Clinical significance and potential pathogenesis of VCAN in adult non-cystic fibrosis bronchiectasis: a retrospective study.

BACKGROUND: The pathogenesis of adult non-cystic fibrosis (CF) bronchiectasis is complex, and the relevant molecular mechanism remains ambiguous. Versican (VCAN) is a key factor in inflammation through interactions with adhesion molecules. This study constructs a stable panoramic map of mRNA, reveals the possible pathogenesis of bronchiectasis, and provides new ideas and methods for bronchiectasis. METHODS: Peripheral blood and tissue gene expression data from patients with bronchiectasis and normal control were selected by bioinformatics analysis. The expression of VCAN in peripheral blood and bronchial tissues of bronchiectasis were obtained by transcriptome sequencing. The protein expression levels of VCAN in serums were verified by the enzyme-linked immunosorbent assay (ELISA). The mRNA expression levels of VCAN in co-culture of Pseudomonas aeruginosa and bronchial epithelial cells were verified by real-time quantitative polymerase chain reaction (RT-qPCR). In addition, the biological function of VCAN was detected by the transwell assay. RESULTS: The expression of VCAN was upregulated in the bronchiectasis group by sequencing analysis (P < 0.001). The expression of VCAN in the bronchial epithelial cell line BEAS-2B was increased in P. aeruginosa (P.a), which was co-cultured with BEAS-2B cells (P < 0.05). The concentration of VCAN protein in the serum of patients with bronchiectasis was higher than that in the normal control group (P < 0.05). Transwell experiments showed that exogenous VCAN protein induced the migration of neutrophils (P < 0.0001). CONCLUSIONS: Our findings indicate that VCAN may be involved in the development of bronchiectasis by increasing the migration of neutrophils and play an important role in bronchial pathogenesis.

Effect of spinal-pelvic sagittal balance on the clinical outcomes after lumbar fusion surgery.

BACKGROUND: Spinal-pelvic sagittal balance is important for maintaining energy-efficient posture in normal and diseased states.Few reports to date have evaluated the effect of spinal-pelvic sagittal balance on clinical outcomes after lumbar interbody fusion in patients with lumbar degenerative diseases (LDD). METHODS: A total of 303 patients treated with posterior lumbar interbody fusion surgery for lumbar degenerative disease from January 2012 to December 2019 were enrolled in this retrospective study according to the inclusion criteria. Preoperative and postoperative spinal-pelvic sagittal parameters including pelvic incidence (PI), pelvic tilt (PT), sacral slope (SS) and lumbar lordosis (LL) of the patients were evaluated and compared. 163 patients whose postoperative PI-LL ≤ 10° were divided into the spinal-pelvic match group (Group M), while 140 patients were divided into the spinal-pelvic mismatch group (Group MM). Preoperative and postoperative Oswestry Disability Index (ODI) and Visual Analog Scale (VAS) for back pain of both groups were compared. RESULTS: There was no significant difference between the two groups in demographic and surgical data, except for blood loss in surgery. LL, PI, PT and SS of the patients at final follow-up were all statistically different from the preoperative values in the two groups(P < 0.05). There was no significant difference in LL, PI, PT and SS between the two groups before surgery. At the final follow-up, LL, PI and PT differed significantly between the two groups(P < 0.05). Compared with the preoperative results, ODI and VAS of low back in both groups decreased significantly at the final follow-up (P < 0.05). Significant differences in VAS and ODI were found between the two groups at the final follow-up (P < 0.05). The improvement rates of VAS and ODI of Group M are both significantly higher than Group MM. Regression analysis showed that age and spinal-pelvic match had significant effects on the improvement of patients' low back pain at the final follow-up. CONCLUSIONS: lumbar interbody fusion can significantly improve the prognosis of patients with LDD. In terms of outcomes with an average follow-up time of more than 2 years, the spinal-pelvic match has a positive effect on patients' quality of life and the release of low back pain.

A urine extracellular vesicle circRNA classifier for detection of high-grade prostate cancer in patients with prostate-specific antigen 2-10 ng/mL at initial biopsy.

