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.

Alzheimer’s disease (AD) is a central neurodegenerative disease characterized by progressive cognitive decline and memory impairment in clinical. Currently, there are no effective treatments for AD. In recent years, a variety of therapeutic approaches from different perspectives have been explored to treat AD. Although the drug therapies targeted at the clearance of amyloid β-protein (Aβ) had made a breakthrough in clinical trials, there were associated with adverse events. Neuroinflammation plays a crucial role in the onset and progression of AD. Continuous neuroinflammatory was considered to be the third major pathological feature of AD, which could promote the formation of extracellular amyloid plaques and intracellular neurofibrillary tangles. At the same time, these toxic substances could accelerate the development of neuroinflammation, form a vicious cycle, and exacerbate disease progression. Reducing neuroinflammation could break the feedback loop pattern between neuroinflammation, Aβ plaque deposition and Tau tangles, which might be an effective therapeutic strategy for treating AD. Traditional Chinese herbs such as Polygonum multiflorum and Curcuma were utilized in the treatment of AD due to their ability to mitigate neuroinflammation. Non-steroidal anti-inflammatory drugs such as ibuprofen and indomethacin had been shown to reduce the level of inflammasomes in the body, and taking these drugs was associated with a low incidence of AD. Biosynthetic nanomaterials loaded with oxytocin were demonstrated to have the capability to anti-inflammatory and penetrate the blood-brain barrier effectively, and they played an anti-inflammatory role via sustained-releasing oxytocin in the brain. Transplantation of mesenchymal stem cells could reduce neuroinflammation and inhibit the activation of microglia. The secretion of mesenchymal stem cells could not only improve neuroinflammation, but also exert a multi-target comprehensive therapeutic effect, making it potentially more suitable for the treatment of AD. Enhancing the level of TREM2 in microglial cells using gene editing technologies, or application of TREM2 antibodies such as Ab-T1, hT2AB could improve microglial cell function and reduce the level of neuroinflammation, which might be a potential treatment for AD. Probiotic therapy, fecal flora transplantation, antibiotic therapy, and dietary intervention could reshape the composition of the gut microbiota and alleviate neuroinflammation through the gut-brain axis. However, the drugs of sodium oligomannose remain controversial. Both exercise intervention and electromagnetic intervention had the potential to attenuate neuroinflammation, thereby delaying AD process. This article focuses on the role of drug therapy, gene therapy, stem cell therapy, gut microbiota therapy, exercise intervention, and brain stimulation in improving neuroinflammation in recent years, aiming to provide a novel insight for the treatment of AD by intervening neuroinflammation in the future.

Heatstroke,especially in high-temperature and high-humidity environments,is a life-threatening acute heat-injury disease that seriously endangers human health.Timely and effective on-site treatment is crucial for patients'survival and prognosis.Early recognition,rapid assessment,and on-site cooling are the core of pre-hospital treatment of heatstroke.Currently,there is a lack of standardized application procedures for pre-hospital emergency care of heatstroke.Therefore,the"Expert Consensus on Pre-hospital Emergency Management of Heatstroke(2024 edition)"was initiated by the Expert Group on Heatstroke Prevention of the People's Liberation Army and developed in collaboration with experts from local pre-hospital emergency care,emergency departments,and intensive care units.This consensus focuses on heatstroke prevention,on-site and ambulance-based treatment,and early emergency room interventions,and puts forward 10 evidence-based recommendations,aiming to provide a reference for scientific and standardized pre-hospital emergency care of heatstroke.

Aim To explore the possible regulatory effect of leptin on acyl-CoA synthetase long chain fami-ly member ACSL5 and their effect on migration and in-vasion of breast cancer cell,and to explore the underly-ing mechanism.Methods The expression of leptin receptor was detected by immunofluorescence assay.The migration and invasion ability of MCF-7 cells were detected by wound healing assay and Transwell assay respectively.The downstream target gene of leptin was analyzed by PCR microarray data.The expression of ACSL5 in breast cancer and its correlation with the staging and prognosis of breast cancer patients were as-sessed uing bioinformatics methods.The expression of ACSL5 in MCF-7 cells treated with different concentra-tions of leptin was detected using real time fluorescence quantitative polymerase chain reaction(RT-qPCR).Overexpressing ACSL5 was constructed by lentiviral transfection;the expressions of EMT related proteins,AMPK-α and p-AMPK-α were detected by Western blot.Results Leptin promoted breast cancer cell mi-gration and invasion and EMT.ACSL5 was significant-ly low expressed in breast cancer and related to progno-sis.Leptin downregulated the expression of ACSL5 through OBR.Leptin activated AMPK pathway to downregulate ACSL5 and promote migration,invasion and EMT of breast cancer cells.Conclusions Leptin may promote the migration,invasion and EMT of breast cancer by downregulating ACSL5 through activating AMPK pathway.

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.

Aim To explore the possible regulatory effect of leptin on acyl-CoA synthetase long chain fami-ly member ACSL5 and their effect on migration and in-vasion of breast cancer cell,and to explore the underly-ing mechanism.Methods The expression of leptin receptor was detected by immunofluorescence assay.The migration and invasion ability of MCF-7 cells were detected by wound healing assay and Transwell assay respectively.The downstream target gene of leptin was analyzed by PCR microarray data.The expression of ACSL5 in breast cancer and its correlation with the staging and prognosis of breast cancer patients were as-sessed uing bioinformatics methods.The expression of ACSL5 in MCF-7 cells treated with different concentra-tions of leptin was detected using real time fluorescence quantitative polymerase chain reaction(RT-qPCR).Overexpressing ACSL5 was constructed by lentiviral transfection;the expressions of EMT related proteins,AMPK-α and p-AMPK-α were detected by Western blot.Results Leptin promoted breast cancer cell mi-gration and invasion and EMT.ACSL5 was significant-ly low expressed in breast cancer and related to progno-sis.Leptin downregulated the expression of ACSL5 through OBR.Leptin activated AMPK pathway to downregulate ACSL5 and promote migration,invasion and EMT of breast cancer cells.Conclusions Leptin may promote the migration,invasion and EMT of breast cancer by downregulating ACSL5 through activating AMPK pathway.

