Development of a nomogram model for prediction of new adjacent vertebral compression fractures after vertebroplasty.

BACKGROUND: Vertebroplasty is the main minimally invasive operation for osteoporotic vertebral compression fracture (OVCF), which has the advantages of rapid pain relief and shorter recovery time. However, new adjacent vertebral compression fracture (AVCF) occurs frequently after vertebroplasty. The purpose of this study was to investigate the risk factors of AVCF and establish a clinical prediction model. METHODS: We retrospectively collected the clinical data of patients who underwent vertebroplasty in our hospital from June 2018 to December 2019. The patients were divided into a non-refracture group (289 cases) and a refracture group (43 cases) according to the occurrence of AVCF. The independent predictive factors for postoperative new AVCF were determined by univariate analysis, least absolute shrinkage and selection operator (LASSO) logistic regression, and multivariable logistic regression analysis. A nomogram clinical prediction model was established based on relevant risk factors, and the receiver operating characteristic curve (ROC), calibration curve, and decision curve analysis (DCA) were used to evaluate the prediction effect and clinical value of the model. After internal validation, patients who underwent vertebroplasty in our hospital from January 2020 to December 2020, including a non-refracture group (156 cases) and a refracture group (21 cases), were included as the validation cohort to evaluate the prediction model again. RESULTS: Three independent risk factors of low bone mass density (BMD), leakage of bone cement and "O" shaped distribution of bone cement were screened out by LASSO regression and logistic regression analysis. The area under the curve (AUC) of the model in the training cohort and the validation cohort was 0.848 (95%CI: 0.786-0.909) and 0.867 (95%CI: 0.796-0.939), respectively, showing good predictive ability. The calibration curves showed the correlation between prediction and actual status. The DCA showed that the prediction model was clinically useful within the whole threshold range. CONCLUSION: Low BMD, leakage of bone cement and "O" shaped distribution of bone cement are independent risk factors for AVCF after vertebroplasty. The nomogram prediction model has good predictive ability and clinical benefit.

Prevalence and risk factors for kidney disease among hospitalized PLWH in China.

BACKGROUND: Kidney disease is an important comorbidity in people living with HIV(PLWH), and is associated with poor outcomes. However, data on renal function of PLWH are limited in China so far. In this study we assessed the prevalence of kidney disease in patients either on antiretroviral therapy (ART) or not respectively in a single center in China and explored the possible risk factors associated. METHODS: In the cross-sectional study, we recruited hospitalized adult PLWH. Demographic characteristics, clinical information and laboratory variables were collected. Kidney disease was defined as estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2, and/or isolated hematuria, proteinuria, microalbuminuria. We calculated the prevalence of kidney disease and used logistic regression to assess its associated risk factors. RESULTS: A total of 501 adult PLWH were enrolled, 446 (89.0%) males and 55 (11.0%) females. The median age was 39 (IQR 30-50) years old. The prevalence of kidney disease was 19.0%, 22 (4.4%) patients with eGFR < 60 mL/min/1.73 m2, 53 (10.6%) patients with hematuria, 11 (2.2%) patients with proteinuria, and 40 (8.0%) patients with microalbuminuria. 297 (59.3%) patients were receiving ART. The patients on ART had a higher prevalence of renal disease than those had not been administrated with ART (22.6% vs. 13.7%, P = 0.013). On the multivariate logistic regression analysis among patients not on ART, lower haemoglobin (OR 0.994, 95%CI: 0.902-0.988, P = 0.013) were significantly associated with kidney disease. While among those on ART, older age (OR 1.034, 95%CI: 1.003-1.066, P = 0.032), lower haemoglobin (OR 0.968, 95%CI: 0.948-0.988, P = 0.002) and lower albumin (OR 0.912, 95%CI: 0.834-0.997, P = 0.044) were significantly associated with kidney disease. CONCLUSIONS: The prevalence of kidney disease among hospitalized PLWH in China is high, especially in patients on ART. A larger scale study on Chinese outpatient PLWH should be conducted, so as to precisely assess prevalence of kidney disease in general Chinese PLWH.

Spinal cord injury-activated C/EBPß-AEP axis mediates cognitive impairment through APP C586/Tau N368 fragments spreading.

Spinal cord injury (SCI) leads to mental abnormalities such as dementia and depression; however, the molecular mechanism of SCI-induced dementia remains a matter of debate. Asparagine endopeptidase (AEP) mediated dementia by enhancing amyloid plaque and Tau hyperphosphorylation, indicating that it played an important role in neurodegeneration. Here we revealed that SCI stimulated AEP activation in mice with T9 contusion injury. Activated-AEP cleaved APP and Tau, resulting in APP C586 and Tau N368 formations, and consequentially accelerated Aß deposit and Tau hyperphosphorylation, respectively. At 9 months following injury, mice demonstrated a severe deterioration in cognitive-behavioral function, which was corroborated by the presence of accumulated AD-specific pathologies. Surprisingly, activated AEP was found in the brains of mice with spinal cord injury. In contrast, AEP knockout reduced SCI-induced neuronal death and neuroinflammation, resulting in cognitive-behavioral restoration. Interestingly, compared to the full-length proteins, truncated Tau N368 and APP C586 were easier to bind to each other. These AEP-processed fragments can not only be induced to pre-formed fibrils, but also amplified their abilities of spreading and neurotoxicity in vitro. Furthermore, as a critical transcription factor of AEP, C/EBPß was activated in injured spinal cord. Elevated C/EBPß level, as well as microglia population and inflammatory cytokines were also noticed in the cortex and hippocampus of SCI mice. These neuroinflammation pathologies were close related to the amount of Tau N368 and APP C586 in brain. Moreover, administration with the AEP-specific inhibitor, compound #11, was shown to decelerate Aß accumulation, tauopathy and C/EBPß level in both spinal cord and brain of SCI mice. Thus, this study highlights the fact that spinal cord injury is a potential risk factor for dementia, as well as the possibility that C/EBPß-AEP axis may play a role in SCI-induced cognitive impairment.

