Objective To explore the impact of number of positive regional lymph nodes (nPRLN) in N1 stage on the prognosis of non-small cell lung cancer (NSCLC) patients. Methods Patients with TxN1M0 stage NSCLC who underwent lobectomy and mediastinal lymph node dissection from 2010 to 2015 were screened from SEER database (17 Regs, 2022nov sub). The optimal cutoff value of nPRLN was determined using X-tile software, and patients were divided into 2 groups according to the cutoff value: a nPRLN≤optimal cutoff group and a nPRLN>optimal cutoff group. The influence of confounding factors was minimized by propensity score matching (PSM) at a ratio of 1 : 1. Kaplan-Meier curves and Cox proportional hazards models were used to evaluate overall survival (OS) and lung cancer-specific survival (LCSS) of patients. Results A total of 1316 patients with TxN1M0 stage NSCLC were included, including 662 males and 654 females, with a median age of 67 (60, 73) years. The optimal cutoff value of nPRLN was 3, with 1165 patients in the nPRLN≤3 group and 151 patients in the nPRLN>3 group. After PSM, there were 138 patients in each group. Regardless of before or after PSM, OS and LCSS of patients in the nPRLN≤3 group were superior to those in the nPRLN>3 group (P<0.001). N1 stage nPRLN>3 was an independent prognostic risk factor for OS [HR=1.52, 95%CI (1.22, 1.89), P<0.001] and LCSS [HR=1.72, 95%CI (1.36, 2.18), P<0.001]. Conclusion N1 stage nPRLN>3 is an independent prognostic risk factor for NSCLC patients in TxN1M0 stage, which may provide new evidence for future revision of TNM staging N1 stage subclassification.

Background/Aims: Biliary tract cancer (BTC) frequently harbors KRAS mutations, which are associated with resistance to traditional treatment and a poor prognosis. Synthetic lethality (SL) strategy may provide other targets of KRAS. Therefore, we aim to identify and validate potential therapeutic targets of KRAS for the treatment of BTC via SL. Methods: The dependency (DepMap) projects were used to predict the synthetic lethal gene of KRAS. FDA-approved anticancer drug library was applied to screen potential drugs effective against KRAS-mutant BTC. Furthermore, the synthetic lethal effects or corresponding mechanisms of potential genes and drugs on BTC were investigated using KRAS-mutant and KRAS-wild type BTC cell lines, patient-derived xenografts (PDX), and KRAS oncogene-driven tumor models, as well as other KRAS-mutant cancer cell lines. Results: Initially, we discovered that the loss of GATA2 reduced the viability of KRAS-mutant but not KRAS-wild-type BTC. Subsequently, the drug library screened out disulfiram, which primarily exerts a synthetic lethal effect by inhibiting interleukin-1β (IL-1β) in KRAS-mutant BTC. Mechanistically, GATA2 specifically enhanced the transcription of IL-1β to promote NF-κB signaling in KRAS-mutant BTC. IL-1β inhibition phenocopied GATA2 deficiency, leading to reduced KRAS-mutant BTC viability. These synthetically lethal effects were confirmed using PDX, a KRAS oncogene-driven tumor model, as well as in other KRAS-mutant cancer cell lines. Conclusions In summary, these results indicate that inhibiting GATA2/IL1β could be a therapeutic strategy in KRAS-mutant BTC and potentially other cancers.

