Objective:To discuss the effect of zanubrutinib(BGB-3111)combined with bortezomib(Btz)on the apoptosis of the human multiple myeloma(MM)cells,and to clarify its possible mechanism.Methods:The human MM cell lines U266,PS-R,RPMI8226,KMS28-PE,KMS28-BM,and H929 were cultured in vitro.Western blotting method was used to detect the expression level of Bruton's tyrosine kinase(BTK)protein in various cells;cell counting kit-8(CCK-8)method was used to detect the survival rates of the RPMI8226,U266,and KMS28-BM cells after treated with 0,10,20,30,40,and 50 μmol·L?1 BGB-3111.The RPMI8226,U266,and KMS28-BM cells at the logarithmic growth phase were selected and divided into control group,BGB-3111 group,Btz group,and BGB-3111+Btz group.Flow cytometry was used to detect the apoptotic rates of the cells in various groups;Western blotting method was used to detect the expression levels of myeloid cell leukemia 1(MCL-1),B-cell lymphoma-2(Bcl-2),Bcl-2-interacting mediator of cell death(Bim),phosphorylated Bim(p-Bim),P65,phosphorylated P65(p-P65),tumor necrosis factor receptor-associated factor(TRAF)2,and tumor necrosis factor alpha-induced protein 3(A20)in different kinds of cells.The U266 cells were divided into A20 overexpression group(A20-OE group)and empty vector control group(EV group).Each group was further divided into control group,BGB-3111 group,Btz group,and BGB-3111+Btz group.The corresponding plasmids were transfected;Western blotting method was used to detect the transfection efficiency of the cells in various groups;flow cytometry was used to detect the apoptotic rates of the cells in various groups after over-expression of A20.Results:The Western blotting results showed that compared with KMS28-BM cells,the expression levels of BTK protein in the U266,RPMI8226,and H929 cells were significantly increased(P<0.05 or P<0.01).The CCK-8 results showed that compared with 0 μmol·L?1 BGB-3111 group,the survival rates of the RPMI8226 and U266 cells in 10,20,30,40,and 50 μmol·L?1 BGB-3111 groups were significantly decreased(P<0.05 or P<0.01),and the survival rates of the KMS28-BM cells in 20,30,40,and 50 μmol·L?1 BGB-3111 groups were significantly decreased(P<0.05).Compared with RPMI8226 and U266 cells,the survival rates of the KMS28-BM cells in 20,30,and 40 μmol·L?1 BGB-3111 groups were significantly increased(P<0.05).Therefore,10 μmol·L?1 BGB-3111 was selected for subsequent experiments.The flow cytometry results showed that compared with control group,the apoptotic rates of the RPMI8226 and U266 cells in BGB-3111 group,Btz group,and BGB-3111+Btz group were significantly increased(P<0.05 or P<0.01);compared with BGB-3111 group and Btz group,the apoptotic rates of the RPMI8226 and U266 cells in BGB-3111+Btz group were significantly increased(P<0.01);compared with control group,the apoptotic rates of the KMS28-BM cells in Btz group and BGB-3111+Btz group were significantly increased(P<0.01);compared with BGB-3111 group,the apoptotic rate of the KMS28-BM cells in BGB-3111+Btz group was significantly increased(P<0.01);compared with EV group,the apoptotic rates of the cells in A20-OE group in Btz group and BGB-3111+Btz group were significantly increased(P<0.05).The Western blotting results showed that compared with control group,the expression levels of Bim protein in the RPMI8226 and U266 cells in BGB-3111 group,Btz group,and BGB-3111+Btz group were significantly increased(P<0.05),while the expression levels of MCL-1,p-Bim,and Bcl-2 proteins in the RPMI8226 and U266 cells in Btz group and BGB-3111+Btz group were significantly decreased(P<0.05);compared with BGB-3111 group and Btz group,the expression levels of Bim protein in the RPMI8226 and U266 cells in BGB-3111+Btz group were significantly increased(P<0.05),while the expression levels of MCL-1,p-Bim,and Bcl-2 proteins were significantly decreased(P<0.05).Compared with control group,the expression levels of p-P65 protein in the RPMI8226 and U266 cells in Btz group and BGB-3111+Btz group were significantly increased(P<0.05),while the expression levels of TRAF2 and A20 proteins were significantly decreased(P<0.05);compared with BGB-3111 group and Btz group,the expression levels of p-P65 protein in the RPMI8226 and U266 cells in BGB-3111+Btz group were significantly increased(P<0.05),while the expression levels of TRAF2 and A20 proteins were significantly decreased(P<0.05).The flow cytometry results showed that compared with EV group,the expression level of A20 protein in A20-OE group cells was significantly increased(P<0.01).Conclusion:BGB-3111 induces apoptosis in the MM cells by inhibiting BTK activity and enhances the pro-apoptotic effect of Btz.Over-expression of A20 increases the sensitivity of the MM cells to the combined treatment.The antitumor effect may be related to the inhibition of the nuclear factor kappa B(NF-κB)signaling pathway.

