Background::Bladder cancer, characterized by a high potential of tumor recurrence, has high lifelong monitoring and treatment costs. To date, tumor cells with intrinsic softness have been identified to function as cancer stem cells in several cancer types. Nonetheless, the existence of soft tumor cells in bladder tumors remains elusive. Thus, our study aimed to develop a microbarrier microfluidic chip to efficiently isolate deformable tumor cells from distinct types of bladder cancer cells.Methods::The stiffness of bladder cancer cells was determined by atomic force microscopy (AFM). The modified microfluidic chip was utilized to separate soft cells, and the 3D Matrigel culture system was to maintain the softness of tumor cells. Expression patterns of integrin β8 (ITGB8), protein kinase B (AKT), and mammalian target of rapamycin (mTOR) were determined by Western blotting. Double immunostaining was conducted to examine the interaction between F-actin and tripartite motif containing 59 (TRIM59). The stem-cell-like characteristics of soft cells were explored by colony formation assay and in vivo studies upon xenografted tumor models. Results::Using our newly designed microfluidic approach, we identified a small fraction of soft tumor cells in bladder cancer cells. More importantly, the existence of soft tumor cells was confirmed in clinical human bladder cancer specimens, in which the number of soft tumor cells was associated with tumor relapse. Furthermore, we demonstrated that the biomechanical stimuli arising from 3D Matrigel activated the F-actin/ITGB8/TRIM59/AKT/mTOR/glycolysis pathways to enhance the softness and tumorigenic capacity of tumor cells. Simultaneously, we detected a remarkable up-regulation in ITGB8, TRIM59, and phospho-AKT in clinical bladder recurrent tumors compared with their non-recurrent counterparts.Conclusions::The ITGB8/TRIM59/AKT/mTOR/glycolysis axis plays a crucial role in modulating tumor softness and stemness. Meanwhile, the soft tumor cells become more sensitive to chemotherapy after stiffening, that offers new insights for hampering tumor progression and recurrence.

Objective:To systematically integrate qualitative studies on the experience of self-advocacy in cancer patients, so as to provide basis for formulating targeted intervention strategies and improving the level of self-advocacy in cancer patients.Methods:Qualitative studies on the self-advocacy experience of cancer patients were systematically searched from PubMed, Embase, Web of Science, Cochrane Library, China National Knowledge Infrastructure, Wanfang Database, VIP database, and China Biomedical Literature Service System, and the search period was from the establishment of the database to December 31, 2023. The quality of literature was evaluated using the qualitative research quality evaluation criteria of JBI Evidence-Based Health Care Center in Australia, and the results were integrated by aggregative meta-integration method.Results:A total of 12 literatures were included, and 51 research results were extracted, which were summarized into 12 categories, and four integrated results were obtained: different voices of self-advocacy rights, positive power of self-advocacy rights, obstacles to self-advocacy rights, and multi-dimensional demand for advocacy rights.Conclusions:Medical staff should adhere to the concept of "patient-centered", guide cancer patients to enhance their awareness of self-advocacy rights, attach importance to positive power, stimulate internal drive, create a good atmosphere of advocacy rights, improve patients′advocacy ability in multiple ways, and meet multi-dimensional needs.

OBJECTIVE: To investigate the clinical efficacy of unicompartmental knee arthroplasty (UKA) in the treatment of knee osteoarthritis in patients over 75 years old. METHODS: The clinical efficacy of primary fixed platform UKA in patients with osteoarthritis, was retrospectively analyzed from October 2014 to November 2020. Age, body mass index (BMI), range of motion (ROM), preoperative joint function score, the quality of life score and other preoperative indicators were measured by propensity score matching (PSM). The patients were divided into elderly group (≥75 years old) and control group (<75 years old). Oxford knee score(OKS), Western Ontario McMaster Universities osteoarthritis index(WOMAC), Short Form-12 including physical component summary (PCS), mental component summary(MCS), minimal clinically important difference(MCID ) and clinical complications were evaluated preoperatively and postoperatively. RESULTS: A total of 514 patients were analyzed, 428 patients fulfilled the inclusion criteria. A propensity-score matching study was conducted to eliminate confounding factors. After 1∶2 propensity match, there were 84 patients in elderly group (≥75 years), age ranged from 75 to 88 years old, with an average of (78.79±3.08) years old, and 168 patients in control group (<75 years), age ranged from 47 to 74 years old, with an average of (64.10±5.96)years old. The follow-up duration of two groups ranged from 12 to 84 months with an average of (29.35±16.52) months in elderly group, and 12 to 85 months with an average of (31.83±17.34) months in control group. There was only significant difference in age between the elderly and control groups preoperatively (P<0.01). Postoperatively, the elderly group showed significantly higher WOMAC (P<0.01) and lower SF-12 PCS scores (P<0.01) as compared to the control group. There was no significant difference between the elderly group and the control group in knee range of motion, OKS and the proportion of each scoring system reaching the minimum clinical difference value (P>0.05). In the aspect of preperative complications, the elderly group exhibited more surgical site complications and postoperative delirium compared to control group(P<0.05). The differences in other indicators including deep vein thrombosis, acute urinary retention, cardiovascular events, cerebrovascular events and radiolucent lines around prothesis were not statistically significant(P>0.05). CONCLUSION UKA in the treatment of elderly patients over 75 years old with knee osteoarthritis was safe and feasible, and could obtain satisfactory short-term efficacy.
Humans ; Aged ; Aged, 80 and over ; Middle Aged ; Osteoarthritis, Knee/surgery* ; Knee Prosthesis ; Retrospective Studies ; Propensity Score ; Quality of Life ; Knee Joint/surgery* ; Arthroplasty, Replacement, Knee/methods* ; Treatment Outcome