Objective To simulate modern social stress using a pre-pregnancy chronic mild stress(CMS)model and to explore the mechanisms of emotional,behavioral,and neurodevelopmental changes in male offspring of pre-pregnancy liver qi stagnation female mice through corticosterone(CORT)-brain-derived neurotrophic factor(BDNF)extracellular signal-regulated kinase(ERK)1/2 signaling cascade-mediated hippocampal injury.This study aimed to elucidate the impact of negative life events on offspring and the interventional mechanism of Shuyu Capsules.Methods CMS stress was used to induce pre-pregnancy depression in female rats(liver qi stagnation state),followed by intervention with Shuyu and fluoxetine capsules.After screening,male rats were mated and 12 male offspring from each group were selected for behavioral testing and detection of serum CORT levels by enzyme-linked immunosorbent assay.BDNF,ERK1/2,phospho(p)-ERK1/2,cAMP-response element binding protein(CREB),and p-CREB protein levels in the hippocampus were detected by Western Blot,and BDNF,ERK1,ERK2,and CREB mRNA levels in the hippocampus were detected by reverse transcription-polymerase chain reaction(RT-PCR),to verify the effects of pre-pregnancy CMS on the BDNF-ERK1/2-CREB signaling pathway and to investigate the key micro-mechanisms of Shuyu Capsules on emotional and learning memory-related behaviors of male offspring of females with pre-pregnancy liver qi stagnation syndrome.Results The distance,number of entries,and duration of stay in the central area in open-field experiments were significantly reduced in offspring in the model group(all P＜0.05).The escape latency during the exploration period of the water-maze experiment was significantly prolonged(P＜0.05)and the swimming distance,duration of the target quadrant,and number of platform crossings were significantly reduced(P＜0.05,P＜0.05,P＜0.01),the suspension time and frequency in the forced-swimming experiment were increased(P＜0.05,P＜0.01),and the incubation period was shortened(P＜0.05)in offspring in the model group.Prophylactic treatment with Shuyu Capsules and fluoxetine improved the depression-like behavior and cognitive impairment in the offspring in the model group.Biochemical tests showed that CORT levels were increased in the CMS model group(P＜0.05),BDNF,p-ERK1/2,and p-CREB protein levels in the hippocampus were decreased(all P＜0.05),and BDNF,ERK1,ERK2,and CREB mRNA levels were significantly reduced(P＜0.01,P＜0.05,P＜0.01,P＜0.05).Treatment with Shuyu Capsules and fluoxetine increased the CORT content and BDNF,ERK1/2,and CREB protein and mRNA levels in male offspring to varying degrees.Conclusions High levels of CORT in offspring act selectively on the hippocampus,exerting adverse effects on the emotional and learning memory functions of rats by downregulating the BDNF-ERK1/2 signaling cascade.The Chinese medicine Shuyu Capsules can reduce the impact of an adverse intrauterine environment on offspring development by correcting abnormal levels and pathways of glucocorticoids.

Objective To simulate modern social stress using a pre-pregnancy chronic mild stress(CMS)model and to explore the mechanisms of emotional,behavioral,and neurodevelopmental changes in male offspring of pre-pregnancy liver qi stagnation female mice through corticosterone(CORT)-brain-derived neurotrophic factor(BDNF)extracellular signal-regulated kinase(ERK)1/2 signaling cascade-mediated hippocampal injury.This study aimed to elucidate the impact of negative life events on offspring and the interventional mechanism of Shuyu Capsules.Methods CMS stress was used to induce pre-pregnancy depression in female rats(liver qi stagnation state),followed by intervention with Shuyu and fluoxetine capsules.After screening,male rats were mated and 12 male offspring from each group were selected for behavioral testing and detection of serum CORT levels by enzyme-linked immunosorbent assay.BDNF,ERK1/2,phospho(p)-ERK1/2,cAMP-response element binding protein(CREB),and p-CREB protein levels in the hippocampus were detected by Western Blot,and BDNF,ERK1,ERK2,and CREB mRNA levels in the hippocampus were detected by reverse transcription-polymerase chain reaction(RT-PCR),to verify the effects of pre-pregnancy CMS on the BDNF-ERK1/2-CREB signaling pathway and to investigate the key micro-mechanisms of Shuyu Capsules on emotional and learning memory-related behaviors of male offspring of females with pre-pregnancy liver qi stagnation syndrome.Results The distance,number of entries,and duration of stay in the central area in open-field experiments were significantly reduced in offspring in the model group(all P＜0.05).The escape latency during the exploration period of the water-maze experiment was significantly prolonged(P＜0.05)and the swimming distance,duration of the target quadrant,and number of platform crossings were significantly reduced(P＜0.05,P＜0.05,P＜0.01),the suspension time and frequency in the forced-swimming experiment were increased(P＜0.05,P＜0.01),and the incubation period was shortened(P＜0.05)in offspring in the model group.Prophylactic treatment with Shuyu Capsules and fluoxetine improved the depression-like behavior and cognitive impairment in the offspring in the model group.Biochemical tests showed that CORT levels were increased in the CMS model group(P＜0.05),BDNF,p-ERK1/2,and p-CREB protein levels in the hippocampus were decreased(all P＜0.05),and BDNF,ERK1,ERK2,and CREB mRNA levels were significantly reduced(P＜0.01,P＜0.05,P＜0.01,P＜0.05).Treatment with Shuyu Capsules and fluoxetine increased the CORT content and BDNF,ERK1/2,and CREB protein and mRNA levels in male offspring to varying degrees.Conclusions High levels of CORT in offspring act selectively on the hippocampus,exerting adverse effects on the emotional and learning memory functions of rats by downregulating the BDNF-ERK1/2 signaling cascade.The Chinese medicine Shuyu Capsules can reduce the impact of an adverse intrauterine environment on offspring development by correcting abnormal levels and pathways of glucocorticoids.

