OBJECTIVES:To investigate the genetic etiology of a three-generation pedigree affected with piebaldism. METHODS:Next-generation sequencing and Sanger sequencing were employed to detect and verify gene variants. Bioinformatics tools were used to predict the effects of candidate variants on splicing and protein function. RT-PCR and Sanger sequencing were further performed to validate the impact of the variant on RNA splicing, and homology modeling was applied to predict its effect on the three-dimensional structure of the KIT protein. The pathogenicity of the variant was then classified according to the guidelines of the American College of Medical Genetics and Genomics (ACMG) and the UK Association for Clinical Genomic Science (ACGS). RESULTS:A heterozygous insertion variant near the splice site, c.1990+8_1990+9insTGCACCATTGGAGGTAAA, was identified in the KIT gene in the proband and was found to co-segregate with the phenotype within the family. RT-PCR and cDNA sequencing revealed that this variant led to aberrant splicing during transcription, resulting in a 21 bp in-frame insertion in the mRNA, which encodes an extra 7 amino acids within the tyrosine kinase domain and may thus affect protein function. In silico predictions, together with the experimental findings, supported classification of this variant as likely pathogenic according to relevant variant interpretation guidelines. CONCLUSIONS:The heterozygous splice-site insertion variant KIT:c.1990+8_1990+9insTGCACCATTGGAGGTAAA is the genetic cause of piebaldism in this pedigree.
T-cell lymphoblastic lymphoma (T-LBL) is a highly aggressive non-Hodgkin lymphoma derived from precursor T cells, characterized by rapid clinical progression and a high relapse rate, with a particularly unfavorable prognosis in adult patients. Accumulating evidence indicates that the NOTCH signaling pathway plays a central oncogenic role in the initiation and progression of T-LBL. Its sustained aberrant activation is driven by multiple layers of mechanisms, including NOTCH1 gene mutations or fusions, synergistic amplification through multiple oncogenic signaling cascades, and dysregulated epigenetic control. Aberrantly activated NOTCH signaling promotes tumor cell proliferation, suppresses apoptosis, and contributes to chemotherapy resistance and disease relapse. This review focuses on the mechanisms underlying aberrant NOTCH activation in T-LBL and summarizes the principal therapeutic strategies targeting this pathway, along with their limitations, aiming to provide a framework for deeper under-standing of the molecular pathogenesis of T-LBL and for the development of more precise targeted therapies.
Substance use disorder (SUD) is characterized by the persistent prioritization of drug-related cues, which readily trigger intense craving and relapse even after prolonged abstinence. Although previous studies have primarily focused on the mesolimbic dopamine system and fronto-striatal circuits, the mechanisms underlying the aberrant integration of reward value, affective states, attentional allocation, and memory representations remain largely elusive. The claustrum-owing to its extensive bidirectional connectivity with both cortical and subcortical networks and its hypothesized role in salience processing-has increasingly been recognized as a key hub in SUD. Accumulating evidence suggests that the claustrum may contribute to drug-cue salience attribution and reward memory encoding, modulate prefrontal information processing and executive control via its reciprocal projections, and interact with limbic systems to sustain withdrawal-related negative affect, thereby influencing relapse vulnerability. Furthermore, emerging findings from psychedelic research indicate that claustrum-related networks are highly plastic and participate in salience reconfiguration. Collectively, the claustrum may act as a cross-network hub that links reward processing, cognitive control, and affective memory, thereby extending classical circuit models of addiction. This review systematically summarizes the structural connectivity, neuroimaging correlates, and functional mechanisms of the claustrum, and discusses its translational implications for relapse prediction and the development of novel intervention strategies.
OBJECTIVES:To evaluate the effects of digital-driven cardiac rehabilitation on clinical outcomes in patients undergoing transcatheter aortic valve replacement (TAVR). METHODS:We retrospectively analyzed data from 1,012 patients who underwent TAVR at the Second Affiliated Hospital, Zhejiang University School of Medicine, between March 2013 and January 2023. Patients receiving conventional rehabilitation were assigned to the control group, whereas those receiving a digital-driven cardiac rehabilitation program, comprising preoperative screening and functional preparation, intraoperative eligibility assessment, postoperative stepwise rehabilitation management, and intelligent home-based rehabilitation, were assigned to the intervention group. Propensity score matching was performed to adjust for baseline confounding. Postoperative intensive care unit (ICU) stay and hospital stay, the incidence of cardiovascular and cerebrovascular adverse events at 30 days, 1 year, and 2 years after TAVR, and functional outcomes, including the 5-meter walk test, 6-minute walk test, and Katz Index, were compared between the two groups. RESULTS:After propensity score matching, 251 patients were included in each group. Compared with the control group, the intervention group had significantly shorter postoperative ICU stays [0 (0, 0) h vs. 0 (0, 1) h, P<0.01] and postoperative hospital stays [3 (1, 7) days vs. 8 (7, 11) days, P<0.01]. The time required to complete the 5-meter walk test was significantly shorter in the intervention group than in the control group at 30 days, 1 year, and 2 years after TAVR (all P<0.01). No apparent increase in the incidence of adverse events was observed in the intervention group at 30 days, 1 year, or 2 years after TAVR. CONCLUSIONS:The present findings suggest that digital-driven cardiac rehabilitation may shorten hospital stay and improve selected functional outcomes in patients undergoing TAVR without an observed increase in postoperative cardiovascular and cerebrovascular adverse events.
