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.

Objective: To systematically review the effect of physical activity (PA) on health related quality of life (HRQoL) among children and adolescents and the magnitude of association, so as to provide an evidence based support for optimizing health promotion strategies for children and adolescents. Methods: Medline (PubMed), EMBASE, the Cochrane Library, SCIELO, PEDro, CNKI, Wanfang and VIP databases were searched to collect literature on PA and HRQoL in children and adolescents, which were published up to January 1, 2025. Cochrane ROB tool and specific evaluation system were used to assess literature quality, Stata 16.0 software was used for Meta analysis. For descriptive studies, correlation( r ) and 95% confidence interval( CI ) were used as effect indicators, and the inverse variance method was used to merge the data. Standardized mean difference( SMD ) and 95% CI were used to calculate the combined effect size of intervention studies. Results: A total of 22 studies involving 27 303 healthy children and adolescents were included, including 9 descriptive studies and 13 intervention studies. The results of descriptive analysis showed that PA level was positively correlated with HRQoL ( r =0.27, 95% CI =0.21-0.32, P <0.01). The analysis of intervention studies showed that PA had significant effects on overall HRQoL ( SMD =0.10, 95% CI =0.05-0.16), physical functioning ( SMD =0.16, 95% CI =0.08-0.23), and mental functioning ( SMD =0.17, 95% CI =0.10-0.25)( P <0.01). Subgroup analysis found that the effects of physical activity on overall HRQoL, physiological function, and psychological function in children and adolescents were maximized when the intervention duration was less than 6 months ( SMD =0.13, 0.18, 0.20), the frequency was≥5 times per week ( SMD =0.13, 0.19, 0.24) and there was a supplementary plan( SMD =0.10, 0.18, 0.23)( P <0.01). Conclusion PA is an important factor affecting the HRQoL of healthy children and adolescents, and the systematic PA intervention has a effect on improving the HRQoL.

Background Although current evidence suggests a link between outdoor air pollution and depressive symptoms, the effect of solid fuel use (a significant indoor air pollutant) on depressive symptoms in China's rural middle-aged and elderly population remains poorly understood. Objective To explore the association between solid fuel use for cooking and depressive symptoms among middle-aged and elderly people in rural areas of China, and to provide a basis for the prevention and control of depressive symptoms among residents in rural areas. Methods Data were obtained from the 2020 China Family Panel Studies (CFPS), depressive symptoms were assessed using 8-item Center for Epidemiologic Studies Depression Scale (CES-D), and cooking fuel type was self-reported. Subsequently, two-level binary unconditional logistic regression models were fitted to assess the impact of solid fuel use for cooking on depressive symptoms. Results A total of 7991 participants aged 45 years and older [mean age (58.52±9.18) years] were included in the study, with a mean CES-D score of 6.07±4.48 and a mean positive depressive symptoms rate of 34% (40.54% in the solid fuel group and 30.81% in the clean fuel group, χ²=74.40, P<0.001). After controlling for potential confounding covariates, rural middle-aged and elderly residents in the solid fuel group had a higher risk of reporting depressive symptoms than those in the clean fuel group (OR=1.36, 95%CI: 1.20-1.54), an association that was unaffected by participant characteristics and was positive across age and gender groups. Conclusion There is a positive association between solid fuel use for cooking and depressive symptoms in middle-aged and elderly people in rural areas of China. It is recommended that rural areas promote the upgrading of stoves through the installation of ventilation equipment or the switch from solid cooking fuel to clean fuel. This approach is directed toward reducing exposure to household air pollution, alleviating the prevalence of depression among middle-aged and elderly residents in vast rural areas, and enhancing their mental health.

