Identification of molecular subtypes and diagnostic model in clear cell renal cell carcinoma based on collagen-related genes may predict the response of immunotherapy.

Background: Collagen represents a prominent constituent of the tumor's extracellular matrix (ECM). Nonetheless, its correlation with the molecular subtype attributes of clear cell renal cell carcinoma (ccRCC) remains elusive. Our objective is to delineate collagen-associated molecular subtypes and further construct diagnostic model, offering insights conducive to the precise selection of ccRCC patients for immunotherapeutic interventions. Methods: We performed unsupervised non-negative matrix factorization (NMF) analysis on TCGA-KIRC samples, utilizing a set of 33 collagen-related differentially expressed genes (33CRDs) for clustering. Our analysis encompassed evaluations of subtype-associated differences in pathways, immune profiles, and somatic mutations. Through weighted gene co-expression network analysis (WGCNA) and four machine learning algorithms, two core genes were found and a diagnostic model was constructed. This was subsequently validated in a clinical immunotherapy cohort. Single cell sequencing analysis and experiments demonstrated the role of core genes in ccRCC. Finally, we also analyzed the roles of MMP9 and SCGN in pan-cancer. Results: We described two novel collagen related molecular subtypes in ccRCC, designated subtype 1 and subtype 2. Compared with subtype 1, subtype 2 showed more infiltration of immune components, but had a higher TIDE (tumor immunedysfunctionandexclusion) score and increased levels of immune checkpoint molecules. Furthermore, reduced prognosis for subtype 2 was a consistent finding in both high and low mutation load subgroups. MMP9 and SCGN were identified as key genes for distinguishing subtype 1 and subtype 2. The diagnostic model based on them could better distinguish the subtype of patients, and the differentiated patients had different progression free survival (PFS) in the clinical immunotherapy cohort. MMP9 was predominantly expressed in macrophages and has been extensively documented in the literature. Meanwhile, SCGN, which was overexpressed in tumor cells, underwent experimental validation, emphasizing its role in ccRCC. In various cancers, MMP9 and SCGN were associated with immune-related molecules and immune cells. Conclusion: Our study identifies two collagen-related molecular subtypes of ccRCC and constructs a diagnostic model to help select appropriate patients for immunotherapy.

A Pilot Study of a Finger Kinematic Parameter-Based Tool for Evaluating Degenerative Cervical Myelopathy.

STUDY DESIGN: This is a cross-sectional study. OBJECTIVE: To evaluate the effectiveness of a novel finger Kinematic Parameter-Based Tool in the grip and release (G&R) test for assessing degenerative cervical myelopathy (DCM). SUMMARY OF BACKGROUND DATA: The development and progression of DCM symptoms are gradual and obscure. Although previous studies have objectively evaluated hand movements specific to myelopathy using the G&R test, virtual reality, or wearable sensors, these methods have limitations, such as limited discrimination or inconvenience for simple screening. Consequently, there is a need to develop effective screening methods. MATERIALS AND METHODS: Totally, 297 asymptomatic volunteers and 258 DCM patients were enrolled. This system comprises a wearable acceleration/gyro sensor. The acceleration/gyro sensor was placed on the little finger of the participants to perform 40 cycles of full-range G&R as quickly as possible. The collected data were then transformed into kinematic parameters using sensor-based software and R studio software (version: RStudio 2022.07.2+576, Boston, USA). Gender, age, and body mass index (BMI) subgroups (classified as BMI<18.5-below normal weight; 18.5≤BMI<25-normal weight group; BMI≥25-overweight group) were matched as predictor variables, and 201 pairs were matched. Nonparametric analysis using the Mann-Whitney U test was used for diagnosing the differences between the two groups, and Kruskal-Wallis's test followed by the Mann-Whitney U test was used for analyzing the differences among three different age groups (<40, 41-60, and >60 yr group). The cut-off value of 10s G&R cycles and a combined parameter were determined using receiver operating characteristics curve analysis, area under the curve, and Youden index. RESULTS: The authors found that little finger kinematic parameters were significantly lower in DCM patients than in asymptomatic participants. The optimal diagnostic indicator appeared to be the average of the top 10 linear accelerations with an area under the curve of 0.923. CONCLUSION: The Finger Kinematic Test System is an objective, practical, and quantitative utility that appears to have the capacity to diagnose and evaluate the severity of DCM. LEVEL OF EVIDENCE: 3.

Predictive value of vertebral Hounsfiled Unit for titanium mesh cage subsidence following ACCF surgery.

