The Janus kinase/signal transducers and activators of transcription (JAK-STAT) control natural killer (NK) cells development and cytotoxic functions, however, whether long non-coding RNAs (lncRNAs) are involved in this pathway remains unknown. We found that miR155HG was elevated in activated NK cells and promoted their proliferation and effector functions in both NK92 and induced-pluripotent stem cells (iPSCs)-derived NK (iPSC-NK) cells, without reliance on its derived miR-155 and micropeptide P155. Mechanistically, miR155HG bound to miR-6756 and relieved its repression of JAK3 expression, thereby promoting the JAK-STAT pathway and enhancing NK cell proliferation and function. Further investigations disclosed that upon cytokine stimulation, STAT3 directly interacts with miR155HG promoter and induces miR155HG transcription. Collectively, we identify a miR155HG-mediated positive feedback loop of the JAK-STAT signaling. Our study will also provide a power target regarding miR155HG for improving NK cell generation and effector function in the field of NK cell adoptive transfer therapy against cancer, especially iPSC-derived NK cells.

Approximately 30%-40% of epilepsy patients do not respond well to adequate anti-seizure medications (ASMs), a condition known as pharmacoresistant epilepsy. The management of pharmacoresistant epilepsy remains an intractable issue in the clinic. Its early prediction is important for prevention and diagnosis. However, it still lacks effective predictors and approaches. Here, a classical model of pharmacoresistant temporal lobe epilepsy (TLE) was established to screen pharmacoresistant and pharmaco-responsive individuals by applying phenytoin to amygdaloid-kindled rats. Ictal electroencephalograms (EEGs) recorded before phenytoin treatment were analyzed. Based on ictal EEGs from pharmacoresistant and pharmaco-responsive rats, a convolutional neural network predictive model was constructed to predict pharmacoresistance, and achieved 78% prediction accuracy. We further found the ictal EEGs from pharmacoresistant rats have a lower gamma-band power, which was verified in seizure EEGs from pharmacoresistant TLE patients. Prospectively, therapies targeting the subiculum in those predicted as "pharmacoresistant" individual rats significantly reduced the subsequent occurrence of pharmacoresistance. These results demonstrate a new methodology to predict whether TLE individuals become resistant to ASMs in a classic pharmacoresistant TLE model. This may be of translational importance for the precise management of pharmacoresistant TLE.
Epilepsy, Temporal Lobe/diagnosis* ; Animals ; Drug Resistant Epilepsy/drug therapy* ; Electroencephalography/methods* ; Rats ; Anticonvulsants/pharmacology* ; Neural Networks, Computer ; Male ; Humans ; Phenytoin/pharmacology* ; Adult ; Disease Models, Animal ; Female ; Rats, Sprague-Dawley ; Young Adult ; Convolutional Neural Networks

Effective axon regeneration is essential for the successful restoration of nerve functions in patients suffering from axon injury-associated neurological diseases. Certain self-regeneration occurs in injured peripheral axonal branches of dorsal root ganglion (DRG) neurons but does not occur in their central axonal branches. By performing rat sciatic nerve or dorsal root axotomy, we determined the expression of the dysbindin domain containing 2 (DBNDD2) in the DRGs after the regenerative peripheral axon injury or the non-regenerative central axon injury, respectively, and found that DBNDD2 is down-regulated in the DRGs after peripheral axon injury but up-regulated after central axon injury. Furthermore, we found that DBNDD2 expression differs in neonatal and adult rat DRGs and is gradually increased during development. Functional analysis through DBNDD2 knockdown revealed that silencing DBNDD2 promotes the outgrowth of neurites in both neonatal and adult rat DRG neurons and stimulates robust axon regeneration in adult rats after sciatic nerve crush injury. Bioinformatic analysis data showed that transcription factor estrogen receptor 1 (ESR1) interacts with DBNDD2, exhibits a similar expression trend as DBNDD2 after axon injury, and may targets DBDNN2. These studies indicate that reduced level of DBNDD2 after peripheral axon injury and low abundance of DBNDD2 in neonates contribute to axon regeneration and thus suggest the manipulation of DBNDD2 expression as a promising therapeutic approach for improving recovery after axon damage.
Animals ; Ganglia, Spinal/metabolism* ; Nerve Regeneration/genetics* ; Rats ; Axons/metabolism* ; Sciatic Nerve/injuries* ; Rats, Sprague-Dawley ; Male

