Recent studies have indicated that the expression of ubiquitin-specific protease 51 (USP51), a novel deubiquitinating enzyme (DUB) that mediates protein degradation as part of the ubiquitin‒proteasome system (UPS), is associated with tumor progression and therapeutic resistance in multiple malignancies. However, the underlying mechanisms and signaling networks involved in USP51-mediated regulation of malignant phenotypes remain largely unknown. The present study provides evidence of USP51's functions as the prominent DUB in chemoresistant triple-negative breast cancer (TNBC) cells. At the molecular level, ectopic expression of USP51 stabilized the 78 kDa Glucose-Regulated Protein (GRP78) protein through deubiquitination, thereby increasing its expression and localization on the cell surface. Furthermore, the upregulation of cell surface GRP78 increased the activity of ATP binding cassette subfamily B member 1 (ABCB1), the main efflux pump of doxorubicin (DOX), ultimately decreasing its accumulation in TNBC cells and promoting the development of drug resistance both in vitro and in vivo. Clinically, we found significant correlations among USP51, GRP78, and ABCB1 expression in TNBC patients with chemoresistance. Elevated USP51, GRP78, and ABCB1 levels were also strongly associated with a poor patient prognosis. Importantly, we revealed an alternative intervention for specific pharmacological targeting of USP51 for TNBC cell chemosensitization. In conclusion, these findings collectively indicate that the USP51/GRP78/ABCB1 network is a key contributor to the malignant progression and chemotherapeutic resistance of TNBC cells, underscoring the pivotal role of USP51 as a novel therapeutic target for cancer management.

Objective:To explore the capability of deep learning image reconstruction (DLIR) compared to adaptive statistical iterative reconstruction (ASiR-V) in improving the image quality and myocardial edge sharpness of dynamic stress myocardial CT perfusion imaging (CTP).Methods:Thirty subjects who underwent dynamic stress myocardial CTP at Guangdong Provincial People′s Hospital from September 2023 to February 2024 were recruited. Image data of all enrolled patients were reconstructed using ASiR-V 50%, ASiR-V 80%, medium-intensity DLIR(DLIR-M), and high-intensity DLIR(DLIR-H), respectively. Regions of interest were selected in the left ventricular cavity, interventricular septum, and left ventricular lateral wall for measurement of CT values and standard deviations (SD), and calculation of signal to noise ratio (SNR) and contrast to noise ratio (CNR). Matlab was utilized to obtain the differences (d) and slopes (s) of CT value changes at four left ventricular myocardial edges for objective edge sharpness evaluation. Two radiologists subjectively scored the images for noise, natural appearance, and edge sharpness. In case of disagreement between the two radiologists, a third senior radiologist′s score was decisive. Left ventricular myocardial blood flow (MBF) of ASiR-V and DLIR images with lower SD, higher SNR and CNR were calculated, respectively. When the normal distribution was satisfied, the independent sample t test was used for comparison between two groups, and the random block design ANOVA was used for comparison between multiple groups. And analysis was conducted using Friedman test for non-normally distributed data, and Bonferroni correction for pairwise comparisons. Results:There were statistically significant differences in SD, SNR, and CNR among the four images in the interventricular septum and left ventricular lateral wall (all P<0.05), with ASiR-V 80% and DLIR-H demonstrating the lowest SD, highest SNR and CNR, and the subjective image noise score. Statistically significant differences were observed in d and s for the four left ventricular myocardial edges (all P<0.05), with DLIR-M and DLIR-H exhibiting the best objective edge sharpness [5 (5, 5)], and ASiR-V 80% the worst [3.5 (3, 4)]. In the subjective scores for natural appearance, DLIR-M and DLIR-H received the highest scores [5 (5, 5)], while ASiR-V 80% received the lowest scores [3 (3, 4)], with statistically significant differences (all P<0.05). There was no statistically significant difference in MBF values calculated from ASiR-V 80% and DLIR-H images (all P>0.05). Conclusions:The SD value, SNR and CNR of dynamic stress myocardial CTP images reconstructed by DLIR-H are equivalent to ASiR-V 80%, and using DLIR-H can improve the edge sharpness of left ventricular myocardium without affecting the calculation of MBF.