Aim To examine the pathogenesis of disul-fide death gene in vascular dementia(VD)by bioin-formatics analysis of disulfide death differentially ex-pressed genes(DEGs)combined with experimental verification.Methods The death DEGs of disulfide were screened and their correlation was analyzed.The VD patients data in the data set were analyzed by clus-tering and typing and gene set variation.The clustering risk of DEGs was tested with a nomogram model,and the optimal learning model was predicted.After the es-tablishment of VD rat model,water maze test,HE stai-ning and RT-qPCR detection were performed to verify the results of health information.Results Four DEGs including SLC7A11 were obtained,which had antago-nistic or synergistic interaction with each other.The genetic data could be divided into two subtypes with significant differences.After typing,VD disulfide DEGs were mainly concentrated in GnRH signaling pathways.The accuracy of the nomogram prediction model was high.Generalized linear was the best ma-chine learning model.Compared with the sham opera-tion group,the escape latency of rats in the model group was prolonged,the number of crossing platforms decreased,the relative mRNA expression levels of Slc3a2 and Slc7a11 decreased,and LRPPRC in-creased.Conclusions SLC7A11 and other disulfide death DEGs and its related GnRH signaling pathway may be an important part of the pathogenesis of VD di-sulfide death.SLC3A2,LRPPRC and SLC7A11 can be used as characteristic genes in the regulation of VD by disulfide death,which may affect VD progression through the regulation of disulfide death.

Paraplegia caused by spinal cord injury is a serious neurological complication, for which surgery is currently the main treatment method. Due to different surgical approaches, patients are usually expected to maintain a passive prone position for a long time or switch between the supine and prone positions. Affected by multiple factors such as neurogenic sensory disorders, pathological changes in muscle tone and operative duration, the risk of intraoperative acquired pressure injury (IAPI) is significantly increased. Current clinical prevention strategies for IAPI in these patients predominantly focus on localized pressure relief during positioning, lacking systematic, standardized comprehensive prevention protocols or evidence-based guidelines. To address it, Department of Nursing, Orthopedics Branch, China International Exchange and Promotive Association for Medical and Health Care, Spinal Trauma Professional Committee, Orthopedics Branch, Chinese Medical Doctor Association, Nursing Group of Spine and Spinal Cord Professional Committee of Chinese Association of Rehabilitation Medicine organized experts in relevant fields to formulate Guideline for the prevention of intraoperative acquired pressure injury in paraplegic patients with spinal cord injury ( version 2025), based on evidence-based medical evidence and latest research results and clinical practice at home and abroad. Eleven recommendations were put forward from the aspects of preoperative risk assessment, intraoperative prevention strategies, postoperative handover and monitoring, and supportive mechanisms for IAPI prevention, aiming to standardize the prevention measures and management strategies of IAPI in paraplegic patients with spinal cord injury and accelerate the recovery of patients and improve the therapeutic effect.

Objective:To determine if preoperative 68Ga-fibroblast activation protein inhibitor (FAPI)-04 PET/MR could contribute to predicting pathological complete response (pCR) in patients with gastrointestinal cancer undergoing neoadjuvant immunotherapy. Methods:In this retrospective study, 35 patients (23 males, 12 females, age (59.1±7.9) years) with gastrointestinal cancer who underwent 68Ga-FAPI-04 PET/MR after receiving neoadjuvant immunotherapy between February 2021 and January 2024 were enrolled. Clinical data, PET imaging parameters including SUV, peak of SUV normalized by lean body mass (SUL peak), FAPI-positive tumor volume (FTV), and total FAPI-positive lesion burden (TLF), and pathological data were collected and analyzed. Patients were divided into pCR group and non-pCR group, and the independent-sample t test or Mann-Whitney U test was performed to compare those parameters between the 2 groups. ROC curve analysis (Delong test) was performed to evaluate the diagnostic efficiency of each parameter to predict pCR. Results:The overall pCR rate of the neoadjuvant therapy was 40.0%(14/35). In the visual evaluation, 68Ga-FAPI-04 PET was limited in predicting pCR, showing false positivity in 12 patients and false negative in 1 patent. While SUV max( t=2.50, P=0.018), SUL peak( t=3.11, P=0.004), FTV( U=3.00, P=0.030) and TLF( U=2.96, P=0.042) in non-pCR group were all higher than those in pCR group. The predictive efficiency of FTV <1.925cm 3 for pCR was better than the efficiency of PET visual evaluation ( Z=3.61, P<0.001), with the prediction accuracy of 82.86%(29/35). Conclusions:68Ga-FAPI-04 PET/MR may provide an effective clinical tool for guiding further treatment of patients with gastrointestinal cancer undergoing neoadjuvant immunotherapy. The quantitative features derived from 68Ga-FAPI-04 PET appear promising in predicting pCR, which are expected to provide a reference for avoiding surgery.