Correlation between direction of pedicle screw and restoration of lumbar degenerative scoliosis in degenerative lumbar spondylolisthesis: a retrospective study.

Background: Inferior clinical outcomes have been reported in patients with degenerative lumbar spondylolisthesis (DLS) accompanied by lumbar degenerative scoliosis, but little attention has been paid to its radiologic assessment or preoperative planning. The aim of this study was to analyze the effect of transforaminal lumbar interbody fusion on patients with DLS and lumbar degenerative scoliosis and explore the surgical aspects benefiting the restoration of lumbar degenerative scoliosis. Methods: All patients with DLS and lumbar degenerative scoliosis undergoing single-level unilateral transforaminal lumbar interbody fusion surgery between July 1, 2015, and April 30, 2021, were screened in this retrospective cohort study. Clinical outcomes including visual analog scale (VAS), Oswestry disability index (ODI), and radiographic parameters of sagittal and coronal alignment, cage spatial locations, and angle of pedicle screw (parallel, cranial, and caudad angle) were assessed. Coronal asymmetry was demonstrated by the intervertebral height difference between the medial and lateral margins of indexed intersegmental space. The correlations between Δintervertebral height difference (postoperative intervertebral height difference-preoperative intervertebral height difference) and radiographic parameters and clinical outcomes were analyzed by univariable, multivariable, mediation, and correlation analyses. Significance was set at a bilateral P<0.05. Results: A total of 57 included patients were followed up for a minimum of 1 year. Reduction of VAS, ODI, and improvement of radiographic parameters were found after surgery. The cranial angle of the lower pedicle screw positively correlated with Δintervertebral height difference restoration (b=0.54; standard error=0.11; P<0.001). Conclusions: Transforaminal lumbar interbody fusion surgery appears to be an effective approach to improving the radiographic and clinical outcomes of patients with DLS and lumbar degenerative scoliosis. The cranial direction of the lower pedicle screws in single-level unilateral transforaminal lumbar interbody fusion surgery may be associated with a better postoperative restoration of lumbar degenerative scoliosis.

Shentao Ruangan formula promotes apoptosis via the E2F2-p53 pathway in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is a malignant tumor with high morbidity and mortality rates. E2F2 is an independent predictor of poor prognosis in HCC; however, The mechanism by which E2F2 promotes the progression of HCC remains unclear. The Shentao Ruangan (STR) formula exhibits antitumor efficacy against HCC; however, the underlying antitumor mechanisms remain unknown. PURPOSE: To explore the regulatory effect of E2F2 on the p53 signaling pathway and reveal the role and mechanism of STR in promoting cell apoptosis via the E2F2-p53 signaling pathway in HCC. METHODS: E2F2 overexpression or silencing by lentivirus in HepG2 cells were used to explore their influence on apoptosis and the p53 pathway. An H22 tumor-bearing mice model was used to determine the therapeutic efficacy of STR and its effects on the E2F2-p53 pathway. STR-mediated serum (STR-MS) was prepared, and its chemical constituents were identified using mass spectrometry. The effects of STR-MS on viability and apoptosis of HepG2 cells and the E2F2-p53 pathway were investigated and validated using rescue experiments. RESULTS: E2F2 overexpression significantly inhibited apoptosis and the p53 pathway in HepG2 cells, whereas E2F2-silenced HepG2 cells showed the reverse. This increased apoptosis was rescued by the addition of a p53 inhibitor (PFT-α) to E2F2-silenced HepG2 cells. In vivo, high doses of STR could remarkably inhibit the growth of xenografts, promote the apoptosis of hepatoma cells, downregulate E2F2, and activate the p53-dependent mitochondrial apoptotic pathway with good safety. In vitro, STR-MS exhibited similar effectiveness, and the best effect was achieved at 30% STR-MS concentration for 48 h. When 30% STR-MS was added to E2F2-overexpressing cells, the increased apoptosis and expression of key proteins in the p53-dependent mitochondrial apoptosis pathway were significantly rescued. CONCLUSION: Our findings demonstrate, for the first time, that E2F2 inhibits hepatoma cell apoptosis in a p53-dependent manner and that STR may promote apoptosis by regulating the E2F2-p53 pathway in HCC.

Emodin inhibits invasion and migration of hepatocellular carcinoma cells via regulating autophagy-mediated degradation of snail and ß-catenin.