The aim of this study was to identify a urine extracellular vesicle circular RNA (circRNA) classifier that could detect high-grade prostate cancer (PCa) of Grade Group (GG) 2 or greater. For this purpose, we used RNA sequencing to identify candidate circRNAs from urinary extracellular vesicles from 11 patients with high-grade PCa and 11 case-matched patients with benign prostatic hyperplasia. Using ddPCR in a training cohort (n = 263), we built a urine extracellular vesicle circRNA classifier (Ccirc, containing circPDLIM5, circSCAF8, circPLXDC2, circSCAMP1, and circCCNT2), which was evaluated in two independent cohorts (n = 497, n = 505). Ccirc showed higher accuracy than two standard of care risk calculators (RCs) (PCPT-RC 2.0 and ERSPC-RC) in both the training cohort and the validation cohorts. In all three cohorts, this novel urine extracellular vesicle circRNA classifier plus RCs was statistically more predictive than RCs alone for predicting ≥ GG2 PCa. This assay, which does not require precollection digital rectal examination nor special handling, is repeatable, noninvasive, and can be easily implemented as part of the basic clinical workflow.

Repeated subarachnoid administrations of allogeneic human umbilical cord mesenchymal stem cells for spinal cord injury: a phase 1/2 pilot study.

BACKGROUND AIMS: Stem cell transplantation is a potential treatment for intractable spinal cord injury (SCI), and allogeneic human umbilical cord mesenchymal stem cells (hUC-MSCs) are a promising candidate because of the advantages of immune privilege, paracrine effect, immunomodulatory function, convenient collection procedure and little ethical concern, and there is an urgent need to develop a safe and effective protocol regarding their clinical application. METHODS: A prospective, single-center, single-arm study in which subjects received four subarachnoid transplantations of hUC-MSCs (1 × 106 cells/kg) monthly and were seen in follow-up four times (1, 3, 6 and 12 months after final administration) was conducted. At each scheduled time point, safety and efficacy indicators were collected and analyzed accordingly. Adverse events (AEs) were used as a safety indicator. American Spinal Injury Association (ASIA) and SCI Functional Rating Scale of the International Association of Neurorestoratology (IANR-SCIFRS) total scores at the fourth follow-up were determined as primary efficacy outcomes, whereas these two indicators at the remaining time points as well as scores of pinprick, light touch, motor and sphincter, muscle spasticity and spasm, autonomic system, bladder and bowel functions, residual urine volume (RUV) and magnetic resonance imaging (MRI) were secondary efficacy outcomes. Subgroup analysis of primary efficacy indicators was also performed. RESULTS: Safety and efficacy assessments were performed on 102 and 41 subjects, respectively. Mild AEs involving fever (14.1%), headache (4.2%), transient increase in muscle tension (1.6%) and dizziness (1.3%) were observed following hUC-MSC transplantation and resolved thoroughly after conservative treatments. There was no serious AE. ASIA and IANR-SCIFRS total scores revealed statistical increases when compared with the baselines at different time points during the study, mainly reflected in the improvement of pinprick, light touch, motor and sphincter scores. Moreover, subjects showed a continuous and remarkable decrease in muscle spasticity. Regarding muscle spasm, autonomic system, bladder and bowel functions, RUV and MRI, data/imaging at final follow-up showed significant improvements compared with those at first collection. Subgroup analysis found that hUC-MSC transplantation improved neurological functions regardless of injury characteristics, including level, severity and chronicity. CONCLUSIONS: The authors' present protocol demonstrates that intrathecal administration of' allogeneic hUC-MSCs at a dose of 106 cells/kg once a month for 4 months is safe and effective and leads to significant improvement in neurological dysfunction and recovery of quality of life.

Risk factor of contralateral radiculopathy following microendoscopy-assisted minimally invasive transforaminal lumbar interbody fusion.