OBJECTIVE: To investigate the predictive value of cervical Hounsfiled Unit (HU) values for postoperative titanium mesh cage (TMC) subsidence. METHODS: Clinical data of patients who underwent ACCF surgery for degenerative cervical myelopathy between January 2016 and August 2018 were analyzed. Among the 126 patients included, 74 were male and 52 were female, with a mean age of 61.0 ± 9.9 years. The mean follow-up was 37.1 ± 11.2 months. Preoperative vertebral HU values were measured and the degree of TMC subsidence during follow-up was assessed. Patients were divided into two groups according to the presence or absence of subsidence: the subsidence group and the control group. Vertebral HU values were compared between the two groups, and correlation analysis was performed between HU values and TMC subsidence values. In addition, the predictive value and threshold of HU were analyzed by using ROC. RESULTS: There were 22 patients (14 males and 8 females) who developed TMC subsidence (subsidence group), while 104 patients (60 males and 44 females) did not develop TMC subsidence (control group) during follow-up. Comparative analysis of demographic characteristics between the two groups showed no significant differences in gender, age, BMI, diagnosis, surgical levels, and follow-up duration (all P values > 0.05). There was a significant difference in mean HU between the subsidence group (287.6 ± 49.6) and the control group (342.4 ± 61.4) (t = -3.92, P < 0.01). In the subsidence group, there was a significant correlation between subsidence values and HU values (r = -0.52, P = 0.01), whereas no such correlation was observed in the control group (r = - 0.07, P = 0.51). ROC analysis indicated that vertebral HU values could potentially be used to predict subsidence after ACCF, with an area under the ROC curve of 0.77 (95% CI 0.66-0.87; P < 0.01). The optimal HU threshold was found to be 298, with a sensitivity of 76.9% and specificity of 68.2%. CONCLUSION: Preoperative vertebral HU values were associated with postoperative TMC subsidence. Vertebral HU may be a valuable predictor of postoperative subsidence.

Targeting CBX3 with a Dual BET/PLK1 Inhibitor Enhances the Antitumor Efficacy of CDK4/6 Inhibitors in Prostate Cancer.

The development of castration-resistant prostate cancer (CRPC) is a significant factor that reduces life expectancy among patients with prostate cancer. Previously, it is reported that CDK4/6 inhibitors can overcome the resistance of CRPC to BET inhibitors by destabilizing BRD4, suggesting that the combination of CDK4/6 inhibitors and BET inhibitors is a promising approach for treating CRPC. In this study, candidates that affect the combined antitumor effect of CDK4/6 inhibitors and BET inhibitors on CRPC is aimed to examine. The data demonstrates that CBX3 is abnormally upregulated in CDK4/6 inhibitors-resistant cells. CBX3 is almost positively correlated with the cell cycle in multiple malignancies and is downregulated by BET inhibitors. Mechanistically, it is showed that CBX3 is transcriptionally upregulated by BRD4 in CRPC cells. Moreover, it is demonstrated that CBX3 modulated the sensitivity of CRPC to CDK4/6 inhibitors by binding with RB1 to release E2F1. Furthermore, it is revealed that PLK1 phosphorylated CBX3 to enhance the interaction between RB1 and CBX3, and desensitize CRPC cells to CDK4/6 inhibitors. Given that BRD4 regulates CBX3 expression and PLK1 affects the binding between RB1 and CBX3, it is proposed that a dual BRD4/PLK1 inhibitor can increase the sensitivity of CRPC cells to CDK4/6 inhibitors partially through CBX3.

Risk Factors for Short-Term and Long-Term Low Back Pain After Transforaminal Endoscopic Lumbar Discectomy.

