A primary hallmark of pathological cardiac hypertrophy is excess protein synthesis due to enhanced translational activity. However, regulatory mechanisms at the translational level under cardiac stress remain poorly understood. Here we examined the translational regulations in a mouse cardiac hypertrophy model induced by transaortic constriction (TAC) and explored the conservative networks versus the translatome pattern in human dilated cardiomyopathy (DCM). The results showed that the heart weight to body weight ratio was significantly elevated, and the ejection fraction and fractional shortening significantly decreased 8 weeks after TAC. Puromycin incorporation assay showed that TAC significantly increased protein synthesis rate in the left ventricle. RNA-seq revealed 1,632 differentially expressed genes showing functional enrichment in pathways including extracellular matrix remodeling, metabolic processes, and signaling cascades associated with pathological cardiomyocyte growth. When combined with ribosome profiling analysis, we revealed that translation efficiency (TE) of 1,495 genes was enhanced, while the TE of 933 genes was inhibited following TAC. In DCM patients, 1,354 genes were upregulated versus 1,213 genes were downregulated at the translation level. Although the majority of the genes were not shared between mouse and human, we identified 93 genes, including Nos3, Kcnj8, Adcy4, Itpr1, Fasn, Scd1, etc., with highly conserved translational regulations. These genes were remarkably associated with myocardial function, signal transduction, and energy metabolism, particularly related to cGMP-PKG signaling and fatty acid metabolism. Motif analysis revealed enriched regulatory elements in the 5' untranslated regions (5'UTRs) of transcripts with differential TE, which exhibited strong cross-species sequence conservation. Our study revealed novel regulatory mechanisms at the translational level in cardiac hypertrophy and identified conserved translation-sensitive targets with potential applications to treat cardiac hypertrophy and heart failure in the clinic.
Animals ; Humans ; Cardiomegaly/physiopathology* ; Ribosomes/physiology* ; Protein Biosynthesis/physiology* ; Mice ; Cardiomyopathy, Dilated/genetics* ; Ribosome Profiling

With the rapid development of competitive sports, the incidence of anterior cruciate ligament (ACL) injury is on the rise. Such injuries may shorten athletes′ career and lead to other long-term adverse consequences. Although athletes generally recover well after ACL reconstruction, many still struggle to return to their pre-injury performance levels. Advances in the understanding of ACL anatomy and injury mechanisms, along with the evolution of surgical techniques and rehabilitation methods, have provided more individualized and tailored options for athletes following ACL injuries. However, there is currently no consensus in China regarding surgical and rehabilitation strategies for competitive athletes aiming to return to sports after ACL injuries. To this end, the Sports Medicine Committee of the Chinese Research Hospital Association and the Editorial Board of the Chinese Journal of Trauma jointly formulated the Expert consensus on surgical treatment and rehabilitation for competitive sports athletes returning to sports after anterior cruciate ligament injury ( version 2025), and presented 14 recommendations covering surgical indications, preoperative rehabilitation, surgical timing, surgical strategies and postoperative rehabilitation strategies, aiming to improve the surgical treatment and rehabilitation system for ACL injuries in competitive athletes and facilitate their return to high-level sports performance after injury.

Programmed cell death protein 1(PD-1)and its ligand,programmed cell death 1 ligand 1(PD-L1),represent a pair of prototypical immune checkpoint that plays a critical role in tumor immune evasion.However,the development of targeted therapeutics against these two proteins is limited by their low levels and high glycosylation modifications in eukaryotic cells.In this study,we designed two func-tional but truncated variants of PD-1(PD-133-150)and PD-L1(PD-L1 19-239);and subcloned them into eukaryotic expression vectors using golden gate assembly technology.Using these vectors,we achieved high level yields of these two proteins in transiently-transfected HEK-293T cells.After one-step affinity purification,the yields of PD-133-150 and PD-L119 239 proteins reached 5 mg and 3 mg per liter of cell cul-ture medium,with over 95％purity.Using biolayer interferometry and flow cytometry analysis,we deter-mined the binding kinetics,equilibrium constants,and the cellular binding activities of these proteins.Compared with the PD-1 extracellular domain expressed in insect or E.coli cells,the PD-133-150 purified from HEK-293T cells has a 24-fold and a 50-fold increase in its binding affinity to PD-L1.In addition,the dissociation rate of the binding decreased to less than l/400th of the original rate.Thus,we speculate that N-glycosylation could modulate the PD-1/PD-L1 interactions.Together,we established an effective eukaryotic expression and purification platform for functional characterization of PD-133150/PD-L119239 in-teractions,thereby providing high-quality molecular tools for PD-1/PD-L1 antibody screening and im-mune checkpoint research.