BACKGROUND: Previous studies reported that emodin extracted from Rheum palmatum L. exerts antiproliferation and antimetastatic effects in a variety of human cancer types. However, the role of emodin in hepatocellular carcinoma (HCC) remain unknown. METHODS: EdU and colony formation assays were performed to evaluate the effects of emodin on proliferation. The mobility capacities of HCC treated with emodin were evaluated using wound healing assay. Transwell invasion and migration assays were performed to evaluate anti-migratory and anti-invasive effects of emodin on HCC. Annexin V-FITC/PI was performed to analyze the apoptosis. PI stain was performed to analyze cell cycle. RNA sequencing technology was used to identify the differentially expressed genes (DEGs) induced by emodin in HCC. The impact of emodin on autophagic flux in HepG2 cells was examined by mCherry-GFP-LC3 analysis. Western blot was used to assess the protein expressions of epithelial-mesenchymal transition (EMT), autophagy, PI3K/AKT/mTOR and Wnt/ß-catenin signaling pathway. RESULTS: We found that emodin inhibited the growth of HepG2 cells in a dose- and time-dependent manner. In addition, emodin inhibited cell proliferation, induced S and G2/M phases arrest, and promoted apoptosis in HepG2 cells. The migration and invasion of HepG2 cells were also suppressed by emodin. Enrichment analysis revealed that DEGs involved in cell adhesion, cancer metastasis and cell cycle arrest. Moreover, western bolt results show that emodin-induced autophagy promotes Snail and ß-catenin degradation. We also found that blocking autophagic flux after emodin treatment caused EMT reversal. Furthermore, the PI3K agonist Y-P 740 significantly reversed the phosphorylation levels of GSK3ß and mTOR. These results indicated that emodin induced autophagy and inhibited the EMT in part through suppression of the PI3K/AKT/mTOR and Wnt/ß-catenin pathways. CONCLUSION: Our study indicated that emodin inhibited cell metastasis in HCC via the crosstalk between autophagy and EMT.

Highly expressed centromere protein L indicates adverse survival and associates with immune infiltration in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is characterized by rapid progression, high recurrence rate and poor prognosis. Early prediction for the prognosis and immunotherapy efficacy is of great significance to improve the survival of HCC patients. However, there is still no reliable predictor at present. This study is aimed to explore the role of centromere protein L (CENPL) in predicting prognosis and its association with immune infiltration in HCC. METHODS: The expression of CENPL was identified through analyzing the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) data. The association between CENPL expression and clinicopathological features was investigated by the Wilcoxon signed-rank test or Kruskal Wallis test and logistic regression. The role of CENPL in prognosis was examined via Kaplan-Meier method and Log-rank test as well as univariate and multivariate Cox regression analysis. Besides, in TIMER and GEPIA database, we investigated the correlation between CENPL level and immunocyte and immunocyte markers, and the prognostic-related methylation sites in CENPL were identified by MethSurv. RESULTS: CENPL had a high expression in HCC samples. Increased CENPL was prominently associated with unfavorable survival, and maybe an independent prognostic factor of worse overall survival (OS), disease-specific survival (DSS), disease-free interval (DFI), progression-free interval (PFI). Additionally, CENPL expression was significantly correlated with immune cell infiltration and some markers. CENPL also contained a methylation site that was notably related to poor prognosis. CONCLUSIONS: Elevated CENPL may be a promising prognostic marker and associate with immune infiltration in HCC.

Caudad Insertion of Pedicle Screws Facilitates Interbody Distraction During Spondylolisthetic Vertebrae Restoration: A Retrospective Study.

INTRODUCTION: Based on the results of long-term clinical and radiological follow-up studies of decompression and fusion with internal fixation for degenerative lumbar spondylolisthesis (DLS), we recognized that the direction of the pedicle screw affects the stability of the fixation. However, few studies have analyzed the role of pedicle screw insertion trajectory in disc height recovery after fusion. We therefore analyzed patients' general information, clinical efficacy and sagittal, coronal and implant parameters to determine whether there is a correlation between the insertion trajectory of screws and the recovery of intervertebral space height, with the ultimate aim to provide a basis for improving the clinical efficacy and radiological outcomes of patients with DLS and to identify an optimal technique for spine surgeons that would benefit patients with spondylolisthesis. METHODS: From May 2015 to October 2019, patients who underwent single-segment decompression and fusion with internal fixation for DLS at our department were screened for enrollment in the study. The clinical history, pre- and post-operative lumbar sagittal parameters, intervertebral height, rate of recovery from spondylolisthesis and pedicle screw angle of inpatients were recorded and followed up for at least 6 months. Clinical assessments included the Oswestry Disability Index (ODI) and the Visual Analogue Scale (VAS) for lower back and leg pain. Data on screw angle, fusion segment intervertebral space height and clinical outcome were the primary outputs. Pearson correlation and multivariate regression analyses were performed to investigate the relationship between the pedicle screw angle, the sagittal parameters of the fusion segment and clinical efficacy. RESULTS: A total of 50 patients were initially enrolled, two patients were lost to follow-up after 6 months, 48 patients (17 men, 31 women) were eventually enrolled, and the follow-up rate was 96%. At least 6 months after the operation, vertebral spondylolisthesis improved to varying degrees [> 80% in 17 cases (35.4%) and > 20% in 43 cases (87.5%), respectively]. Changes in disc height (DH) were significantly associated with lower pedicle screw angle, while lumbar lordosis and segment lordosis remained the same. Multivariate regression analysis showed a significant negative correlation between the upper and lower pedicle screw angles and the change in DH (P < 0.05). At 2 weeks post-operation, the VAS score for low back pain and the ODI had improved significantly compared to pre-operation (P < 0.05). CONCLUSIONS: These results suggest that the Caudad insertion trajectory technique of pedicle screws may be an ideal alternative for the treatment of DLS. TRIAL REGISTRATION NUMBER: Chinese Clinical Trial Registry (ChiCTR): ChiCTR1800020368.