Introduction: Low back pain following transforaminal endoscopic lumbar discectomy (TELD) is prevalent (15-25% incidence). Modifying TELD techniques to avoid excessive disc removal has been suggested to reduce such pain. Facet injury, re-herniation, and disc space collapse might contribute. This retrospective study aimed to explore factors linked to post-TELD low back pain. Methods: A total of 351 patients with L3/4, L4/5, and L5/S1 intervertebral lumbar disc herniations, who underwent TELD at two spine centers, were included. Patients were followed for one year. Low back and leg pain visual analogue scale (VAS) scores, Oswestry Disability Index (ODI), Pfirrmann grade, and disc height were measured at 3 months and 1 year. Correlation analyses examined links between postoperative low back pain VAS scores, age, sex, disc/vertebrae height ratio (D/V H ratio), Pfirrmann grade, cannula position grade, re-herniation grade, high-intensity zone (HIZ), disc calcification, surgical grade, and other factors. Significant variables were identified using partial least square tests, with variable importance in projection (VIP) values quantifying their impact on low back pain. Results: Univariate analysis indicated that surgical grade correlated with long-term postoperative low back pain (P = 0.023), while re-herniation (P = 0.008, P = 0.000), disc height (P = 0.001, P = 0.034), and sex (P = 0.025, P = 0.003) correlated with both short- and long-term postoperative low back pain. Trephine/cannula position is correlated with short-term low back pain (P = 0.036). Worsening low back pain was associated with female sex, improper trephine/cannula position, re-herniation, and post-surgical disc space collapse. Intradiscal irrigation was linked to decreased low back pain. Discussion: This study highlights factors influencing low back pain after TELD. Loss of disc height, extent of re-herniation, quality of trephine/cannula position, and sex were associated with low back pain at both 3 months and 1-year post-TELD. Proper techniques, like minimizing disc height loss and re-herniation, may help mitigate postoperative low back pain.

Metronomic capecitabine inhibits liver transplant rejection in rats by triggering recipients' T cell ferroptosis.

BACKGROUND: Capecitabine (CAP) is a classic antimetabolic drug and has shown potential antirejection effects after liver transplantation (LT) in clinical studies. Our previous study showed that metronomic CAP can cause the programmed death of T cells by inducing oxidative stress in healthy mice. Ferroptosis, a newly defined non-apoptotic cell death that occurs in response to iron overload and lethal levels of lipid peroxidation, is an important mechanism by which CAP induces cell death. Therefore, ferroptosis may also play an important role in CAP-induced T cell death and play an immunosuppressive role in acute rejection after trans-plantation. AIM: To investigate the functions and underlying mechanisms of antirejection effects of metronomic CAP. METHODS: A rat LT model of acute rejection was established, and the effect of metronomic CAP on splenic hematopoietic function and acute graft rejection was evaluated 7 d after LT. In vitro, primary CD3+ T cells were sorted from rat spleens and human peripheral blood, and co-cultured with or without 5-fluorouracil (5-FU) (active agent of CAP). The levels of ferroptosis-related proteins, ferrous ion concentration, and oxidative stress-related indicators were observed. The changes in mito-chondrial structure were observed using electron microscopy. RESULTS: With no significant myelotoxicity, metronomic CAP alleviated graft injury (Banff score 9 vs 7.333, P < 0.001), prolonged the survival time of the recipient rats (11.5 d vs 16 d, P < 0.01), and reduced the infiltration rate of CD3+ T cells in peripheral blood (6.859 vs 3.735, P < 0.001), liver graft (7.459 vs 3.432, P < 0.001), and spleen (26.92 vs 12.9, P < 0.001), thereby inhibiting acute rejection after LT. In vitro, 5-FU, an end product of CAP metabolism, induced the degradation of the ferritin heavy chain by upregulating nuclear receptor coactivator 4, which caused the accumulation of ferrous ions. It also inhibited nuclear erythroid 2 p45-related factor 2, heme oxygenase-1, and glutathione peroxidase 4, eventually leading to oxidative damage and ferroptosis of T cells. CONCLUSION: Metronomic CAP can suppress acute allograft rejection in rats by triggering CD3+ T cell ferroptosis, which makes it an effective immunosuppressive agent after LT.

Application of TVD-Net for sagittal alignment and instability measurements in cervical spine radiographs.

