ABSTRACT
Pulmonary fibrosis (PF) is the pathological structure of incurable fibroproliferative lung diseases that are attributed to the repeated lung injury-caused failure of lung alveolar regeneration (LAR). Here, we report that repetitive lung damage results in a progressive accumulation of the transcriptional repressor SLUG in alveolar epithelial type II cells (AEC2s). The abnormal increased SLUG inhibits AEC2s from self-renewal and differentiation into alveolar epithelial type I cells (AEC1s). We found that the elevated SLUG represses the expression of the phosphate transporter SLC34A2 in AEC2s, which reduces intracellular phosphate and represses the phosphorylation of JNK and P38 MAPK, two critical kinases supporting LAR, leading to LAR failure. TRIB3, a stress sensor, interacts with the E3 ligase MDM2 to suppress SLUG degradation in AEC2s by impeding MDM2-catalyzed SLUG ubiquitination. Targeting SLUG degradation by disturbing the TRIB3/MDM2 interaction using a new synthetic staple peptide restores LAR capacity and exhibits potent therapeutic efficacy against experimental PF. Our study reveals a mechanism of the TRIB3-MDM2-SLUG-SLC34A2 axis causing the LAR failure in PF, which confers a potential strategy for treating patients with fibroproliferative lung diseases.
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Objective:To evaluate the diagnostic value of the 18F-prostate specific membrane antigen (PSMA)-1007 PET/CT in seminal vesicle invasion (SVI) of prostate cancer. Methods:Clinical and pathological materials of 88 patients (age: 51-84 years) who underwent radical prostatectomy (RP) between May 2019 and December 2021 in the First Affiliated Hospital of Xi′an Jiaotong University were analyzed retrospectively. All patients underwent 18F-PSMA-1007 PET/CT examination for primary staging before surgery. The diagnostic efficiency of 18F-PSMA-1007 PET/CT in SVI was obtained using postoperative pathological results as the " gold standard" and ROC curve was drawn. Furthermore, univariate and multivariate logistic regression analyses were used to screen the influencing factors for 18F-PSMA-1007 PET/CT prediction of SVI. Results:The accuracy, sensitivity, specificity, positive predictive value and negative predictive value of 18F-PSMA-1007 PET/CT in diagnosing SVI were 79.55%(70/88), 72.73%(16/22), 81.82%(54/66), 57.14%(16/28) and 90.00%(54/60), respectively. The ROC AUC was 0.77. Results of univariate logistic regression showed that total prostate specific antigen (tPSA), primary SUV max, Gleason score, International Society of Urological Pathology (ISUP) grade group were associated with 18F-PSMA-1007 PET/CT prediction of SVI. Results of multivariate logistic regression showed that Gleason score (odds ratio ( OR)=2.04, 95% CI: 1.19-3.50, P=0.009) was a predictor of SVI in prostate cancer. Conclusion:18F-PSMA-1007 PET/CT has certain diagnostic value in SVI of prostate cancer, and combining with Gleason score can improve the diagnostic efficiency.
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Objective:To investigate the risk factors of cement vascular leakage after vertebral augmentation for osteoporotic vertebral compression fracture (OVCF).Methods:A case-control study was conducted to analyze the clinical data of 217 patients with OVCF undergone vertebral augmentation [percutaneous vertebroplasty (PVP) or percutaneous kyphoplasty (PKP)] in First and Second Affiliated Hospital of Kunming Medical University from October 2019 to October 2020. There were 79 males and 138 females, at the age range of 58-88 years [(73.1±6.9)years]. According to the occurrence of bone cement vascular leakage, the patients were divided into vascular leakage group ( n=39) and vascular leakage free group ( n=178). The gender, age, bone mineral density, time from injury to operation, anatomical position of injured vertebrae, degree of vertebral compression, integrity of posterior wall, intravertebral fissure sign, vertebrobasilar venous foramen, surgical approach, surgical method, cement injection period, cement injection speed, cement injection volume and cement injection area were recorded. Univariate analysis was used to detect the correlation of those indices with cement vascular leakage after vertebral augmentation. Multivariate Logistic regression analysis was used to identify the independent risk factors for cement vascular leakage after vertebral augmentation. Results:Univariate analysis showed that there was a correlation of cement vascular leakage after vertebral augmentation with time from injury to operation, degree of vertebral compression, integrity of posterior wall, intravertebral fissure sign, vertebrobasilar venous foramen, surgical method, cement injection period, cement injection speed, cement injection volume and cement injection area (all P<0.05), apart from gender, age, bone mineral density, anatomical position of injured vertebrae or surgical approach (all P>0.05). Multivariate Logistic regression analysis showed intravertebral fissure sign ( OR=7.00, 95% CI 1.57-31.30, P<0.05), vertebrobasilar venous foramen ( OR=7.52, 95% CI 1.94-29.16, P<0.01), PVP ( OR=10.98, 95% CI 2.51-47.94, P<0.01), injection of cement in thinning period ( OR=5.91, 95% CI 1.45-24.15, P<0.05), injection of large volume of cement ( OR=3.60, 95% CI 1.70-7.65, P<0.01) and marginal injection of cement ( OR=24.80, 95% CI 5.28-116.37, P<0.01) were significantly associated with cement vascular leakage after vertebral augmentation for OVCF. Conclusion:Intravertebral fissure sign, vertebrobasilar venous foramen, PVP, injection of cement in thinning period, injection of large volume of cement and marginal injection of cement are independent risk factors for cement vascular leakage after vertebral augmentation for OVCF.
