Glioma is difficult to treat due to the unique tumor microenvironment and blood-brain barrier. (13aS)-3-Hydroxyl-6,7-dimethoxyphenanthro[9,10-b] indolizidine (PF403), a phenanthroindolizidine alkaloid, has been identified as a promising therapeutic agent for the treatment of glioma. However, the anti-glioma mechanism of PF403 in vivo has not been conclusively verified and must be further elucidated. Hence, a strategy without chemical modification was applied to identify the target of PF403. In this study, we identified nicotinamide phosphoribosyl transferase (NAMPT) as the target of PF403 by using thermal proteome profiling (TPP). Moreover, microscale thermophoresis (MST), surface plasmon resonance (SPR), and isothermal titration calorimetry (ITC) experiments confirmed that NAMPT exhibits good affinity for PF403. Direct and indirect enzyme activity assays revealed that PF403 inhibited the catalytic activity of NAMPT, leading to a decrease in the concentration of nicotinamide adenine dinucleotide (NAD⁺) in U87 cells. X-ray diffraction and amino acid spot mutation experiments revealed that PF403 primarily relies on the formation of pi-pi interactions with residue Tyr188 to maintain binding with NAMPT (PDB code 8Y55). After NAMPT was knocked down with lentivirus, PF403 lost or partially lost its antitumor activity at the cellular and animal levels. These findings suggest that PF403 exerts antitumor activity by directly targeting NAMPT.

BACKGROUND:Achilles tendon adhesion after Achilles tendon injury can lead to decreased biomechanical properties,weakened healing ability,and ultrastructural changes of Achilles tendon,which further affects patients'daily life and work ability.Therefore,how to effectively deal with and prevent Achilles tendon adhesion has become a hot and difficult problem in clinical treatment. OBJECTIVE:To analyze the effects of biological amniotic membranes on postoperative Achilles tendon adhesion,biomechanics,and ultrastructural changes in rats with Achilles tendon rupture. METHODS:Sixty 6-week-old SD rats were selected to establish bilateral Achilles tendon rupture models and divided into two groups(n=30 per group)by the random number table method.In the model group,the severed end of the tendon was sutured directly.In the amniotic membrane group,the biological amniotic membrane was wrapped around the broken anastomosis and fixed by a suture.The adhesion,biomechanics,morphology,and structure of the Achilles tendon and the expression of p38 and ERK1/2 protein were evaluated 1,2,and 4 weeks after surgery. RESULTS AND CONCLUSION:(1)1 week after operation,the Achilles tendon and peritendinous tissues of the two groups were mildly edema,and the adhesion of the Achilles tendon tissues in the model group was more obvious.2 weeks after the intervention,the Achilles tendon and peritendinous tissues of the model group still had edema,and the adhesion degree between the Achilles tendon and the surrounding tissues was heavier than that of the amniotic membrane group.4 weeks after operation,there was no edema around the Achilles tendon in both groups,and the healing was well.The adhesion degree of the Achilles tendon in the amniotic membrane group was less than that in the model group.The maximum tension of Achilles tendons in the amniotic membrane group was higher than that in the model group at 2 and 4 weeks after operation(P<0.001).(2)Hematoxylin-eosin staining and transmission electron microscopy revealed that 1 week after operation,the tendon structure of rats of the two groups was disordered and the collagen fibers were sparsely arranged,in which the model group demonstrated obvious inflammatory reaction and adhesion to the Achilles tendon.Two weeks after operation,the model group still demonstrated obvious inflammatory response,adhesion of Achilles tendon,and irregular ordering of collagen fibers.The amniotic membrane group exhibited an orderly arrangement of collagen fibers and expansion of the endoplasmic reticulum of fibroblasts.At 4 weeks after operation,the collagen fibers of the Achilles tendon in the model group were thickened and disordered,and the rough endoplasmic reticulum was less in the fibroblasts,while the collagen fibers in the amniotic membrane group were ordered and thin,and the fibroblasts contained a large number of rough endoplasmic reticulum.(3)Four weeks after operation,western blot assay exhibited that the expressions of p38 and ERK1/2 protein in the Achilles tendon tissue of rats in the amniotic membrane group were lower than those in the model group(P<0.05).(4)The results confirm that the biologic amniotic membrane can promote the healing and inhibit the adhesion of Achilles tendon after the operation of the ruptured Achilles tendon,which may be associated with the regulation of the MAPK/ERK signaling pathway.