Objective To investigate the effect of ATP synthase inhibitory factor 1 (ATPIF1) on the antitumor activity of chimeric antigen receptor (CAR)-NK92 cells. Methods HER2-targeted CAR-NK92 cells with ATPIF1 overexpression or knockdown were constructed. CAR-positive expression rate was detected by flow cytometry. Cell proliferation capacity was measured using CCK-8 assay. Glycolytic capacity was analyzed by Seahorse metabolic analyzer. Mitochondrial membrane potential levels were detected using JC-1 probe. Target cell lysis rate was evaluated by firefly luciferase reporter assay. Expression levels of CD107a, natural-killer group 2 member D (NKG2D), granzyme B (GzmB), perforin, and interleukin 2 (IL-2) were detected via flow cytometry. Quantitative real-time PCR was used to measure the expression of interferon-induced protein with tetratricopeptide repeats 1 (IFIT1), tumor necrosis factor α (TNF-α), ATPIF1, and hexokinase 1 (HK1). The impact of glycolytic inhibition by 2-Deoxy-D-glucose (2-DG) on CAR-NK92 antitumor capacity was examined. Results Successfully generated HER2-targeting control CAR-NK92 cells, as well as ATPIF1-overexpressing and ATPIF1 knockdown CAR-NK92 cells. The ATPIF1-overexpressing CAR-NK92 cells showed significantly enhanced target cell lysis rate, elevated expression levels of NKG2D and CD107a, increased secretion capacities of Granzyme B (GzmB) and IL-2, and upregulated mRNA expression levels of IFIT1 and TNF-α, while ATPIF1-knockdown cells exhibited opposite effects. ATPIF1 overexpression induced metabolic reprogramming in CAR-NK92 cells, manifested by significantly decreased mitochondrial membrane potential (δpsim), markedly upregulated HK1 mRNA expression, and enhanced basal glycolysis and glycolytic capacity. After glycolysis inhibition with 2-DG (5 μmol/L), both ATPIF1-overexpressing and knockdown CAR-NK92 cells showed no significant differences in NKG2D and CD107a expression levels compared to control cells. Conclusion ATPIF1 regulates the antitumor activity of CAR-NK92 cells through modulating glycolytic metabolism. Overexpression of ATPIF1 can enhance the antitumor efficacy of CAR-NK92 cells.
Humans ; Glycolysis ; Killer Cells, Natural/metabolism* ; Receptors, Chimeric Antigen/immunology* ; Granzymes/genetics* ; Hexokinase/metabolism* ; Cell Line, Tumor ; Interleukin-2/genetics* ; Cell Proliferation ; NK Cell Lectin-Like Receptor Subfamily K/genetics* ; Membrane Potential, Mitochondrial

OBJECTIVE To evaluate the efficacy of oral and facial muscle functional training in treating adult obstructive sleep apnea(OSA)and to identify clinical indicators influencing treatment outcomes.METHODS Through a prospective cohort study,patients diagnosed with OSA in the study unit were recruited to undergo a 3-month myofunctional therapy,including soft palate-related muscles,tongue muscles,buccal muscles,and labial muscles in multiple muscle groups,once a day,five times a week,with the use of offline clinic guidance,and the APP program video follow up training for effective training.Data were collected on multiple dimensions including physical signs,sleep breathing monitoring parameters,and airway measurements from imaging studies.Treatment efficacy was assessed by comparing subjective and objective sleep indicators before and after training.Patients were categorized into effective and ineffective groups based on treatment outcomes.Differences in baseline clinical indicators between these groups were analyzed using univariate and multivariate regression analyses.RESULTS The study finally included 58 people,51 males and 7 females,age(38.36±8.96)years,BMI(27.14±3.68)kg/m2,AHI of the enrolled patients was reduced from(31.27±22.28)times/h pre-training to(26.27±21.38)times/h post-training,the minimum oxygen saturation was increased from(78.43±10.07)%to(80.50±10.06)%,snoring index decreased from(62.80±75.20)times/h to(36.40±43.19)times/h,and ESS score decreased from 7.00±5.31 pre-training to 5.50±3.17.By comparing the effective and ineffective groups,it was found that there was a statistically significant difference in the tongue position and ESS scores between the two groups(both P<0.05),while no significant differences were found in gender,age,neck circumference,posterior soft palate area,uvula area,posterior tongue area,or posterior epiglottic area(all P>0.05).Univariate logistic regression analysis indicated that tongue position,AHI,and ESS scores were factors affecting the efficacy of oral and facial muscle function training.Multivariate regression analysis revealed that AHI was an independent prognostic factor for this training in OSA patients.CONCLUSION Oral and facial muscle function training can improve both subjective and objective sleep breathing indices in OSA patients.Tongue position,AHI,and ESS scores may serve as prognostic factors for OSA treatment,aiding in guiding subsequent individualized intervention therapies.