The biomechanical effect of preexisting different types of disc herniation in cervical hyperextension injury.

OBJECTIVE: Preexisting severe cervical spinal cord compression is a significant risk factor in cervical hyperextension injury, and the neurological function may deteriorate after a slight force to the forehead. There are few biomechanical studies regarding the influence of pathological factors in hyperextension loading condition. The aim of this study is to analyze the effects of preexisting different types of cervical disc herniation and different degrees of compression on the spinal cord in cervical hyperextension. METHOD: A 3D finite element (FE) model of cervical spinal cord was modeled. Local type with median herniation, local type with lateral herniation, diffuse type with median herniation, and diffuse type with lateral herniation were simulated in neutral and extention positions. The compressions which were equivalent to 10%, 20%, 30%, and 40% of the sagittal diameter of the spinal cord were modeled. RESULTS: The results of normal FE model were consistent with those of previous studies. The maximum von Mises stresses appeared in the pia mater for all 32 loading conditions. The maximum von Mises stresses in extension position were much higher than in neutral position. In most cases, the maximum von Mises stresses in diffuse type were higher than in local type. CONCLUSION: Cervical spinal cord with preexisting disc herniation is more likely to be compressed in hyperextension situation than in neutral position. Diffuse type with median herniation may cause more severe compression with higher von Mises stresses concentrated at the anterior horn and the peripheral white matter, resulting in acute central cord syndrome from biomechanical point of view.

Do the positioning variables of the cage contribute to adjacent facet joint degeneration? Radiological and clinical analysis following intervertebral fusion.

BACKGROUND: Compared to other risk factors, adjacent facet joint degeneration (AFD) is the main contributor to adjacent segment disease (ASD). The interbody cage may be a potential indirect risk of AFD. This study investigated the correlations among the lumbar sagittal balance parameters, the inter-body cage's intraoperative positioning variables, and adjacent facet joint degeneration following the transforaminal lumbar interbody fusion (TLIF) technique. METHODS: Patients who accepted single-level TLIF for symptomatic lumbar degenerative disease and were followed up for at least six months were enrolled in this study. According to the inclusive and exclusive criteria, 93 patients were included (44 males and 49 females). X-ray and computed tomography (CT) images were obtained before and six months after surgery. The vertebral contour and the center of the marker mass in the cage were calculated using a geometric algorithm. Orthopedic surgeons measured the disc height, lordosis angle, and facet joint degeneration. Patient-reported outcomes, including the Oswestry Disability Index (ODI) and the visual analog scale (VAS), were used to assess the clinical outcomes. The Student's t-test, Wilcoxon rank-sum test, and Chi-square test were used for the statistical analyses. RESULTS: The average age was 53.7 years old (range, 27-84 years). The average functional disability outcome assessed by the ODI was 61.2, and the average back and leg pain assessed by the VAS was 6.2 and 6.9, respectively. The patients were categorized into a normal group and an abnormal (AFD) group according to whether the facet joint degeneration was aggravated. The abnormal group had a higher back pain VAS score (P=0.031) and lower sagittal vertical position (P=0.027). The other parameters were similar at baseline (P>0.05). The cage's sagittal vertical position decreased significantly with AFD aggravation (OR, 0.737; 95% CI, 0.561-0.969). CONCLUSIONS: In patients with AFD aggravation, the preoperative VAS and postoperative ODI scores were significantly higher. The cage position parameters were related to AFD. A lower cage center was associated with a greater incidence of AFD.

Estimation of renal function by three CKD-EPI equations in Chinese HIV/AIDS patients: A STROBE-compliant article.

ABSTRACT: Assessing renal function accurately is important for human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) patients. Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) recommended three equations to calculate estimated glomerular filtration rate (eGFR). There is evidence that eGFR based on the combination of serum creatinine and cystatin C is the most accurate of the three equations. But there is limited data on the comparison of three CKD-EPI equations in Chinese HIV/AIDS patients. The aim of our study was to compare the three CKD-EPI equations in Chinese HIV/AIDS population and assess renal function.Cross-sectional, single center, prospective study.One hundred seventy two Chinese adult HIV/AIDS patients were enrolled, including 145 (84.3%) males and 27 (15.7%) females. Mean age was 40(±12) years old. Overall mean eGFR based on serum creatinine, cystatin C and the combination of the 2 markers was 112.6(±19.0) mL/min/1.73 m2, 92.0(±24.2)mL/min/1.73 m2, and 101.7(±21.8)mL/min/1.73 m2, respectively (P = .000). The eGFR calculated by serum creatinine alone is higher than eGFR calculated by combination of serum creatinine and cystatin C, and eGFR calculated by cystatin C individual is lower than eGFR calculated by combination of the 2 markers.Of the 3 CKD-EPI equations, the CKD-EPIscr-cys equation may have the most accuracy in evaluating renal function in Chinese HIV/AIDS patients while the CKD-EPIscr equation may overestimate renal function and the CKD-EPIcys equation may underestimate renal function.