We took the surface spike S protein of transmissible gastroenteritis virus(TGEV)as the research object.Based on the Gram-positive enhancer matrix(GEM)-anchor protein(PA)display platform,two kinds of bacteria-like particles(BLPs)with surface-displayed TGEV DA and S1 were prepared using the insect cell-baculovirus expression system.The results showed that the lev-els of IL-4,IFN-γ,IgG,IgA,and sIgA induced by 50 μg BLP-DA were higher than those of the 25μg group.The levels of IL-4,IFN-γ,and sIgA induced by 50 μg BLP-S1 were higher than those of the 25 μg group,while the levels of IgG and IgA were lower than those of the 25 μg group.Under the same dose,when the dose was 25 μg,the levels of IFN-γ,IgG,IgA,and sIgA induced by BLP-S1 were higher than those of BLP-DA,while the level of IL-4 was lower than that of BLP-DA.When the dose was 50 μg,the level of IgG induced by BLP-DA was higher than that of BLP-S1,while the other indicators were lower than those of BLP-S1.Under different immunization routes,the levels of IgA and sIgA in the gavage group were higher than those in the intramuscular injec-tion group,and the levels of some cytokines were significantly higher in the gavage group than in the intramuscular injection group at specific time points,but there was no significant difference in the levels of IgG antibodies.In conclusion,the two types of TGEV BLPs constructed in this study both have good immunogenicity and can induce cellular and humoral immunity in mice.When the immunization doses are the same,the immunogenicity of BLP-S1 is better than that of BLP-DA.

Objective·To investigate the longitudinal changes in amygdala and hippocampal subfield volumes before and after transcranial magnetic stimulation(TMS)treatment in patients with major depressive disorder(MDD)and explore their correlation with the antidepressant and anxiolytic efficacy of TMS.Methods·A total of 58 patients diagnosed with MDD at Shanghai Mental Health Center,Shanghai Jiao Tong University School of Medicine,were included in this study between January 2018 and August 2023.Clinical depressive and anxiety symptoms were assessed by using the Hamilton Depression Scale(HAMD),Montgomery-Asberg Depression Rating Scale(MADRS),and Hamilton Anxiety Scale(HAMA)at baseline and post-TMS treatment.Patients underwent a baseline magnetic resonance imaging(MRI)scan followed by TMS treatment targeting the left dorsolateral prefrontal cortex(DLPFC)at a frequency of 10 Hz,totaling 20 sessions.A follow-up MRI scan was conducted on the same day the TMS treatment concluded.Amygdala and hippocampal subfield volumes were segmented and calculated by using FreeSurfer v6.0.0 software.Longitudinal changes in the subfield volumes were analyzed with two-way analysis of variance.Controlling for age,sex,and intracranial volume,partial correlation analysis was conducted between subfield volumes and baseline clinical scores.The association between the rate of volume change in brain regions with significant volume changes and symptom improvement(reduction in HAMD,MADRS,and HAMA scores)was evaluated.Results·Following TMS treatment,a significant increase in the volume of the right amygdala central nucleus was observed(t=-2.441,P=0.018).While the volumes of bilateral hippocampal fimbria decreased,the volumes of most hippocampal subfield and the total hippocampus increased(P<0.05).No significant correlations were found between baseline amygdala or hippocampal subfield volumes and clinical depressive and anxiety symptoms.However,only in patients who responded effectively to TMS treatment,a positive correlation was found between the volume change rate of the left hippocampal tail and reductions in anxiety symptoms(HAMA:r=0.334,P=0.044).Conclusion·High-frequency TMS targeting the left DLPFC may induce volume increases in the right amygdala central nucleus and specific hippocampal subfields.Additionally,the volume change rate of the left hippocampal tail is associated with anti-anxiety effects in TMS responders,suggesting that high-frequency TMS targeting the left DLPFC may induce neuroplastic changes in the central nucleus of the right amygdala and key subfields of the hippocampus.

