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.

Although global brain science research has progressed rapidly in recent decades, several fundamental questions in neuroscience remain unresolved. In particular, the physical mechanism underlying neural signal transmission remains controversial, and the carriers responsible for neural information storage and retrieval have not yet been fully clarified. These unresolved issues motivate us to re-examine the processes of neural information generation, transmission, integration, storage, and retrieval from multiple perspectives. A key observation is that neural electromagnetic activities are closely associated with time. Their duration, temporal structure, and dynamic evolution play crucial roles in neural information processing. In this work, we analyze neural electromagnetic activities from the perspective of temporal scales (referred to here as the “time course”). By reviewing and integrating findings from previous studies, we examine the characteristic time requirements and dynamic features of neural processes occurring at different stages of information processing. These stages include neural signal generation, signal transmission along axons, synaptic integration, synaptic plasticity, and memory formation and retrieval. Based on this temporal analysis, we outline a framework describing neural electromagnetic activities across a wide range of time scales, spanning from microseconds to minutes, hours, or even longer periods associated with long-term memory, which suggests that neural information processing involves multiple physical processes operating at different time levels. Rapid electromagnetic events may occur on microsecond scales, whereas electrophysiological phenomena such as action potentials typically last on the order of milliseconds. Longer time scales are associated with synaptic plasticity and memory-related processes. From this perspective, we propose that the physical carrier of neural information may be transient electromagnetic pulses with durations on the microsecond scale. In this framework, action potentials can be interpreted as the macroscopic electrophysiological manifestation of underlying electromagnetic processes triggered by ionic currents across neuronal membranes. Rather than being the fundamental neural signal itself, the action potential may represent a measurable membrane-level response associated with the successful activation of these electromagnetic events. Moreover, we discuss a possible mechanism for long-term memory storage. Considering the apparent temporal contradiction between the millisecond-scale excitation of neurons and the long-term persistence of memories, we believe that long-term memory information may be stored within neural network topologies formed by electrical synapse coupling. Such structures, referred to as electrically coupled memory networks (ECMNs), may enable neurons within the same network to respond rapidly and synchronously to stimuli, thereby facilitating efficient memory retrieval. Overall, this study emphasizes the importance of considering the temporal organization of neural electromagnetic activities when interpreting neural signaling mechanisms. It may provide new insights into the physical nature of neural information carriers and the mechanisms of memory storage and retrieval. Furthermore, highlighting the potential role of electromagnetic interactions in neural activity may contribute to the development of new theoretical frameworks and experimental approaches in neuroscience. Such perspectives may also offer valuable references for future research on neural coding, brain function mechanisms, and neuromodulation technologies.

Objective To systematically evaluate the risk prediction models for acute kidney injury in patients with acute coronary syndrome (ACS) based on machine learning, providing a reference for clinical selection of appropriate risk assessment tools. Methods Clinical studies using machine learning methods for predicting the risk of acute kidney injury in ACS patients were retrieved from PubMed, Cochrane Library, Embase, Web of Science core database, CNKI, Wanfang Database, CBM, and VIP. The retrieval time was from the establishment of the database to May 24, 2025. The quality of the models were evaluated using the prediction model risk of bias assessment tool. Results Nine articles were included, and a total of 58 prediction models were constructed using 20 machine learning methods. The area under the receiver operating characteristic curve ranged from 0.733 to 0.894. The most commonly used predictors were age and creatinine. The overall bias risk of the included studies was relatively high, but the applicability was good.Conclusion Machine learning models can identify the risk of acute kidney injury in ACS patients. All models have good predictive potential, but they are still in the development stage. It is recommended that future studies adopt prospective design with external validation to improve the stability and predictive accuracy of the models.

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.