Objective To investigate the changes and clinical significance of plasminogen activator inhibi-tor-1(PAI-1),transforming growth factor-β(TGF-β),vascular endothelial growth factor(VEGF),and inter-leukin-6(IL-6)in patients with tuberculous pleurisy and pleural fibrosis.Methods A total of 103 patients with tuberculous pleurisy and pleural fibrosis who were treated in a hospital from July 2020 to July 2023 were selected as the research subjects.After 2 weeks of treatment,they were divided into a significant effect group and a non-significant effect group based on the therapeutic efficacy of glucocorticoid treatment.The levels of PAI-1,TGF-β,VEGF,and IL-6 in serum and pleural effusion were compared before treatment,after 1 and 2 weeks of treatment.The correlation between the levels of PAI-1,TGF-β,VEGF,and IL-6 in serum and pleural effusion and the therapeutic efficacy was analyzed by Spearman correlation analysis.Pearson correlation analy-sis was used to analyze the correlation between the levels of PAI-1,TGF-β,VEGF,and IL-6 in serum and pleu-ral effusion and the levels of these indicators in pleural effusion after 2 weeks of treatment.A receiver operat-ing characteristic curve was drawn to analyze the predictive value of the levels of PAI-1,TGF-β,VEGF,and IL-6 in serum and pleural effusion for the efficacy of tuberculous pleurisy and pleural fibrosis patients after 1 and 2 weeks of treatment.Results The levels of PAI-1,TGF-β,VEGF,and IL-6 in serum and pleural effusion after 1 and 2 weeks of treatment in both groups were lower than those before treatment,and the levels of PAI-1,TGF-β,VEGF,and IL-6 in serum and pleural effusion after 1 and 2 weeks of treatment in the significant effect group were lower than those in the non-significant effect group,with statistically significant differences(P＜0.05).The levels of PAI-1,TGF-β,VEGF,and IL-6 in serum and pleural effusion after 1 and 2 weeks of treatment were negatively correlated with the efficacy(P＜0.05).The levels of PAI-1,TGF-β,VEGF,and IL-6 in serum and pleural effusion after 2 weeks of treatment were positively correlated(r=0.761,0.783,0.812,0.741,all P＜0.05).The area under the curve(AUC)of combined detection of serum and pleural effusion in-dicators after 1 and 2 weeks of treatment was greater than the AUC of individual indicators(P＜0.05).Con-clusion The levels of PAI-1,TGF-β,VEGF,and IL-6 in serum and pleural effusion of patients with tubercu-lous pleurisy and pleural fibrosis are related to the efficacy of treatment.The combined detection of PAI-1,TGF-β,VEGF,and IL-6 in serum and pleural effusion has good predictive value and can provide reference for clinical intervention.

Dynamic changes in gut dysbiosis and metabolomic dysregulation are associated with immune-complex glomerulonephritis(ICGN).However,an in-depth study on this topic is currently lacking.Herein,we report an ICGN model to address this gap.ICGN was induced via the intravenous injection of cationized bovine serum albumin(c-BSA)into Sprague-Dawley(SD)rats for two weeks,after which mycophenolate mofetil(MMF)and losartan were administered orally.Two and six weeks after ICGN establishment,fecal samples were collected and 16S ribosomal DNA(rDNA)sequencing and untargeted metabolomic were conducted.Fecal microbiota transplantation(FMT)was conducted to determine whether gut normali-zation caused by MMF and losartan contributed to their renal protective effects.A gradual decline in microbial diversity and richness was accompanied by a loss of renal function.Approximately 18 genera were found to have significantly different relative abundances between the early and later stages,and Marvinbryantia and Allobaculum were markedly upregulated in both stages.Untargeted metabolomics indicated that the tryptophan metabolism was enhanced in ICGN,characterized by the overproduction of indole and kynurenic acid,while the serotonin pathway was reduced.Administration of losartan and MMF ameliorated microbial dysbiosis and reduced the accumulation of indoxyl conjugates in feces.FMT using feces from animals administered MMF and losartan improved gut dysbiosis by decreasing the Firmicutes/Bacteroidetes(F/B)ratio but did not improve renal function.These findings indicate that ICGN induces serous gut dysbiosis,wherein an altered tryptophan metabolism may contribute to its pro-gression.MMF and losartan significantly reversed the gut microbial and metabolomic dysbiosis,which partially contributed to their renoprotective effects.