Objective·To investigate the longitudinal changes in amygdala and hippocampal subfield volumes before and after transcranial magnetic stimulation(TMS)treatment in patients with major depressive disorder(MDD)and explore their correlation with the antidepressant and anxiolytic efficacy of TMS.Methods·A total of 58 patients diagnosed with MDD at Shanghai Mental Health Center,Shanghai Jiao Tong University School of Medicine,were included in this study between January 2018 and August 2023.Clinical depressive and anxiety symptoms were assessed by using the Hamilton Depression Scale(HAMD),Montgomery-Asberg Depression Rating Scale(MADRS),and Hamilton Anxiety Scale(HAMA)at baseline and post-TMS treatment.Patients underwent a baseline magnetic resonance imaging(MRI)scan followed by TMS treatment targeting the left dorsolateral prefrontal cortex(DLPFC)at a frequency of 10 Hz,totaling 20 sessions.A follow-up MRI scan was conducted on the same day the TMS treatment concluded.Amygdala and hippocampal subfield volumes were segmented and calculated by using FreeSurfer v6.0.0 software.Longitudinal changes in the subfield volumes were analyzed with two-way analysis of variance.Controlling for age,sex,and intracranial volume,partial correlation analysis was conducted between subfield volumes and baseline clinical scores.The association between the rate of volume change in brain regions with significant volume changes and symptom improvement(reduction in HAMD,MADRS,and HAMA scores)was evaluated.Results·Following TMS treatment,a significant increase in the volume of the right amygdala central nucleus was observed(t=-2.441,P=0.018).While the volumes of bilateral hippocampal fimbria decreased,the volumes of most hippocampal subfield and the total hippocampus increased(P<0.05).No significant correlations were found between baseline amygdala or hippocampal subfield volumes and clinical depressive and anxiety symptoms.However,only in patients who responded effectively to TMS treatment,a positive correlation was found between the volume change rate of the left hippocampal tail and reductions in anxiety symptoms(HAMA:r=0.334,P=0.044).Conclusion·High-frequency TMS targeting the left DLPFC may induce volume increases in the right amygdala central nucleus and specific hippocampal subfields.Additionally,the volume change rate of the left hippocampal tail is associated with anti-anxiety effects in TMS responders,suggesting that high-frequency TMS targeting the left DLPFC may induce neuroplastic changes in the central nucleus of the right amygdala and key subfields of the hippocampus.

We took the surface spike S protein of transmissible gastroenteritis virus(TGEV)as the research object.Based on the Gram-positive enhancer matrix(GEM)-anchor protein(PA)display platform,two kinds of bacteria-like particles(BLPs)with surface-displayed TGEV DA and S1 were prepared using the insect cell-baculovirus expression system.The results showed that the lev-els of IL-4,IFN-γ,IgG,IgA,and sIgA induced by 50 μg BLP-DA were higher than those of the 25μg group.The levels of IL-4,IFN-γ,and sIgA induced by 50 μg BLP-S1 were higher than those of the 25 μg group,while the levels of IgG and IgA were lower than those of the 25 μg group.Under the same dose,when the dose was 25 μg,the levels of IFN-γ,IgG,IgA,and sIgA induced by BLP-S1 were higher than those of BLP-DA,while the level of IL-4 was lower than that of BLP-DA.When the dose was 50 μg,the level of IgG induced by BLP-DA was higher than that of BLP-S1,while the other indicators were lower than those of BLP-S1.Under different immunization routes,the levels of IgA and sIgA in the gavage group were higher than those in the intramuscular injec-tion group,and the levels of some cytokines were significantly higher in the gavage group than in the intramuscular injection group at specific time points,but there was no significant difference in the levels of IgG antibodies.In conclusion,the two types of TGEV BLPs constructed in this study both have good immunogenicity and can induce cellular and humoral immunity in mice.When the immunization doses are the same,the immunogenicity of BLP-S1 is better than that of BLP-DA.

Prolonged disorders of consciousness(pDoC)are complex and prolonged conditions that severely impact patient prognosis and remain a clinical treatment challenge.In recent years,neural regulation-based awakening therapies have been widely applied in the assessment and treatment of pDoC patients.Repetitive transcranial magnetic stimulation(rTMS)technology can regulate neural activity and improve patients'consciousness states,demonstrating positive awakening effects for pDoC patients.However,the optimal stimulation parameters and awakening mechanisms of rTMS remain unclear.This article reviews the pathological mechanisms of pDoC,clinical applications of rTMS at different targeting sites and stimulation frequencies,and focuses on exploring how rTMS promotes consciousness recovery through neural mechanisms such as altering neural pathways,reshaping brain networks,promoting synaptic plasticity and neurotransmitter release,regulating neurotrophic factor expression,and modulating cerebral hemodynamics.Based on artificial intelligence,the article also prospects the future clinical research applications of rTMS.