BACKGROUND: Cervical spinal malalignment and instability are frequently occurring pathological conditions involving neck pain, radiculopathy, and myelopathy, often requiring surgical intervention. Accurate assessment of cervical alignment and instability are essential in surgical planning and evaluating postoperative outcomes. PURPOSE: To automatically measure the sagittal alignment and instability of the cervical spine, we develop a novel deep-learning model by detecting landmarks on cervical radiographs. METHODS: We introduce the transformer-embedded residual network (ResNet) as the network's core to automatically identify vertebral landmarks on digital and film-transformed cervical radiographs, and simultaneously measure the segmental Cobb angle and horizontal displacement. A Transformer Module was embedded into the latent space to extract the relationship between different vertebrae. Then a Rotating Attention Module was integrated between the encoder-decoder pairs to highlight the key points and maintain more details. Finally, a Vector Loss Module was proposed to restrain the orientation of the adjacent vertebra to reduce misdetection. All images were obtained from local hospital. Digital images were split into training, validation, and test subsets (896, 225, and 353 images, respectively). Likewise, film-transformed images were split into 404, 115, and 150 images, respectively. The results of the model were compared with manual measurements. RESULTS: Our deep learning algorithm achieved mean absolute difference (MAD) at a level of 2.20° and 2.33°, symmetric mean absolute error(SMAPE)at 16.63% and 19.35%, respectively, when measuring Cobb angle on digital images and films. On evaluating cervical instability, the diagnostic accuracy, sensitivity, specificity, precision, and F1-score evaluation metrics were calculated. The corresponding values were 89.80%, 86.49%, 90.68%, 71.11%, and 78.05% on digital images, and 90.00%, 83.78%, 91.15%, 75.61%, and 79.49% on film-transformed images, which were comparable to experienced surgeons. Visualization results demonstrated robust effectiveness in subjects with severe osteophytes or artifacts. CONCLUSION: This study presents a novel and efficient deep-learning model to assist landmarks identification and angulation and displacement calculation on lateral cervical spine radiographs, and demonstrates excellent accuracy in measuring cervical alignment and sound sensitivity and specificity in cervical instability diagnosis. It should be helpful for future research and clinical applications.

Low-dose celecoxib-loaded PCL fibers reverse intervertebral disc degeneration by up-regulating CHSY3 expression.

Intervertebral disc degeneration (IDD) has been identified as one of the predominant factors leading to persistent low back pain and disability in middle-aged and elderly people. Dysregulation of Prostaglandin E2 (PGE2) can cause IDD, while low-dose celecoxib can maintain PGE2 at the physiological level and activate the skeletal interoception. Here, as nano fibers have been extensively used in the treatment of IDD, novel polycaprolactone (PCL) nano fibers loaded with low-dose celecoxib were fabricated for IDD treatment. In vitro studies demonstrated that the nano fibers had the ability of releasing low-dose celecoxib slowly and sustainably and maintain PGE2. Meanwhile, in a puncture-induced rabbit IDD model, the nano fibers reversed IDD. Furthermore, low-dose celecoxib released from the nano fibers was firstly proved to promote CHSY3 expression. In a lumbar spine instability-induced mouse IDD model, low-dose celecoxib inhibited IDD in CHSY3wt mice rather than CHSY3-/- mice. This model indicated that CHSY3 was indispensable for low-dose celecoxib to alleviate IDD. In conclusion, this study developed a novel low-dose celecoxib-loaded PCL nano fibers to reverse IDD by maintaining PGE2 at the physiological level and promoting CHSY3 expression.

A novel predictive model of microvascular invasion in hepatocellular carcinoma based on differential protein expression.

BACKGROUND: This study aims to construct and verify a nomogram model for microvascular invasion (MVI) based on hepatocellular carcinoma (HCC) tumor characteristics and differential protein expressions, and explore the clinical application value of the prediction model. METHODS: The clinicopathological data of 200 HCC patients were collected and randomly divided into training set and validation set according to the ratio of 7:3. The correlation between MVI occurrence and primary disease, age, gender, tumor size, tumor stage, and immunohistochemical characteristics of 13 proteins, including GPC3, CK19 and vimentin, were statistically analyzed. Univariate and multivariate analyzes identified risk factors and independent risk factors, respectively. A nomogram model that can be used to predict the presence of MVI was subsequently constructed. Then, receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA) were conducted to assess the performance of the model. RESULTS: Multivariate logistic regression analysis indicated that tumor size, GPC3, P53, RRM1, BRCA1, and ARG were independent risk factors for MVI. A nomogram was constructed based on the above six predictors. ROC curve, calibration, and DCA analysis demonstrated the good performance and the clinical application potential of the nomogram model. CONCLUSIONS: The predictive model constructed based on the clinical characteristics of HCC tumors and differential protein expression patterns could be helpful to improve the accuracy of MVI diagnosis in HCC patients.

Serum estradiol to testosterone ratio as a novel predictor of severe preeclampsia in the first trimester.

