Cortical ensembles orchestrate social competition through hypothalamic outputs.

Most social species self-organize into dominance hierarchies1,2, which decreases aggression and conserves energy3,4, but it is not clear how individuals know their social rank. We have only begun to learn how the brain represents social rank5-9 and guides behaviour on the basis of this representation. The medial prefrontal cortex (mPFC) is involved in social dominance in rodents7,8 and humans10,11. Yet, precisely how the mPFC encodes relative social rank and which circuits mediate this computation is not known. We developed a social competition assay in which mice compete for rewards, as well as a computer vision tool (AlphaTracker) to track multiple, unmarked animals. A hidden Markov model combined with generalized linear models was able to decode social competition behaviour from mPFC ensemble activity. Population dynamics in the mPFC predicted social rank and competitive success. Finally, we demonstrate that mPFC cells that project to the lateral hypothalamus promote dominance behaviour during reward competition. Thus, we reveal a cortico-hypothalamic circuit by which the mPFC exerts top-down modulation of social dominance.

Effect of the mRNA decapping enzyme scavenger (DCPS) inhibitor RG3039 on glioblastoma.

BACKGROUND: Patients with glioblastoma (GBM) have a poor prognosis and limited treatment options. The mRNA decapping enzyme scavenger (DCPS) is a cap-hydrolyzing enzyme. The DCPS inhibitor RG3039 exhibited excellent central nervous system bioavailability in vivo and was safe and well tolerated in healthy volunteers in a phase 1 clinical trial. In this study, we investigated the expression of DCPS in GBM and the anti-tumor activity of RG3039 in various preclinical models of GBM. METHODS: DCPS expression was examined in human GBM and paired peritumoral tissues. Its prognostic role was evaluated together with clinicopathological characteristics of patients. The anti-GBM effect of RG3039 was determined using GBM cell lines, patient-derived organoids, and orthotopic mouse models. The therapeutic mechanisms of DCPS inhibition were explored. RESULTS: DCPS is overexpressed in GBM and is associated with poor survival of patients with GBM. The DCPS inhibitor RG3039 exhibited robust anti-GBM activities in GBM cell lines, patient-derived organoids and orthotopic mouse models, with drug exposure achievable in humans. Mechanistically, RG3039 downregulated STAT5B expression, thereby suppressing proliferation, survival and colony formation of GBM cells. CONCLUSIONS: DCPS is a promising target for GBM. Inhibition of DCPS with RG3039 at doses achievable in humans downregulates STAT5B expression and reduces proliferation, survival and colony formation of GBM cells. Given the excellent anti-cancer activity and central nervous system bioavailability in vivo and good tolerance in humans, RG3039 warrants further study as a potential GBM therapy.

Swine acute diarrhea syndrome coronavirus Nsp1 suppresses IFN-λ1 production by degrading IRF1 via ubiquitin-proteasome pathway.

Swine acute diarrhea syndrome coronavirus (SADS-CoV) is a novel porcine enteric coronavirus that causes acute watery diarrhea, vomiting, and dehydration in newborn piglets. The type III interferon (IFN-λ) response serves as the primary defense against viruses that replicate in intestinal epithelial cells. However, there is currently no information available on how SADS-CoV modulates the production of IFN-λ. In this study, we utilized IPI-FX cells (a cell line of porcine ileum epithelium) as an in vitro model to investigate the potential immune evasion strategies employed by SADS-CoV against the IFN-λ response. Our results showed that SADS-CoV infection suppressed the production of IFN-λ1 induced by poly(I:C). Through screening SADS-CoV-encoded proteins, nsp1, nsp5, nsp10, nsp12, nsp16, E, S1, and S2 were identified as antagonists of IFN-λ1 production. Specifically, SADS-CoV nsp1 impeded the activation of the IFN-λ1 promoter mediated by MAVS, TBK1, IKKε, and IRF1. Both SADS-CoV and nsp1 obstructed poly(I:C)-induced nuclear translocation of IRF1. Moreover, SADS-CoV nsp1 degraded IRF1 via the ubiquitin-mediated proteasome pathway without interacting with it. Overall, our study provides the first evidence that SADS-CoV inhibits the type III IFN response, shedding light on the molecular mechanisms employed by SADS-CoV to evade the host immune response.