Based on the target recognition ability of split aptamer and intelligent analytical capability of molecular logic gate,in this work,two split aptamers were integrated into"AND"logic gate to construct a novel ortho-nucleic acid fluorescence sensor for simultaneous detection of thrombin and myoglobin.When there was one target,the response of the signal was only a single fluorescence output signal,which was used as an evaluation standard for early low-risk judgment.When two targets coexisted,the split aptamer bound to the target to form a ternary complex and led to the head and tail ortho-nucleic acid effect respectively,and triggered the G4 chain to enhance the fluorescence signal of thioflavin T and the fluorescence signal quenching of Cyanine 3,which could be used as an evaluation criterion for early high-risk judgement.Under the optimal conditions,the linear range for detection of thrombin was 3-200 nmol/L,with a correlation coefficient of 0.9931 and a detection limit of 0.97 nmol/L,and the linear range for detection of myoglobin was 6-400 nmol/L,with a correlation coefficient of 0.9933,and a detection limit of 2.14 nmol/L.The method was applied to simultaneous determination of thrombin and myoglobin in clinical serum samples,and the recoveries were 85.4%-118.3%and 85.8%-119.9%,respectively,with relative standard deviations of less than 6.5%.Compared with the standard method,the relative error range was from-8.8%to 5.6%.In addition,the logical diagnosis results of 4 serum samples were high-risk of acute myocardial infarction in 2 cases and low-risk in 2 cases.The ″AND″ logic gate ortho-nucleic acid fluorescence sensing method showed many advantages such as high selectivity,rapidity,accuracy and simultaneous detection,which offered important reference for early diagnosis of acute myocardial infarction,and also provided a general detection design strategy and platform for simultaneous detection of biomarkers.

Objective To analyze the tumor characteristics associated with achieving pathological complete response(pCR) and tumor prognosis in the patients undergoing laparoscopic rectal cancer surgery after neoadjuvant chemoradiotherapy(nCRT). Methods A retrospective review was conducted on clinical and pathological data of locally advanced rectal cancer(LARC) patients who underwent nCRT at Renji Hospital from January 2017 to January 2024. Factors influencing the achievement of pCR were analyzed, and the patients prognosis of pCR group and non-pCR group was compared. Results Univariate analysis, multivariate Logistic regression analysis, and receiver operating characteristic (ROC) curve analysis showed that tumor length less than 5 cm(cutoff value 5.24 cm) and baseline carcinoembryonic antigen(CEA) less than 5 μg/L(cutoff value 5.33 μg/L) were independent predictors of achieving pCR after nCRT in LARC patients. Prognostic survival analysis showed that the 3-year overall survival(OS) rate for pCR group and non-pCR group were 92.86% and 82.46%, respectively (P=0.193), and the 3-year disease-free survival (DFS) rate were 85.71% and 70.18%, respectively (P=0.141), with no statistically significant differences between the two groups. Conclusions Tumor length and baseline CEA level are independent predictors for achieving pCR after nCRT in LARC patients. Additionally, there were no statistically significant differences in 3-year OS and DFS between pCR group and non-pCR group.