PURPOSE: Microendoscopy-assisted minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) is an advantageous method for treating lumbar degenerative disease; however, some patients show contralateral radiculopathy postoperatively. This study aims to investigate its risk factor. METHODS: A total of 130 cases who underwent microendoscopy-assisted MIS-TLIF at L4-5 level were divided into symptomatic and asymptomatic groups according to the presence of postoperative contralateral radiculopathy. Both preoperative and postoperative radiographic parameters, as well as their changes were compared between the two groups, including lumbar lordosis (LL), surgical segmental angle (SSA), disc height (DH), contralateral foramen area (CFA) and contralateral canal area (CCA). Screw breach on contralateral L4 pedicle and decompression method (ipsilateral or bilateral canal decompression through unilateral route) were also analyzed as potential risk factors. Receiver operating characteristic (ROC) curve was drawn for the risk factor to determine the optimal threshold for predicting postoperative contralateral radiculopathy. Besides, clinical outcome assessment, involving Visual Analog Score (VAS) for back and leg, Japanese Orthopaedics Association Score (JOA) and Oswestry Disability Index (ODI), was also compared between the two groups before surgery and at final follow-up (at least 3 months after the surgery for asymptomatic patients or final treatments of contralateral radiculopathy for symptomatic cases). RESULTS: Postoperative contralateral radiculopathy occurred in 11 (8.5%) of the 130 patients. Both preoperative and postoperative CFA as well as its change were significantly decreased in symptomatic group compared with asymptomatic group (all P < 0.05). For the remaining four parameters (LL, SSA, DH, CCA), their preoperative, postoperative and change values showed no statistical difference between the two groups (all P > 0.05). Neither screw breach nor decompression method revealed statistical association with this complication (both P > 0.05). Based on ROC curve, the optimal threshold of preoperative CFA was 0.76 cm2. At final follow-up, significant improvement in VAS (back and leg), JOA and ODI was observed in both groups compared with preoperative baseline (all P < 0.05), while no difference was found between the two groups (all P > 0.05). CONCLUSIONS: Preoperative contralateral foramen stenosis is the risk factor of contralateral radiculopathy following microendoscopy-assisted MIS-TLIF. If preoperative CFA at L4-5 level is not larger than 0.76 cm2, prophylactic measures, including both indirect and direct decompression of contralateral foramen, are recommended.

Analysis of the differences of serum protein mass spectrometry in patients with triple negative breast cancer and non-triple negative breast cancer.

The objective of the present study was to investigate differences of serum protein mass spectrometry in patients with triple negative breast cancer (TNBC) and non-TNBC and thus to search for candidate serum protein biomarkers for identification and diagnosis of TNBC. Thirty serum samples from patients with TNBC without any treatment and 30 serum samples from patients with non-TNBC without any treatment were detected by using two-dimensional gel electrophoresis and matrix-assisted laser dissociation tandem time-of-flight mass spectrometry (MALDI-TOF-MS). PDQest 7.0 software of Bio-Rad was adopted to screen differentially expressed proteins. Protein ID retrieval was conducted by using Mascot software to confirm the results of differential proteins. Two-dimensional gel electrophoresis profiles were obtained successfully. A total of 16 differential protein loci were discovered by analyzing patient sera of the two groups using two-dimensional gel electrophoresis analysis software. Ten differential proteins were identified by mass spectrometric analysis in the 16 differential proteins. Combined with database and literature search results, it is speculated that the specifically upregulated proteins and downregulated proteins including transthyretin, haptoglobin, and antitrypsin may be the potential markers for early diagnosis of TNBC. Comparing the TNBC patients with the non-TNBC patients, there are differences in serum protein compositions. The ten differential proteins discovered in the present study provide reference basis for further improving early diagnosis and identification and diagnosis index of TNBC. Especially, transthyretin, haptoglobin, and antitrypsin show dramatic significances for the early diagnosis of TNBC.

Prospective Blinded Comparison of Computed Tomographic Enterography and Small Bowel Endoscopy in Obscure Gastrointestinal Bleeding.

BACKGROUND/AIMS: This study investigated the value of computed tomographic enterography with new techniques, such as multi-planar reformation, curved planar reformation, and blood vessel reformation technique, in evaluation of obscure gastrointestinal bleeding by comparing computed tomographic enterography and small bowel endoscopy. METHODOLOGY: We retrospectively evaluated 30 patients with pathologically proven obscure gastrointestinal bleeding. Patients with acute gastrointestinal bleeding were excluded. All patients successfully underwent computed tomographic enterography and small bowel endoscopy at Yantai Yuhuangding Hospital. Results of both methods in the same patient were compared with pathologic biopsy results from clinical operations or endoscopy. RESULTS: Among the 30 patients retrospectively examined by computed tomographic enterography and small bowel endoscopy, the clinical diagnostic accuracy of the two methods was 70% (21/30) and 80% (24/30), respectively. Computed tomographic enterography and small bowel endoscopy showed no statistical difference in the diagnosis of obscure gastrointestinal bleeding (P = 0.37). CONCLUSIONS: Computed tomographic enterography can supplement or partly replace small bowel endoscopy in the diagnosis of obscure gastrointestinal bleeding. Computed tomographic enterography not only costs patients less and causes them less suffering, but is also technically easy to perform.