NeoSCORE II: three vs four cycles of neoadjuvant sintilimab + chemotherapy for squamous non-small-cell lung cancer.

Immune checkpoint inhibitors (ICIs) plus chemotherapy has demonstrated efficacy in resectable non-small-cell lung cancer (NSCLC), yet the optimal period of neoadjuvant immunochemotherapy is undetermined. In a phase II study (neoSCORE, NCT04459611), more neoadjuvant therapy cycles appeared to provide greater pathological remission, and patients with squamous NSCLC had a better major pathological response rate than those with nonsquamous NSCLC. Sintilimab, a monoclonal anti-PD-1 antibody, has shown encouraging antitumor activity and safety in multiple cancers, including NSCLC. Here, we describe the study design of neoSCORE II (NCT05429463), a randomized, open-label, multicenter phase III trial comparing the efficacy and safety of three cycles with four cycles of neoadjuvant sintilimab plus platinum-based chemotherapy in resectable stage IIA-IIIB squamous NSCLC. Trial registration number: NCT05429463 (ClinicalTrials.gov).

The development of posterior reduction forceps for atlantoaxial dislocation and its preliminary application in irreducible atlantoaxial dislocation.

OBJECTIVE: To develop posterior reduction forceps for atlantoaxial dislocation and evaluate the preliminary clinical application of this forceps in assisting simple posterior screw-rod system reduction and fixation in the treatment of irreducible atlantoaxial dislocation. METHODS: Based on the posterior atlantoaxial screw-rod system, posterior reduction forceps was developed to assist simple posterior screw-rod system for the treatment of irreducible atlantoaxial dislocation. From January 2021 to October 2022, 10 cases with irreducible atlantoaxial dislocation were treated with this technique. The Japanese Orthopaedic Association (JOA) score was applied before and after surgery to evaluate the neurological status of the patient, and the Atlanto-dental interval (ADI) was measured before and after surgery to evaluate the atlantoaxial reduction. X-ray and CT were performed to evaluate internal fixation, atlantoaxial sequence and bone graft fusion during regular follow-up. MRI was performed to evaluate the status of atlantoaxial reduction and spinal cord compression after surgery. RESULTS: All 10 patients were successfully operated, and there were no complications such as spinal nerve and vascular injury. Postoperative clinical symptoms were significantly relieved in all patients, and postoperative JOA score and ADI were significantly improved compared with those before surgery (P < 0.05). CONCLUSIONS: The developed posterior reduction forceps for atlantoaxial dislocation can assist the simple posterior screw-rod system in the treatment of irreducible atlantoaxial dislocation to avoid the release in anterior or posterior approach and reduce the difficulty of surgery. The preliminary results of this technique are satisfactory and it has a good application prospect.

Chromosome instability region analysis and identification of the driver genes of the epithelial ovarian cancer cell lines A2780 and SKOV3.

Epithelial ovarian cancer (EOC) is one of the most prevalent gynaecological cancers worldwide. The molecular mechanisms of serous ovarian cancer (SOC) remain unclear and not well understood. SOC cases are primarily diagnosed at the late stage, resulting in a poor prognosis. Advances in molecular biology techniques allow us to obtain a better understanding of precise molecular mechanisms and to identify the chromosome instability region and key driver genes in the carcinogenesis and progression of SOC. Whole-exome sequencing was performed on the normal ovarian cell line IOSE80 and the EOC cell lines SKOV3 and A2780. The single-nucleotide variation burden, distribution, frequency and signature followed the known ovarian mutation profiles, without chromosomal bias. Recurrently mutated ovarian cancer driver genes, including LRP1B, KMT2A, ARID1A, KMT2C and ATRX were also found in two cell lines. The genome distribution of copy number alterations was found by copy number variation (CNV) analysis, including amplification of 17q12 and 4p16.1 and deletion of 10q23.33. The CNVs of MED1, GRB7 and MIEN1 located at 17q12 were found to be correlated with the overall survival of SOC patients (MED1: p = 0.028, GRB7: p = 0.0048, MIEN1: p = 0.0051), and the expression of the three driver genes in the ovarian cell line IOSE80 and EOC cell lines SKOV3 and A2780 was confirmed by western blot and cell immunohistochemistry.