This article reports a case of extensive ocular inflammation following zoledronic acid infusion for the treatment of osteoporosis. The patient developed pain, eyelid edema, conjunctival congestion, and decreased vision in the right eye one day after receiving intravenous zoledronic acid, and was diagnosed with uveitis, scleritis, and periorbital soft tissue inflammation. The patient′s symptoms were evaluated using the clinical activity score(CAS). After high-dose corticosteroid pulse therapy combined with other comprehensive treatments, the symptoms improved markedly. This article reviews the incidence, clinical features, potential mechanisms, management, and prognosis of ocular adverse reactions induced by zoledronic acid, and highlights the importance of early recognition and timely treatment of ocular inflammation after zoledronic acid therapy.

BACKGROUND:Observations from several clinical studies suggest a close relationship between hypertension and osteoporosis,but the causal relationship between hypertension and osteoporosis is unclear. OBJECTIVE:To determine whether there is a causal relationship between hypertension and osteoporosis,multisite bone mineral density and osteoporosis with fractures in Asian and European populations,respectively,using a comprehensive two-sample Mendelian randomized analysis. METHODS:Data of osteoporosis in Asian populations were obtained through Japan biological bank. Data of osteoporosis in European populations were obtained from UK Biobank,a British biological bank. Data of hypertension,multisite bone mineral density and osteoporosis with fractures were all from FinnGen R10 database. Inverse variance weighted method,MR-Egger regression method,weighted median method,weighted model method and simple model method were used to study the causal relationship between hypertension and osteoporosis,multisite bone mineral density and osteoporosis with fracture in Asian and European populations. Comprehensive sensitivity analysis was used to verify the robustness,heterogeneity and level pleiotropy of the results. Stsiger test was used to determine whether there was a reverse causal relationship between osteoporosis and hypertension. RESULTS AND CONCLUSION:In Asian populations,there was no significant genetic predictive causal relationship between hypertension and osteoporosis,and there was a positive causal relationship between hypertension and calcaneal bone mineral density. In European populations,hypertension had a negative causal relationship with osteoporosis,and there was no significant causal relationship between hypertension and systemic bone mineral density,calcaneal bone mineral density,forearm bone mineral density and osteoporosis with fracture. According to the stsiger test,there was no reverse causal relationship between osteoporosis,multiplesite bone mineral density,osteoporosis with fracture and hypertension in Asian and European populations. These results indicate that there is a causal relationship between hypertension and osteoporosis,that is,in Asian populations,hypertension and calcaneal bone mineral density show a positive causal relationship;in European populations,hypertension and osteoporosis show a negative causal relationship,but no reverse causal relationship.

This article reports a case of extensive ocular inflammation following zoledronic acid infusion for the treatment of osteoporosis. The patient developed pain, eyelid edema, conjunctival congestion, and decreased vision in the right eye one day after receiving intravenous zoledronic acid, and was diagnosed with uveitis, scleritis, and periorbital soft tissue inflammation. The patient′s symptoms were evaluated using the clinical activity score(CAS). After high-dose corticosteroid pulse therapy combined with other comprehensive treatments, the symptoms improved markedly. This article reviews the incidence, clinical features, potential mechanisms, management, and prognosis of ocular adverse reactions induced by zoledronic acid, and highlights the importance of early recognition and timely treatment of ocular inflammation after zoledronic acid therapy.

Objective To observe hierarchical differences in brain functional networks in unilateral mesial temporal lobe epilepsy(mTLE)patients with different outcomes after surgery.Methods A total of 69 unilateral mTLE patients who underwent resection of epileptogenic lesion on the affected side were retrospectively enrolled.Based on Engel classification 1 year after surgery,the patients were divided into seizure free(SF)group and non-seizure free(NSF)group.Functional connectivity gradient analysis was employed to extract principal gradient explaining the highest variance on preoperative resting-state functional MRI(rs-fMRI),then the whole-brain gradient characteristics and principal gradient values within specific functional networks were compared between groups.Results Principal gradient connected default mode network(DMN)with sensorimotor network(SMN)along a continuous axis.Compared to SF group,NSF group showed a contracted gradient range at both ends(DMN and SMN)of the functional network and weakened hierarchical differentiation,and principal gradient value of DMN was higher,while that of SMN was lower than those in SF group(both P＜0.05).Conclusion Hierarchical differences in brain functional networks in unilateral mTLE patients with different outcomes after surgery mainly present as enhanced DMN and weakened SMN in NSF ones,and the latter two might serve as important neuroimaging markers for evaluating postoperative seizure recurrence.