Construction of a panoramic mRNA map of adult noncystic fibrosis bronchiectasis and a preliminary study of the underlying molecular mechanisms.

BACKGROUND: The pathogenesis of noncystic fibrosis bronchiectasis in adults is complex, and the relevant molecular mechanisms remain unclear. In this study, we constructed a panoramic map of bronchiectasis mRNA, explored the potential molecular mechanisms, and identified potential therapeutic targets, thus providing a new clinical perspective for the preventive management of bronchiectasis and its acute exacerbation. METHODS: The mRNA profiles of peripheral blood and bronchiectasis tissues were obtained through transcriptome sequencing and public databases, and bioinformatics methods were used to screen for differentially expressed genes (DEGs). The DEGs were then subjected to biological function and pathway analyses. Some DEGs were validated using a real-time quantitative polymerase chain reaction (RT-qPCR) in peripheral blood. Spearman's correlation analysis was used to analyse the correlation between DEGs and clinical indicators. RESULTS: Based on transcriptome sequencing and public databases, the mRNA profile of bronchiectasis was determined. DEGs were obtained from the peripheral blood sequencing dataset (985 DEGs), tissue sequencing dataset (2919 DEGs), and GSE97258 dataset (1083 DEGs). Bioinformatics analysis showed that upregulated DEGs had enriched neutrophil-related pathways, and downregulated DEGs had enriched ribosome-related pathways. RT-qPCR testing confirmed the upregulated expression of VCAN, SESTD1, SLC12A1, CD177, IFI44L, SIGLEC1, and RSAD2 in bronchiectasis. These genes were related to many clinical parameters, such as neutrophils, C-reactive protein, and procalcitonin (P < 0.05). CONCLUSIONS: Transcriptomic methods were used to construct a panoramic map of bronchiectasis mRNA expression. The findings showed that neutrophil activation, chronic inflammation, immune regulation, impaired ribosomal function, oxidative phosphorylation, and energy metabolism disorders are important factors in the development of bronchiectasis. VCAN, SESTD1, SLC12A1, CD177, IFI44L, SIGLEC1, and RSAD2 may play important roles in the pathogenesis of bronchiectasis and are potential therapeutic targets.

The Pharmacological Mechanism of Xiyanping Injection for the Treatment of Novel Coronavirus Pneumonia (COVID-19): Based on Network Pharmacology Strategy.

Purpose: The possible mechanism of Xiyanping injection treatment COVID-19 is discussed through the network pharmacology. Methods: Obtaining the chemical structure of Xiyanping injection through the patent application and obtaining control compounds I, II, III, IV, V, Yanhuning injection (VI, VII), Chuanhuning injection (VIII, IX), 10 compounds were analyzed by D3Targets-2019-nCoV. The human anti-COVID-19 gene in COVID-19 DisGeNET was intersected with the CTD Andrographolide target gene and then combined with D3Targets-2019-nCoV, resulting in 93 genes, using the Venny 2.1 platform. The PPI network was constructed by the String platform and Cytoscape 3.8.2 platform. The GO, KEGG, and tissue of the target were analyzed using the Metascape platform and DAVID platform. The gene expression in the respiratory system was analyzed using the ePlant platform. The CB-Dock is used for the docking verification and degree values of the first 20 genes. Results: Finally, 1599 GO and 291 KEGG results were obtained. GO is mostly associated with the cell stress response to chemicals, the cell response to oxidative stress, and the cell response to reactive oxygen species. In total, 218 KEGG pathway concentrations were related to infection and other diseases and 73 signaling pathways mostly related to inflammation and immune pathways, such as TNF signaling pathway and MAPK signaling pathway. The molecular docking results show that Xiyanping injection, compound III, has a good docking relationship with 20 target proteins such as HSP90AA1. Tissue has 22 genes that are pooled in the lungs. Conclusion: Xiyanping injection may inhibit the release of various inflammatory factors by inhibiting intracellular pathways such as MAPK and TNF. It acts on protein targets such as HSP90AA1 and plays a potential therapeutic role in COVID-19. Thus, compound III may be treated as a potential new drug for the treatment of COVID-19 and the Xiyanping injection may treat patients with COVID-19 infection.

Human umbilical cord mesenchymal stem cells to treat spinal cord injury in the early chronic phase: study protocol for a prospective, multicenter, randomized, placebo-controlled, single-blinded clinical trial.