Objective To analyze the risk factors for increased drainage volume after open transforaminal lumbar interbody fusion(TLIF),and to establish a predictive model and then validate it.Methods The clinical data of 680 patients who underwent open TLIF at the General Hospital of Northern Theater Command from January 2016 to December 2019 were collected and the patients were randomly divided into the training group(n=476)and the validation group(n=204).Taking the predictive factors screened out by LASSO regression analysis as independent variables,a multivariate Logistic regression predictive model was constructed.The model was internally validated through the receiver operating characteristic(ROC)curve,Hosmer-Lemeshow goodness-of-fit test,and calibration curve,and its clinical utility was assessed via decision curve analysis(DCA).Results LASSO regression analysis screened out four predictive variables:age,number of surgical segments,operative duration,and intraoperative blood loss.The multivariate Logistic regression predictive model demonstrated that age≥60 years,number of surgical segments≥4,operative duration≥2 hours,and intraoperative blood loss≥200 mL were independent influencing factors for the increased postoperative drainage volume in patients undergoing TLIF(P<0.05).ROC curve analysis revealed an area under the curve(AUC)of 0.816(95%CI:0.798 to 0.867)in the training group and 0.783(95%CI:0.685 to 0.823)in the validation group,indicating that the predictive model had good discriminatory ability.Additionally,the Hosmer-Lemeshow goodness-of-fit test and calibration curve indicated that the predictive model had a good degree of fit,and the predicted probability was basically consistent with the actual probability,demonstrating a good calibration.The DCA results confirmed that this predictive model could be applied in clinical practice.Conclusion The risk factors for increased drainage volume after open TLIF include age,number of surgical segments,operative duration,and intraoperative blood loss.The predictive model established based on these factors demonstrates good performance,and it can be applied in clinical guidance for the selection of drainage tube removal time after TLIF.

Objective:To evaluate the efficacy and safety of blinatumomab in adult patients with relapsed/refractory(R/R)or measurable residual disease(MRD)positive B-cell acute lymphoblastic leukemia(B-ALL)in the real world.Methods:The clinical data of 30 B-ALL patients received at least 1 course of blinatumomab therapy in the Chinese PLA General Hospital from January 1st,2021 to December 31st,2023 were retrospectively analyzed,including pre-treatment baseline clinical feature,post-treatment complete response(CR),CR with partial hematologic recovery(CRh),CR with incomplete hematologic recovery(CRi),complete MRD response rate,MRD response rate(MRD＜10-4),overall survival(OS),and disease-free survival(DFS),as well as drug-related adverse reactions.Results:Among 5 patients who were not assessed 4 were MRD negative and 1 did not receive bone marrow biopsy.In the R/R B-ALL group(13 cases),11 patients achieved CR/CRh/CRi and 10 patients achieved complete MRD response.In MRD+group(12 cases),9 patients achieved overall MRD response and 7 patients achieved complete MRD response.The median follow-up time was 8.4(95％CI:6.3-10.4)months.The median OS was 15.5(95％CI:0.7-30.3)months in the R/R group,while not reached in the MRD+group.The median DFS of the two groups were not reached.Drug-related adverse reactions occurred in 22 patients,and pyrexia was the most common(13 cases).Grade ≥3 adverse reactions occurred in 15 patients,and neutropenia was the most common(9 cases).Cytokine release syndrome occurred in 6 patients,including 5 cases with grade 1 and 1 case with grade 3.No patients interrupted therapy or died due to drug-related adverse reactions.Conclusion:Blinatumomab is effective in the treatment of R/R or continuous MRD+B-ALL with acceptable adverse reactions.