Estimation of Incubation Period and Serial Interval for SARS-CoV-2 in Jiangxi, China, and an Updated Meta-Analysis.

INTRODUCTION: This paper aims to estimate the incubation period and serial intervals for SARS-CoV-2 based on confirmed cases in Jiangxi Province of China and meta-analysis method. METHODOLOGY: Distributions of incubation period and serial interval of Jiangxi epidemic data were fitted by "fitdistrplus" package of R software, and the meta-analysis was conducted by "meta" package of R software. RESULTS: Based on the epidemic data of Jiangxi, we found the median days of incubation period and serial interval were 5.9 days [IQR: 3.8 - 8.6] and 5.7 days [IQR: 3.6 - 8.3], respectively. The median days of the infectivity period at pre-symptomatic was 1.7 days [IQR: 1.1 - 2.4]. The meta-analysis based on 64 papers showed the pooled means of the incubation period and serial interval were 6.25 days (95% CrI: 5.75 - 6.75) and 5.15 days (95% CrI: 4.73 - 5.57), respectively. CONCLUSIONS: Our results contribute to a better understanding of COVID-19 and provide useful parameters for modelling the dynamics of disease transmission. The serial interval is shorter than the incubation period, which indicates that the patients are infectious at pre-symptomatic period, and isolation of detected cases alone is likely to be difficult to halt the spread of SARS-CoV-2.

A Retrospective Analysis of Superior Facet Joint Violation Between Open and Minimally Invasive Transforaminal Lumbar Interbody Fusion and its Relation to Adjacent Segment Disease.

STUDY DESIGN: A retrospective study. OBJECTIVE: The aim was to analyze the superior facet joint violation (SFV) between open transforaminal lumbar interbody fusion (open-TLIF) and minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) and its effect on the superior and inferior adjacent segment disc height, segmental lordosis, lumbar lordosis, and facet joint degeneration. SUMMARY OF BACKGROUND DATA: We compared SFV between open-TLIF and MIS-TLIF and its correlation with different factors as well as its effect on adjacent segment disease. MATERIALS AND METHODS: We retrospectively studied data of patients undergoing single level TLIF surgery from January 2013 to February 2016 in single institutional hospital. Axial and coronal postoperative computed tomography scan images were used to analyze SFV. In secondary analysis patients were divided into nonfacet violation group (NSFVG) and facet violation group (SFVG) and compared the changes on the superior and inferior adjacent level disc height, segmental lordosis, lumbar lordosis, and facet joint degeneration. RESULTS: Mean SFV grade was significantly greater in MIS-TLIF compared with open-TLIF (odds ratio: 0.638, confidence interval: 0.431-0.944; P=0.025). There was more grade 2 (10.71% vs. 5.60%) and grade 3 (4.46% vs. 1.29%) SFV in MIS-TLIF. Patient with age below 60 and body mass index (BMI) >30 kg/m2 in MIS-TLIF were more prone to high-grade SFV compared with open-TLIF. Further, logistic regression showed patients with BMI ≥30 kg/m2 has 7.137 increased odds of high-grade SFV (95% confidence interval: 3.261-15.618; P=0.000) compared with patients with BMI <30 kg/m2. Compared with NSFVG, SFVG has more SFV (0.096±0.244 vs. 0.177±0.317; P=0.012) and less improvement in lumbar visual analog scale scores -0.65±0.073 versus -0.67±0.074 (P=0.006). CONCLUSION: MIS-TLIF has more high-grade SFV as well as overall mean SFV in comparison to open-TLIF with BMI >30 kg/m2 and location of pedicle screw as an independent risk factor for SFV and risk of adjacent segment disease increases with SFV. LEVEL OF STUDY: Level III.