Human umbilical cord mesenchymal stem cells (hUC-MSCs) support revascularization, inhibition of inflammation, regulation of apoptosis, and promotion of the release of beneficial factors. Thus, they are regarded as a promising candidate for the treatment of intractable spinal cord injury (SCI). Clinical studies on patients with early chronic SCI (from 2 months to 1 year post-injury), which is clinically common, are rare; therefore, we will conduct a prospective, multicenter, randomized, placebo-controlled, single-blinded clinical trial at the Third Affiliated Hospital of Sun Yat-sen University, West China Hospital of Sichuan University, and Shanghai East Hospital, Tongji University School of Medicine, China. The trial plans to recruit 66 early chronic SCI patients. Eligible patients will undergo randomization at a 2:1 ratio to two arms: the observation group and the control group. Subjects in the observation group will receive four intrathecal transplantations of stem cells, with a dosage of 1 × 106/kg, at one calendar month intervals. Subjects in the control group will receive intrathecal administrations of 10 mL sterile normal saline in place of the stem cell transplantations. Clinical safety will be assessed by the analysis of adverse events and laboratory tests. The American Spinal Injury Association (ASIA) total score will be the primary efficacy endpoint, and the secondary efficacy outcomes will be the following: ASIA impairment scale, International Association of Neural Restoration-Spinal Cord Injury Functional Rating Scale, muscle tension, electromyogram, cortical motor and cortical sensory evoked potentials, residual urine volume, magnetic resonance imaging-diffusion tensor imaging, T cell subtypes in serum, neurotrophic factors and inflammatory factors in both serum and cerebrospinal fluid. All evaluations will be performed at 1, 3, 6, and 12 months following the final intrathecal administration. During the entire study procedure, all adverse events will be reported as soon as they are noted. This trial is designed to evaluate the clinical safety and efficacy of subarachnoid transplantation of hUC-MSCs to treat early chronic SCI. Moreover, it will establish whether cytotherapy can ameliorate local hostile microenvironments, promote tracking fiber regeneration, and strengthen spinal conduction ability, thus improving overall motor, sensory, and micturition/defecation function in patients with early chronic SCI. This study was approved by the Stem Cell Research Ethics Committee of the Third Affiliated Hospital of Sun Yat-sen University, China (approval No. [2018]-02) on March 30, 2018, and was registered with ClinicalTrials.gov (registration No. NCT03521323) on April 12, 2018. The revised trial protocol (protocol version 4.0) was approved by the Stem Cell Research Ethics Committee of the Third Affiliated Hospital of Sun Yat-sen University, China (approval No. [2019]-10) on February 25, 2019, and released on ClinicalTrials.gov on April 29, 2019.

Survival Benefit and Genetic Profile of Pemetrexed as Initial Chemotherapy in Selected Chinese Patients With Advanced Lung Adenocarcinoma.

Objective: This study investigated survival in selected Chinese patients with advanced lung adenocarcinoma who received initial chemotherapy with pemetrexed. We also explored the relationship between genetic biomarkers and pemetrexed efficacy. Methods: We retrospectively collected patients (n = 1,047) enrolled in the Chinese Patient Assistance Program from multiple centers who received pemetrexed alone or combined with platinum as initial chemotherapy and continued pemetrexed maintenance therapy for advanced lung adenocarcinoma from November 2014 to June 2017. The outcomes were duration of treatment (DOT) and overall survival (OS). Clinical features were analyzed for their influence on the treatment effect and prognosis. Next-generation sequencing (NGS) was performed to identify genetic biomarkers associated with the efficacy of pemetrexed. Results: The median DOT was 9.1 months (95% CI: 8.5-9.8), and the median OS was 26.2 months (95% CI: 24.2-28.1). OS was positively correlated with DOT (r = 0.403, P < 0.001). Multivariable analysis showed that smoking status and Eastern Cooperative Oncology Group (ECOG) performance status (PS) were independently associated with DOT; smoking status, ECOG PS, targeted therapy, and EGFR/ALK/ROS1 status were independently associated with OS. NGS in 22 patients with available samples showed genes with high mutation rates were: TP53 (54.5%), EGFR (50.0%), MYC (18.2%), and PIK3CA (13.6%). When grouped based on progression-free survival (PFS) reported in the PARAMOUNT study, the DOT > 6.9 months set was associated with PIK3CA, ALK, BRINP3, CDKN2A, CSMD3, EPHA3, KRAS, and RB1 mutations, while ERBB2 mutation was observed only in the DOT ≤ 6.9 months set. Conclusion: This study shows that initial chemotherapy with pemetrexed is an effective regimen for advanced lung adenocarcinoma in selected Chinese patients. There is no specific genetic profile predicting the benefit of pemetrexed found by NGS. Biomarkers predicting the efficacy of pemetrexed need further exploration.