Objective:To explore the influence of different time intervals after stent implantation on the efficacy and prognosis of elective surgery in patients with malignant obstructive colorectal cancer(MOCRC).Methods:A total of 182 MOCRC patients were enrolled,including 92 who underwent emergency surgery(ES group)and 90 who received elective surgery after stent placement(SEMS group).The SEMS group was further divided into three subgroups based on the interval between stent placement and surgery:<11 d(n=27),11-17 d(n=39),and>17 d(n=24).Kaplan-Meier analysis was used to compare overall survival(OS)and disease-free survival(DFS),and Cox proportional hazards re-gression was employed to identify prognostic factors.Prognostic models based on surgical timing were constructed,and receiver operating characteristic(ROC)curves were drawn with area under the curve(AUC)calculated to assess model discrimination.A total of 182 patients with MOCRC were included.Among them,92 underwent emergency sur-gery(ES group),and 90 underwent elective surgery after stent implantation(SEMS group).The SEMS group was di-vided into the<11 d group(n=27),the 11-17 d group(n=39),and the>17 d group(n=24)according to the operation interval.Overall survival(OS)and disease-free survival(DFS)were compared using the Kaplan-Meier method,and prognostic factors were analyzed by Cox regression.Result:Compared with the ES group,the SEMS group had a higher rate of laparoscopic surgery and significantly less intraoperative blood loss(P<0.05),with no significant differ-ences in postoperative complication rate,stoma formation rate(P>0.05).Among SEMS patients,the 11～17 d group had the shortest hospital stay and the lowest complication rate(7.69%).Multivariate Cox analysis showed that surgery performed 11-17 d group significantly reduced the risk of death compared to emergency surgery(HR=0.650,P=0.034),while surgery 11 d group significantly increased the risk(HR=2.051,P=0.042).Independent predictors of OS in-cluded age(HR=1.060,P<0.001),preoperative CEA level(HR=1.323,P=0.002),tumor size(HR=1.421,P=0.028),tumor differentiation(HR=1.123,P=0.005),and venous invasion(HR=2.792,P<0.001).For DFS,age,tumor size,venous inva-sion,and perineural invasion were identified as independent risk factors(P<0.05),while surgical timing showed no sig-nificant association(P>0.05).Kaplan-Meier analysis revealed no significant difference in OS among different groups in stage Ⅰ-Ⅱ patients,whereas in stage Ⅲ patients,the 11-17 d group had better OS,and the>17 d group had signifi-cantly worse DFS than other groups(P=0.017).ROC curve analysis showed that the AUCs for OS prediction were 0.636(<11 d),0.601(11-17 d),and 0.750(>17 d);and for DFS prediction were 0.655,0.567,and 0.874,respectively,indicating that surgical timing has moderate discriminative value for survival outcomes.Conclusion:Elective surgery performed 11 to 17 d after stent placement can reduce mortality and improve postoperative recovery,although it has no significant impact on recurrence risk.Venous and peripheral nerve invasion are major factors affecting disease-free survival(DFS);therefore,clinical management should focus on identifying high-risk patients and optimizing individual-ized treatment strategies.

Objective To explore the predictive value of automated breast ultrasound(ABUS)features combined with Ki-67 in predicting pathological complete response(pCR)after neoadjuvant chemotherapy(NAC)in triple-negative breast cancer(TNBC).Methods A retrospective analysis was conducted on 127 female TNBC patients treated at Xijing Hospital,Air Force Medical University from March 2019 to December 2023.All patients underwent NAC and surgical treatment after ABUS examination.Based on postoperative pathological results,patients were divided into pCR group(n=60)and non-pathological complete response(npCR)group(n=67).Differences in various parameters before NAC were compared between the two groups.LASSO regression was used to identify independent factors influencing pCR after NAC in TNBC patients,and a predictive model was constructed using multivariate logistic regression.The prediction model was internally validated using the Bootstrap method(1000 resamples).The discriminative ability of the model was evaluated using receiver operating characteristic(ROC)curves,and the area under the curves(AUCs)of different prediction models were compared using De-long's test.The accuracy of the model was assessed using calibration curves,and the clinical benefit of the model was evaluated using clinical decision curve analysis(DCA).Results Significant differences were observed between two groups in terms of age,Ki-67,menopausal status,tumor type,posterior echo,coronal plane convergence sign,coronal plane skip sign,and coronal plane white wall sign before NAC(P<0.05).LASSO regression analysis showed that Ki-67,coronal plane convergence sign,and coronal plane white wall sign were independent influencing factors of pCR after NAC in TNBC patients(P<0.05).The AUC of the multivariate logistic regression model based on Ki-67 was 0.733(95%CI 0.646-0.819),the AUC of ABUS model was 0.777(95%CI 0.695-0.858),and the AUC of ABUS combined with Ki-67 model was 0.816(95%CI 0.741-0.890).De-long's test showed that the AUC of the combined model was higher than those of ABUS feature model and Ki-67 model,with statistically significant differences(P<0.05).There was no significant difference in the AUC between ABUS feature model and Ki-67 model(P=0.40).Hosmer-Lemeshow test indicated that the combined model had a good fit(P=0.304).Internal validation results showed that the combined model had a good stability with a consistency index(C-index)of 0.820(95%CI 0.726-0.879).The calibration curve demonstrated good consistency between the predicted and actual probabilities of the combined prediction model,and the DCA curve indicated that the model had favorable clinical benefit.Conclusion The combined ABUS feature and Ki-67 model can be used to predict the probability of pCR after NAC in TNBC patients,providing a reference for the formulation of clinical treatment plans in TNBC patients.