OBJECTIVES: To investigate the relationship between the polygenic risks for various psychiatric disorders and clinical and neuropsychological characteristics in children with attention-deficit/hyperactivity disorder (ADHD). METHODS: Using a cross-sectional design, 285 children with ADHD and 107 healthy controls were assessed using the Child Behavior Checklist, the Behavior Rating Inventory of Executive Function for parents, the Wechsler Intelligence Scale for Children, Fourth Edition, and the Cambridge Neuropsychological Test Automated Battery. Blood samples were collected for genetic data. Polygenic risk scores (PRSs) for various psychiatric disorders were calculated using the PRSice-2 software. RESULTS: Compared with the healthy controls, the children with ADHD displayed significantly higher PRSs for ADHD, major depressive disorder, anxiety disorder, and obsessive-compulsive disorder (P<0.05). In terms of daily-life executive function, ADHD-related PRS was significantly correlated with the working memory factor; panic disorder-related PRS was significantly correlated with the initiation factor; bipolar disorder-related PRS was significantly correlated with the shift factor; schizophrenia-related PRS was significantly correlated with the inhibition, emotional control, initiation, working memory, planning, organization, and monitoring factors (P<0.05). The PRS related to anxiety disorders was negatively correlated with total IQ and processing speed index (P<0.05). The PRS related to obsessive-compulsive disorder was negatively correlated with the processing speed index and positively correlated with the stop-signal reaction time index of the stop-signal task (P<0.05). CONCLUSIONS PRSs for various psychiatric disorders are closely correlated with the behavioral and cognitive characteristics in children with ADHD, which provides more insights into the heterogeneity of ADHD.
Humans ; Attention Deficit Disorder with Hyperactivity/genetics* ; Child ; Male ; Female ; Cross-Sectional Studies ; Neuropsychological Tests ; Multifactorial Inheritance ; Adolescent ; Mental Disorders/etiology* ; Executive Function ; Genetic Risk Score

Hemorrhagic shock is a common clinical emergency that can aggravate cell injury after resuscitation. Astrocytes are crucial for the survival of neurons because they regulate the surrounding ionic microenvironment of neurons. Although hemorrhagic shock and resuscitation (HSR) injury can impair cognition, it remains unclear how this insult directly affects astrocytes. In this study, we established an HSR model by bleeding and re-transfusion in mice. The social interaction test and new object recognition test were applied to evaluate post-operative cognitive changes, and the results suggest that mice experience cognitive impairment following exposure to HSR. In the HSR group, the power spectral density of β and γ oscillations decreased, and the coupling of the θ oscillation phase and γ oscillation amplitude was abnormal, which indicated abnormal neuronal oscillation and cognitive impairment after HSR exposure. In brief, cognitive impairment in mice is strongly correlated with Ca²⁺ signal strength in lateral septum astrocytes following HSR.
Animals ; Astrocytes/metabolism* ; Shock, Hemorrhagic/metabolism* ; Resuscitation/adverse effects* ; Male ; Mice ; Calcium Signaling/physiology* ; Mice, Inbred C57BL ; Septal Nuclei/metabolism* ; Cognitive Dysfunction/etiology* ; Disease Models, Animal ; Cognition Disorders/etiology*

Spinal cord injury(SCI)is a structural and functional disruption of the spinal cord caused by various factors,leading to neurological dysfunction.As a common central nervous system disorder in clinical practice,SCI poses significant risks to human life and health.Its pathological mechanism is exceedingly complex,involving multiple pathological processes.Given the irreversibility of primary injury,targeting secondary injury has gradually become the main direction for the clinical treatment of SCI in recent years.Recent studies have highlighted the crucial role of blood-spinal cord barrier damage and microvascular dysfunction in the progression of secondary injury following SCI.Therefore,investigating the pathological mechanisms of microcirculation and exploring targeted therapies could provide valuable insights for clinical SCI treatment.This paper aims to provide an objective review of the role of microcirculation in SCI,identify the critical regulators of microvascular function,and summarize strategies for treating SCI by targeting microcirculation.The findings of this study may offer novel references for the clinical management of SCI.