Identification of potential bioactive compounds and mechanisms of GegenQinlian decoction on improving insulin resistance in adipose, liver, and muscle tissue by integrating system pharmacology and bioinformatics analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: GegenQinlian Decoction (GQD), a classical formula in traditional Chinese medicine, is widely used in the treatment of diabetes. While studies have demonstrated that GQD is an efficacious treatment for insulin resistance (IR) in type 2 diabetes mellitus (T2DM), the potential bioactive compounds and mechanisms remain unclear. AIM OF THE STUDY: To further investigate the potential bioactive compounds, targets, and pathways of GQD on improving IR in T2DM for adipose, liver, and muscle tissue using an integrated strategy of system pharmacology and bioinformatics analysis. MATERIALS AND METHODS: We screened the candidate compounds and targets of GQD and identified IR-associated differentially expressed genes (DEGs) of adipose, liver, and muscle tissue, respectively. Then the intersecting target genes between candidate targets and DEGs were used for "GQD-compounds-targets-tissue" network construction in each type of tissue. The top 10 bioactive compounds acting on each type of tissue were intersected and consequently identified as potential bioactive compounds of GQD. Furthermore, pathway enrichment, protein-protein interaction (PPI) network construction, and hub target identification were performed based on the targets of GQD and the targets of quercetin in each type of tissue, respectively. Finally, to further confirm the role of quercetin, we intersected the hub targets of quercetin and the hub targets of GQD, and the pathways were intersected as well. RESULTS: 132 compounds and 119 potential targets of these compounds were obtained. 1,765, 3,206, and 3594 DEGs were identified between IR and insulin sensitivity (IS) tissue in adipose, liver, and muscle, respectively. There were 21, 23, 45 targets and 103, 73, 123 compounds in the "GQD-compounds-targets-tissue" network of adipose, liver, and muscle tissue, respectively. Then compounds such as quercetin, kaempferol, baicalein, wogonin, isorhamnetin, beta-sitosterol and licochalcone A, were identified as the potential bioactive compounds of GQD, and quercetin had the highest degree among the compounds. Moreover, based on the targets of GQD, hub targets like PPARG, RELA, EGFR, CASP3, VEGFA, AR, ESR1 and CCND1, and signaling pathways such as insulin signaling pathway, endocrine resistance, TNF signaling pathway, PI3K-Akt signaling pathway, AMPK signaling pathway, MAPK signaling pathway, NF-κB signaling pathway, HIF-1 signaling pathway, apoptosis, and VEGF signaling pathway, were filtered out as the underlying mechanisms of GQD on improving diabetic IR. In addition, the hub targets and pathways of quercetin coincided with most of the hub targets and pathways of GQD in each type of tissue, respectively, suggesting that quercetin may be a potential representative compound of GQD. CONCLUSIONS: Our analysis identifies the potential bioactive compounds, targets, and pathways of GQD on improving IR in T2DM for adipose, liver, and muscle tissue, which shows the characteristics of multi-compounds, multi-targets, multi-pathways, and multi-mechanisms of GQD and lays a solid foundation for further experimental research and clinical application.

Elevated CDK5R1 predicts worse prognosis in hepatocellular carcinoma based on TCGA data.

BACKGROUND: Hepatocellular carcinoma (HCC) is a malignant tumor with rapid progression, high recurrence rate and poor prognosis. The objective of our investigation was to explore the prognostic value of CDK5R1 in HCC. METHODS: The raw data of HCC raw data were downloaded from The Cancer Genome Atlas (TCGA) database. The Wilcoxon signed-rank test, Kruskal-Wallis test and logistic regression were applied to investigate the relevance between the CDK5R1 expression and clinicopathologic characteristics in HCC. Kaplan-Meier and Cox regression analysis were employed to examine the association between clinicopathologic features and survival. Gene set enrichment analysis (GSEA) was applied to annotate the biological function of CDK5R1. RESULTS: CDK5R1 was highly expressed in HCC tissues. The high expression of CDK5R1 in HCC tissues was significantly associated with tumor status (P=0.00), new tumor event (P=0.00), clinical stage (P=0.00) and topography (P=0.00). Elevated CDK5R1 had significant correlation with worse overall survival (OS; P=7.414e-04), disease-specific survival (DSS; P=5.642e-04), disease-free interval (DFI; P=1.785e-05) and progression-free interval (PFI; P=2.512e-06). Besides, univariate and multivariate Cox regression analysis uncovered that increased CDK5R1 can independently predict adverse OS (P=0.037, hazard ratio [HR]= 1.7 (95% CI [1.0-2.7])), DFI (P=0.007, hazard ratio [HR]= 3.0 (95% CI [1.4-6.7])), PFI (P=0.007, hazard ratio [HR]= 2.8 (95% CI [1.3-5.9])). GSEA disclosed that notch signaling pathway and non-small cell lung cancer were prominently enriched in CDK5R1 high expression phenotype. CONCLUSIONS: Increased CDK5R1 may act as a promising independent prognostic factor of poor survival in HCC.

Increased E2F2 predicts poor prognosis in patients with HCC based on TCGA data.