Whole-exome mutational landscape and molecular marker study in mucinous and clear cell ovarian cancer cell lines 3AO and ES2.

BACKGROUND: Ovarian cancer is one of the most lethal cancers in women because it is often diagnosed at an advanced stage. The molecular markers investigated thus far have been unsatisfactory. METHODS: We performed whole-exome sequencing on the human ovarian cancer cell lines 3AO and ES2 and the normal ovarian epithelial cell line IOSE-80. Molecular markers of ovarian cancer were screened from shared mutation genes and copy number variation genes in the 6q21-qter region. RESULTS: We found that missense mutations were the most common mutations in the gene (93%). The MUC12, FLG and MUC16 genes were highly mutated in 3AO and ES2 cells. Copy number amplification occurred mainly in 4p16.1 and 11q14.3, and copy number deletions occurred in 4q34.3 and 18p11.21. A total of 23 hub genes were screened, of which 16 were closely related to the survival of ovarian cancer patients. The three genes CCDC170, THBS2 and COL14A1 are most significantly correlated with the survival and prognosis of ovarian cancer. In particular, the overall survival of ovarian cancer patients with high CCDC170 gene expression was significantly prolonged (P < 0.001). The expression of CCDC170 in normal tissues was significantly higher than that in ovarian cancer tissues (P < 0.05), and its expression was significantly decreased in advanced ovarian cancer. Western blotting and immunofluorescence assays also showed that the expression of CCDC170 in ovarian cancer cells was significantly lower than that in normal cells (P < 0.001, P < 0.01). CONCLUSIONS: CCDC170 is expected to become a new diagnostic molecular target and prognostic indicator for ovarian cancer patients, which can provide new ideas for the design of antitumor drugs.

Applications of lung cancer organoids in precision medicine: from bench to bedside.

As the leading cause of cancer-related mortality, lung cancer continues to pose a menacing threat to human health worldwide. Lung cancer treatment options primarily rely on chemoradiotherapy, surgery, targeted therapy, or immunotherapy. Despite significant progress in research and treatment, the 5-year survival rate for lung cancer patients is only 10-20%. There is an urgent need to develop more reliable preclinical models and valid therapeutic approaches. Patient-derived organoids with highly reduced tumour heterogeneity have emerged as a promising model for high-throughput drug screening to guide treatment of lung cancer patients. Organoid technology offers a novel platform for disease modelling, biobanking and drug development. The expected benefit of organoids is for cancer patients as the subsequent precision medicine technology. Over the past few years, numerous basic and clinical studies have been conducted on lung cancer organoids, highlighting the significant contributions of this technique. This review comprehensively examines the current state-of-the-art technologies and applications relevant to the formation of lung cancer organoids, as well as the potential of organoids in precision medicine and drug testing. Video Abstract.

Patient-Derived Tumor Organoids Can Predict the Progression-Free Survival of Patients With Stage IV Colorectal Cancer After Surgery.

BACKGROUND: Recent studies have shown patient-derived tumor organoids can predict the drug response of patients with cancer. However, the prognostic value of patient-derived tumor organoid-based drug tests in predicting the progression-free survival of patients with stage IV colorectal cancer after surgery remains unknown. OBJECTIVE: This study aimed to explore the prognostic value of patient-derived tumor organoid-based drug tests in patients with stage IV colorectal cancer after surgery. DESIGN: Retrospective cohort study. SETTINGS: Surgical samples were obtained from patients with stage IV colorectal cancer at the Nanfang Hospital. PATIENTS: A total of 108 patients who underwent surgery with successful patient-derived tumor organoid culture and drug testing were recruited between June 2018 and June 2019. INTERVENTIONS: Patient-derived tumor organoid culture and chemotherapeutic drug testing. MAIN OUTCOMES MEASURES: Progression-free survival. RESULTS: According to the patient-derived tumor organoid-based drug test, 38 patients were drug sensitive and 76 patients were drug resistant. The median progression-free survival was 16.0 months in the drug-sensitive group and 9.0 months in the drug resistant group ( p < 0.001). Multivariate analyses showed that drug resistance (HR, 3.38; 95% CI, 1.84-6.21; p < 0.001), right-sided colon (HR, 3.50; 95% CI, 1.71-7.15; p < 0.001), mucinous adenocarcinoma (HR, 2.47; 95% CI, 1.34-4.55; p = 0.004), and non-R0 resection (HR, 2.70; 95% CI, 1.61-4.54; p < 0.001) were independent predictors of progression-free survival. The new patient-derived tumor organoid-based drug test model, which includes the patient-derived tumor organoid-based drug test, primary tumor location, histological type, and R0 resection, was more accurate than the traditional clinicopathological model in predicting progression-free survival ( p = 0.001). LIMITATIONS: A single-center cohort study. CONCLUSIONS: Patient-derived tumor organoids can predict progression-free survival in patients with stage IV colorectal cancer after surgery. Patient-derived tumor organoid drug resistance is associated with shorter progression-free survival, and the addition of patient-derived tumor organoid drug tests to existing clinicopathological models improves the ability to predict progression-free survival.