Hypoxic-ischemic (HI) brain damage poses a high risk of death or lifelong disability, yet effective treatments remain elusive. Here, we demonstrated that miR-100-5p levels in the lesioned cortex increased after HI insult in neonatal mice. Knockdown of miR-100-5p expression in the brain attenuated brain injury and promoted functional recovery, through inhibiting the cleaved-caspase-3 level, microglia activation, and the release of proinflammation cytokines following HI injury. Engineered extracellular vesicles (EVs) containing neuron-targeting rabies virus glycoprotein (RVG) and miR-100-5p antagonists (RVG-EVs-Antagomir) selectively targeted brain lesions and reduced miR-100-5p levels after intranasal delivery. Both pre- and post-HI administration showed therapeutic benefits. Mechanistically, we identified protein phosphatase 3 catalytic subunit alpha (Ppp3ca) as a novel candidate target gene of miR-100-5p, inhibiting c-Fos expression and neuronal apoptosis following HI insult. In conclusion, our non-invasive method using engineered EVs to deliver miR-100-5p antagomirs to the brain significantly improves functional recovery after HI injury by targeting Ppp3ca to suppress neuronal apoptosis.
Animals ; MicroRNAs/metabolism* ; Extracellular Vesicles/metabolism* ; Mice ; Recovery of Function/physiology* ; Hypoxia-Ischemia, Brain/therapy* ; Mice, Inbred C57BL ; Antagomirs/administration & dosage* ; Male ; Animals, Newborn ; Apoptosis/drug effects* ; Brain Injuries/metabolism* ; Glycoproteins ; Peptide Fragments ; Viral Proteins

Ginsenoside Rg_2(GRg2) is a triterpenoid compound found in Panax notoginseng. This study explored its effects and mechanisms on diabetic retinopathy and angiogenesis. The study employed endothelial cell models induced by glucose or vascular endothelial growth factor(VEGF), the chorioallantoic membrane(CAM) model, the oxygen-induced retinopathy(OIR) mouse model, and the db/db mouse model to evaluate the therapeutic effects of GRg2 on diabetic retinopathy and angiogenesis. Transwell assays and endothelial tube formation experiments were conducted to assess cell migration and tube formation, while vascular area measurements were applied to detect angiogenesis. The impact of GRg2 on the retinal structure and function of db/db mice was evaluated through retinal thickness and electroretinogram(ERG) analyses. The study investigated the mechanisms of GRg2 by analyzing the activation of Yes-associated protein(YAP) and Toll-like receptors(TLRs) pathways. The results indicated that GRg2 significantly reduced cell migration numbers and tube formation lengths in vitro. In the CAM model, GRg2 exhibited a dose-dependent decrease in the vascular area ratio. In the OIR model, GRg2 notably decreased the avascular and neovascular areas, ameliorating retinal structural disarray. In the db/db mouse model, GRg2 increased the total retinal thickness and enhanced the amplitudes of the a-wave, b-wave, and oscillatory potentials(OPs) in the ERG, improving retinal structural disarray. Transcriptomic analysis revealed that the TLR signaling pathway was significantly down-regulated following YAP knockdown, with PCR results consistent with the transcriptome sequencing findings. Concurrently, GRg2 downregulated the expression of Toll-like receptor 4(TLR4), TNF receptor-associated factor 6(TRAF6), and nuclear factor-kappaB(NF-κB) proteins in high-glucose-induced endothelial cells. Collectively, GRg2 inhibits cell migration and tube formation and significantly reduces angiogenesis in CAM and OIR models, improving retinal structure and function in db/db mice, with its pharmacological mechanism likely involving the down-regulation of YAP expression.
Animals ; Ginsenosides/pharmacology* ; Diabetic Retinopathy/physiopathology* ; Mice ; YAP-Signaling Proteins ; Humans ; Male ; Signal Transduction/drug effects* ; Cell Movement/drug effects* ; Adaptor Proteins, Signal Transducing/genetics* ; Mice, Inbred C57BL ; Neovascularization, Pathologic/metabolism* ; Drugs, Chinese Herbal/administration & dosage* ; Panax notoginseng/chemistry* ; Endothelial Cells/metabolism* ; Transcription Factors/genetics* ; Angiogenesis