BACKGROUND: The E2F family of transcription factor 2 (E2F2) plays an important role in the development and progression of various tumors, but its association with hepatocellular carcinoma (HCC) remains unknown. Our study aimed to investigate the role and clinical significance of E2F2 in HCC. METHODS: HCC raw data were extracted from The Cancer Genome Atlas (TCGA). Wilcoxon signed-rank test, Kruskal-Wallis test and logistic regression were applied to analyze the relationship between the expression of E2F2 and clinicopathologic characteristics. Cox regression and Kaplan-Meier were employed to evaluate the correlation between clinicopathologic features and survival. The biological function of E2F2 was annotated by Gene Set Enrichment Analysis (GSEA). RESULTS: The expression of E2F2 was increased in HCC samples. The expression of elevated E2F2 in HCC samples was prominently correlated with histologic grade (OR = 2.62 for G3-4 vs. G1-2, p = 1.80E-05), clinical stage (OR = 1.74 for III-IV vs. I-II, p = 0.03), T (OR = 1.64 for T3-4 vs.T1-2, p = 0.04), tumor status (OR = 1.88 for with tumor vs. tumor free, p = 3.79E-03), plasma alpha fetoprotein (AFP) value (OR = 3.18 for AFP ≥ 400 vs AFP<20, p = 2.16E-04; OR = 2.50 for 20 ≤ AFP<400 vs AFP<20, p = 2.56E-03). Increased E2F2 had an unfavorable OS (p = 7.468e- 05), PFI (p = 3.183e- 05), DFI (p = 0.001), DSS (p = 4.172e- 05). Elevated E2F2 was independently bound up with OS (p = 0.004, hazard ratio [HR] = 2.4 (95% CI [1.3-4.2])), DFI (P = 0.029, hazard ratio [HR] = 2.0 (95% CI [1.1-3.7])) and PFI (P = 0.005, hazard ratio [HR] = 2.2 (95% CI [1.3-3.9])). GSEA disclosed that cell circle, RNA degradation, pyrimidine metabolism, base excision repair, aminoacyl tRNA biosynthesis, DNA replication, p53 signaling pathway, nucleotide excision repair, ubiquitin-mediated proteolysis, citrate cycle TCA cycle were notably enriched in E2F2 high expression phenotype. CONCLUSIONS: Elevated E2F2 can be a promising independent prognostic biomarker and therapeutic target for HCC. Additionally, cell cycle, pyrimidine metabolism, DNA replication, p53 signaling pathway, ubiquitin-mediated proteolysis, the citrate cycle TCA cycle may be the key pathway by which E2F2 participates in the initial and progression of HCC.

Identification of diagnostic and prognostic biomarkers, and candidate targeted agents for hepatitis B virus-associated early stage hepatocellular carcinoma based on RNA-sequencing data.

Primary liver cancer is a rapidly progressing neoplasm with high morbidity and mortality rates. The present study aimed to identify potential diagnostic and prognostic biomarkers, and candidate targeted agents for hepatitis B virus (HBV)-associated early stage hepatocellular carcinoma (HCC). The gene expression profiles were extracted from the Gene Expression Omnibus database. Differentially expressed genes (DEGs), hub genes and the enrichment of signaling pathways were filtered out via a high-throughput sequencing method. The association between hub genes and the effects of the abnormal expression of hub genes on the rate of genetic variation, overall survival (OS), relapse-free survival (RFS), progression-free survival (PFS) and disease-free survival (DSS) of patients with HCC, as well as pathological stage and grade, were analyzed using different databases. A total of 1,582 DEGs were identified. Gene Ontology analysis revealed that the DEGs were mainly involved in the 'oxidation-reduction process', 'steroid metabolic process', 'metabolic process' and 'fatty acid beta-oxidation'. Enrichment analysis of Kyoto Encyclopedia of Genes and Genomes pathways revealed that the DEGs were mainly associated with 'metabolic pathways', 'PPAR signaling pathway', 'fatty acid degradation' and the 'cell cycle'. A total of 8 hub genes were extracted. Additionally, the abnormal expression levels of hub genes were closely associated with the OS, RFS, PFS and DSS of patients, the pathological stage and the grade. Furthermore, abnormal expression levels of the 8 hub genes were found in >30% of all samples. Several small molecular compounds that may reverse the altered DEGs were identified based on Connectivity Map analysis, including phenoxybenzamine, GW-8510, resveratrol, 0175029-0000 and daunorubicin. In conclusion, the dysfunction of fat metabolic pathways, the cell cycle, oxidation-reduction processes and viral carcinogenesis may serve critical roles in the occurrence of HBV-associated early stage HCC. The identified 8 hub genes may act as robust biomarkers for diagnosis and prognosis. Some small molecular compounds may be promising targeted agents against HBV-associated early stage HCC.

Distinct fusion intersegmental parameters regarding local sagittal balance provide similar clinical outcomes: a comparative study of minimally invasive versus open transforaminal lumbar interbody fusion.

BACKGROUND: Most contemporary studies suggested that intersegmental parameters including disc height and local lordosis contribute to the sagittal balance of fused lumbar. Although similar clinical outcomes following MIS- and Open-TLIF were reported essentially at the early postoperative time, the comparison of local balance variables after these two different techniques was lack. The radiological differences maybe not relevant to the postoperative efficacy at an earlier post-operation stage. But during the long-term follow-up, the complications with regards to the sagittal imbalance might occur due to the distinct biomechanical properties of fusion level after MIS- and Open-TLIF. METHODS: The patients who underwent a single-level MIS- and Open-TLIF were reviewed retrospectively. The anterior disc height (ADH), posterior disc height (PDH), and segmental lordosis (SL) of the fusion segment were measured using recognition technical fluoroscopy. The mean disc height (MDH) was calculated by (ADH + PDH)/2. The relative DH was normalized by the anterior height of the upper vertebrae. The body mass index (BMI), the pain score of low back and leg visual analogue scale (VAS), Oswestry disability index (ODI), estimated blood loss, and hospital stay length was collected. RESULTS: A total of 88 patients undergoing a single-level TLIF (MIS and Open) were included. The pre- and post-operative ADH, PDH, MDH, and SL of MIS-TLIF group were 1.57 ± 0.33 cm, 0.79 ± 0.20 cm, 1.18 ± 0.21 cm, 7.36 ± 3.07 and 1.63 ± 0.30 cm, 1.02 ± 0.28 cm, 1.32 ± 0.24 cm, 10.24 ± 4.79 respectively. Whereas, the pre- and post-operative ADH, PDH, MDH, and SL of Open-TLIF group were 1.61 ± 0.40 cm, 0.77 ± 0.21 cm, 1.19 ± 0.24 cm, 9.05 ± 5.48 and 1.81 ± 0.33 cm, 0.98 ± 0.24 cm, 1.39 ± 0.24 cm, 12.34 ± 4,74 respectively. MIS- and Open-TLIF group showed no significant differences in low back VAS, leg VAS, and ODI both in pre-operation and post-operation (P > 0.05). The estimated blood loss and hospital stay length in the MIS-TLIF group were significantly lower than those in the Open-TLIF group (P < 0.05). CONCLUSION: MIS- and Open-TLIF provided similar clinical outcomes as the respect of low back VAS, leg VAS, and ODI. MIS-TLIF significantly reduced the blood loss and length of hospital stay though. The intervertebral parameters of DH and SL were both increased significantly, Open-TLIF group presented better sagittal balance in term of ADH and SL variables. The contrast investigation of intersegmental parameters may help the surgeons to figure out the further advantages of MIS-TLIF technique, and then better manage the rehabilitation and prevent the reoperation.