Objective:To investigate the relationship between the changes in extracellular vesicles (EVs) size distribution before and after cardiopulmonary bypass (CPB) cardiac surgery and postoperative coagulation function.Methods:A total of 103 patients undergoing cardiac surgery with CPB were enrolled. Venous blood samples were collected at preoperation, postoperative 12 h and 3 days. Additionally, 50 age- and gender-matched healthy volunteers served as a control group. EVs were isolated using gradient centrifugation, and their size distribution was assessed by dynamic light scattering (DLS). The relationship between EV size characteristics, including peak diameter, peak height, and interquartile range( IQR), and postoperative coagulation function was analyzed. Results:Compared to patients with normal postoperative coagulation function, those with postoperative coagulation dysfunction had lower size at peak and IQR, and significantly higher peak intensity. Logistic regression analysis indicated that elevated peak intensity and lower size at peak and IQR were risk factors for coagulation dysfunction. The area under the curve ( AUC) for diagnosing coagulation dysfunction with 12 h postoperative EVs peak intensity was 0.76, with a positive predictive value of 85% at the optimal cutoff of 8.2; the AUC for IQR was 0.84, with a sensitivity of 83%, specificity of 82%, and negative predictive value of 86% at the optimal cutoff of 125.05 nm. Conclusion:The size distribution of circulating EVs show a correlation with coagulation function after cardiac surgery with CPB and may serve as a novel biomarker to predict postoperative coagulation dysfunction.

Objective:To investigate the relationship between the changes in extracellular vesicles (EVs) size distribution before and after cardiopulmonary bypass (CPB) cardiac surgery and postoperative coagulation function.Methods:A total of 103 patients undergoing cardiac surgery with CPB were enrolled. Venous blood samples were collected at preoperation, postoperative 12 h and 3 days. Additionally, 50 age- and gender-matched healthy volunteers served as a control group. EVs were isolated using gradient centrifugation, and their size distribution was assessed by dynamic light scattering (DLS). The relationship between EV size characteristics, including peak diameter, peak height, and interquartile range( IQR), and postoperative coagulation function was analyzed. Results:Compared to patients with normal postoperative coagulation function, those with postoperative coagulation dysfunction had lower size at peak and IQR, and significantly higher peak intensity. Logistic regression analysis indicated that elevated peak intensity and lower size at peak and IQR were risk factors for coagulation dysfunction. The area under the curve ( AUC) for diagnosing coagulation dysfunction with 12 h postoperative EVs peak intensity was 0.76, with a positive predictive value of 85% at the optimal cutoff of 8.2; the AUC for IQR was 0.84, with a sensitivity of 83%, specificity of 82%, and negative predictive value of 86% at the optimal cutoff of 125.05 nm. Conclusion:The size distribution of circulating EVs show a correlation with coagulation function after cardiac surgery with CPB and may serve as a novel biomarker to predict postoperative coagulation dysfunction.

Objective:To explore the capability of deep learning image reconstruction (DLIR) compared to adaptive statistical iterative reconstruction (ASiR-V) in improving the image quality and myocardial edge sharpness of dynamic stress myocardial CT perfusion imaging (CTP).Methods:Thirty subjects who underwent dynamic stress myocardial CTP at Guangdong Provincial People′s Hospital from September 2023 to February 2024 were recruited. Image data of all enrolled patients were reconstructed using ASiR-V 50%, ASiR-V 80%, medium-intensity DLIR(DLIR-M), and high-intensity DLIR(DLIR-H), respectively. Regions of interest were selected in the left ventricular cavity, interventricular septum, and left ventricular lateral wall for measurement of CT values and standard deviations (SD), and calculation of signal to noise ratio (SNR) and contrast to noise ratio (CNR). Matlab was utilized to obtain the differences (d) and slopes (s) of CT value changes at four left ventricular myocardial edges for objective edge sharpness evaluation. Two radiologists subjectively scored the images for noise, natural appearance, and edge sharpness. In case of disagreement between the two radiologists, a third senior radiologist′s score was decisive. Left ventricular myocardial blood flow (MBF) of ASiR-V and DLIR images with lower SD, higher SNR and CNR were calculated, respectively. When the normal distribution was satisfied, the independent sample t test was used for comparison between two groups, and the random block design ANOVA was used for comparison between multiple groups. And analysis was conducted using Friedman test for non-normally distributed data, and Bonferroni correction for pairwise comparisons. Results:There were statistically significant differences in SD, SNR, and CNR among the four images in the interventricular septum and left ventricular lateral wall (all P<0.05), with ASiR-V 80% and DLIR-H demonstrating the lowest SD, highest SNR and CNR, and the subjective image noise score. Statistically significant differences were observed in d and s for the four left ventricular myocardial edges (all P<0.05), with DLIR-M and DLIR-H exhibiting the best objective edge sharpness [5 (5, 5)], and ASiR-V 80% the worst [3.5 (3, 4)]. In the subjective scores for natural appearance, DLIR-M and DLIR-H received the highest scores [5 (5, 5)], while ASiR-V 80% received the lowest scores [3 (3, 4)], with statistically significant differences (all P<0.05). There was no statistically significant difference in MBF values calculated from ASiR-V 80% and DLIR-H images (all P>0.05). Conclusions:The SD value, SNR and CNR of dynamic stress myocardial CTP images reconstructed by DLIR-H are equivalent to ASiR-V 80%, and using DLIR-H can improve the edge sharpness of left ventricular myocardium without affecting the calculation of MBF.