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Objective:To investigate the effect of teriparatide on residual back pain (RBP) after percutaneous kyphoplasty (PKP) for osteoporotic vertebral compression fracture (OVCF).Methods:A retrospective cohort study was used to analyze the clinical data of 90 OVCF patients sustaining RBP after PKP admitted to Second Affiliated Hospital of Kunming Medical University from September 2015 to March 2019, including 18 males and 72 females, at age of 57-85 years［(68.0±5.9) years］. Teriparatide treatment was applied regularly in 32 patients (teriparatide group) and antiosteoporosis drug was administered routinely in 58 patients (routine treatment group). Visual analogue scale (VAS) and Oswestry disability index (ODI) were compared between the two groups before operation, at 24 hours, 1 month, 3 months, 6 months and 12 months after operation. Anterior vertebral body height (ABH), middle vertebral body height (MBH), kyphosis angle (KA), maintenance rate of anterior vertebral body height (MRABH), maintenance rate of middle vertebral body height (MRMBH) and difference of kyphosis angle (DKA) were measured at 24 hours and 12 months after operation to evaluate the maintenance of vertebral height and incidence of vertebral refracture. Levels of type I collagen carboxy-terminal peptide (β-CTX) and serum N-terminal osteocalcin (N-MID) were measured before operation and at 12 months after operation to evaluate the improvement of bone metabolism. The adverse reactions of teriparatide group were observed.Results:All patients were followed up for 12-36 months［(14.3±0.6)months］. VAS and ODI were decreased gradually with time in both groups (all P<0.01). There were no significant differences in VAS between the two groups before operation and at 24 hours after operation (all P>0.05). Teriparatide group showed VAS of (4.4±0.6)points, (3.2±0.5)points, (2.0±0.5)points, (1.1±0.1)points at 1, 3, 6 and 12 months after operation, significantly lower than those in routine treatment group［(4.9±0.6)points, (4.0±0.6)points, (3.2±0.7)points, (2.7±0.1)points, respectively］(all P<0.01). Teriparatide group showed ODI of 26.5±1.3 and 20.6±1.2 at 6 months and 12 months after operation, significantly lower than those in routine treatment group (28.2±1.6, 23.6±1.6) (all P<0.01). There were no significant differences in ODI between the two groups at other time points (all P>0.05). Both groups presented significantly lowered levels of ABH and MBH at 12 months after operation as compared with those at 24 hours after operation (all P<0.01). There were no significant differences in ABH or MBH between the two groups at 24 hours after operation (all P>0.05). ABH, MBH, MRABH and MRMBH in teriparatide group were (1.9±0.2)cm, (1.7±0.2)cm, 0.91±0.02 and 0.92±0.02 at 12 months after operation, significantly higher than those in routine treatment group［(1.7±0.2)cm, (1.6±0.2)cm, 0.86±0.02 and 0.87±0.02］(all P<0.01). KA in both groups showed significant increase at 12 months after operation as compared with that at 24 hours after operation (all P<0.01). There was no significant difference in KA between the two groups at 24 hours after operation ( P>0.05). KA in teriparatide group was (7.3±0.7)° at 12 months after operation, significantly lower than (9.5±0.5)° in routine treatment group ( P<0.01). DKA in teriparatide group was (5.3±1.3)° at 12 months after operation, significantly lower than (6.6±1.4)° in routine treatment group ( P<0.01). Incidence of vertebral refracture in teriparatide group was 7% (2/32), significantly lower than 35% (15/58) in routine treatment group ( P<0.05). Level of β-CTX was not significantly different between and within the two groups before operation and at 12 months after operation (all P>0.05). There was no significant difference in N-MID between the two groups before operation ( P>0.05). After treatment for 12 months, level of N-MID in teriparatide group was significantly increased［19.5 (17.6, 20.9)pg/ml］as compared with that before operation［18.2 (14.6, 21.0)pg/ml］( P<0.01), and was significantly higher than that in routine treatment group［17.6 (15.3, 19.9)pg/ml］( P<0.01). Routine treatment group showed no significant difference in level of N-MID before operation and at 12 months after operation ( P>0.05). Two patients in teriparatide group had orthostatic hypotension after treatment. Conclusion:For OVCF patients with RBP after PKP, teriparatide can effectively alleviate pain, improve motor dysfunction, maintain the height of bone cement vertebral body, reduce incidence of vertebral refracture and enhance the activity of osteoblasts, with less adverse reactions.