Objective To observe the value of machine learning(ML)models based on brain functional network features combining clinical indicators for predicting postoperative outcomes of patients with drug-resistant mesial temporal lobe epilepsy(DR-mTLE).Methods Totally 84 patients with unilateral DR-mTLE who underwent surgery were retrospectively enrolled and classified into seizure free(SF)group(n=55)and non-seizure free(NSF)group(n=29)according to one-year postoperative follow-up.Clinical data were analyzed to screen independent predictors of postoperative outcomes.Based on brain preoperative resting-state functional MRI,brain functional networks were constructed using graph theory analysis,and 587 features were extracted.Five-fold cross validation was used to divide the data into training set and test set,then the optimal brain functional network features related to postoperative outcomes of DR-mTLE patients were selected.Combining with clinically relevant independent predictors,ML models were constructed using classifiers including Gaussian process(GP),logistic regression(LR),support vector machine(SVM)and quadratic discriminant analysis(QDA),respectively,and the prediction efficacy,calibration and clinical value of each ML model were evaluated.Results Both course of disease and lesion location were clinically relevant independent predictors of postoperative outcome of DR-mTLE patients(OR=0.928,5.710,P=0.010,0.016).Four optimal brain function network features were selected,including betweenness centrality of the third zone of cerebellar vermis,degree centrality of right globus pallidus,nodal efficiency of temporal left inferior temporal gyrus and nodal clustering coefficient of left inferior parietal lobule.The average area under the curve(AUC)of GP,LR,SVM and QDA models in test set was 0.868,0.864,0.875 and 0.870,respectively.Calibration curves and decision curve analysis indicated that each ML model had good calibration and high clinical net benefit.Conclusion ML models based on brain functional network features combining with clinical indicators could be used to effectively predict postoperative outcomes in DR-mTLE patients.

OBJECTIVE: To compare the biomechanical properties of personalized Y-shaped plates with horizontal plates, vertical plates, and traditional Y-shaped plates in the treatment of distal humeral intra-articular fractures through finite element analysis, and to evaluate their potential for clinical application. METHODS: The study selected a 38-year-old male volunteer and obtained a three-dimensional model of the humerus by scanning his upper limbs using a 64-slice spiral CT. Four types of fracture-internal fixation models were constructed using Mimics 19.0, Geomagic Wrap 2017, Creo 6.0, and other software: horizontal plates, vertical plates, traditional Y-shaped plate, and personalized Y-shaped plate. The models were then meshed using Hypermesh 14.0 software, and material properties and boundary conditions were defined in Abaqus 6.14 software. AnyBody 7.3 software was used to simulate elbow flexion and extension movements, calculate muscle strength, joint forces, and load torques, and compare the peak stress and maximum displacement of the four fixation methods at different motion angles (10°, 30°, 50°, 70°, 90°, 110°, 130°, 150°) during elbow flexion and extension. RESULTS: Under dynamic loading during elbow flexion and extension, the personalized Y-shaped plate exhibits significant biomechanical advantages. During elbow flexion, the peak internal fixation stress of the personalized Y-shaped plate was (28.8±0.9) MPa, which was significantly lower than that of the horizontal plates, vertical plates, and traditional Y-shaped plate ( P<0.05). During elbow extension, the peak internal fixation stress of the personalized Y-shaped plate was (18.1±1.6) MPa, which was lower than those of the other three models, with significant differences when compared with horizontal plates and vertical plates ( P<0.05). Regarding the peak humeral stress, the personalized Y-shaped plate model showed mean values of (10.9±0.8) and (13.1±1.4) MPa during elbow flexion and extension, respectively, which were significantly lower than those of the other three models ( P<0.05). Displacement analysis showed that the maximum displacement of the humerus with the personalized Y-shaped plate during elbow flexion was (2.03±0.08) mm, slightly higher than that of the horizontal plates, but significantly lower than that of the vertical plates, showing significant differences ( P<0.05). During elbow extension, the maximum displacement of the humerus with the personalized Y-shaped plate was (1.93±0.13) mm, which was lower than that of the other three models, with significant differences when compared with vertical plates and traditional Y-shaped plates ( P<0.05). Stress contour analysis showed that the stress of the personalized Y-shaped plate was primarily concentrated at the bifurcation of the Y-shaped structure. Displacement contour analysis showed that the personalized Y-shaped plate effectively controlled the displacement of the distal humerus during both flexion and extension, demonstrating excellent stability. CONCLUSION The personalized Y-shaped plate demonstrates excellent biomechanical performance in the treatment of distal humeral intra-articular fractures, with lower stress and displacement, providing more stable fixation effects.
Humans ; Male ; Adult ; Healthy Volunteers ; Finite Element Analysis ; Tomography, Spiral Computed ; Models, Anatomic ; Biomechanical Phenomena ; Humeral Fractures, Distal/surgery* ; Fracture Fixation, Internal/instrumentation* ; Bone Plates ; Computer Simulation ; Precision Medicine/methods* ; Elbow Joint/surgery* ; Elbow/surgery* ; Humerus/surgery* ; Torque ; Stress, Mechanical ; Intra-Articular Fractures/surgery* ; Prosthesis Design/methods* ; Imaging, Three-Dimensional ; Range of Motion, Articular