Objective To design a phased array ultrasonic focusing control system based on sinusoidal signal excitation in order to avoid the introduction of high-frequency interference components into the ultrasonic transducer and improve the electronic focusing performance of phased array ultrasound.Methods The system designed mainly used the high-speed field programmable gate array(FPGA)chip combined with the high-speed digital to analog converter(DAC)to realize synchronous output and control of multi-channel sinusoidal signals.There were 8 sinusoidal excitation emission modules based on FPGA and DAC and one sinusoidal ultrasonic excitation control module based on ZYNQ MPSoC involved in the hardware part of the system,in which the emission modules generated multi-channel sinusoidal excitations and timing control of sinusoidal signals within the module and the control module was responsible for controlling the triggering timing between each sinusoidal excitation transmitter module.The system developed had its software designed with MATLAB App Designer to improve the human-computer interaction experience.Performance verification was carried out for the system by testing the output waveform,inter-channel delay error and focused sound field of each channel.Results The system developed achieved generation and timing control of 64-channel sinusoidal ultrasound excitations,with the output channel main frequency being 0.5 MHz,amplitude within 0 and±12.5 V and the inter-channel delay errors not higher than 26.0 ns;a focused sound field with a focal spot diameter of 4.2 mm(-3 dB)at a depth of 50 mm was obtained when the system was applied to driving a 64-array phased-array transducer.Conclusion The system designed is capable of realizing ultrasonic electron focusing under sinusoidal excitation,which helps to improve the focusing resolution of non-invasive and precise deep brain stimulation techniques relying on the accuracy of ultrasonic focusing such as transcranial magneto-acoustic stimulation(TMAS)and transcranial ultrasonic stimulation(TUS).[Chinese Medical Equipment Journal,2025,46(5):14-20]

Purpose Discover new prostate cancer-related single nucleotide variants.Methods Tissue wax blocks from 21 prostate cancer patients who underwent radical surgery and had relatively complete clinical data were collected for somatic mutation detection to analyze new mutated genes associated with prostate cancer.The levels of cor-responding proteins in the urine of prostate cancer patients were tested according to the results of the selected genes.Results All 21 prostate cancer patients showed obvious somatic mutations,and the mutation types were dominated by C＞T and G＞A.The number of somatic mutations was 521,of which 27 genes had high mutation proportions(≥2 ca-ses),including ZSWIM6(5/21),FOXA1(4/21),SPTA1(2/21),FAM47C(2/21),FLG2(2/21),PRSS3(2/21),TP53(2/21),FLG(2/21),UBR4(2/21),and the mutations occurring in ZSWIM6 were all deletion muta-tions,and the mutations occurring in FOXA1 were missense mutations,deletion mutations,and deletion insertion mu-tations.The urinary levels of UPF1,SPTA1,and IDH1 proteins of the 10 prostate cancer patients were significantly different than those of the healthy controls.Correlation analysis showed that FOXA1 was positively correlated with UBR4(r=0.669,P=0.001),SPTA1 was positively correlated with FLG2(r=1.000,P＜0.001),FAM47C was positively correlated with PRSS3(r=1.000,P＜0.001),and there was a significant positive correlation between TP53 and FLG(r=1.000,P＜0.001).ZSWIM6 and FOXA1 were not correlated with biochemical recurrence.SP-TA1 mutation affected progression-free survival(PFS)[(66.0±0)months vs(30.0±7.8)months,P=0.008].FAM47C was positively correlated with PFS[(66.0±0)months vs(19.0±0)months,P＜0.001].ZNF676 was correlated with PFS[(66.0±0)months vs(26.0±5.0)months,P=0.008].FLG2 was correlated with PFS[(66.0±0)months vs(30.0±7.8)months,P=0.008].PRSS3 was correlated with PFS[(66.0±0)months vs(19.0±0)months,P＜0.001].Conclusion All 21 prostate cancer patients harbored somatic mutations,including ZSWIM6(5/21)and FOXA1(4/21)mutations.SPTA1,FAM47C,ZNF676,FLG2,and PRSS3 may be associated with prognosis.

Alzheimer's disease(AD)is a multifactorial condi-tion characterized by the accumulation of toxic proteins and asso-ciated neurodegeneration.AD is distinguished by the pathologi-cal aggregation of amyloid beta(Aβ)and Tau proteins.The in-teraction between Aβ and Tau can further induce neuroinflamma-tion,mitochondrial autophagy dysfunction,and endoplasmic retic-ulum stress,exacerbating synaptic damage and neuronal death.Neuronal cells are particularly susceptible to protein misfolding due to an imbalance between protein production and degrada-tion.The ubiquitin/26S proteasome system(UPS),a major pathway for protein degradation in eukaryotic cells,plays a cruci-al role in recognizing misfolded or damaged proteins within the nervous system.In UPS,the levels of ubiquitin are tightly regu-lated by both ubiquitin ligases(E3s)and deubiquitylases(DUBs).This article reviews the involvement and mechanisms of E3s and DUBs in the pathogenesis of AD,aiming to provide novel research strategies for its treatment.