Preeclampsia (PE) is the most common medical complication during pregnancy and the second leading cause of maternal death worldwide. However, a better predictive model of PE remains to be explored. A total of 15 severe preeclampsia (sPE) and 75 healthy control patients were included in this study. Patient data was obtained from September 2019 to September 2021. Nuchal translucency (NT) and crown-rump length (CRL) of the fetus were acquired by ultrasound. Maternal blood samples were collected at 11+0 to 13+6  weeks of gestation. Chemiluminescent immunoassays were used to detect serum testosterone (T) and estradiol (E2) levels. Time-resolved fluorescence analysis was used to examine the levels of serum pregnancy-associated plasma protein A (PAPPA) and ß-human chorionic gonadotrophin (ß-HCG) protein. The sPE group exhibited increased T levels, and decreased E2 levels and E2/T ratios from 11 to 14 weeks of gestation, compared with the control group. E2 and the E2/T ratio showed positive linear correlation with CRL in pregnant women. Body-mass-index (BMI), T, and E2 were determined to be the main factors that affected the occurrence of sPE at the 12-week gestation period time point. The receiver operating characteristic (ROC) curve revealed that the AUC of the E2/T ratio was .717. The imbalanced T and E2 levels in the patients had a specific intrinsic relevance with sPE, which suggests them as novel predictors of the sPE.

Continuous release of mefloquine featured in electrospun fiber membranes alleviates epidural fibrosis and aids in sensory neurological function after lumbar laminectomy.

Recurrent low back pain after spinal surgeries, such as lumbar laminectomy, is a major complication of excessive epidural fibrosis. Although multiple preclinical and clinical methods have been aimed at ameliorating epidural fibrosis, their safety and efficacy remain largely unclear. Single implanted electrospun fibrous membranes provide physical barriers that can decrease tissue fibrosis after surgery; however, they also trigger local inflammation due to the implantation of a foreign body, thus subsequently attenuating their anti-fibrosis properties. Here, we designed a strategy that permits easy incorporation of mefloquine into polylactic acid membranes, and stable long-term mefloquine release, to potentially improve anti-fibrosis effects and relieve or prevent low back pain. The electrospun fibrous membranes grafted with mefloquine showed a well-controlled early temporary peak release, and secondary drug release occurred smoothly over several weeks. Histopathological and histomorphometric results indicated that the drug-loaded membranes had excellent anti-fibrosis effects after laminectomy in rats. Inflammation and neovascularization at the surgical site indicated that the mefloquine-grafted electrospun fibrous membranes provided sustained anti-inflammatory outcomes while effectively alleviating associated neuropathic pain hypersensitivity. In summary, our study indicated that polylactic acid-mefloquine grafted electrospun fibrous membranes may be a potential local agent to mitigate epidural fibrosis and support sensory neurological function after laminectomy, thereby potentially improving patients' postoperative outcomes.

Sensory Nerve Maintains Intervertebral Disc Extracellular Matrix Homeostasis Via CGRP/CHSY1 Axis.

Sensory nerves are long being recognized as collecting units of various outer stimuli; recent advances indicate that the sensory nerve also plays pivotal roles in maintaining organ homeostasis. Here, this study shows that sensory nerve orchestrates intervertebral disc (IVD) homeostasis by regulating its extracellular matrix (ECM) metabolism. Specifically, genetical sensory denervation of IVD results in loss of IVD water preserve molecule chondroitin sulfate (CS), the reduction of CS bio-synthesis gene chondroitin sulfate synthase 1 (CHSY1) expression, and dysregulated ECM homeostasis of IVD. Particularly, knockdown of sensory neuros calcitonin gene-related peptide (CGRP) expression induces similar ECM metabolic disorder compared to sensory nerve denervation model, and this effect is abolished in CHSY1 knockout mice. Furthermore, in vitro evidence shows that CGRP regulates nucleus pulposus cell CHSY1 expression and CS synthesis via CGRP receptor component receptor activity-modifying protein 1 (RAMP1) and cyclic AMP response element-binding protein (CREB) signaling. Therapeutically, local injection of forskolin significantly attenuates IVD degeneration progression in mouse annulus fibrosus puncture model. Overall, these results indicate that sensory nerve maintains IVD ECM homeostasis via CGRP/CHSY1 axis and promotes IVD repair, and this expands the understanding concerning how IVD links to sensory nerve system, thus shedding light on future development of novel therapeutical strategy to IVD degeneration.

Expression of ALG3 in Hepatocellular Carcinoma and Its Clinical Implication.