The chemical constituents from the n-butanol fraction of ethanol extract of safflower (Carthamus tinctorius L.) were isolated and purified using chromatographic process including MCI Gel CHP-20, ODS, Sephadex LH-20 column chromatography, and semi-preparative HPLC method, and one alkyne and two phenylpropanoid derivants were obtained. Their structures were identified as (5R,E)-tetradecane-12-ene-8,10-diyne-1,5,14-triol (1), (E)-8-O-β-D-glucopyranosyl n-butyl cinnamate (2), and (7S,8S)-7-(4-hydroxy-3-methoxybenzene)-7-butyl-8,9-diol (3) by modern spectroscopy methods (1D NMR, 2D NMR, UV, IR and MS). 1-3 are all new compounds. Compounds 1-3 were screened for their anti-renal fibrosis activities in vitro, and none of them showed obvious effect.

AIM To investigate the effects of Shuyu Pills combined with evolimus on the epithelial mesenchymal transformation of triple negative breast cancer cells 4T1 and MDA-MB-231 induced by TGF-β1.METHODS The 4T1 and MDA-MB-231 cells were divided into the blank group and the induction group to induce the epithelial mesenchymal transformation with TGF-β1 cytokine treatment,followed by the assignment into the model group,the Shuyu Pills group,the everolimus group and the Shuyu Pills combined with everolimus group.CCK8 method,plate cloning method,cell scratch test and Transewll test were used to detect the proliferation,cloning formation,migration and invasion ability of the cells whose expressions of E-cadherin,N-cadherin,Vimentin,MMP9,MMP2 and pathway proteins PTEN,PI3K,Akt and mTOR were detected by Western blot.RESULTS Compared with the blank group,the induction group displayed a cell morphological change from epithelioid to stromal,decreased expression of E-cadherin protein(P＜0.01);and increased protein expressions of N-cadherin and Vimentin(P＜0.05).Compared with the model group,each group intervened with the medicine displayed decreased proliferation,clone formation,migration and invasion ability of both kinds of cells(P＜0.01);increased protein expressions of PTEN and E-cadherin(P＜0.05,P＜0.01);and decreased protein expressions of PI3K,Akt,mTOR,N-cadherin,Vimentin,MMP9 and MMP2(P＜0.05,P＜0.01);and more significantly in the Shuyu Pills combined with evolimus group(P＜0.05,P＜0.01).CONCLUSION With a more ideal effect than the single uses in inhibiting the TGF-β1-induced epithelial mesenchymal transformation of triple-negative breast cancer cells,the combination use of Shuyu Pills and everolimus may work through the regulation of PI3K/Akt/mTOR signaling pathway.

Objective:To explore the risk factors of pulmonary infection in patients with non-small cell lung cancer (NSCLC) after thoracoscopic lobectomy and evaluate their predictive value.Methods:A retrospective analysis was conducted on the clinical data of 152 NSCLC patients who underwent thoracoscopic lobectomy at the Central Hospital of Tongchuan Mining Bureau in Shaanxi Province from May 2021 to May 2024. Among them, 45 cases were diagnosed with pulmonary infection by postoperative lung CT examination (postoperative infection group), while the remaining 107 cases did not develop pulmonary infection (non infection group). The levels of serum procalcitonin, serum amyloid A (SAA), and soluble triggering receptor expressed on myeloid cell-1 (sTREM-1) between two groups of patients before and after surgery were compared, and conduct a multivariate logistic regression analysis on the risk factors of pulmonary infection in NSCLC patients undergoing thoracoscopic lobectomy was conducted to evaluate the predictive value of each indicator for pulmonary infection in NSCLC patients after thoracoscopic lobectomy. The normally distributed quantitative data was represented by xˉ± s. Independent sample t-test was used for comparison between two groups, and paired t-test was used for comparison before and after treatment; The count data was presented as an example (%), and the comparison between groups was conducted using the chi square test. The risk factors for postoperative pulmonary infection in NSCLC patients were analyzed using multiple logistic regression analysis. Receiver operating characteristic (ROC) curves were plotted to analyze the predictive value of each indicator for pulmonary infection after thoracoscopic lobectomy. Results:No difference were found in the levels of serum procalcitonin, SAA, and sTREM-1 between two groups of patients before surgery(all P>0.05); 24 hours after surgery, the levels of serum procalcitonin, SAA, and sTREM-1 in both groups of patients were higher than before surgery [Postoperative infection group: (1.16±0.29) μg/L compared to (0.34±0.09) μg/L, (10.2±1.8) mg/L compared to (7.3±0.9) mg/L, (20.3±4.8) ng/L compared to (8.0±1.2) ng/L, t-values were 20.70, 9.70, and 16.89, respectively, all P<0.001; The uninfected group (0.84±0.14) μg/L compared to (0.32±0.08) μg/L, (8.2±1.1) mg/L compared to (7.4±0.9) mg/L, and (13.5±6.3) ng/L compared to (8.1±1.2) ng/L, with t-values of 33.36, 6.13, and 8.73, respectively, all P<0.001, and the infected group was higher than the uninfected group ( t-values of 9.18, 8.32, and 6.52, respectively, all P<0.001). The results of multivariate logistic regression analysis showed that serum procalcitonin, SAA, and sTREM-1 levels at 24 hours after surgery were all risk factors for pulmonary infection in NSCLC patients undergoing thoracoscopic lobectomy (odds ratios of 2.40, 1.61, 1.60, 95% confidence intervals: 1.14~5.04, 1.09~2.38, 1.13~2.26, P values of 0.021, 0.017, 0.009, respectively). The area under curve(AUC) of serum procalcitonin, SAA, and sTREM-1 predicting pulmonary infection after thoracoscopic lobectomy in NSCLC patients 24 hours after surgery were 0.84, 0.74, and 0.79, respectively, with cutoff values of 1.03 μg/L, 9.74 mg/L, and 16.85 ng/L, respectively. Conclusions:The levels of serum procalcitonin, SAA, and sTREM-1 24 hours after surgery are all risk factors for pulmonary infection in NSCLC patients undergoing thoracoscopic lobectomy, and all three had a high predictive value for postoperative pulmonary infection.

