BACKGROUND: Oral squamous cell carcinoma (OSCC) is a prevalent type of cancer with a high mortality rate in its late stages. One of the major challenges in OSCC treatment is the resistance to epidermal growth factor receptor (EGFR) inhibitors. Therefore, it is imperative to elucidate the mechanism underlying drug resistance and develop appropriate precision therapy strategies to enhance clinical efficacy. METHODS: To evaluate the efficacy of the combination of the Ca 2+ /calmodulin-dependent protein kinase II (CAMK2) inhibitor KN93 and EGFR inhibitors, we performed in vitro and in vivo experiments using two FAT atypical cadherin 1 ( FAT1 )-deficient (SCC9 and SCC25) and two FAT1 wild-type (SCC47 and HN12) OSCC cell lines. We assessed the effects of EGFR inhibitors (afatinib or cetuximab), KN93, or their combination on the malignant phenotype of OSCC in vivo and in vitro . The alterations in protein expression levels of members of the EGFR signaling pathway and SRY-box transcription factor 2 (SOX2) were analyzed. Changes in the yes-associated protein 1 (YAP1) protein were characterized. Moreover, we analyzed mitochondrial dysfunction. Besides, the effects of combination therapy on mitochondrial dynamics were also evaluated. RESULTS: OSCC with FAT1 mutations exhibited resistance to EGFR inhibitors treatment. The combination of KN93 and EGFR inhibitors significantly inhibited the proliferation, survival, and migration of FAT1 -mutated OSCC cells and suppressed tumor growth in vivo . Mechanistically, combination therapy enhanced the therapeutic sensitivity of FAT1 -mutated OSCC cells to EGFR inhibitors by modulating the EGFR pathway and downregulated tumor stemness-related proteins. Furthermore, combination therapy induced reactive oxygen species (ROS)-mediated mitochondrial dysfunction and disrupted mitochondrial dynamics, ultimately resulting in tumor suppression. CONCLUSION Combination therapy with EGFR inhibitors and KN93 could be a novel precision therapeutic strategy and a potential clinical solution for EGFR-resistant OSCC patients with FAT1 mutations.
Humans ; ErbB Receptors/metabolism* ; Mouth Neoplasms/metabolism* ; Cell Line, Tumor ; Animals ; Drug Resistance, Neoplasm/genetics* ; Cadherins/metabolism* ; Carcinoma, Squamous Cell/metabolism* ; Mice ; Mutation/genetics* ; Mice, Nude ; Protein Kinase Inhibitors/therapeutic use* ; Cetuximab/pharmacology* ; Afatinib/therapeutic use* ; Cell Proliferation/drug effects* ; Signal Transduction/drug effects*

Despite therapy with potent antiviral agents, chronic hepatitis B (CHB) patients remain at high risk of hepatocellular carcinoma (HCC). While metabolites have been rediscovered as active drivers of biological processes including carcinogenesis, the specific metabolites modulating HCC risk in CHB patients are largely unknown. Here, we demonstrate that baseline plasma from CHB patients who later developed HCC during follow-up exhibits growth-promoting properties in a case-control design nested within a large-scale, prospective cohort. Metabolomics analysis reveals a reduction in long-chain acylcarnitines (LCACs) in the baseline plasma of patients with HCC development. LCACs preferentially inhibit the proliferation of HCC cells in vitro at a physiological concentration and prevent the occurrence of HCC in vivo without hepatorenal toxicity. Uptake and metabolism of circulating LCACs increase the intracellular level of acetyl coenzyme A, which upregulates histone H3 Lys14 acetylation at the promoter region of KLF6 gene and thereby activates KLF6/p21 pathway. Indeed, blocking LCAC metabolism attenuates the difference in KLF6/p21 expression induced by baseline plasma of HCC/non-HCC patients. The deficiency of circulating LCACs represents a driver of HCC in CHB patients with viral control. These insights provide a promising direction for developing therapeutic strategies to reduce HCC risk further in the antiviral era.