Background: Recent studies have shown that alpha-1,3-mannosyltransferase (ALG3) promoted tumorigenesis and progression in multiple cancer types. Our study planned to explore the clinical implication and potential function of ALG3 in hepatocellular carcinoma. Materials and Methods: Data from public databases were used to analyze the ALG3 expression and its impact on the clinical significance of patients with HCC. The ALG3 expression was confirmed by qRT-PCR and Western blot. Immunohistochemistry was used to confirm the ALG3 expression and explore its clinical implication in HCC. KEGG, GO, and GSEA enrichment analyses were utilized to explore the biological pathways related to ALG3 in HCC. TIMER2.0 was applied to assess the association between ALG3 and immune infiltration. CCK8, MTT, and transwell assays were used to investigate the role of ALG3 downregulation in HCC cell lines. Results: qRT-PCR, WB, and IHC proved ALG3 was highly overexpressed in HCC tissues. The Kaplan-Meier analysis verified the overexpression of ALG3 was related to poor overall survival (p < 0.001). Multivariate cox regression analysis showed that the high ALG3 expression was an independent risk prognostic factor. GSEA and TIMER2.0 predicted that ALG3 participates in cell differentiation and cycle and correlates with immune cell infiltration. Transwell assay results showed that ALG3 silencing also impaired the invasion ability of HCC cells. Conclusion: ALG3 was overexpressed and considered a potential indicator of survival in HCC, and our findings provided a novel therapeutic target for HCC.

Analysis of time-space variations during dynamic cervical spine motion in cervical spondylosis myelopathy patients.

BACKGROUND CONTEXT: Decreased cervical range of motion (ROM) is a common symptom of myelopathy patients. Many previous studies have relied on a variety of experimental approaches for quantifying static cervical range of motion. However, the change rules of time-space variation during dynamic cervical spine motion remains unknown. PURPOSE: To develop and validate the effectiveness of a novel wearable robot-based sensor system, Analysis of Dynamic Cervical spine Motion (ADCM), in evaluating the dynamic cervical spine motion dysfunction of patients with cervical spondylotic myelopathy (CSM). STUDY DESIGN/SETTING: A cross-sectional study. PATIENT SAMPLE: One hundred forty consecutive healthy individuals (70 men and 70 women) and 120 CSM patients (60 men and 60 women) were enrolled in the present study. OUTCOME MEASURES: The cervical motion process parameters, including the flexion and extension ROM, the flexion and extension time, and the Japanese Orthopedic Association scores (JOA) for cervical spine were measured. METHODS: Two hundred and sixty consecutive participants were asked to wear ADCM system and then fully flex and extend their neck rapidly and evenly at tolerable maximum speed. The cervical motion process was recorded and converted into waveforms. Relevant waveform parameters were measured and analyzed. The number of complete flexion-extension motions in 10 seconds has been defined as 10s F-E cycles. The Japanese Orthopedics Association (JOA) scores of CSM patients were marked. RESULTS: CSM patients had a lower number of 10s F-E cycles than healthy subjects. There were significant differences in flexion and extension time and ROM between two groups. The waveforms of myelopathy patients were wider and lower than those in healthy individuals. The average ratio value (defined as F) of wave height to wave width (a+b/c+d) could quantitatively reflect such differences of waveforms. The average F value was correlated with the JOA scores of the cervical motion function (r=0.7538), and F value declined as JOA scores decreased. According to receiver operating characteristic curve analysis, the optimal threshold value of the normal average ratio was more than 34.7. CONCLUSIONS: ADCM appears to be an objective and quantitative severity assessment tool for confirmed CSM patients by evaluating dynamic cervical spine motion dysfunction.

Bi-Needle PELD with Intra-Discal Irrigation Technique for the Management of Lumbar Disc Herniation.