Objective To investigate the effects of Chaihuang Qingyi Huoxue Granules on multiple organ damage induced by caerulein combined with lipopolysaccharide in mice with severe acute pancreatitis(SAP).Methods Twenty-four C57BL/6J mice were randomly divided into three groups:control(n=8),SAP(n=8)and Chaihuang Qingyi Huoxue Granules(CHQY group,n=8).Mice in SAP and CHQY groups were intraperitoneally injected with caerulein(50 μg/kg)at hourly intervals for 7 consecutive times,followed by an immediate intraperitoneal injection of lipopolysaccharide(10 mg/kg).Mice in control group received an equal volume of normal saline.After the successful establishment of the model,CHQY group mice were administered Chaihuang Qingyi Huoxue Granules[3.185 g/(kg·d)]via gavage,while control and SAP group mice received an equal volume of normal saline.Twenty-four hours post-modeling,mice were anesthetized,and serum was collected and separated for analysis of the activities of amylase(AMY),lipase(LPS),aspartate transaminase(AST),alanine transaminase(ALT)and the contents of creatinine(CREA)and urea(UREA)using an automatic biochemical analyzer.Serum levels of interleukin(IL)-1β,IL-6,IL-8,IL-18,and tumor necrosis factor-α(TNF-α)were measured by ELISA.Tissue samples from pancreas,lung,liver,kidney,and small intestine were collected for histopathological examination using hematoxylin-eosin(HE)staining and scored.The expression of nuclear factor-κB p65(NF-κB p65)was detected in all tissues by immunohistochemistry.Results Compared with control group,the activities of AMY,LPS,AST and ALT,and the contents of CREA,UREA,IL-1β,IL-6,IL-8,IL-18,and TNF-α were increased(P<0.05).Pathological injuries in the pancreas,lung,liver,kidney,and small intestine was significant,with increased pathological scores and a higher proportion of NF-κB p65 positive cells(P<0.05).Compared with SAP group,the activities of AMY,LPS,AST,ALT,and the contents of CREA,UREA,IL-1β,IL-6,IL-8,IL-18,and TNF-α in the serum of CHQY group were decreased(P<0.05).Pathological injuries in the pancreas,lung,liver,kidney and small intestine were reduced,with lower pathological scores and a decreased proportion of NF-κB p65 positive cells(P<0.05).Conclusion Chaihuang Qingyi Huoxue Granules have a certain therapeutic effect on SAP model mice,which may be related to reducing inflammation response and improving multiple organ damage such as the pancreas,lung,liver,kidney and small intestine.

Objective To establish a stable,reliable,and clinically relevant porcine model of endotoxin-induced acute respiratory distress syndrome(ARDS).Methods Ten 8-month-old male Bama minipigs were deeply sedated,followed by invasive mechanical ventilation and electrocardiographic monitoring.Lipopolysaccharide(LPS)was intravenously pumped at 600 μg/(kg·h)for 3 hours,then maintained at 15 μg/(kg·h)thereafter.Dynamic monitoring was performed at five time points after LPS injection(LPS 0,1,3,5,and 8 h),including arterial blood gas analysis and chest computed tomography(CT)scans.Pathological examination of lung tissues obtained via bronchoscopic biopsy(HE staining and transmission electron microscopy)was conducted.These indicators were comprehensively used to evaluate the success of the animal model.Results At 5 hours after LPS administration,8 minipigs developed symptoms such as skin cyanosis,elevated body temperature,and respiratory distress.The oxygenation index decreased to<300 mmHg.Chest CT scans showed diffuse pulmonary infiltrates.Histopathology revealed alveolar edema and hyaline membrane formation.Transmission electron microscopy demonstrated disruption of pulmonary blood-air barrier,depletion of lamellar bodies in type Ⅱ pneumocytes,inflammatory cell infiltration,and exudation of plasma proteins and fibrin.Compared with LPS 0 h,at LPS 8 h,the oxygenation index and arterial blood pH were significantly decreased(P<0.001),while blood lactic acid and serum potassium were significantly increased(P<0.05);serum calcium and base excess were significantly decreased(P<0.05),and the lung injury score based on HE-stained lung sections was significantly increased(P<0.01).Conclusion The porcine ARDS model established by continuous LPS injection can dynamically simulate the pathophysiological characteristics and typical pathological manifestations of clinical septic ARDS,making it an effective tool to study the pathogenesis,prevention,and treatment strategies of septic ARDS.