【Objective】 To investigate the effect of polymerized human cord hemoglobin (PolyCHb) in chemoimmunotherapy for breast cancer in mice. 【Methods】 A 4T1 breast cancer in situ tumor model was established, and 15 mice were randomly divided into 3 groups: blank group: no intervention; Control group: doxorubicin + PD-1 inhibitor was given intraperitoneal injection of doxorubicin 5 mg·kg^-1 once a week and PD-1 inhibitor 12.5 mg·kg^-1 once a week; Experimental group: DOX+ a-PD-1+ PolyCHb, the usage of DOX and a-PD-1 was the same as above, PolyCHb: PolyCHb 600 mg·kg^-1 was injected into the tail vein, three times a week; The administration period was 4 weeks. During the administration, the tumor volume was recorded 3 times per week, the tumor growth curve of each group was drawn and the tumor inhibition rate was calculated. The mice were killed on the 29th day, and the tumor was removed and weighed to calculate the tumor inhibition rate. Immunofluorescence, HE staining, TUNEL method and immunohistochemistry was used to detect the expression of HIF-1α, observe the pathological changes of tumor tissue, detect the apoptosis of tumor cells, and detect the expression of tumor proliferation index Ki67. 【Results】 Compared with the blank group and the control group, the tumor volume in the experimental group decreased significantly (P<0.05) and the tumor inhibition rate (%) increased significantly (P<0.05). The content of HIF-1α in tumor tissue in experimental group decreased (P<0.05). In the experimental group, the growth area of tumor tissue decreased, accompanied by the increase of necrosis area; The positive rates (%) of apoptosis in tumor tissues of blank group, control group and experimental group were 18.79±0.62, 20.68±1.19 and 41.65±2.99 respectively (F=135.2, P<0.001). In addition, the results of tumor proliferation index Ki67 showed that there was a statistical difference between the control group and the experimental group (P<0.05). 【Conclusion】 PolyCHb increases the sensitivity of chemoimmunotherapy in breast cancer mouse model, and the mechanism may be related to the decrease of HIF-1α expression, the promotion of apoptosis and the inhibition of cell proliferation.

A novel technology is proposed for non-contact and real-time detection of atrial fibrillation using millimeter-wave radar.A 60 GHz PCR millimeter wave radar is used to continuously detect the chest echo signal of the subject.After signal acquisition,I-Q signal is generated through I-Q demodulation,and the signal phase information is extracted using effective points phase trend evaluation for obtaining the signals from oscillations in the chest wall,from which the respiratory signals and cardiac signals are extracted through digital filtering for the analysis of cardiac movement.Whether the atrial fibrillation occurs or not is determined by the characteristics of atrial fibrillation wave in the time domain.The effective points phase trend evaluation for extracting more accurate signal phase information and the time-domain method for real-time atrial fibrillation detection are the innovations of the study.The experimental results show that the proposed method achieves a detection accuracy of 99.2%in clinic.

Objective To explore clinical effect of closed reduction percutaneous elastic intramedullary nail assisted by arthrography in the treatment of radial neck fracture in children.Methods A retrospective analysis was performed on 23 chil-dren with radial neck fracture treated with arthrography assisted closed reduction and percutaneous elastic intramedullary nail internal fixation(arthrography with elastic nail group)from January 2019 to December 2022,including 12 males and 11 fe-males,aged from 2 to 12 years old with an average of(7.36±1.89)years old;According to Judet fracture types,14 children were type Ⅲ and 9 children were type Ⅳ.In addition,23 children with radial neck fracture were selected from January 2015 to December 2018 who were treated with closed reduction and percutaneous elastic intramedullary nail fixation(elastic nail group),including 11 males and 12 females,aged from 2 to 14 years old with an average of(7.50±1.91)years old;Judet classi-fication included 15 children were type Ⅲ and 8 children were type Ⅳ.Operative time and intraoperative fluoroscopy times were compared between two groups.Metaizeau evaluation criteria was used to evaluate fracture reduction,and Tibone-Stoltz evaluation criteria was used to evaluate functional recovery of elbow between two groups.Results Both groups were followed up for 12 to 24 months with an average of(16.56±6.34)months.Operative time and intraoperative fluoroscopy times of elastic nail group were(56.64±19.27)min and(21.13±7.87)times,while those of joint angiography with elastic nail group were(40.33±1 1.50)min and(12.10±3.52)times;there were difference between two groups(P＜0.05).According to Metaizeau evaluation,11 patients got excellent result,9 good and 3 fair in joint angiography with elastic nail group,while in elastic nail group,5 ex-cellent,13 good,4 acceptable,and 1 poor;the difference between two groups was statistically significant(P＜0.05).According to Tibone-Stoltz criteria,14 patients got excellent result,8 good,and 1 fair in joint arthrography with elastic nail group;while in elastic nail group,12 patients got excellent result,9 good,1 fair and 1 poor;there was no significant difference between two groups(P＞0.05).Conclusion Compared to percutaneous elastic intramedullary nail fixation,closed reduction assisted by arthrography has advantages of reduced operation time,decreased intraoperative fluoroscopy frequency,and improved fracture reduction.Arthrography enables clear visualization of the anatomical structures of radius,head,neck,bone,and cartilage in children,facilitating comprehensive display of fracture reduction and brachioradial joint alignment.This technique more pre-cisely guides the depth of elastic intramedullary nail implantation in radius neck,thereby enhancing surgical efficiency and success rate.