BACKGROUND: Lumbar disc herniation (LDH) is the most common cause of sciatica. Percutaneous endoscopic discectomy (PELD) is indicated when conservative treatments fail, which has been proved effective. During conventional PELD, ruptured discs and loose fragments inside discs are removed as much as possible to guarantee a lower reherniation rate, but it inevitably would lead to deterioration of disc degeneration and loss of disc height after PELD. Ensuring sufficient decompression while alleviating the post-operation disc degeneration process is still a clinical problem. OBJECTIVE: To evaluate the imaging and clinical outcomes of bi-needle PELD with intradiscal irrigation technique for the treatment of lumbar disc herniation (LDH). STUDY DESIGN: Multicenter retrospective cohort study. SETTING: Shanghai Changzheng Hospital, Naval Medical University, Shanghai, China. METHODS: A total of 48 patients who underwent bi-needle PELD (B-PELD) or conventional-PELD (C-PELD) for LDH in our 2 spine centers were included in this study. There were 26 cases in the C-PELD group (male 12 cases, female 14 cases) with an average age of 34.6 ± 6.8 years. And there were 22 patients in the B-PELD group (male 10 cases, female 12 cases) with an average age of 35.1 ± 6.4 years. The difference in postoperative disc degeneration (Pfirrmann grades, disc-vertebra height ratios [D-V H ratios]), visual analog scale (VAS) of low back pain, and reoperation rates were compared between the 2 groups. RESULTS: There was no significant difference in gender, age, disease duration, and surgical level between the 2 groups (P > 0.05). The postoperative VAS of back pain was 2.31 ± 0.53 for the C-PELD group and 0.63 ± 0.74 for the B-PELD group; the difference was significant (P = 0.013). The difference between the preoperative and postoperative D-V H ratios in the C-PELD group was significant (P < 0.0001), while it was not significant in the B-PELD group (P = 0.6708). The difference between the loss of D-V H ratios after surgery was significant between the 2 groups (P = 0.0003). The loss of D-V H ratios was higher in the C-PELD group. The difference between the preoperative and postoperative Pfirrmann grades in the B-PELD group was not significant (P = 0.7261); however, it was significant in the C-PELD group (P = 0.0012). The reoperation rate in the C-PELD group was 7.7%, and the reoperation rate in the B-PELD group was 4.5%; the difference was not significant (P = 1). LIMITATIONS: This study employed a retrospective design, and its inherent selection bias and limited statistical power should be considered. CONCLUSIONS: Bi-needle technique with saline irrigation maneuver showed a significant advantage of restoration of disc height and amelioration of disc degeneration compared to conventional PELD surgery.

Beneficial effects of endoscopic screening on gastric cancer and optimal screening interval: a population-based study.

BACKGROUND : The effectiveness of endoscopic screening on gastric cancer has not been widely investigated in China and the screening interval of repeated screening has not been determined. METHODS : In a population-based prospective study, we included 375,800 individuals, 14,670 of whom underwent endoscopic screening (2012-2018). We assessed the associations between endoscopic screening and risk of incident gastric cancer and gastric cancer-specific mortality, and examined changes in overall survival and disease-specific survival following screening. The optimal screening interval for repeated endoscopy for early detection of gastric cancer was explored. RESULTS : Ever receiving endoscopic screening significantly decreased the risk of invasive gastric cancer (age- and sex-adjusted relative risk [RR] 0.69, 95 % confidence interval [CI] 0.52-0.92) and gastric cancer-specific mortality (RR 0.33, 95 %CI 0.20-0.56), particularly for noncardia gastric cancer. Repeated screening strengthened the beneficial effect on invasive gastric cancer-specific mortality of one-time screening. Among invasive gastric cancers, screening-detected individuals had significantly better overall survival (RR 0.18, 95 %CI 0.13-0.25) and disease-specific survival (RR 0.18, 95 %CI 0.13-0.25) than unscreened individuals, particularly for those receiving repeated endoscopy. For individuals with intestinal metaplasia or low grade intraepithelial neoplasia, repeated endoscopy at an interval of < 2 years, particularly within 1 year, significantly enhanced the detection of early gastric cancer, compared with repeated screening after 2 years (P-trend = 0.02). CONCLUSION : Endoscopic screening prevented gastric cancer occurrence and death, and improved its prognosis in a population-based study. Repeated endoscopy enhanced the effectiveness. Screening interval should be based on gastric lesion severity.

Increased Expression of Integrin Alpha 6 in Nucleus Pulposus Cells in Response to High Oxygen Tension Protects against Intervertebral Disc Degeneration.

The destruction of the low oxygen microenvironment in nucleus pulposus (NP) cells played a critical role in the pathogenesis of intervertebral disc degeneration (IVDD). The purpose of this study was to determine the potential role of integrin alpha 6 (ITG α6) in NP cells in response to high oxygen tension (HOT) in IVDD. Immunofluorescence staining and western blot analysis showed that the levels of ITG α6 expression were increased in the NP tissue from IVDD patients and the IVDD rat model with mild degeneration, which were reduced as the degree of degeneration increases in severity. In NP cells, the treatment of HOT resulted in upregulation of ITG α6 expression, which could be alleviated by blocking the PI3K/AKT signaling pathway. Further studies found that ITG α6 could protect NP cells against HOT-induced apoptosis and oxidative stress and protect NP cells from HOT-inhibited ECM protein synthesis. Upregulation of ITG α6 expression by HOT contributed to maintaining NP tissue homeostasis through the interaction with hypoxia-inducible factor-1α (HIF-1α). Furthermore, silencing of ITG α6 in vivo could obviously accelerate puncture-induced IVDD. Taken together, these results revealed that the increase of ITG α6 expression by HOT in NP cells might be a protective factor in IVD degeneration as well as restore NP cell function.