Objective To construct and validate a risk prediction model for enteral nutrition feeding intolerance (FI) in patients with severe cerebral hemorrhage based on machine learning algorithms. Methods The clinical data of 485 patients with cerebral hemorrhage admitted to the neurological intensive care unit of Northern Jiangsu People's Hospital Affiliated to Yangzhou University from January 2020 to December 2022 were retrospectively analyzed. The patients were randomly divided into training set (n=339) and validation set (n=146) in a 7 to 3 ratio. Five machine learning algorithms were used to construct FI risk prediction models. The receiver operating characteristic (ROC) curve was plotted, and the model with the best predictive performance was selected based on the area under the curve (AUC). A nomogram model was constructed based on the optimal model. The calibration curve and decision curve analysis (DCA) were used to evaluate the calibration and clinical net benefit of the nomogram model. Results The incidence of enteral nutrition FI in patients with severe cerebral hemorrhage was 38.4%(186/485). Among the five machine learning algorithm models, the Logistic regression model had the best predictive performance(AUC=0.88). The analysis results of the Logistic regression model showed that the use of diuretics, mechanical ventilation, Glasgow Coma Scale score ≤5, vasoactive drugs, and albumin level<35 g/L were risk factors for enteral nutrition FI in patients with severe cerebral hemorrhage. A nomogram model was further constructed based on these five risk factors. The calibration curve analysis showed that the calibration curve fitted well with the ideal curve, indicating a high calibration degree of the nomogram model. The DCA results showed that when the threshold probability was 5% to 73%, the application of the nomogram model for screening could clinically benefit patients. Conclusion The construction of a nomogram model for predicting the risk of enteral nutrition FI in patients with severe cerebral hemorrhage based on machine learning methods can help to early screen high-risk patients for enteral nutrition FI and timely formulate preventive measures, thereby reducing the incidence of enteral nutrition FI in patients with severe cerebral hemorrhage.

This article reports a case of Prader-Willi syndrome(PWS) diagnosed in adulthood. PWS is a rare genetic disease with most of the reported cases being diagnosed in infancy and childhood, and adulthood case is rarely reported. The patient had insidious symptoms in infancy and was diagnosed as PWS using genetic test in adulthood due to diabetes and menstrual disorders. This article focuses on the patient′s clinical manifestations in adulthood, and reviews relevant literature to improve the understanding of the disease.

Objective:To explore the team construction and treatment strategy of the Diabetic Foot-Multidisciplinary Team.Methods:The clinical data of 19 patients with severe ischemic diabetic foot treated by our Diabetic Foot-Multidisciplinary Team Center from Apr 2021 to Mar 2022 were collected, and the overall amputation rate, above-ankle major amputation rate, minor amputation rate and mortality, Diabetic Foot-Multidisciplinary Team consultation discipline participation rate and treatment participation degree were retrospectively analyzed.Results:Nineteen patients (15 males and 4 females) were enrolled, aged 26 to 94 (68.6±14.2). All were with severe ischemic diabetic foot ulcer:Rutherford grade 5 or up and dysfunction in 2 or more organs. Complications included arteriosclerosis obliterans of the lower extremities in 18 cases, heart diseases in 18, hypertension in 15, and renal insufficiencies in 10. The overall amputation rate was 36.8%, major amputation rate in 21.1%, minor amputation rate in 15.8%, and mortality rate was 15.8%. A total of 16 disciplines participated in Diabetic Foot-Multidisciplinary Team; the main participating disciplines were vascular surgery (19 times), endocrinology (12 times), and cardiology (11 times). The main treatment disciplines were vascular surgery (14 times), plastic surgery (3 times), and cardiology (2 times).Conclusion:For the diagnosis and treatment of diabetic foot, it is necessary to set up a multidisciplinary team as early as possible to control the causes of diabetic foot ulcer, prevent the recurrence of diabetic foot ulcer, reduce the mortality and amputation rate, and improve the quality of life of patients.

