explore the nutritional status in elderly patients with type 2 diabetes mellitus (T2DM) and analyze its relationship with the risk of sarcopenia. Methods A retrospective analysis was conducted on 312 elderly patients with T2DM admitted to the 904th Hospital of the Joint Logistics Support Force of the People's Liberation Army between January 2023 and December 2025. Based on the presence or absence of sarcopenia, the patients were classified into a sarcopenia group (121 cases) and a non-sarcopenia group (191 cases). The nutritional status and related factors were compared between the two groups. Binary logistic regression analysis was adopted to analyze the correlation and influencing factors. Results The incidence rate of sarcopenia among elderly patients with T2DM was 38.78%. Compared with the non-sarcopenia group, the sarcopenia group had older age and higher proportions of patients with daily activity dependence, coronary heart disease, and gastrointestinal diseases. Conversely, the proportions of patients exercising ≥4 times per week and those paying attention to nutritional knowledge were lower in the sarcopenia group than those in the non-sarcopenia group (P<0.05). The body mass index (BMI), calf circumference (CC), body weight, albumin (ALB), hemoglobin (Hb), and MNA-SF score in the sarcopenia group were lower compared with those in the non-sarcopenia group (P<0.05). After logistic regression analysis, it was found that low BMI, exercising ≥4 times per week, dependence on daily activity, and low ALB and Hb were independent factors influencing sarcopenia in elderly patients with T2DM (P<0.05). Conclusion The incidence rate of sarcopenia is relatively high in elderly patients with T2DM. Low BMI, low ALB, low Hb, reduced weekly exercise frequency, and daily activity dependence are independent related factors. It is necessary to pay clinical attention to nutritional assessment and intervention.

Testicular radiation injury is a structural and functional abnormality of the testes caused directly or indirectly by radiation, which disrupts spermatogenesis and compromises male fertility. The development of effective preventive and therapeutic interventions is essential because of the high prevalence of this condition in clinical settings and its profound effect on patients′ reproductive health and overall well-being. The concept of "the struggle between vital qi and pathogen" is first seen in the Treatise on Cold Pathogenic Diseases. It denotes the dynamic struggle between vital and pathogenic qi. The occurrence, development, and sequelae of all diseases reflect this ongoing conflict. In this context, this study defines the "vital qi" of the testis as its capacity to generate and preserve the essence of reproduction and to resist damage. The pathogenic qi associated with testicular radiation injury is categorized into two types: ionizing poison and retaining evil. The pathogenesis of testicular radiation damage is delineated into three stages by integrating the characteristics of vital and pathogenic qi: the injury, adhesion, and recovery phases. Based on the theoretical framework advanced by this study, the therapeutic approach for testicular radiation injury should adhere to the fundamental principle of strengthening vital qi and eliminating pathogenic factors. Although the primary focus of treatment should be on strengthening vital qi, it should also be complemented by strategies to eliminate pathogenic influences. This paper aims to provide a novel perspective and strategic approach to the traditional Chinese medicine diagnosis, prevention, and treatment of testicular radiation injury. By elucidating the process of testicular radiation injury and its corresponding treatment principles, it seeks to offer valuable insights for clinical practice.

Background/Aims: Metabolic dysfunction-associated steatohepatitis (MASH) is a significant risk factor for gallstone formation, but mechanisms underlying MASH-related gallstone formation remain unclear. Golgi membrane protein 1 (GOLM1) participates in hepatic cholesterol metabolism and is upregulated in MASH. Here, we aimed to explore the role of GOLM1 in MASH-related gallstone formation. Methods: The UK Biobank cohort was used for etiological analysis. GOLM1 knockout (GOLM1-/-) and wild-type (WT) mice were fed with a high-fat diet (HFD). Livers were excised for histology and immunohistochemistry analysis. Gallbladders were collected to calculate incidence of cholesterol gallstones (CGSs). Biles were collected for biliary lipid analysis. HepG2 cells were used to explore underlying mechanisms. Human liver samples were used for clinical validation. Results: MASH patients had a greater risk of cholelithiasis. All HFD-fed mice developed MASH, and the incidence of gallstones was 16.7% and 75.0% in GOLM1-/- and WT mice, respectively. GOLM1-/- decreased biliary cholesterol concentration and output. In vivo and in vitro assays confirmed that GOLM1 facilitated cholesterol efflux through upregulating ATP binding cassette transporter subfamily G member 5 (ABCG5). Mechanistically, GOLM1 translocated into nucleus to promote osteopontin (OPN) transcription, thus stimulating ABCG5-mediated cholesterol efflux. Moreover, GOLM1 was upregulated by interleukin-1β (IL-1β) in a dose-dependent manner. Finally, we confirmed that IL-1β, GOLM1, OPN, and ABCG5 were enhanced in livers of MASH patients with CGSs. Conclusions In MASH livers, upregulation of GOLM1 by IL-1β increases ABCG5-mediated cholesterol efflux in an OPN-dependent manner, promoting CGS formation. GOLM1 has the potential to be a molecular hub interconnecting MASH and CGSs.

