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.

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.

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.

Thoracic de-kyphosis for revision surgery of a failure case of endoscopic discectomy: a case report and literature review.

BACKGROUND: Indications and clinical outcomes of percutaneous endoscopic thoracic discectomy(PETD) in treating thoracic disc herniation is rarely reported and still controversial. We reported an unsatisfied recovery of thoracic disc herniation with PETD, treated by a second posterior thoracic laminectomy and Ponte osteotomy. CASE DESCRIPTION: A male presented with lower extremity weakness and stagger caused by T3/4 intervertebral disc herniation. The upper thoracic curve was in excessive kyphosis with T2-5 Cobb angle of 34.3 degrees. The preoperative ODI score was 34 and Roelzs's JOA score was 14. Percutaneous transforaminal endoscopic thoracic discectomy (PETD) from a posterior lateral approach was performed. At five-month follow-up, his thoracic back pain and staggering gait did not improve. The postoperative T2-5 Cobb angle was 32.1 degrees, the ODI score was 24 and Roelzs's JOA score was 14. A second posterior thoracic decompression this time with fixation was performed, but no disc herniation was detected. A Ponte osteotomy was performed to correct the kyphosis. One month after the second surgery, muscle strength of the lower limbs was improving with the T2-5 Cobb angle decreased to 19.4 degrees, the ODI score decreased to 10 and Roelzs's JOA score increase to 16. Six month later, the ODI score decreased to 0 and Roelzs's JOA score improved to 18. In review of the literature, PETD doesn't guarantee the patient a satisfactory neurological recovery for kyphotic thoracic disc herniation. Posterior decompression with Ponte osteotomy may be beneficial to release the tension and decompression of the spinal cord tension. CONCLUSIONS: Thoracic disc herniation with kyphosis angle >20 degrees (T2-5), percutaneous endoscopic thoracic discectomy is not likely to get good neurologic results. Posterior laminectomy with ponte osteotomy might be beneficial for these patients to induce dorsal drifting of the spinal cord from anterior herniation.

Percutaneous Endoscopic Lumbar Discectomy in Treating Calcified Lumbar Intervertebral Disc Herniation.

BACKGROUND: We retrospectively analyzed and report the clinical results of percutaneous endoscopic lumbar discectomy (PELD) in treating patients with calcified lumbar intervertebral disc herniation (CLDH). METHODS: The data from 40 patients with CLDH treated with PELD in our hospital from June 2013 to June 2017 were reviewed. Of the 40 patients, 27 (19 men; 8 women; average age, 45.5 ± 7.5 years) had undergone percutaneous endoscopic transforaminal discectomy and 13 (8 men, 5 women; average age, 46.9 ± 6.9 years) had undergone percutaneous endoscopic interlaminar discectomy. The Peak method was used for both groups. The preoperative demographic data of both groups were analyzed. The pre- and postoperative leg visual analog scale scores and Oswestry disability index were compared and complications were evaluated. RESULTS: All procedures were performed successfully, and follow-up data were obtained for all patients for 24 months. The leg visual analog scale and Oswestry disability index scores at the last follow-up visit had decreased in both groups and were significantly different statistically from the preoperative data. No nerve root injury, intestinal injury, intervertebral disc infection, or recurrence was detected in any patient. Dural tear and cerebrospinal fluid leakage were observed in 3 patients (2, percutaneous endoscopic transforaminal discectomy; 1, percutaneous endoscopic interlaminar discectomy), because of adhesions between the calcification and nerve root. However, their symptoms resolved, and they were discharged after 1 week of bed rest. CONCLUSIONS: With the application of Peak philosophy, PELD is safe and effective in treating patients with CLDH. The use of PELD results in good neurological recovery, pain relief, and a low incidence of complications.

Tantalum-coated pedicle screws enhance implant integration.

Because titanium alloy (Ti) has the natural advantage of a low elastic modulus, it has become the most commonly used material for the manufacturing of pedicle screws. However, its poor shear strength and osteogenic ability are undesirable properties. The superior osteoinductivity demonstrated by tantalum (Ta) in oral and maxillofacial surgery and joint surgery leads us to assume that the tantalum-coated pedicle screws may have better osteogenic properties and bone anchoring strength. To verify this hypothesis, MC3T3-E1 cells and human mesenchymal stem cells (hBMSCs) were seeded on the surface of Ta and Ti disks to compare the effects of two different metals on cell adhesion, proliferation, and differentiation. At the same time, we observed the inhibitory effect of Ta on osteoclasts. As an in vivo study, conventional Ti pedicle screws and Ta-coated screws were implanted in bilateral pedicles of Bama pigs. The results showed that compared to titanium, tantalum promoted greater cell adhesion and proliferation and improved the level of hBMSC mineralization, and Ta-coated screws exerted an inhibitory effect on osteoclasts. More importantly, we found that the effect of tantalum on osteogenic differentiation was mediated through the Wnt/ß-catenin and TGF-ß/smad signaling pathways. Ta-coated screws significantly promoted trabecular bone growth compared with Ti as evidenced by micro-CT, histology and biomechanical examination. Our study clearly indicated that tantalum was a superior promoter of osteogenesis and proved that tantalum coating is an effective improvement for titanium alloy implants.

Cut-off optimization for 13C-urea breath test in a community-based trial by mathematic, histology and serology approach.