Objective:To evaluate the role of hypoxia-inducible factor 1α (HIF-1α)-glycolytic pathway in propofol-induced attenuation of brain injury in acute sleep-deprived aged rats.Methods:Forty-eight male SPF-grade healthy Sprague-Dawley rats, aged 20-22 weeks, weighing 500-600 g, were divided into 4 groups ( n=12 each) using a random number table method: control group (Con group), sleep deprivation group (SD group), sleep deprivation + propofol group (SP group), and sleep deprivation + propofol + DMOG group (SPD group). The sleep deprivation model was developed using a sleep deprivation apparatus in rats. At 20 and 3 h before sleep deprivation, 1% propofol at a dose of 0.04 mg/g was intraperitoneally injected in SP group, and 1% propofol at a dose of 0.04 mg/g and HIF-1α activator DMOG at a dose of 0.05 mg/g were intraperitoneally injected in SPD group. Cognitive function was assessed by fear conditioning test and novel object recognition test. After the behavioral testing, the blood and brain tissue samples were collected for determination of blood-brain barrier permeability (by Evans blue staining), apoptosis rate (by TUNEL staining), serum levels of neurofilament light chain protein (NfL) and neuron-specific enolase (NSE), contents of reactive oxygen species (ROS), interleukin-6 (IL-6), inducible nitric oxide synthase (iNOS), lactate and pyruvate (by enzyme-linked immunosorbent assay) and expression of HIF-1α, pyruvate kinase M2 (PKM2), hexokinase 2 (HK2), ionized calcium-binding adaptor molecule 1 (IBA1), and cleaved caspase-3 (by Western blot) and for microscopic examination of pathological changes of the hippocampal tissues. The lactate/pyruvate ratio was calculated. Results:Compared to Con group, the percentage of freezing time and recognition index were significantly decreased, serum concentrations of NSE and NfL, EB content in brain tissues, contents of ROS, IL-6 and iNOS in hippocampal tissues, and lactate/pyruvate ratio were increased, the expression of HIF-1α, PKM2, HK2, IBA1 and cleaved caspase-3 was up-regulated, the apoptosis rate was increased ( P<0.05), and the pathological damage to nerve cells in the hippocampus was found in SD group and SPD group. Compared to SD group, the percentage of freezing time and recognition index were significantly increased, serum concentrations of NSE and NfL, EB content in brain tissues, contents of ROS, IL-6 and iNOS in hippocampal tissues, and lactate/pyruvate ratio were decreased, the expression of HIF-1α, PKM2, HK2, IBA1 and cleaved caspase-3 was down-regulated, the apoptosis rate was decreased ( P<0.05), and the pathological damage to nerve cells in the hippocampus was significantly attenuated in SP group. Compared to SP group, the percentage of freezing time and recognition index were significantly decreased, the serum concentrations of NSE and NfL, EB content in brain tissues, contents of ROS, IL-6 and iNOS in hippocampal tissues, and lactate/pyruvate ratio were increased, the expression of HIF-1α, PKM2, HK2, IBA1 and cleaved caspase-3 was up-regulated, the apoptosis rate was increased ( P<0.05), and the pathological damage to nerve cells in the hippocampus was aggravated in SPD group. Conclusions:Propofol can attenuate acute sleep deprivation-induced brain injury in aged rats, and the mechanism may be related to inhibition of the HIF-1α-glycolytic pathway and reduction of neuroinflammatory responses.