Negative Correlation of Serum Total Bile Acid With Albuminuria in Patients With Type 2 Diabetes Mellitus: A Cross-sectional Study.

Context: The treatment of diabetic nephropathy (DN) is still quite limited. DN remains poorly understood due to the complexity of and differences in its etiology. Therefore, potential biomarkers for diagnosis and targeted treatments are urgently needed. Objective: The study aimed to analyze the associations between circulating total bile acid (TBA) levels and the risk of DN in Chinese patients with type 2 diabetes mellitus (T2DM) and to determine the differences in the TBA levels of males and females, including pre- and postmenopausal women, to find clues for the screening of DN. Design: The research team performed a retrospective study. Setting: The study took place at the Second Affiliated Hospital at the School of Medicine of Zhejiang University in Zhejiang, China. Participants: Participants were 1785 T2DM patients admitted to the hospital between April 2008 and November 2013. Groups: The research team separated participants into three groups: (1) the normoalbuminuria or normal group, with a UACR <30 mg/g·Cr (2) the microalbuminuria (MAU) group, with a UACR of 30-299 mg/g·Cr; and (3) the macroalbuminuria (MAC) group, with a UACR of ≥300 mg/g·Cr. Outcome Measures: Between the three groups, the research team compared: (1) the demographic and clinic characteristics of the normal, MAU, and MAC groups; (2) TBA distribution by age; (3) TBA distribution by gender; and (4) TBA quartiles. The team also examined the associations between TBA and albuminuria, identifying the odds ratios (OR) and relevant 95% confidence intervals (CI) using multiple logistic regression. Results: The study found that: (1) the MAC group's TBA was significantly lower than those of the normal and MAU groups; (2) the TBA of postmenopausal women was significantly higher than that of premenopausal women; (3) the incidence of MAC was obviously increased with TBA levels; (4) the risks for MAU group didn't change significantly with increasing TBA levels; (5) the MAC group's odds ratios (ORs) were 0.61 between Q2 and Q1, 0.44 between Q3 and Q1, and 0.38 between Q4 and Q1; and (6) for men and postmenopausal women, the TBA levels of those in Q3 and Q4 might decrease the risk of MAC, whereas no such correlation existed for MAU. Conclusions: An independent negative association exists between TBA levels and MAC in T2DM. The decrease of circulating TBA might be a prospective clinical factor for determining established DN, especially for males and postmenopausal females.

Maximum probability directed blind phase search for PS-QAM with variable shaping factors.

We report the maximum probability directed blind phase search (MPD-BPS) solution to enhance the carrier phase estimation (CPE) capability for the probabilistically shaped-quadrature amplitude modulation (PS-QAM) with variable shaping factors. We first investigate the trade-off between the shaping factor (SF) and the noise rejection window of the BPS for the PS-64/256QAM at a fixed signal to noise ratio (SNR). Next, we carry out the joint optimization of the SF and the noise rejection window, in order to obtain the maximum achievable information rate (AIR) at the fixed SNR. Then, we numerically compare the performance of the MPD-BPS and the traditional BPS for the PS-64/256QAM with variable SFs. Finally, we conduct the experimental verification of 32 Gbaud PS-64QAM with the SFs of 0.02, 0.025, 0.03, and 0.035, under scenarios of back-to-back (B2B) transmission and the standard single mode fiber (SSMF) loop transmission. The experimental results indicate that the proposed MPD-BPS can obtain an average 0.13 dB SNR enhancement under the B2B transmission and the 1.67% reach enhancement for the SSMF transmission, in comparison with the use of traditional BPS.