OBJECTIVE: To evaluate the efficacy and safety of Wuda Granule (WDG) on recovery of gastrointestinal function after laparoscopic bowel resection in the setting of enhanced recovery after surgery (ERAS)-based perioperative care. METHODS: A total of 108 patients aged 18 years or older undergoing laparoscopic bowel resection with a surgical duration of 2 to 4.5 h were randomly assigned (1:1) to receive either WDG or placebo (10 g/bag) twice a day from postoperative days 1-3, combining with ERAS-based perioperative care. The primary outcome was time to first defecation. Secondary outcomes were time to first flatus, time to first tolerance of liquid or semi-liquid food, gastrointestinal-related symptoms and length of stay. Subgroup analysis of the primary outcome according to sex, age, tumor site, surgical time, histories of underlying disease or history of abdominal surgery was undertaken. Adverse events were observed and recorded. RESULTS: A total of 107 patients [53 in the WDG group and 54 in the placebo group; 61.7 ± 12.1 years; 50 males (46.7%)] were included in the intention-to-treat analysis. The patients in the WDG group had a significantly shorter time to first defecation and flatus [between-group difference -11.01 h (95% CI -20.75 to -1.28 h), P=0.012 for defecation; -5.41 h (-11.10 to 0.27 h), P=0.040 for flatus] than the placebo group. Moreover, the extent of improvement in postoperative gastrointestinal-related symptoms in the WDG group was significantly better than that in the placebo group (P<0.05). Subgroup analyses revealed that the benefits of WDG were significantly superior in patients who were male, or under 60 years old, or surgical time less than 3 h, or having no history of basic disease or no history of abdominal surgery. There were no serious adverse events. CONCLUSION The addition of WDG to an ERAS postoperative care may be a viable strategy to enhance gastrointestinal function recovery after laparoscopic bowel resection surgery. (Registry No. ChiCTR2100046242).
Humans ; Laparoscopy/adverse effects* ; Male ; Female ; Middle Aged ; Double-Blind Method ; Recovery of Function ; Drugs, Chinese Herbal/adverse effects* ; Treatment Outcome ; Gastrointestinal Tract/physiopathology* ; Defecation ; Aged ; Intestines/physiopathology*

Objective:To investigate the hemodynamic changes in the ascending aorta (AAo) before and after interventricular septal myocardial resection in obstructive hypertrophic cardiomyopathy (HOCM) using cardiac magnetic resonance four-dimensional blood flow (CMR 4D Flow) technology.Methods:HOCM patients who underwent interventricular septal myocardial resection at Guangdong Provincial People′s Hospital from May 2021 to September 2022 were prospectively included. Age and gender matched healthy volunteers (control group) were included during the same period. Both the control group and HOCM patients underwent CMR examination (including cine sequence and 4D Flow sequence) before and 6 months after surgery. CMR 4D flow technology was used to evaluate changes in AAo preoperative and postoperative blood flow patterns (eddy currents, spiral flow), maximum energy loss (EL max), and average energy loss (EL avg). HOCM patients underwent laboratory tests, including N-terminal pro-brain natriuretic peptide (N-pro BNP) and high-sensitivity troponin T (hsTnT). At the same time, the correlation between postoperative energy loss in HOCM patients and the degree of improvement in laboratory biomarkers was explored. Results:A total of 15 HOCM patients and 15 healthy volunteers were included. (1) In terms of blood flow patterns, the preoperative spiral flow degree of HOCM patients was significantly higher than that of the control group ( P=0.001), but the postoperative difference was not statistically significant ( P=0.059). The degree of eddy currents in HOCM patients before and after surgery was higher than that in the control group (all P<0.05). (2) In terms of energy loss, the preoperative EL max [21.17(14.30-28.10)mW vs 10.17(7.66-13.07)mW, P<0.001] and EL avg [4.87(3.46-5.77)mW vs 2.27(2.19-2.27)mW, P=0.023] of HOCM patients were higher than those of the control group, but there was no statistically significant difference between the postoperative and control groups (all P>0.05). Compared with preoperative, the postoperative EL max [12.33(8.70-17.41)mW] and EL avg [3.10(2.25-4.40)mW] of AAo in HOCM patients were significantly reduced (mean P=0.001). (3) Correlation analysis showed that there was a positive correlation ( r=0.587, P=0.021) between the EL max of AAo and the degree of improvement in hsTNT after interventricular septum myocardial resection, but no significant correlation ( r=0.229, P=0.413) with the degree of improvement in NT-pro BNP. Conclusions:The degree of postoperative AAo blood flow disorder in HOCM patients is reduced, and EL max and EL avg are significantly reduced. The EL max of postoperative AAo is positively correlated with the degree of improvement in hsTNT, suggesting that EL max may be applicable for prognostic evaluation of patients.