OBJECTIVE: To retrospectively analyze the clinical efficacy of anterior cruciate ligament (ACL) reconstruction combined with anterolateral complex repair and ACL reconstruction combined with ALL reconstruction in the treatment of anterior cruciate ligament injuries with high-grade pivot shift. METHODS: From January 2018 to June 2022, 49 patients combined ACL and ALL injuries with high-grade pivot shift were retrospectively studied from three hospitals, 29 of them underwent ACL reconstruction with anterolateral complex repair (repair group), including 23 males and 6 females with an average age of (27.5±4.8) years old, ranged from 20 to 37 years old;the injured sides were 13 on the left and 16 on the right, and 11 patients were suffered with meniscus injury. The other 20 patients underwent ACL and ALL reconstruction (reconstruction group) including 17 males and 3 females with the mean age of (27.1±4.5) years old, ranged from 20 to 38 years old;the injured sides were 8 on the left and 12 on the right, and 6 patients were suffered with meniscus injury. Knee stability (pivot shift test, KT-2000), range of motion, knee function (Lysholm scoring scale, Cincinnati sports activity scale (CSAS) scoring scale, and Tegner activity level score between two groups were compared. RESULTS: A total of 49 patients were followed up, the repair group receiving 13 to 20(15.3±1.8) months and the reconstruction group receiving 12 to 21(16.0±2.2) months. There was no statistically significant difference in the preoperative pivot shift test grading distribution between two groups (P>0.05). At the last postoperative follow-up, there were 24 patients with grade 0 and 5 patients with grade 1 in the repair group, and there were 18 patients with grade 0 and 2 patients with grade 1 in the reconstruction group, there is no significant difference in the distribution of axial shift test grading between two groups(P>0.05). The preoperative KT-2000 tibial displacement of two groups were (9.39±0.77) mm (repair group) and (9.14±0.78) mm (reconstruction group) respectively, with no statistically significant difference (P>0.05). At the final postoperative follow-up, there were 24 patients with KT-2000 tibial displacement <3 mm and 5 patients with 3 to 5 mm in the repair group, while 18 patients with <3 mm and 2 patients with 3 to 5 mm in the reconstruction group, KT-2000 tibial displacement distribution of two groups was no significant difference (P>0.05), but the KT-2000 tibial displacement in the reconstruction group (1.30±0.86) mm was significantly smaller than that in the repair group (1.99±1.11) mm (P<0.05). The final postoperative follow-up range of motion of the contralateral side knee between two groups was no significant difference (P>0.05). The range of motion of the suffering knee in the repair group was less than that in the reconstruction group (P<0.05). There was no significant difference in preoperative Lysholm and CSAS scores between two groups (P>0.05). At the final postoperative follow-up, both groups showed significant improvement in Lysholm and CSAS scores, while the Lysholm and CSAS scores of the reconstruction group were better than those of the repair group, and the difference was statistically significant (P<0.05). Significant differences was found in Tegner scores between two groups, which 16 patients in the repair group returned to their pre-injury activity level, and 17 patients in the reconstruction group returned to their pre-injury level (P<0.05). CONCLUSION Compared to anterolateral complex repair, combined ACL and ALL reconstruction in the treatment of ACL injuries with high-grade pivot shift results in better knee joint function and stability. This is advantageous in reducing the risk of ACL reconstruction failure.
Humans ; Male ; Female ; Adult ; Anterior Cruciate Ligament Reconstruction/methods* ; Anterior Cruciate Ligament Injuries/surgery* ; Young Adult ; Retrospective Studies ; Anterior Cruciate Ligament/surgery* ; Range of Motion, Articular

Immunoglobulin (IgG) glycosylation affects the effector functions of IgG in a myriad of biological processes and has been closely associated with numerous autoimmune diseases, including systemic lupus erythematosus (SLE), thus underlining the pathogenic role of glycosylation aberration in autoimmunity. This study aims to explore the relationship between IgG sialylation patterns and lupus pregnancy. Relative to that in serum samples from the control cohort, IgG sialylation level was aberrantly downregulated in serum samples from the SLE cohort at four stages (from preconception to the third trimester of pregnancy) and was significantly associated with lupus activity and fetal loss during lupus pregnancy. The type I interferon signature of pregnant patients with SLE was negatively correlated with the level of IgG sialylation. The lack of sialylation dampened the ability of IgG to suppress the functions of plasmacytoid dendritic cells (pDCs). RNA-seq analysis further revealed that the expression of genes associated with the spleen tyrosine kinase (SYK) signaling pathway significantly differed between IgG- and deSia-IgG-treated pDCs. This finding was confirmed by the attenuation of the ability to phosphorylate SYK and BLNK in deSia-IgG. Finally, the coculture of pDCs isolated from pregnant patients with SLE with IgG/deSia-IgG demonstrated the sialylation-dependent anti-inflammatory function of IgG. Our findings suggested that IgG influences lupus activity through regulating pDCs function via the modulation of the SYK pathway in a sialic acid-dependent manner.
Humans ; Pregnancy ; Female ; Lupus Erythematosus, Systemic/pathology* ; Signal Transduction ; N-Acetylneuraminic Acid/metabolism* ; Immunoglobulin G ; Dendritic Cells/pathology*