Deficiencies in the clearance of peripheral amyloid β (Aβ) play a crucial role in the progression of Alzheimer's disease (AD). Previous studies have shown that the ability of blood monocytes to phagocytose Aβ is decreased in AD. However, the exact mechanism of Aβ clearance dysfunction in AD monocytes remains unclear. In the present study, we found that blood monocytes in AD mice exhibited decreases in energy metabolism, which was accompanied by cellular senescence, a senescence-associated secretory phenotype, and dysfunctional phagocytosis of Aβ. Improving energy metabolism rejuvenated monocytes and enhanced their ability to phagocytose Aβ in vivo and in vitro. Moreover, enhancing blood monocyte Aβ phagocytosis by improving energy metabolism alleviated brain Aβ deposition and neuroinflammation and eventually improved cognitive function in AD mice. This study reveals a new mechanism of impaired Aβ phagocytosis in monocytes and provides evidence that restoring their energy metabolism may be a novel therapeutic strategy for AD.
Animals ; Mice ; Alzheimer Disease ; Amyloid beta-Peptides ; Monocytes ; Cognition ; Energy Metabolism ; Phagocytosis

Objective:To explore the differences of functional small airway and pulmonary vascular parameters in chronic obstructive pulmonary disease (COPD) of different imaging phenotypes.Methods:One hundred and thirty COPD patients underwent biphasic CT scanning in Shanghai Changzheng Hospital from August 2018 to August 2020 were analyzed retrospectively. The patients were classified into three phenotypes based on the presence of emphysema and bronchial wall thickening on CT images. Phenotype A: no emphysema or mild emphysema, with or without bronchial wall thickening; Phenotype E: obvious emphysema without bronchial wall thickening; phenotype M: significant emphysema and bronchial wall thickening were present. Parametric response map (PRM) and pulmonary vascular parameters were quantitatively measured at the whole lung level. PRM parameters included the volume of emphysema (PRMV Emphysema), the volume of functional small airway (PRMV fSAD), the volume of normal pulmonary parenchyma (PRMV Normal) and its volume percentage (%). Pulmonary vascular parameters included the number of vessels (N) and cross-sectional area vessels<5 mm 2 (N -CSA<5) at 6, 9, 12, 15, 18 21, 24 mm distance from the pleura. ANOVA or Kruskal-Wallis H tests were used to compare the differences for PRM and pulmonary vascular parameters among the three phenotypes, and LSD or Bonferroni tests were used for multiple comparisons. Results:There were significant differences among the three phenotypes for PRMV fSAD, PRMV Emphysema, PRMV fSAD%, PRMV Emphysema%, and PRMV Normal% at the whole lung level ( P<0.05). PRMV Emphysema, PRMV Emphysema%, PRMV Fsad, PRMV fSAD% of phenotype A were lower than those of phenotype E and M ( P<0.001), while there was no significant difference for PRMV Emphysema, PRMV Emphysema%, PRMV fSAD, PRMV fSAD% between phenotype E and phenotype M ( P>0.05). There were significant differences in N and N -CSA<5 that 6 mm distance from the pleura among the three groups( P<0.05). Among them, N and N -CSA<5 that 6 mm distance from pleura in phenotype M were significantly lower than those in phenotype A( P<0.001,0.002); No significant differences was found in N between phenotype M and phenotype E( P>0.05), while there was significant differences in N -CSA<5 between phenotype M and phenotype E( P=0.034). Conclusion:Biphasic quantitative CT analysis can reflect the heterogeneity of the functional small airways and pulmonary vascular abnormality in COPD with different phenotypes, and provide objective evidence for individualized diagnosis and treatment.