High-resolution pediatric age-specific 18F-FDG PET template: a pilot study in epileptogenic focus localization.

BACKGROUND: PET imaging has been widely used in diagnosis of neurological disorders; however, its application to pediatric population is limited due to lacking pediatric age-specific PET template. This study aims to develop a pediatric age-specific PET template (PAPT) and conduct a pilot study of epileptogenic focus localization in pediatric epilepsy. METHODS: We recruited 130 pediatric patients with epilepsy and 102 age-matched controls who underwent 18F-FDG PET examination. High-resolution PAPT was developed by an iterative nonlinear registration-averaging optimization approach for two age ranges: 6-10 years (n = 17) and 11-18 years (n = 50), respectively. Spatial normalization to the PAPT was evaluated by registration similarities of 35 validation controls, followed by estimation of potential registration biases. In a pilot study, epileptogenic focus was localized by PAPT-based voxel-wise statistical analysis, compared with multi-disciplinary team (MDT) diagnosis, and validated by follow-up of patients who underwent epilepsy surgery. Furthermore, epileptogenic focus localization results were compared among three templates (PAPT, conventional adult template, and a previously reported pediatric linear template). RESULTS: Spatial normalization to the PAPT significantly improved registration similarities (P < 0.001), and nearly eliminated regions of potential biases (< 2% of whole brain volume). The PAPT-based epileptogenic focus localization achieved a substantial agreement with MDT diagnosis (Kappa = 0.757), significantly outperforming localization based on the adult template (Kappa = 0.496) and linear template (Kappa = 0.569) (P < 0.05). The PAPT-based localization achieved the highest detection rate (89.2%) and accuracy (80.0%). In postsurgical seizure-free patients (n = 40), the PAPT-based localization also achieved a substantial agreement with resection areas (Kappa = 0.743), and the highest detection rate (95%) and accuracy (80.0%). CONCLUSION: The PAPT can significantly improve spatial normalization and epileptogenic focus localization in pediatric epilepsy. Future pediatric neuroimaging studies can also benefit from the unbiased spatial normalization by PAPT. TRIAL REGISTRATION: NCT04725162: https://clinicaltrials.gov/ct2/show/NCT04725162.

A novel analytic approach for outcome prediction in diffuse large B-cell lymphoma by [18F]FDG PET/CT.

PURPOSE: This study aimed to develop a novel analytic approach based on 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography/computed tomography ([18F]FDG PET/CT) radiomic signature (RS) and International Prognostic Index (IPI) to predict the progression-free survival (PFS) and overall survival (OS) of patients with diffuse large B-cell lymphoma (DLBCL). METHODS: We retrospectively enrolled 152 DLBCL patients and divided them into a training cohort (n = 100) and a validation cohort (n = 52). A total of 1245 radiomic features were extracted from the total metabolic tumor volume (TMTV) and the metabolic bulk volume (MBV) of pre-treatment PET/CT images. The least absolute shrinkage and selection operator (LASSO) algorithm was applied to develop the RS. Cox regression analysis was used to construct hybrid nomograms based on different RS and clinical variables. The performances of hybrid nomograms were evaluated using the time-dependent receiver operator characteristic (ROC) curve and the Hosmer-Lemeshow test. The clinical utilities of prediction nomograms were determined via decision curve analysis. The predictive efficiency of different RS, clinical variables, and hybrid nomograms was compared. RESULTS: The RS and IPI were identified as independent predictors of PFS and OS, and were selected to construct hybrid nomograms. Both TMTV- and MBV-based hybrid nomograms had significantly higher values of area under the curve (AUC) than IPI in training and validation cohorts (all P < 0.05), while no significant difference was found between TMTV- and MBV-based hybrid nomograms (P > 0.05). The Hosmer-Lemeshow test showed that both TMTV- and MBV-based hybrid nomograms calibrated well in the training and validation cohorts (all P > 0.05). Decision curve analysis indicated that hybrid nomograms had higher net benefits than IPI. CONCLUSION: The hybrid nomograms combining RS with IPI could significantly improve survival prediction in DLBCL. Radiomic analysis on MBV may serve as a potential approach for prognosis assessment in DLBCL. TRIAL REGISTRATION: NCT04317313. Registered March 16, 2020. Public site: https://clinicaltrials.gov/ct2/show/NCT04317313.