Narcotic drug addiction is characterized not only by compulsive drug use and persistent craving after withdrawal but also by systemic consequences of long-term exposure. These include alterations in neural circuits subserving reward, stress, and executive control, as well as skeletal impairments such as reduced bone mineral density and strength, disrupted bone turnover, muscle weakness, and elevated fracture risk. The bone-brain axis, which mediates bidirectional communication between the central nervous system and the skeleton via neural, endocrine, immune, metabolic, and bone-derived signaling, offers an integrative framework for understanding the concurrent neuro-skeletal impairments seen in addiction. Such impairments may not arise independently; rather, they may reflect cross-system pathology driven by interactions among neuroendocrine dysregulation, inflammatory and immune activation, oxidative stress, neurotransmitter disturbances, and feedback from bone-derived factors. Specifically, prolonged drug exposure can alter bone remodeling through the sympathetic nervous system, the hypothalamic-pituitary-adrenal (HPA) axis, and the hypothalamic-pituitary-gonadal (HPG) axis, while simultaneously disrupting the tissue microenvironment of both brain and bone via inflammatory/immune activation and redox imbalance. Abnormalities in monoamines-dopamine, serotonin, and norepinephrine-may further link addiction-related neurobehavioral changes to bone cell dysfunction. Meanwhile, bone-derived factors such as osteocalcin, sclerostin, lipocalin-2, and bone-derived extracellular vesicles may contribute to feedback regulation of brain function by skeletal tissue. This review summarizes the concurrent impairments of the nervous and skeletal systems associated with narcotic drug addiction, analyzes the potential pathways by which bone-brain axis dysregulation may mediate their interrelationship, and aims to provide a reference for elucidating the mechanisms of somatic comorbidity in addiction and for informing comprehensive intervention strategies.
The clinical efficacy of tumor immunotherapy is constrained by the immuno-suppressive nature of the tumor microenvironment, within which mechanical signals serve as critical modulators of immune responses. Alterations in tumor tissue mechanics-including matrix stiffening, elevated interstitial pressure, and aberrant fluid shear stress-create physical barriers that impede immune cell infiltration and cytotoxic function. Conversely, immune cells detect and interpret these mechanical cues through mechanosensi-tive pathways involving Piezo1, TRPV4, and YAP/TAZ, which regulate their activation, migration, and effector functions. Small-molecule agents targeting these pathways can precisely modulate key mechanosensitive molecules and emerging mechanical immune checkpoints, thereby bridging mechanical sensing with immune effector reprogramming. Interventions that modify microenvironmental mechanical properties-for instance, through extracellular matrix remodeling or softening-can enhance immune cell infiltration and amplify anti-tumor immunity at the tissue level. Engineered mechano-immunotherapeutic strategies, leveraging biomaterials and biomechanical principles, directly modulate membrane mechanics and mechanotransduction in immune or tumor cells to potentiate immune activity and microenvironmental responsiveness. This review synthesizes current knowledge on the mechanical properties of tumors and their microenvironments, the mechanoregulatory mechanisms operating in immune cells, and recent progress in the development of mechanically targeted therapeutics, with the goal of informing future innovation in immuno-oncology.
Methamphetamine (METH) is highly addictive and can cause neurotoxicity when misused over a prolonged period. METH-induced neurotoxicity and addiction involve multi-level biological alterations, including nucleotide polymorphisms, aberrant epigenetic modifications, transcriptional imbalance, protein dysfunction, metabolic dysregulation, and microbial dysbiosis with changes in microbiota-derived metabolites. To systematically dissect these multifaceted changes, genomics has been deployed to identify key gene polymorphisms linked to METH addiction susceptibility and epigenetic changes such as DNA methylation in brain regions following METH exposure. Tran-scriptomics dynamically profiles differential gene expression in addiction-relevant brain areas, particularly in pathways governing synaptic plasticity and neuroinflammation. Proteomics pinpoints the dysregulation of functional proteins associated with synaptic plasticity in response to METH. Metabolomics quantifies neurotransmitter depletion and redox imbalance induced by the drug, while microbiomics reveals gut microbiota dysbiosis and subsequent neural damage via the gut-brain axis. The integrated application of these multi-omics technologies-spanning genetic variation, transcriptional regulation, protein function, metabolic dynamics, and host-microbe interactions-systematically illuminates the complex molecular events underlying METH neurotoxicity and addiction, thereby providing a robust theoretical framework and technical roadmap for identifying early warning biomarkers and devising multi-target combination strategies against METH neurotoxicity and relapse. This review summarizes the current state of single-omics and multi-omics applications in METH neurotoxicity and addiction research, aiming to provide a reference for elucidating pathogenic mechanisms, identifying biomarkers, and discovering potential therapeutic targets.