Objective To explore the mechanism by which curcumin improves behavioral deficits in mice with Parkinson's disease(PD)through fecal microbiota transplantation.Methods A subacute model of PD in mice was induced by intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP).Fecal microbiota from both the model group and the curcumin(Cur)-treated group(80 m g/kg)were collected and analyzed.The experiment involving fecal microbiota transplantation was structured into four distinct groups,fecal microbiota solvent transplantation group(FMTcon),model fecal microbiota transplantation group(FMTmodel),MPTP-induced model group(model),and model group subjected to fecal microbiota transplantation following curcumin treatment(model+FMTCur).The motor skills of the mice were assessed by using rod rotation,pole climbing experiment,and open field tests.Immunofluorescence techniques were employed to observe the expression tyrosine hydroxylase(TH)-positive neurons in the substantia nigra of the brain.Additionally,the gene expression of tumor necrosis factor-α(TNF-α)in the midbrain of mice was analyzed,alongside the protein expression of nuclear factor-κB(NF-κB)and nucleotide binding oligomerization domain-like receptor protein 3(NLRP3).Results The subacute PD animal model in mice was successfully established,and fecal microbiota were separated and gathered.The model group exhibited significant motor impairment,as evidenced by a shortened rod rotation time(P＜0.05),prolonged pole climbing time(P＜0.05),significantly reduced total movement distance within the open field(P＜0.001),and decreased time spent in the central zone(P＜0.01).The relative expression level of TH+neurons in the substantia nigra was significantly reduced(P＜0.01).Moreover,mRNA expression of TNF-α in the midbrain increased significantly(P＜0.01),along with significant elevations in protein expression of NF-κB(P＜0.001),phosphorylated NF-κB(p-NF-κB)(P＜0.01),NLRP3(P＜0.001),and Caspase-1(P＜0.01).The transplanted model microbial group(FMTmodel)also exhibited motor impairment,manifested by a trend of shortened rod rotation time,prolonged pole climbing time,a significant decrease in total movement distance within the open field(P＜0.01),and a trend of shortened time spent in the central zone.The relative expression level of TH+neurons in the substantia nigra decreased significantly(P＜0.05).Additionally,mRNA expression of TNF-α in the midbrain increased significantly(P＜0.01),along with notable elevations in the protein expression of NF-κB(P＜0.05),and Caspase-1(P＜0.01).Treatment with curcumin in the fecal microbiota transplantation group of mice(model+FMTCur)showed improvements in motor abilities,evidenced by shortened pole climbing time(P＜0.05),significantly prolonged rod rotation time(P＜0.01),and extended time spent in the central zone(P＜0.05).The relative expression level of TH+dopaminergic neurons in the substantia nigra increased significantly(P＜0.05).Moreover,mRNA expression of TNF-α in the midbrain decreased significantly(P＜0.01),along with notable reductions in the protein expression of NF-κB(P＜0.001),p-NF-κB(P＜0.01),NLRP3(P＜0.05),and Caspase-1(P＜0.01).Conclusion Fecal microbiota transplantation in PD model mice can induce behavioral deficits,damage TH+neurons in the substantia nigra,and trigger neuroinflammation in the brain.Subsequent curcumin treatment can ameliorate these deficits,reverse damage to TH+neurons,reduce neuroinflammatory factors,and decrease the expression of NF-κB and NLRP3 pathways.This preliminary evidence suggests that curcumin may improve Parkinsonian behavioral deficits in mice by modulating the gut microbiota.