OBJECTIVE: To explore the factors for the failure of non-invasive prenatal testing (NIPT) through multifactorial unconditional Logistic regression analysis. METHODS: A total of 3 410 pregnant women who had visited Dalian Women and Children Medical Group from July 2019 to June 2020 were selected as the study subjects and divided into first success NIPT group (n = 3 350) and first failed group (n = 60). Clinical data including age, weight, body mass index (BMI), gestational week, type of pregnancy (singleton/twin), history of delivery, heparin treatment, and conception method [natural conception/assisted reproductive technology (ART)] were collected. Independent sample t-test and Chi-square test were carried out for comparing the two groups, and multi-factorial unconditional Logistic regression analysis was carried out to explore the factors for the failure of NIPT, and receiver operating characteristic curve (ROC) analysis was used to evaluate the diagnosis and predictive effects. RESULTS: Among the 3 410 pregnant women, 3 350 were assigned to the first success NIPT group, and 60 were assigned to the first failed group, and the first-time failure rate was 1.76% (60/3 410). No significant difference was found in age, weight, BMI and method of conception between the two groups (P > 0.05). Compared with first success group, first failed group had lower sampling gestational weeks, lower proportion of women with previous history of delivery, and higher proportion of twin pregnancies and heparin treatment (P < 0.05). Multi-factorial unconditional Logistic regression analysis indicated that sampling gestational week (OR = 0.931, 95%CI: 0.845 ~ 1.026, P < 0.001) and history of heparin use (OR = 8.771, 95%CI: 2.708 ~ 28.409, P < 0.001) are independent factors for first failed NIPT. One-way unconditional Logistic regression analysis for sampling gestational weeks indicated that the regression equation for NIPT screening failure was Logit (P) = -9.867 + 0.319 × sampling gestational week, with the area under the ROC curve being 0.742, a Jordan index of 0.427, and a cutoff value of 16.36 weeks. CONCLUSION Gestational week and heparin treatment are independent factors for the first failed NIPT. A regression equation has been established and determined the optimal sampling gestational week to be 16.36 weeks, which may provide a reference for the timing of NIPT screening.
Child ; Pregnancy ; Female ; Humans ; Logistic Models ; Prenatal Diagnosis/methods* ; Pregnancy, Twin ; Reproductive Techniques, Assisted

The Omicron family of SARS-CoV-2 variants are currently driving the COVID-19 pandemic. Here we analyzed the clinical laboratory test results of 9911 Omicron BA.2.2 sublineages-infected symptomatic patients without earlier infection histories during a SARS-CoV-2 outbreak in Shanghai in spring 2022. Compared to an earlier patient cohort infected by SARS-CoV-2 prototype strains in 2020, BA.2.2 infection led to distinct fluctuations of pathophysiological markers in the peripheral blood. In particular, severe/critical cases of COVID-19 post BA.2.2 infection were associated with less pro-inflammatory macrophage activation and stronger interferon alpha response in the bronchoalveolar microenvironment. Importantly, the abnormal biomarkers were significantly subdued in individuals who had been immunized by 2 or 3 doses of SARS-CoV-2 prototype-inactivated vaccines, supporting the estimation of an overall 96.02% of protection rate against severe/critical disease in the 4854 cases in our BA.2.2 patient cohort with traceable vaccination records. Furthermore, even though age was a critical risk factor of the severity of COVID-19 post BA.2.2 infection, vaccination-elicited protection against severe/critical COVID-19 reached 90.15% in patients aged ≽ 60 years old. Together, our study delineates the pathophysiological features of Omicron BA.2.2 sublineages and demonstrates significant protection conferred by prior prototype-based inactivated vaccines.
Humans ; Aged ; Middle Aged ; COVID-19/prevention & control* ; SARS-CoV-2 ; Pandemics/prevention & control* ; China/epidemiology* ; Disease Outbreaks/prevention & control* ; Vaccination

Objective:To explore the application value of non-invasive prenatal testing (NIPT) technology in twin pregnancy.Methods:A total of 339 twin pregnant women who underwent NIPT at Dalian Municipal Women and Children′s Medical Center(Group), Dalian Jinpu New District Maternity and Child Health Hospital, and Dalian Lvshunkou District People′s Hospital from July 1, 2019 to June 30, 2021 were continuously retrospectively included. The clinical characteristics and test results of pregnant women with high-risk and low-risk were analyzed.Results:Among 339 pregnant women, 336 were successfully tested, with a success rate of 99.12%(336/339); 6 pregnant women were at high risk of NIPT, with a positive screening rate of 1.77%(6/339), including 1 case of high risk of trisomy 13, 2 cases of high risk of trisomy 18, and 3 cases of high risk of Trisomy 21; the results of amniocentesis for 2 high-risk pregnant women were not abnormal.Conclusions:NIPT technology is non-invasive, safe and efficient, and is suitable for large-scale prenatal screening. However, the detection accuracy of pregnant women with twin pregnancy needs to be improved.