OBJECTIVES:To develop a health information-seeking behavior (HISB) questionnaire for patients with chronic diseases and evaluate its reliability and validity. METHODS:Based on Wilson's information behavior model, a preliminary questionnaire was developed through literature review, team discussions, two rounds of expert consulta-tions, and a pilot survey. A convenience sample of 368 patients with chronic diseases was recruited from medical institutions in Hangzhou, Jinhua, Lishui, Ningbo, Taizhou, and Wenzhou of Zhejiang Province, between March-May 2023 and August-September 2025. The dimension of health information-seeking channels was analyzed using descriptive statistics. Item analysis for the other three dimensions was performed using item-total correlation and critical ratio methods. Reliability was evaluated using Cronbach's α coefficient and split-half reliability. Content validity was assessed by expert ratings, and structural validity was evaluated using exploratory factor analysis (EFA) and confirmatory factor analysis (CFA). RESULTS:The final questionnaire comprised 30 items across four dimensions: health information needs, health information-seeking channels, health information search and acquisition, and health information evaluation. The overall Cronbach's α coefficient was 0.970, and the split-half reliability was 0.781. The scale-level content validity index (S-CVI) was 0.830, and the item-level content validity index (I-CVI) ranged from 0.890 to 1.000. EFA extracted three common factors with a cumulative variance contribution rate of 75.181%. CFA indicated a good model fit. CONCLUSIONS:The HISB questionnaire developed in this study demonstrates good reliability and validity. It can serve as a reliable and valid tool to assess HISB among patients with chronic diseases, providing a basis for healthcare professionals to develop targeted health education interventions.
OBJECTIVES:To systematically evaluate the therapeutic effects of exercise interventions on anxiety and depressive symptoms in patients with fibromyalgia syndrome, compare the efficacy across different exercise modalities, and provide an evidence-based reference for individualized exercise prescription in clinical practice. METHODS:We searched CNKI, VIP, Wanfang Data, SinoMed, Web of Science, PubMed, Cochrane Library and Embase from inception to August 25, 2025. Literature screening followed the PICOS framework, and methodological quality was assessed using the Cochrane Risk of Bias tool. A traditional pairwise meta-analysis estimated the overall efficacy. Heterogeneity was evaluated using the I² statistic, and either a fixed- or random-effects model was selected accordingly. Subgroup analyses, meta-regression, and leave-one-out sensitivity analyses were performed to explore heterogeneity sources and verify the robustness of the results. A network meta-analysis compared the relative efficacy of different exercise modalities. Inconsistency was examined to ensure evidence consistency. League tables were constructed for pairwise comparisons, and the surface under the cumulative ranking curve (SUCRA) was used to rank the interventions. Publication bias was assessed via funnel plots. RESULTS:A total of 30 articles (33 studies, 1844 participants) were included. Meta-analysis showed that, compared with controls, exercise interventions significantly improved anxiety (SMD=－0.407, 95%CI: －0.515 to －0.298, P0.01) and depressive symptoms (SMD=－0.526, 95%CI: －0.741 to －0.312, P0.01). For anxiety, the largest pooled effect was observed with the State-Trait Anxiety Inventory (SMD=－0.651, 95%CI: －0.969 to －0.333), interventions lasting ≥17 weeks (SMD=－0.771, 95%CI: －1.207 to －0.278), 3-4 sessions/week (SMD=－0.588, 95%CI: －0.812 to －0.364), and 40 min/session (SMD=－0.556, 95%CI: －0.855 to －0.257). For depression, the largest effect was found with the Beck Depression Inventory (SMD=－0.758, 95%CI: －1.186 to －0.329), interventions of 9-12 weeks (SMD=－0.893, 95%CI: －1.484 to －0.303), 3-4 sessions/week (SMD=－1.199, 95%CI: －1.805 to －0.593), and ≥60 min/session (SMD=－0.708, 95%CI: －1.080 to －0.336). Network meta-analysis indicated that mind-body exercise ranked highest for anxiety (SUCRA=88.8%), while aerobic exercise ranked highest for depression (SUCRA=94.0%). Eight studies reported safety outcomes, with no serious adverse events. Sensitivity analyses confirmed the stability of the results, and funnel plots showed no significant publication bias. CONCLUSIONS:Exercise interventions are safe and effective in ameliorating anxiety and depressive symptoms in patients with fibromyalgia syndrome. Mind-body exercise and aerobic exercise may be the optimal choices for anxiety and depression, respectively, and their efficacy is associated with exercise prescription parameters.