Spinal cord injury(SCI)is a central nervous system disease with high morbidity and disability rates,bringing serious economic and psychological burdens to families and society worldwide.AMP-activated protein kinase(AMPK)is an important sensor in the energy metabolism process in living organisms,which plays a central role in maintaining energy balance.It is currently considered a key target for the prevention and treatment of multiple diseases.Studies have shown that AMPK signaling can regulate autophagy,neuroinflammation,oxidative stress,mitochondrial function and other processes after SCI,thus affecting the pathological process of SCI.This review summarizes the research progress on AMPK signaling pathway involved in the regulation of SCI,in order to provide new ideas for the treatment and drug development of SCI.

In this work,a fluorescent probe PIN was synthesized using indole-3-carbohydrazide and pyrenecarboxaldehyde as raw materials.PIN showed weak fluorescence emission in aqueous solution with acetonitrile volume fraction of 70％.However,when Cu2+was added to this aqueous solution of PIN,a new fluorescence emission peak appeared at 495 nm,and the intensity of this peak gradually increased with the increase of concentration of Cu2+,and also caused a significant change in the fluorescence color of the solution.In contrast,the addition of 15 kinds of other common metal ions did not cause such change.The detection limit of PIN for Cu2+was 78.7 nmol/L,which was much lower than the maximum permitting level of Cu2+in drinking water in hygienic standard for drinking water in China.Therefore,PIN was a highly selective and sensitive fluorescence-enhanced probe for Cu2+.Meanwhile,the addition of Cu2+could also cause a new absorption peak at 440 nm in the ultraviolet-visible absorption spectrum of the aqueous solution of PIN,and meanwhile the colorless PIN solution changed into yellow,exhibiting the performance of PIN as a colorimetric probe for Cu2+.By fitting with the Levenberg-Marquardt algorithm equation,the binding ratio of PIN to Cu2+was 2:1,and the binding constant was 3.42×1012 L2/mol2.In addition,the binding mode of PIN with Cu2+was explored by using proton nuclear magnetic resonance(1H NMR)titration experiments and density functional theory simulations.The results showed that the addition of Cu2+could cause the aggregation of PIN molecules to form excimers,thus showing highly selective recognition.Finally,PIN was made into a simple test strip,which could achieve rapid and convenient fluorescence detection of Cu2+in actual water samples.

Objective To construct an aptamer-functionalized carboxylated graphene oxide(CGO)fluo-rescent sensor to achieve highly sensitive and specific detection of ketamine(KET)and its metabolite norketamine(NK)using an aptamer capable of simultaneously recognizing KET and NK.Methods A specific aptamer for simultaneous recognition of KET and NK was screened using graphene oxide-sys-tematic evolution of ligand by exponential enrichment(GO-SELEX)and molecular docking tech-niques.The aptamer,labeled with Cy5 fluorescence,was chemically conjugated to CGO to construct an aptamer-functionalized CGO fluorescent sensor.By optimizing detection conditions,including the mass concentration of CGO,aptamer concentration,reaction temperature,and incubation time,quantita-tive analysis of the target analytes was achieved using the ratio of fluorescence intensity changes be-fore and after target addition.The stability of the sensor in biological matrices was evaluated by moni-toring fluorescence intensity changes over incubation time in blank blood and urine,in comparison with the traditional physical adsorption-based CGO fluorescent sensor.Spiked recovery experiments in blank blood and urine were conducted to compare performance with that of HPLC-MS/MS.Results A specific aptamer A5 was selected and chemically conjugated with CGO to construct the aptamer-functionalized CGO fluorescent sensor.Under optimized conditions,the proposed fluorescent sensor ex-hibited a linear detection range of 1.0-5.0 ng/mL for KET,with a limit of detection(LOD)of 0.86 ng/mL;while for NK,the linear detection range was 1.0-5.0 ng/mL,with an LOD of 0.70 ng/mL.Com-pared with the CGO fluorescent sensor constructed via physical adsorption,this sensor demonstrated greater stability in blood and urine.The spiked recovery rates of KET and NK in blank blood and urine ranged from 81.50%to 110.03%,exhibiting detection performance comparable to that of HPLC-MS/MS.Conclusion The aptamer screening method offers a novel approach for selecting aptamers tar-geting drugs and their metabolites.The constructed aptamer-functionalized CGO fluorescent sensor pro-vides an efficient and reliable strategy for the high-performance detection of KET and NK.