ABSTRACT
The cell cycle inhibitor P21 has been implicated in cell senescence and plays an important role in the injury-repair process following lung injury. Pulmonary fibrosis (PF) is a fibrotic lung disorder characterized by cell senescence in lung alveolar epithelial cells. In this study, we report that P21 expression was increased in alveolar epithelial type 2 cells (AEC2s) in a time-dependent manner following multiple bleomycin-induced PF. Repeated injury of AEC2s resulted in telomere shortening and triggered P21-dependent cell senescence. AEC2s with elevated expression of P21 lost their self-renewal and differentiation abilities. In particular, elevated P21 not only induced cell cycle arrest in AEC2s but also bound to P300 and β-catenin and inhibited AEC2 differentiation by disturbing the P300-β-catenin interaction. Meanwhile, senescent AEC2s triggered myofibroblast activation by releasing profibrotic cytokines. Knockdown of P21 restored AEC2-mediated lung alveolar regeneration in mice with chronic PF. The results of our study reveal a mechanism of P21-mediated lung regeneration failure during PF development, which suggests a potential strategy for the treatment of fibrotic lung diseases.
ABSTRACT
Objective:To explore the risk factors of adjacent segment diseases (ASDis) after lumbar fusion, summarize the prevention strategies and provide reference for clinical treatment.Methods:All of 258 patients who underwent lumbar interbody fusion from March 2014 to March 2019 were retrospectively analyzed, including 95 males and 163 females, the age of whom was 61.8±8.4 years (range, 39-77 years). The patients were divided into ASDis group and non-ASDis group according to whether ASDis occurred at the follow-up of 24 months after operation. The patient's individual factors [gender, age, body mass index (BMI), main diagnosis, preoperative paraspinal muscle fatty degree, etc.] and surgical factors (operation type, fixed segment, fusion segment, etc.), sagittal parameters [lumbar lordosis (LL), pelvic incidence (PI), pelvic tilt (PT), sacral slope (SS), PI-LL] were recorded. After univariate analysis of potential risk factors, the factors with P<0.05 were substituted into logistic regression model for multivariate analysis to determine the risk factors of ASDis after lumbar fusion. Results:ASDis occurred in 24 patients after lumbar fusion, with an incidence of 9.3% (24/258); univariate analysis showed that age ≥ 60 years old, complicated with osteoporosis, preoperative fatty degree of paraspinal muscle (GCS grade≥3), PLIF operation, suspension fixation, total laminectomy and multi-segment fusion (≥ 3 segments) were the potential risk factors for ASDis after operation (P<0.05); Gender, education level, partner status, type of work, BMI, obesity (BMI≥24 kg/m 2) , smoking, use of bisphosphonates, concomitant lumbar spinal stenosis, lumbar lordosis angle, pelvic incidence angle, pelvic tilt angle, sacral slope angle, and PI-LL had no significant correlation with ASDis. Logistic regression analysis showed that age ≥ 60 years ( OR=5.63, 95% CI: 1.56, 20.29, P=0.008), preoperative paravertebral muscle fatty GCS ≥ 3 ( OR=4.82, 95% CI: 1.36, 17.13, P=0.015), combined with osteoporosis ( OR=14.04, 95% CI: 2.53, 77.79, P=0.002), PLIF ( OR=9.69, 95% CI: 1.91, 49.03, P=0.001), and multi-segment fixation ( OR=9.36, 95% CI: 1.77, 49.41, P=0.008) were the risk factors for ASDis after lumbar fusion; Incomplete laminectomy ( OR=0.09, 95% CI: 0.02, 0.37, P=0.001) and suspension fixation ( OR=0.16, 95% CI: 0.02, 0.94, P=0.042) were the protective factors of ASDis after lumbar fusion. Conclusion:The patients with age ≥ 60 years old, osteoporosis and preoperative paraspinal muscle fatty degree ≥ 3 grade GCS should be more careful in choosing the surgical methods, and try to choose transforaminal interbody fusion, posterolateral fusion, short segment fusion, decompression with preservation of vertebral lamina, suspension fixation and other surgical methods to reduce the incidence of postoperative ASDis.