OBJECTIVE: To investigate the effect of celastrol on the proliferation and apoptosis of human multiple myeloma (MM) cell lines, reveal the relationship between IRAK4/ERK/p38 signaling pathway and celastrol regulating the proliferation and apoptosis of H929 and ARP-1 cells, and explore whether celastrol combined with bortezomib has synergistic effect. METHODS: CCK-8 method was used to detect the viability of MM cell lines H929 and ARP-1 treated by different concentrations of celastrol, bortezomib, and their combination, and the synergistic effect was determined by Kim's formula. The apoptosis rate of H929 cells and necrosis rate of ARP-1 were detected by Annexin V/PI method. The expression of key proteins and apoptosis proteins in IRAK4/ERK/p38 signaling pathway were detected by Western blot. RESULTS: Celastrol could significantly inhibit the proliferation of H929 and ARP-1 cells (r=0.9018, r=0.9244) and induce apoptosis in a time-dependent manner. Compared with the control group, celastrol could significantly up-regulate the expression of PARP and cleaved caspase-3 while down-regulate the expression of p-IRAK4, p-ERK, and p-p38 in H929 and ARP-1 cells. Celastrol and bortezomib alone inhibited the proliferation of H929 and ARP-1 cells. Compared with celastrol and bortezomib alone, their combination had lower cell survival rate and higher apoptosis rate (P<0.05). CONCLUSION Celastrol can inhibit the proliferation and promote the apoptosis of H929 and ARP-1 cells, which may be related to inhibiting the phosphorylation of IRAK4 and blocking the activation of IRAK4/ERK/p38 signaling pathway. Celastrol combined with bortezomib has synergistic effect, which can more effectively inhibit the proliferation and induce apoptosis of H929 and ARP-1 cells.
Apoptosis ; Bortezomib/pharmacology* ; Cell Line, Tumor ; Cell Proliferation ; Humans ; Interleukin-1 Receptor-Associated Kinases ; Multiple Myeloma ; Pentacyclic Triterpenes ; Signal Transduction

Due to the special physiological and pathological characteristics of gliomas, most therapeutic drugs are prevented from entering the brain. To improve the poor prognosis of existing therapies, researchers have been continuously developing non-invasive methods to overcome barriers to gliomas therapy. Although these strategies can be used clinically to overcome the blood‒brain barrier (BBB), the accurate delivery of drugs to the glioma lesions cannot be ensured. Nano-drug delivery systems (NDDS) have been widely used for precise drug delivery. In recent years, researchers have gathered their wisdom to overcome barriers, so many well-designed NDDS have performed prominently in preclinical studies. These meticulous designs mainly include cascade passing through BBB and targeting to glioma lesions, drug release in response to the glioma microenvironment, biomimetic delivery systems based on endogenous cells/extracellular vesicles/protein, and carriers created according to the active ingredients of traditional Chinese medicines. We reviewed these well-designed NDDS in detail. Furthermore, we discussed the current ongoing and completed clinical trials of NDDS for gliomas therapy, and analyzed the challenges and trends faced by clinical translation of these well-designed NDDS.

This study aimed to assess the role of prostate-specific antigen density (PSAD) and negative multiparametric magnetic resonance imaging (mpMRI) in predicting prostate cancer for biopsy-naïve men based on a large cohort of the Chinese population. From a prostate biopsy database between March 2017 and July 2021, we retrospectively identified 240 biopsy-naïve patients with negative prebiopsy mpMRI (Prostate Imaging Reporting and Data System version 2 [PI-RADS v2] score <3). Logistic regression analysis was performed to select the potential predictors for clinically significant prostate cancer (csPCa). Receiver operating characteristic (ROC) curve analysis and area under the ROC curve (AUC) were performed to assess the diagnostic accuracy. The negative predictive values of mpMRI in excluding any cancer and csPCa were 83.8% (201/240) and 90.8% (218/240), respectively. ROC curve analysis indicated that PSAD was the most promising predictor, with an AUC value of 0.786 (95% confidence interval [CI]: 0.699-0.874), and multiparametric logistic regression analysis confirmed that higher PSAD remained a significant marker for predicting csPCa (odds ratio [OR]: 10.99, 95% CI: 2.75-44.02, P < 0.001). Combining negative mpMRI and PSAD below 0.20 ng ml^-2 obviously increased the predictive value in excluding PCa (91.0%, 101/111) or csPCa (100.0%, 111/111). If a PSAD below 0.20 ng ml^-2 was set as the criterion to omit biopsy, nearly 46.3% of patients (463 per 1000) with negative mpMRI could safely avoid unnecessary biopsy, with approximately 4.2% of patients (42 per 1000) at risk of missed diagnosis of PCa and no patients with csPCa missed. A PI-RADS v2 score <3 and a PSAD <0.20 ng ml^-2 could be potential criteria for the Chinese population to omit prompt biopsy safely.
Male ; Humans ; Prostatic Neoplasms/pathology* ; Prostate-Specific Antigen ; Multiparametric Magnetic Resonance Imaging ; Magnetic Resonance Imaging/methods* ; Retrospective Studies ; Biopsy ; Image-Guided Biopsy/methods*