Tumor Cell-Derived Exosomal Circ-0072088 Suppresses Migration and Invasion of Hepatic Carcinoma Cells Through Regulating MMP-16.

Background: Tumor-derived exosomes (EXOs), commonly differentially expressed in circular RNAs, have been shown to be crucial determinants of tumor progression and may regulate the development and metastasis of hepatic carcinoma (HCC). Methods: Possibly differentially expressed circRNAs in patients with HCC were screened out from the Gene Expression Omnibus (GEO). EXOs were isolated from the culture medium of HCC cells and plasma of patients with HCC, followed by characterization by transmission electron microscope, NanHCCight, and western blotting. Additionally, RNA immunoprecipitation and luciferase reporter gene assays were carried out to explore the molecular mechanism of hsa_circRNA_103809 (circ-0072088) in HCC cells. Results: The screening results showed that circ-0072088 was highly expressed in patients with HCC, and its increase indicated unfavorable prognosis of patients according to quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Additionally, circ-0072088 was mainly secreted by HCC cells via EXOs in plasma of such patients, and its high level in plasma EXOs was closely associated with tumor node metastasis (TNM) staging and tumor size. Moreover, HCC-secreted EXOs mediated the degradation of miR-375 via circ-0072088 and upregulated MMP-16, thus suppressing the metastasis of HCC. Conclusion: Upregulated in patients with HCC, circ-0072088 may be an index for diagnosis and prognosis of HCC. In addition, HCC-derived EXOs coated with circ-0072088 might be a treatment for HCC, with the ability to inhibit the metastasis of HCC cells.

Capecitabine Can Induce T Cell Apoptosis: A Potential Immunosuppressive Agent With Anti-Cancer Effect.

Capecitabine (CAP) is now widely used in the comprehensive treatment of digestive system tumors. Some clinical observations have shown that CAP may have immunosuppressive effects, but there is still a lack of clear experimental verification. In this study, different doses of CAP were administered to normal mice by gavage. Our results confirmed that CAP did not cause myelosuppression in bone marrow tissue; CAP selectively reduced the proportion of T cells and the concentration of related pro-inflammatory cytokines, while it increased the concentration of anti-inflammatory cytokines. Thymidylate phosphorylase (TP) is the key enzyme for the transformation of CAP in vivo; this study confirmed that T cells express TP, but the bone marrow tissue lacks TP expression, which explains the selectivity in pharmacodynamic effects of CAP. In addition, it was confirmed that CAP can induce T cell apoptosis in vivo and in vitro. In vitro experiments showed that CAP-induced T cell apoptosis was related to TP expression, endoplasmic reticulum stress (ERS) induction, reactive oxygen species (ROS) production, and mitochondria-mediated apoptosis activation. Therefore, this study confirmed that the differential expression of TP in cells and tissues explains why CAP avoids the toxic effects of myelosuppression while inducing T cell apoptosis to exert the immunosuppressive effect. Therefore, CAP may become an immunosuppressive agent with a simultaneous anti-cancer effect, which is worthy of further studies.

Fever as a rare combined symptom of degenerative cervical myelopathy: a case report and literature review.

A 60-year-old male patient complained of weakness of both legs for one year, intermittent fever for two months, up to 38.0 °C. Physical examination showed bilateral hyperreflexia of knee tendon and positive Hoffman sign on the right side. MR imaging of the cervical spine showed central herniation of the cervical 5-7 disc and compression of the spinal cord. The WBC was normal, C-reactive protein was 24.42mg/l, ESR was 55mm/h, TB antibody, anti acid staining and T-SPOT were negative. Autoantibody was negative and thyroid function was normal. The JOA score was 9 points. During the operation, the herniated disc tissue was taken out for pathological examination and bacterial culture. The posterior longitudinal ligament was removed and no abscess was found. The symptom of asthenia in both legs was relieved and fever disappeared. No growth of aerobe, anaerobe or tubercle bacilli was found in the culture of resected tissue. One year after the operation, the fever did not recur, JOA score increased to 14 points, and MR imaging showed no protrusion in cervical spinal canal. In this case, the fever disappeared after the operation for cervical spondylosis, which may be a special manifestation of sympathetic nerve stimulation or autonomic dysfunction by chronic compression of spinal cord.