Long Term Prognostic Value Of SYNTAX Score II Among Stemi Patients-A Comprehensive Result From Meta-Analysis.

PURPOSE: To assess the predictive value of SS II (SYNTAX score II) for long-term outcomes in ST-elevated myoarial infarction (STEMI) patients.  Source: PubMed, EMBASE and Cochrane databases were searched up until September 24, 2021. Two investigators extracted data independently from the relevant articles. A random-effects model was conducted to combine the pooled hazard ratio (HR) or risk ratio (RR) for association between SS II and long term outcomes.  Principal findings: A total of 12 articles (7,195 subjects) were included in the final meta-analyses. Analysis of nine of the articles showed that higher SS II predicted poor long term all-cause mortality among STEMI patients (pooled RRs=4.09,95%CI: 3.49-4.80). A similar association of SS II with poor long term mortality was observed when the crude HRs and adjusted HRs were pooled (crude HRs: pooled HR=1.07, 95%CI: 1.04-1.09; adjusted HRs: pooled HR=1.05, 95%CI:1.04-1.07). The STEMI patients with higher SS II also showed a higher associated with increased risk of long term major adverse cardiac events (pooled HR = 1.05, 95% CI: 1.02-1.07; pooled RR=2.28, 95%CI:2.02-2.57). A consistent association was found for heart failure among STEMI patients.  Conclusion: Higher SS II predicted poor long term all-cause mortality, major adverse cardia events and heart failure among STEMI patients.

Fast and blind chromatic dispersion estimation with one sample per symbol.

We propose a fast and blind chromatic dispersion (CD) estimation method by one sample per symbol after coherent detection. The CD estimation process is non-data aided, without the iterative scanning to obtain the CD values. Moreover, we identify that the proposed CD estimation method is transparent to the used modulation format and robust to the transmission impairments, including amplified spontaneous emission (ASE) noise and fiber nonlinearity. When the 35-GBaud DP-16QAM signal with a roll-off factor of 0.1 is transmitted over standard single mode fiber (SSMF) with a range from 320-km to 560-km, the error of CD estimation is less than 150-ps/nm under the condition of 8192 symbols used.

A deep learning framework for 18F-FDG PET imaging diagnosis in pediatric patients with temporal lobe epilepsy.

PURPOSE: Epilepsy is one of the most disabling neurological disorders, which affects all age groups and often results in severe consequences. Since misdiagnoses are common, many pediatric patients fail to receive the correct treatment. Recently, 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) imaging has been used for the evaluation of pediatric epilepsy. However, the epileptic focus is very difficult to be identified by visual assessment since it may present either hypo- or hyper-metabolic abnormality with unclear boundary. This study aimed to develop a novel symmetricity-driven deep learning framework of PET imaging for the identification of epileptic foci in pediatric patients with temporal lobe epilepsy (TLE). METHODS: We retrospectively included 201 pediatric patients with TLE and 24 age-matched controls who underwent 18F-FDG PET-CT studies. 18F-FDG PET images were quantitatively investigated using 386 symmetricity features, and a pair-of-cube (PoC)-based Siamese convolutional neural network (CNN) was proposed for precise localization of epileptic focus, and then metabolic abnormality level of the predicted focus was calculated automatically by asymmetric index (AI). Performances of the proposed framework were compared with visual assessment, statistical parametric mapping (SPM) software, and Jensen-Shannon divergence-based logistic regression (JS-LR) analysis. RESULTS: The proposed deep learning framework could detect the epileptic foci accurately with the dice coefficient of 0.51, which was significantly higher than that of SPM (0.24, P < 0.01) and significantly (or marginally) higher than that of visual assessment (0.31-0.44, P = 0.005-0.27). The area under the curve (AUC) of the PoC classification was higher than that of the JS-LR (0.93 vs. 0.72). The metabolic level detection accuracy of the proposed method was significantly higher than that of visual assessment blinded or unblinded to clinical information (90% vs. 56% or 68%, P < 0.01). CONCLUSION: The proposed deep learning framework for 18F-FDG PET imaging could identify epileptic foci accurately and efficiently, which might be applied as a computer-assisted approach for the future diagnosis of epilepsy patients. TRIAL REGISTRATION: NCT04169581. Registered November 13, 2019 Public site: https://clinicaltrials.gov/ct2/show/NCT04169581.