Tripterygium wilfordii is a valuable medicinal plant rich in biologically active diterpenoids, but there are few studies on the origins of these diterpenoids in its secondary metabolism. Here, we identified three regions containing tandemly duplicated diterpene synthase genes on chromosomes (Chr) 17 and 21 of T. wilfordii and obtained 11 diterpene synthases with different functions. We further revealed that these diterpene synthases underwent duplication and rearrangement at approximately 2.3-23.7 million years ago (MYA) by whole-genome triplication (WGT), transposon mediation, and tandem duplication, followed by functional divergence. We first demonstrated that four key amino acids in the sequences of TwCPS3, TwCPS5, and TwCPS6 were altered during evolution, leading to their functional divergence and the formation of diterpene secondary metabolites. Then, we demonstrated that the functional divergence of three TwKSLs was driven by mutations in two key amino acids. Finally, we discovered the mechanisms of evolution and pseudogenization of miltiradiene synthases in T. wilfordii and elucidated that the new function in TwMS1/2 from the terpene synthase (TPS)-b subfamily was caused by progressive changes in multiple amino acids after the WGT event. Our results provide key evidence for the formation of diverse diterpenoids during the evolution of secondary metabolites in T. wilfordii.

Objective:To explore the predictive value of random forest regression model for pulmonary function test.Methods:From August 2018 to December 2019, 615 subjects who underwent screening for three major chest diseases in Shanghai Changzheng Hospital were analyzed retrospectively. According to the ratio of forced expiratory volume in the first second to forced vital capacity (FEV 1/FVC) and the percentage of forced expiratory volume in the first second to the predicted value (FEV 1%), the subjects were divided into normal group, high risk group and chronic obstructive pulmonary disease (COPD) group. The CT quantitative parameter of small airway was parameter response mapping (PRM) parameters, including lung volume, the volume of functional small airways disease (PRMV fSAD), the volume of emphysema (PRMV Emph), the volume of normal lung tissue (PRMV Normal), the volume of uncategorized lung tissue (PRMV Uncategorized) and the percentage of the latter four volumes to the whole lung (%). ANOVA or Kruskal Wallis H was used to test the differences of basic clinical characteristics (age, sex, height, body mass), pulmonary function parameters and small airway CT quantitative parameters among the three groups; Spearman test was used to evaluate the correlation between PRM parameters and pulmonary function parameters. Finally, a random forest regression model based on PRM combined with four basic clinical characteristics was constructed to predict lung function. Results:There were significant differences in the parameters of whole lung PRM among the three groups ( P<0.001). Quantitative CT parameters PRMV Emph, PRMV Emph%, and PRMV Normal% showed a moderate correlation with FEV 1/FVC ( P<0.001). Whole lung volume, PRMV Normal,PRMV Uncategorized and PRMV Uncategorized% were strongly or moderately positively correlated with FVC ( P<0.001), other PRM parameters were weakly or very weakly correlated with pulmonary function parameters. Based on the above parameters, a random forest model for predicting FEV 1/FVC and a random forest model for predicting FEV 1% were established. The random forest model for predicting FEV 1/FVC predicted FEV 1/FVC and actual value was R 2=0.864 in the training set and R 2=0.749 in the validation set. The random forest model for predicting FEV 1% predicted FEV 1% and the actual value in the training set was R 2=0.888, and the validation set was R 2=0.792. The sensitivity, specificity and accuracy of predicting FEV 1% random forest model for the classification of normal group from high-risk group were 0.85(34/40), 0.90(65/72) and 0.88(99/112), respectively; and the sensitivity, specificity and accuracy of predicting FEV 1/FVC random forest model for differentiating non COPD group from COPD group were 0.89(8/9), 1.00 (112/112) and 0.99(120/121), respectively. While the accuracy of two models combination for subclassification of COPD [global initiative for chronic obstructive lung disease (GOLD) Ⅰ, GOLDⅡ and GOLD Ⅲ+Ⅳ] was only 0.44. Conclusions:Small airway CT quantitative parameter PRM can distinguish the normal population, high-risk and COPD population. The comprehensive regression prediction model combined with clinical characteristics based on PRM parameter show good performance differentiating normal group from high risk group, and differentiating non-COPD group from COPD group. Therefore, one-stop CT scan can evaluate the functional small airway and PFT simultaneously.