The performance of diagnostic tests in intervention trials of Helicobacter pylori (H.pylori) eradication is crucial, since even minor inaccuracies can have major impact. To determine the cut-off point for 13C-urea breath test (13C-UBT) and to assess if it can be further optimized by serologic testing, mathematic modeling, histopathology and serologic validation were applied. A finite mixture model (FMM) was developed in 21,857 subjects, and an independent validation by modified Giemsa staining was conducted in 300 selected subjects. H.pylori status was determined using recomLine H.pylori assay in 2,113 subjects with a borderline 13C-UBT results. The delta over baseline-value (DOB) of 3.8 was an optimal cut-off point by a FMM in modelling dataset, which was further validated as the most appropriate cut-off point by Giemsa staining (sensitivity = 94.53%, specificity = 92.93%). In the borderline population, 1,468 subjects were determined as H.pylori positive by recomLine (69.5%). A significant correlation between the number of positive H.pylori serum responses and DOB value was found (rs = 0.217, P < 0.001). A mathematical approach such as FMM might be an alternative measure in optimizing the cut-off point for 13C-UBT in community-based studies, and a second method to determine H.pylori status for subjects with borderline value of 13C-UBT was necessary and recommended.

Human VE-Cadherin Fusion Protein as an Artificial Extracellular Matrix Enhancing the Proliferation and Differentiation Functions of Endothelial Cell.

In an attempt to enhance endothelial cell capture and promote the vascularization of engineered tissue, we biosynthesized and characterized the recombinant fusion protein consisting of human vascular endothelial-cadherin extracellular domain and immunoglobulin IgG Fc region (hVE-cad-Fc) to serve as a bioartificial extracellular matrix. The hVE-cad-Fc protein naturally formed homodimers and was used to construct hVE-cad-Fc matrix by stably adsorbing on polystyrene plates. Atomic force microscop assay showed uniform hVE-cad-Fc distribution with nanorod topography. The hVE-cad-Fc matrix markedly promoted human umbilical vein endothelial cells (HUVECs) adhesion and proliferation with fibroblastoid morphology. Additionally, the hVE-cad-Fc matrix improved HUVECs migration, vWF expression, and NO release, which are closely related to vascularization. Furthermore, the hVE-cad-Fc matrix activated endogenous VE-cadherin/ß-catenin proteins and effectively triggered the intracellular signals such as F-actin stress fiber, p-FAK, AKT, and Bcl-2. Taken together, hVE-cad-Fc could be a promising bioartificial matrix to promote vascularization in tissue engineering.

A large randomised controlled intervention trial to prevent gastric cancer by eradication of Helicobacter pylori in Linqu County, China: baseline results and factors affecting the eradication.

OBJECTIVE: To clarify the full range of benefits and adverse consequences of Helicobacter pylori eradication as a strategy for gastric cancer prevention, the community-based intervention trial was launched in Linqu County, China. DESIGN: A total of 184,786 residents aged 25-54 years were enrolled in this trial and received (13)C-urea breath test. H. pylori positive participants were assigned into two groups, either receiving a 10-day quadruple anti-H. pylori treatment or lookalike placebos together with a single dosage of omeprazole and bismuth. RESULTS: The prevalence of H. pylori in trial participants was 57.6%. A total of 94,101 subjects completed the treatment. The overall H. pylori eradication rate was 72.9% in the active group. Gender, body mass index, history of stomach disease, baseline delta over baseline-value of (13)C-urea breath test, missed medication doses, smoking and drinking were independent predictors of eradication failure. The missed doses and high baseline delta over baseline-value were important contributors in men and women (all Ptrend<0.001). However, a dose-response relationship between failure rate and smoking or drinking index was found in men (all Ptrend<0.001), while high body mass index (Ptrend<0.001) and history of stomach disease were significant predictors in women. The treatment failure rate increased up to 48.8% (OR 2.87, 95% CI 2.24 to 3.68) in men and 39.4% (OR 2.67, 95% CI 1.61 to 4.42) in women with multiple factors combined. CONCLUSIONS: This large community-based intervention trial to eradicate H. pylori is feasible and acceptable. The findings of this trial lead to a distinct evaluation of factors influencing eradication that should be generally considered for future eradication therapies. TRIAL REGISTRATION NUMBER: ChiCTR-TRC-10000979 in accordance with WHO ICTRP requirements.

Neck motion following multilevel anterior cervical fusion: comparison of short-term and midterm results.

OBJECT: Multilevel anterior cervical decompression and fusion is indicated for patients with multilevel compression or stenosis of the spinal cord. Some have reported that this procedure would lead to a loss of cervical range of motion (CROM). However, few studies have demonstrated the exact impact of the procedure on CROM. Here, the authors describe short- and midterm postoperative CROM following multilevel anterior cervical decompression and fusion. METHODS: Thirty-five patients underwent a 3- or 4-level anterior cervical decompression and fusion. In all patients, active CROM was measured preoperatively and at both the short-term (3-4 months) and midterm (12-15 months) follow-ups by using a CROM device. The preoperative and postoperative data were analyzed using ANOVA (α = 0.05). RESULTS: Patients had significantly less ROM in all planes of motion postoperatively. The greater limitation in CROM was observed at the short-term follow-up. However, at the midterm follow-up, an obvious increase in CROM was observed in each cardinal plane compared with that in the short-term (sagittal plane 17.4%, coronal plane 14.1%, and horizontal plane 19.5%). A gradual increase in the CROM in each cardinal plane was observed during the recovery period in 5 patients. In the 6 conventional motions, the major recovery of CROM was observed in flexion (27.5%), while relatively less recovery was seen in extension (10.5%). CONCLUSIONS: Patients had an obvious reduction in active CROM following multilevel anterior cervical decompression and fusion. The greater limitation in CROM was observed at the short-term follow-up. In the midterm follow-up, however, an obvious recovery in CROM was observed in each cardinal plane, reducing the restriction of neck motion further.