Inhibition of Rac1 activity by NSC23766 prevents cartilage endplate degeneration via Wnt/ß-catenin pathway.

Cartilage endplate (CEP) degeneration has been considered as one of important factors related to intervertebral disc degeneration (IVDD). Previous researches have showed that Rac1 played a pivotal role in chondrocyte differentiation. However, the effect of Rac1 during the process of CEP degeneration remains unclear. Herein, we explored the effect of Rac1 on CEP degeneration and elucidated the underlying molecular mechanism. We found expression of Rac1-GTP increased in human-degenerated CEP tissue and IL-1ß-stimulated rat endplate chondrocytes (EPCs). Our study revealed that Rac1 inhibitor NSC23766 treatment promoted the expression of collagen II, aggrecan and Sox-9, and decreased the expression of ADTAMTS5 and MMP13 in IL-1ß-stimulated rat EPCs. Moreover, we also found that NSC23766 could suppress the activation of Wnt/ß-catenin pathway, suggesting that the beneficial effects of Rac1 inhibition in EPCs are mediated through the Wnt/ß-catenin signalling. Besides, puncture-induced rats models showed that NSC23766 played a protective role on CEP and disc degeneration. Collectively, these findings demonstrated that Rac1 inhibition delayed the EPCs degeneration and its potential mechanism may be associated with Wnt/ß-catenin pathway regulation, which may help us better understand the association between Rac1 and CEP degeneration and provide a promising strategy for delaying the progression of IVDD.

The projection of the thoracic nerve roots and their connection with intervertebral discs: a cadaver and radiological study.

BACKGROUND: The anatomical features of the thoracic nerve roots in connection with intervertebral discs may prevent surgery-related complications and improve patients' neurological functional status during thoracic spine surgery. There is limited literature evidence regarding this concept using cadavers. PURPOSE: To elucidate the qualitative anatomical features of the thoracic nerve roots in connection with intervertebral discs. MATERIAL AND METHODS: Fifteen formalin-preserved spine specimens were used in this study. Small pieces of stainless-steel wires were placed along the root sleeves from their points of origin, after exposing the dural sac and bilateral nerve roots. The standard anteroposterior and lateral radiographs were taken after the placement of the wires. Measurements were done on radiographs using the picture archiving communication system. RESULTS: Take-off angles of the nerve roots at the coronal plane gradually increased from the level of T2 (36.1°±2.72°) to T9 (84.1°±1.84°) and from T9, it decreased to T12 (46.3° ± 2.67°). Similar variation tendency was discovered in take-off angles of the nerve roots at the sagittal plane. No consistent tendency was found both in the distance from the origin of the root sleeve to its superior and inferior vertebral endplate. Distance from the origin of the root sleeve to the posterior midline (DM) exponentially decreased from T1 (8.2 ± 0.87 mm) to T4 (6.0 ± 0.93 mm). It slowly increased from T5 (5.5 ± 0.68 mm) to T12 (10.9 ± 1.79 mm), with T5 having the smallest DM. Distance between the origins of neighboring nerve roots showed an obvious increase from the T1-T2 interval (23.1 ± 2.22 mm) to T7-T8 interval (30.9 ± 2.68 mm). However, it progressively decreased at the T10-T11 interval (26.0 ± 2.40 mm). CONCLUSION: The dimensions of the thoracic nerve roots vary greatly from T1 to T12 intervertebral discs. Sound knowledge of these anatomical features of the thoracic nerve is mandatory for the thoracic spine surgery, especially in the posterolateral approach and transforaminal endoscopic surgery.