Objective:To determine the epidemic characteristics of polymyxin resistance ( mcr) genes of Enterobacteriales colonized in patients admitted to hospitals in Zhejiang, Henan, Gansu and Shandong provinces in China in 2023. Methods:A comprehensive collection of 667 fecal specimens from patients admitted to five medical facilities across the provinces of Zhejiang, Henan, Gansu, and Shandong in 2023 was collected. Epidemiological characteristics of Enterobacteriales bacteria positive for the mcr gene were examined, employing techniques such as microbial culturing, using agarose gel electrophoresis, PCR, whole-genome sequencing, bioinformatics analysis, and the induction of antimicrobial resistance. Statistical analysis was subsequently applied to the gathered data. Results:Among 667 fecal samples from admitted patients, five samples were positive for mcr gene, with a carrier rate of 0.75%(5/667), and from two of the samples, two different strains carrying the mcr gene were isolated, respectively. A total of seven strains of Enterobacteriales carrying the mcr gene were detected, of which four strains carried mcr-1 gene and three strains carried mcr-9 gene. The positive isolates included three strains of Escherichia coli, one strain of Citrobacter braakii, Citrobacter freundii, one strain of Klebsiella pneumoniae, and one strain of Enterobacter hormaechei. The seven mcr positive strains were isolated from two distinct geographical locations within China, with four from Zhejiang Province and three from Henan Province. After whole-genome sequencing, it was found that the 16S rRNA sequences of the three strains of mcr-1 positive Escherichia coli had high homology. The three isolates of mcr-9 positive strains preserved a significant degree of homology within the mcr-9 and wbuC regions. Following polymyxin exposure, there was a marked difference in the growth kinetics of the ZJ-307, HN-11-1, and HN-135 strains post-induction compared to their pre-induction growth rates, and their motility capacity was reduced. Conclusions:The prevalence of Enterobacteriales harboring the mcr gene is minimal among hospitalized patients. However, it is noteworthy that these genes are prone to horizontal transfer. They can move into drug-resistant strains, which may have elevate minimum inhibitory concentration(MIC). Resistance to polymyxin can alter the bacterial growth rate and motility, potentially impacting the MIC of other antibiotics, thereby complicating clinical management. Consequently, it is imperative to focus on the proactive screening of susceptible populations to prevent the further dissemination of plasmid-mediated polymyxin resistance among clinically significant gram-negative bacterial pathogens.