Objective:To compare the clinical characteristics of monogenic and non-monogenic early-onset inflammatory bowel disease (EO-IBD) in children and to explore the necessity of genetic analysis in EO-IBD research.Methods:A retrospective analysis of clinical data was conducted on 73 children diagnosed with EO-IBD at the Children's Hospital affiliated with Capital Institute of Pediatrics between January 2017 and December 2023. Genetic analysis was performed utilizing next-generation sequencing technology, with patients stratified into monogenic and non-monogenic groups based on the presence or absence of pathogenic mutations. Subsequently, a comparative analysis of clinical characteristics was conducted between these two cohorts of EO-IBD patients.Results:Among the 73 EO-IBD cases, 27 (37%) were diagnosed as monogenic IBD, and 46 (63%) as non-monogenic IBD. Compared to the non-monogenic group, the monogenic group had an earlier age of onset [1 (0.2, 3.0) months vs. 15 (4.1, 51.3) months, P < 0.001], with a higher incidence within the first month of life (70.4% vs. 13.0%, P < 0.001). Monogenic IBD cases were more likely to present with Crohn's disease (CD) phenotypes (88.9% vs. 52.2%, P = 0.003) and colonic involvement (L2) (91.7% vs. 62.5%, P < 0.001), but were less likely to present with non-penetrating, non-stricturing (B1) disease (87.5% vs. 95.8%, P = 0.019). Children in the monogenic group were more prone to severe malnutrition (74.1% vs. 21.3%, P < 0.001), perianal abscesses (40.7% vs. 8.7%, P < 0.001), perianal tags (22.2% vs. 0%, P = 0.004), fever (74.1% vs. 23.9%, P < 0.001), oral ulcers (44.4% vs. 6.5%, P < 0.001), and skin lesions (33.3% vs. 2.2%, P < 0.001). Regarding treatment, the monogenic group had higher usage of thalidomide (88.9% vs. 54.3%, P = 0.002) and hematopoietic stem cell transplantation (HSCT) (37.0% vs. 0, P < 0.001) and a higher mortality rate (22.2% vs. 2.2%, P = 0.017) . Conclusions:For children with IBD presenting at an early age, especially within the first month of life, and showing symptoms like fever, oral ulcers, skin lesions, severe malnutrition, and perianal disease, monogenic IBD should be considered. Genetic testing results can aid in guiding treatment decisions.

Ion selective electrode(ISE)is a key component of full automatic biochemical analyzer.It is very important to solve the ISE's faults in time in ensuring the operational quality of full automatic biochemical analyzer.This article proposed maintenance ideas and method after analyzed the structural composition and the working principle of full automatic biochemical analyzer,and conducted further analysis for the common faults included reference liquid suction,flushing tower overflow and results'inaccurate,which can effectively resolve the problems of the above faults.In the management for full automatic biochemical analyzer,the metrological verification work should be strengthened,so as to enhance the level of technical support of equipment engineering,and improve the quality of clinical service of equipment.

Objective:To construct decision indicator system for the allocation of life-support equipment on the basis of hospital-based health technology assessment(HB-HTA)theory,and explore its application value in the management for life-support equipment.Methods:The decision indicators of the allocation of life-support equipment were formulated from four dimensions that included equipment safety,effectiveness,suitability and economy on the basis of HB-HTA theory,so as to assess and manage the decision for allocation of equipment.A total of 149 using life-support equipment in clinical work in West China Hospital of Sichuan University from January 2022 to December 2023 were selected,and expert review mode was adopted to conduct decision for allocation of 138 equipment received management for allocation from January to December 2022,and the decision indicator system for the allocation of life-support equipment on the basis of HB-HTA theory was adopted to conduct decision management for the allocation of 143 equipment(included 132 equipment received expert review mode for management of allocation)that received management for allocation from January to December 2023.The predictive assessment value for target,the achievement ratio of HB-HTA performance,the result of examination of management level of 46 personnel from clinical department,15 personnel from department of equipment,and 11 personnel from other department in items of allocation of equipment were compared between two kinds of management modes for allocation.Results:The predictive assessment values for target of the allocation items of heart-support equipment,respiratory-support equipment,anesthesia-support equipment and other support equipment which adopted HB-HTA management mode for allocation were respectively 0.65±0.22,0.68±0.16,0.70±0.15 and 0.58±0.20,which were higher all than those of management mode of expert review for allocation,and the differences were statistically significant(t=3.362,3.585,f4.152,3.247,P<0.05).The achievement ratio of average performance of safety,effectiveness,suitability and economy of allocation items of HB-HTA management mode were respectively(97.29±1.65)%,(96.19±2.08)%,(95.82±2.29)%and(94.92±2.29)%,all of which were higher than those of expert review management mode for allocation,and the differences were statistically significant(t=2.297,2.377,2.753,2.951,P<0.05).The results of the personnel who worked in clinical department,equipment department and other department were respectively(93.24±3.12)scores,(95.35±3.22)scores and(95.78±1.82)scores in adopting HB-HTA management mode for allocation to conduct examination for the management level about allocation items of life-support equipment with allocation decision,all of which were higher than those of expert review management mode for allocation,and the differences of them were statistically significant(t=3.220,2.435,2.404,P<0.05).Conclusion:The application of HB-HTA theory in indicator system of allocation decision of life-support equipment can comprehensively analyze the safety,effectiveness,suitability and economy of equipment allocation,and enhance the scientific nature of declaring project for allocation of life-support equipment,and improve the achievement degree of the target of implementing the project of the allocation of life-support equipment,and raise the business level of the management team for the project of allocation of life-support equipment.