Background/Aims: Metabolic dysfunction-associated steatohepatitis (MASH) is a significant risk factor for gallstone formation, but mechanisms underlying MASH-related gallstone formation remain unclear. Golgi membrane protein 1 (GOLM1) participates in hepatic cholesterol metabolism and is upregulated in MASH. Here, we aimed to explore the role of GOLM1 in MASH-related gallstone formation. Methods: The UK Biobank cohort was used for etiological analysis. GOLM1 knockout (GOLM1-/-) and wild-type (WT) mice were fed with a high-fat diet (HFD). Livers were excised for histology and immunohistochemistry analysis. Gallbladders were collected to calculate incidence of cholesterol gallstones (CGSs). Biles were collected for biliary lipid analysis. HepG2 cells were used to explore underlying mechanisms. Human liver samples were used for clinical validation. Results: MASH patients had a greater risk of cholelithiasis. All HFD-fed mice developed MASH, and the incidence of gallstones was 16.7% and 75.0% in GOLM1-/- and WT mice, respectively. GOLM1-/- decreased biliary cholesterol concentration and output. In vivo and in vitro assays confirmed that GOLM1 facilitated cholesterol efflux through upregulating ATP binding cassette transporter subfamily G member 5 (ABCG5). Mechanistically, GOLM1 translocated into nucleus to promote osteopontin (OPN) transcription, thus stimulating ABCG5-mediated cholesterol efflux. Moreover, GOLM1 was upregulated by interleukin-1β (IL-1β) in a dose-dependent manner. Finally, we confirmed that IL-1β, GOLM1, OPN, and ABCG5 were enhanced in livers of MASH patients with CGSs. Conclusions In MASH livers, upregulation of GOLM1 by IL-1β increases ABCG5-mediated cholesterol efflux in an OPN-dependent manner, promoting CGS formation. GOLM1 has the potential to be a molecular hub interconnecting MASH and CGSs.

Objective:To report the 5-year survival outcomes and recurrence patterns of robotic total gastrectomy (RTG) for locally advanced proximal gastric cancer in order to provide more valuable long-term follow-up results for clinical practice.Methods:This was a prospective, single-arm, open-label clinical trial (FUGES-014; Clinical-Trials.gov, NCT03524287). Patients with locally advanced proximal gastric cancer who underwent RTG at Fujian Medical University Union Hospital from March 5, 2018, to February 10, 2020, were included in the analysis. To evaluate the long-term efficacy of RTG in the most objective manner possible, we performed a propensity score-matched (1∶2) comparative analysis with historical control patients who had undergone laparoscopic total gastrectomy (LTG) from the FUGES-002 study (ClinicalTrials.gov, NCT02333721) in which the 5-year disease-free survival (DFS), 5-year overall survival (OS), and recurrence patterns were compared between the two groups.Results:Prior to matching, there were 48 cases in the RTG group and 263 cases in the LTG group; patients in the LTG group had more advanced cT and pT stages ( P=0.044 and 0.006, respectively) compared to the RTG group. After matching, there were 48 cases in the RTG group and 96 cases in the LTG group; however, no statistically significant differences were observed in the baseline clinical characteristics between the two groups (all P>0.05). Both groups had a median follow-up of 72 months. The 5-year DFS rates were 75.0% (95%CI: 63.7%- 88.3%) in the RTG group and 61.4% (95%CI: 52.5%-72.0%) in the LTG group ( P=0.116). Similarly, the 5-year OS rates were 79.2% (95%CI: 68.5%-91.5%) and 64.6% (95%CI: 55.7%-74.9%) in the RTG and LTG groups, respectively ( P=0.100). Within 5 years after surgery, tumor recurrence occurred in 10 patients (20.8%) in the RTG group and 33 patients (34.4%) in the LTG group ( P=0.124), and peritoneal recurrence was the predominant pattern in both groups (8.3%[4/48] vs. 10.4%[10/96]; risk difference: -0.02, P=0.554). Gastric cancer-related death was the predominant cause of death in both groups (16.7% [8/48] vs. 31.2% [30/96]; risk difference: -0.15, P=0.064). Among patients stratified by different pathological stages, no statistically significant differences were found in DFS, OS, or recurrence rates between the RTG and LTG groups (all P>0.05). Conclusions:We find the long-term oncological outcomes of RTG for locally advanced proximal gastric cancer to be noninferior to those of LTG. RTG should therefore be considered as a valid option for standardized minimally invasive surgery for locally advanced proximal gastric cancer.