Objective:To explore the potential clinical value of 99Tc m-methoxyisobutylisonitrile(MIBI) SPECT/CT muscle imaging in the diagnosis of cervical dystonia (CD). Methods:From January 2021 to April 2022, 50 patients with CD (14 males, 36 females; age (45.8±12.5) years) who were treated in Second Affiliated Hospital of Soochow University were prospectively included. The 99Tc m-MIBI SPECT/CT muscle imaging results of 400 pieces of muscle (bilateral sternocleidomastoid, musculus scapulae, splenius capitis and musculus trapezius; each of 100 pieces) in 50 patients were analyzed and divided into the dystonic muscle group and normal muscle group according to the electromyography (EMG). Toronto western spasmodic torticollis rating scale (TWSTRS) score, SUV max and target-to-background ratio (TBR) of single superficial cervical muscle and total cervical muscle, and EMG diagnosis results were obtained before botulinum toxin injection. ROC curves of SUV max and TBR of dystonic muscles were constructed to determine AUCs and the difference was compared by Delong test. Differences of SUV max and TBR between 2 groups were analyzed by Mann-Whitney U test. Spearman rank correlation analysis was used to analyze the correlation of SUV max, TBR and TWSTRS scores of total cervical muscle. Results:There were 205 pieces of muscle in dystonic muscle group and 195 pieces of muscle in normal muscle group. The uptake of 99Tc m-MIBI in dystonic muscle was significantly increased in CD patients, and the non-whole uptake of 99Tc m-MIBI was increased in some dystonic muscles, which was manifested as uneven uptake of the whole muscle. The sensitivity, specificity, accuracy, positive predictive value and negative predictive value of visual analysis were 95.12%(195/205), 75.90%(148/195), 85.75%(343/400), 85.58%(195/242) and 93.67%(148/158), respectively. There were significant differences of SUV max (1.74(1.42, 2.12) vs 0.92(0.81, 0.99)) and TBR (2.55(1.92, 3.27) vs 1.44(1.22, 1.73)) between the dystonic muscle group and the normal muscle group ( z value: -15.29, -12.69, both P<0.001). The diagnostic efficiency of SUV max in dystonic muscle was better than TBR (AUC: 0.942 vs 0.867; z=5.03, P<0.001). SUV max, TBR and TWSTRS score in the neck muscles of patients with CD showed positive correlation ( rs values: 0.44, 0.45, both P<0.001). Conclusion:99Tc m -MIBI SPECT/CT muscle imaging is a good diagnostic method for dystonic muscle in patients with CD.

Objectives: This study sought to describe our institutional experience of repeated percutaneous stellate ganglion blockade (R-SGB) as a treatment option for drug-refractory electrical storm in patients with nonischemic cardiomyopathy (NICM). Methods: This prospective observational study included 8 consecutive NICM patients who had drug-refractory electrical storm and underwent R-SGB between June 1, 2021 and January 31, 2022. Lidocaine (5 ml, 1%) was injected in the vicinity of the left stellate ganglion under the guidance of ultrasound, once per day for 7 days. Data including clinical characteristics, immediate and long-term outcomes, and procedure related complications were collected. Results: The mean age was (51.5±13.6) years. All patients were male. 5 patients were diagnosed as dilated cardiomyopathy, 2 patients as arrhythmogenic right ventricular cardiomyopathy and 1 patient as hypertrophic cardiomyopathy. The left ventricular ejection fraction was 37.8%±6.6%. After the treatment of R-SGB, 6 (75%) patients were free of electrical storm. 24 hours Holter monitoring showed significant reduction in ventricular tachycardia (VT) episodes from 43.0 (13.3, 276.3) to 1.0 (0.3, 34.0) on the first day following R-SGB (P<0.05) and 0.5 (0.0, 19.3) after whole R-SGB process (P<0.05). There were no procedure-related major complications. The mean follow-up was (4.8±1.1) months, and the median time of recurrent VT was 2 months. Conclusion: Minimally invasive R-SGB is a safe and effective method to treat electrical storm in patients with NICM.
Humans ; Male ; Adult ; Middle Aged ; Aged ; Female ; Stroke Volume ; Stellate Ganglion/surgery* ; Ventricular Function, Left ; Cardiomyopathies/complications* ; Tachycardia, Ventricular/therapy* ; Treatment Outcome ; Catheter Ablation