ObjectiveTo discuss the diagnostic methods of global developmental delay caused by 10q24.3 heterozygous loss. MethodsA retrospective analysis was conducted on the clinical data of one child with global developmental delay， and the results of low depth whole-genome copy number variation sequencing （CNVseq） and family whole exome sequencing （WES） of the child and his parents. ResultsThe patient was a 10-month-old male with developmental retardation in four areas， with some special features （ocular hypertelorism， strabismus， flat nose bridge， protruding forehead， cleft palate， high palatal arch， etc.） and hypotonia of limbs. The CNVseq and WES test showed that the patient had new 10q24.3 heterozygosis loss. Because this region contains the gene SUFU associated with basal cell nevus syndrome and the gene CNNM2 associated with hypomagnesemia， seizures， and mental retardation， and the gene TRIM8 associated of Focal segmental glomerulosclerosis with neurodevelopmental syndrome， we speculated that the cause of the disease in the child was highly related to the heterozygosity deletion of SUFU gene and CNNM2 gene and TRIM8 gene. ConclusionGenetic testing should be improved as soon as possible for children with global developmental delay and special facial manifestations， so as to make clear diagnosis and to judge prognosis.

Objective To explore the value of prophylactic anticoagulation in the 28-day prognosis of patients with severe COVID-19.Methods The clinical data of COVID-19 patients admitted to Guangdong Provincial People's Hospital from December 2022 to January 2023 were collected,including age,gender,past medical history,routine blood test,liver and renal function,procalcitonin,coagulation function,Padua prediction score,antiviral therapy,hormonotherapy,immunotherapy and anticoagulation therapy.The patients were divided into an anticoagula-tion group and a non-anticoagulation group.The differences in various indicators were compared between the two groups.Cox regression was performed to assess the independent risk factors for 28-day mortality and the anticoagula-tion efficacy between the subgroups.Results Among 158 patients,128 received anticoagulation;There were significant differences between the two groups in case number of hypertension and critical condition,lymphocyte count,prothrombin time,D-dimer,and case number of immunotherapy.COX logistic regression showed that antico-agulation(HR = 2.25,95%CI:1.01～5.01,P = 0.048)was an independent risk factor for all-cause mortality of COVID-19 patients within 28 days.Subgroup analysis showed that anticoagulation therapy led to an increase in the 28-day mortality as level of procalcitonin of≥0.5 pg/mL(HR = 2.72,95%CI:1.05～7.04)or D-dimer of<2 000 ng/mL(HR = 9.16,95%CI:1.63～51.48).Conclusions Prophylactic anticoagulation did not reduce all-cause mortality of COVID-19 within 28 days.

Triptolide is a key active component of the widely used traditional Chinese herb medicine Tripterygium wilfordii Hook.F.Although triptolide exerts multiple biological activities and shows promising efficacy in treating inflammatory-related diseases,its well-known safety issues,especially reproductive toxicity has aroused concerns.However,a comprehensive dissection of triptolide-associated testicular toxicity at single cell resolution is still lacking.Here,we observed testicular toxicity after 14 days of triptolide exposure,and then constructed a single-cell transcriptome map of 59,127 cells in mouse testes upon triptolide-treatment.We identified triptolide-associated shared and cell-type specific differentially expressed genes,enriched pathways,and ligand-receptor pairs in different cell types of mouse testes.In addition to the loss of germ cells,our results revealed increased macrophages and the inflammatory response in triptolide-treated mouse testes,suggesting a critical role of inflammation in triptolide-induced testicular injury.We also found increased reactive oxygen species(ROS)signaling and down-regulated pathways associated with spermatid development in somatic cells,especially Leydig and Sertoli cells,in triptolide-treated mice,indicating that dysregulation of these signaling pathways may contribute to triptolide-induced testicular toxicity.Overall,our high-resolution single-cell landscape offers comprehensive information regarding triptolide-associated gene expression profiles in major cell types of mouse testes at single cell resolution,providing an invaluable resource for understanding the underlying mechanism of triptolide-associated testicular injury and additional discoveries of therapeutic targets of triptolide-induced male reproductive toxicity.