Does Quicker Mean Better? Comparison of Rapid Deployment Versus Conventional Aortic Valve Replacement.

The aim of this meta-analysis was to compare the clinical outcomes in patients who underwent rapid deployment aortic valve replacement (RDAVR) and conventional bio prosthetic aortic valve replacement (CAVR).We performed a literature search by August 2018. The primary outcomes were hospital and 1-year mortality, and the secondary endpoints included the aortic cross-clamp (ACC), cardiopulmonary bypass (CPB) time, and postoperative and valve-related complications.Two randomized controlled trials and 13 propensity score-matched studies were included. There was no difference between RDAVR and CAVR in hospital mortality (2.5% versus 2.1%; risk ratio (RR) 1.16 [95% confidence interval (CI) 0.80-1.68]) or 1-year mortality (2.9% versus 4.1%; RR 0.69 [95% CI 0.34-1.34]). RDAVR significantly reduced the ACC time ( (mean difference (MD) -24.33 [95% CI -28.35 to -20.32]) and CPB time (MD -21.51 [95% CI -22.83 to -20.20]). The pooled analysis showed that RDAVR doubled the occurrence of permanent pacemaker implantation (8.6% versus 4.3%; RR 2.05 [95% CI 1.62-2.60]). Meanwhile, the blood transfusion amount (MD -1.54 [95% CI -2.22 to -0.86]) and postoperative atrial fibrillation (POAF) occurrence (RR 0.83 [95% CI 0.69-0.99]) was reduced. The difference of paravalvular leakage frequency between RDAVR and CAVR was marginal (RR 1.77 [95% CI 1.00-3.17]; P = 0.05). Furthermore, RDAVR was related to larger valves (MD 0.70 cm [95% CI 0.33-1.07]) and lower mean pressure gradients (MD -1.93 mmHg [95% CI -3.58 to -0.28]).The hospital and 1-year survival rates between RDAVR and CAVR are comparable. RDAVR reduces POAF occurrence and blood transfusion but is associated with a higher occurrence of pacemaker implantation.

Glioma SOX2 expression decreased after adjuvant therapy.

BACKGROUND: SOX2 is regarded as an important marker in stem cell. The change of SOX2 expression after adjuvant therapy in high grade glioma (HGG) remains unknown so far. Few patients with recurrent glioma have opportunity to undergo operation once again, so the recurrent glioma samples are scarce. This study tries to analyze SOX2 expression in paired primary and recurrent HGG, aims to better understand the transformation law of SOX2 after adjuvant therapy in HGG. METHODS: Twenty-four recurrent HGG patients who undergone a second resection were included. 16 patients received adjuvant therapy, the remaining 8 patients didn't receive any adjuvant therapy at all. The protein expression of SOX2 in paired primary and recurrent HGG was tested by immunohistochemistry. The statistical analysis was conducted by IBM SPSS Statistics 19.0. RESULTS: In primary HGG, SOX2 expression of 3 + , 2 + , 1+ and 0+ were seen in 20 (83.3%), 1 (4.2%), 1 (4.2%) and 2 cases (8.3%), respectively. The expression of SOX2 was decreased in recurrent HGG compared to the paired primary sample (p = 0.001). The decrease of SOX2 was often seen in patients received chemotherapy, radiotherapy or both (p = 0.003). Patients with SOX2 high expression in primary glioma had a longer median PFS than those with SOX2 low expression with marginal statistic significance (12.7 vs. 5.4 months, p = 0.083). For cases with SOX2 high expression in the primary glioma, those had SOX2 low expression after recurrence seemed to have worse prognosis as compared to patients with stable SOX2 high expression (PFS: 10.4 vs. 14.9 months, p = 0.036; OS: 27.0 vs 49.5 months, p = 0.005). CONCLUSIONS: This is the first study comparing the protein expression of SOX2 in recurrent HGG and its paired primary tumor. SOX2 high expression is common in brain HGG, a tendency of decreased SOX2 expression in recurrent gliomas was evidenced. Lower SOX2 expression was seen in those patients who received adjuvant chemotherapy and/or radiotherapy. Patients with low SOX2 expression in primary HGG usually have poorer prognosis, those with SOX2 expression decreased in recurrent HGG had worse outcome.