Objective:To explore behavioral and electrophysiological differences in risky decision-making between depressed patients with and without suicidal ideation.Methods:A total of 61 patients with first-episode untreated depression were enrolled in the depression clinic of Nanjing Brain Hospital from September 2023 to January 2024, which were divided into the suicidal ideation group( n=32) and the non-suicidal ideation group ( n=29).At the same time, healthy controls matched with sex, age and years of education were recruited from the community( n=36).The event-related potentials (ERP) of the participants were detected, and the amplitude and latency of feedback related negative waves (FRN) and P300 during the feedback phase under Iowa gambling task (IGT) were recorded. Statistical analysis was performed using SPSS 26.0 software.The inter-and intra-group differences of ERP indexes were compared using two-way ANOVA, and Spearman correlation analysis was conducted to examine the relationship between ERP indexes and scores of the Beck scale for suicidal ideation. Results:(1)Compared with healthy controls, depressed patients with and without suicidal ideation had both lower net scores in IGT (both P<0.05).(2)When comparing the mean FRN amplitude under different feedback types among the three groups, the main effect of feedback type ( F=8.799, P=0.004), the main effect of group ( F=6.396, P=0.002) and the interaction effect ( F=4.200, P=0.018)were all significant. Under gain feedback conditions, the mean FRN amplitude was lower in both depressed groups compared with healthy controls (both P<0.05). (3)The comparison of the mean P300 amplitude under different feedback types among the three groups showed that the main effect of group ( F=15.719, P<0.001) and the main effect of feedback type ( F=15.949, P=0.001) were both significant, while the interaction effect between group and feedback type was not significant ( F=1.573, P=0.213). The group with suicidal ideation ((0.85±0.21) μV) had a smaller amplitude than both the non-suicidal ideation group ((1.61±0.22) μV) and healthy controls ((2.46±0.20) μV) (both P<0.05). (4)In depressed patients, P300 mean amplitude under both loss and gain feedback conditions were both negatively correlated with suicidal ideation (loss: r=-0.435, P=0.001; gain: r=-0.318, P=0.013). Conclusion:Depressed patients with and without suicidal ideation both exhibit impaired risk decision-making. The decrease of P300 mean amplitude is more significant in depressed patients with suicidal ideation than those without suicidal ideation.P300 mean amplitude may serve as an electrophysiological marker to differentiate depressed patients with suicidal ideation and those without suicidal ideation.

Objective:To analyze the characteristics of electroencephalogram microstate parameters in first-episode drug-naive patients with major depressive disorder (MDD), so as to provide electrophysiological evidence for the pathogenesis and early diagnosis of MDD.Methods:Eighty-four first-episode, drug-naive outpatients diagnosed with MDD(MDD group) and 82 healthy controls(healthy group) participated in this study. Resting-state EEG data (5-6 min, with eyes closed) were recorded for all participants. Data preprocessing and microstate analysis were performed using MATLAB and EEGLAB software. Temporal parameters of resting-state brain network microstates were compared using SPSS 26.0.Results:This study identified four typical microstates: Class A microstate(auditory network), Class B microstate(visual network), Class C microstate(salient network), and Class D microstate(attention and control network). The coverage rate (0.16±0.06, 0.21±0.06), duration (67.72±7.07, 72.28±8.59), and incidence rate (2.38±0.68, 2.82±0.67) of microstate A in MDD group were significantly lower than those in healthy group ( F=22.115, 13.368, 18.779, all P<0.001), while the above indexes of microstate B in MDD group were significantly higher than those in healthy group(coverage rate: 0.24±0.07 vs 0.18±0.06, duration: 76.35±11.28 vs 69.46±8.52, incidence rat: 3.16±0.52 vs 2.52±0.57) ( F=41.287, 18.999, 52.245, all P<0.001). Additionally, the microstate D in MDD group showed significantly lower coverage rate(0.33±0.08, 0.36±0.08) and duration (89.66±15.38, 95.46±16.79)compared with healthy group( F=3.932, 4.215, both P<0.05). Notably, significant differences were observed in the transition probabilities between the following microstates: A→B, A→D, B→A, C→A, C→B, D→A and D→B (all P<0.05). Conclusion:First-episode drug-naive depressive patients are characterized by alterations in microstate A, microstate B, and microstate D, which may be the potential pathogenesis of MDD and may serve as electrophysiological indicators for early diagnosis of MDD.