[Comparison of intervertebral height and lordosis of fusion segment between open- and minimally invasive-transforaminal lumbar interbody fusions].

OBJECTIVE: To analyze the restoration of intervertebral height and lordosis of fusion segment after open-transforaminal lumbar interbody fusion (Open-TLIF) and minimally invasive-TLIF (MIS-TLIF). METHODS: Between January 2013 and February 2016, patients who treated with TLIF due to lumbar degenerative diseases and met the selection criteria were selected as the study objects. Among them, 41 patients were treated with open-TLIF (Open-TLIF group), 34 patients were treated with MIS-TLIF (MIS-TLIF group). There was no significant difference between the two groups ( P>0.05) in gender, age, body mass index, disease type, disease duration, pathological segment, and other general data. The intraoperative bleeding volume, hospital stay, visual analogue scale (VAS) score of waist and leg, and Oswestry disability index (ODI) were recorded before and after operation. The anterior disc height (ADH), posterior disc height (ADH), and segmental lordosis (SL) of fusion segment were measured by X-ray film before and at 6 months after operation. The differences of ADH, PDH, and SL between pre- and post-operation were calculated. RESULTS: The intraoperative bleeding volume and hospital stay in Open-TLIF group were significantly higher than those in MIS-TLIF group ( t=14.619, P=0.000; t=10.021, P=0.000). All incisions healed by first intention without early complications. All patients were followed up 6-24 months (mean, 12.6 months) in Open-TLIF group and 6-24 months (mean, 11.5 months) in MIS-TLIF group. The preoperative VAS scores of waist and leg and ODI of the two groups significantly improved ( P<0.05). There was no significant difference in VAS scores and ODI between the two groups before operation and at 2 weeks and 6 months after operation ( P>0.05). Imaging examination showed the good intervertebral fusion. There was no significant difference in ADH, PDH, and SL between the two groups before operation and at 6 months after operation ( P>0.05). The differences of ADH, PDH, and SL between the two groups were not significant ( P>0.05). The ADH, PDH, and SL after operation significantly increased in the two groups ( P<0.05). CONCLUSION: Open-TLIF and MIS-TLIF show similar effectiveness and radiological change in the treatment of single lumbar degenerative diseases and the improved intervertebral height and lordosis, but MIS-TLIF can significantly reduce hospital stay and intraoperative blood loss.

Cabin1 involves in renal tubular epithelial cells mitochondrial dysfunction through SIRT1/p53 pathway.

Background: Angiotensin II (AngII) induced Calcineurin binding protein 1 (Cabin1) protein expression significantly increased during Renal tubular epithelial cells (RTEC) injury. However, the detailed function of Cabin1 protein in RTEC was not characterized well. In this study, we aimed to explore the downstream target of Cabin1 in vitro model.Methods: Rat kidney epithelial cells were cultured and stimulated with AngII. Electron microscopy was performed to observe mitochondrial morphology change. Immunofluorescence staining was detected to observe the distribution of cytoskeleton and Cabin1. Mitochondrial morphology change and protein expression were detected by electrical microscopy and western blot.Results: AngII induced the disruption of cytoskeleton at 24 and 48 h. Western blot analysis showed AngII significantly induced the overexpression of Cabin1. AngII induced a great deal of small, long and irregular mitochondria in RTEC, aspect ratio which reflects the length-to-width ratio of mitochondria remarkably increased at 12 and 24 h. Knocking down Cabin1 aggravated mitochondrial morphological abnormality in AngII treated RTEC. In comparison with control, Cabin1, p53 and cyto C level were significantly increased in AngII treated cells, while SIRT1 level was obviously decreased. Knocked down Cabin1 plus AngII stimulated, SIRT1 was further decreased, while p53 and cyto C were significantly increased.Conclusions: Cabin1 involves in RTEC mitochondrial dysfunction through SIRT1/p53 pathway. Cabin1 may be used as a new marker for the mechanisms of RTEC injury.