[Inhibitory effect of thalidomide on growth of human hepatoma cell line SMMC-7721 cells].

OBJECTIVE: The aim of this study was to investigate the effect of thalidomide on the growth of human hepatoma cell line SMMC-7721 cells in vitro, and to explore the curative possibility of hepatocellular carcinoma with thalidomide. METHODS: SMMC-7721 cells were treated with Thalidomide at different concentrations. The cell growth and proliferation was assessed by MTT assay. DNA ladder, apoptosis rate and changes of cell nuclei were studied by agarose electrophresis, fluorescence microscopy and flow cytometry, respectively. The expression of caspase-3 was analyzed with flow cytometry. The VEGF content of SMMC-7721 cells in culture medium was tested by ELSIA. RESULTS: When the concentration of Thalidomide solution was increased from 3.125 microg/ml to 200 microg/ml, the cell growth was inhibited by from 11.7% to 34.2%. Compared with the control group, the thalidomide solution at a concentration of 25, 50, 100 and 200 microg/ml solution significantly inhibited the proliferation of SMMC-7721 cells (P < 0.05). A ladder pattern of DNA fragments appeared after SMMC-7721 cells exposed to 200 microg/ml thalidomide for 24 h, especially for 48 h. Fluorescence microscopy revealed that the cell nuclei were condensed and fragmented after the cells were exposed to 200 microg/ml thalidomide for 48 h. In cells treated with 200 microg/ml thalidomide for 12, 24, 48 and 72 h, the apoptotic rate was 3.1% +/- 0.5%, 8.4% +/- 1.3%, 19.4% +/- 3.5% and 25.8% +/- 2.1%, respectively, significantly higher than that in the negative control group 1.6% +/- 0.6%. The cells treated with thalidomide at a concentration of 50, 100, 200 microg/ml for 48 h, the apoptotic rate was 8.7% +/- 1.2%, 16.8% +/- 2.5% and 25.4% +/- 4.5%, respectively, increasing in a dose-dependent manner, also significantly than that in the cells of control group 2.1% +/- 0.5%, (all were P < 0.05). The caspase-3 positivity of SMMC-7721 cells treated with thalidomide was increasing along with the increase of treatment time or drug concentration, but not in the control cells. The VEGF content in SMMC-7721 cells was lowering when thalidomide was used in an increasing concentration. CONCLUSION: Under the conditions used in this study, thalidomide can inhibit the proliferation of SMMC-7721 cells in vitro. Induction of apoptosis and inhibition of angiogenesis may be possibly two mechanisms for its anticancer action.

Less Vertebral Bone Mass after Treatment with Macitentan in Mice: A Pilot Study.

PURPOSE: Blood vessels and skeleton interact together. Endothelin-1 is a potent vasoconstrictor and also has an effect on bone metabolism. The dual antagonist to both endothelin-1 type A and B receptors, Macitentan, has been approved for clinical management of pulmonary arterial hypertension while little is known about the secondary effect of the drug on spine. We aimed to answer how vertebral bone mass responded to Macitentan treatment in mice. METHODS: Sixteen male balb/c mice at 6 months were randomly assigned into 2 groups. Vehicle and Macitentan were administrated via intraperitoneal injection to Control group and Treatment group, respectively, for 4 months. At sacrifice, plasma endothelin-1 was evaluated with ELISA and vertebral bone mass was evaluated with Microcomputed Tomography and histological analysis. RESULTS: We found higher plasma endothelin-1 level (p<0.01) and less vertebral bone mass (p<0.05) in Treatment group compared to controls. Moreover, less osteoblasts and more osteoclasts were observed in the vertebral trabecular bone in the Treatment group compared to controls, by immunohistochemistry of the cell-specific markers. CONCLUSIONS: Treatment with Macitentan is associated with significant lower vertebral bone mass and therefore the secondary effect of dual antagonists to endothelin-1 receptors on the skeleton should be monitored and investigated in clinical practice. Both osteoblasts and osteoclasts may be involved while the molecular mechanism needs to be further explored.

Microendoscopy-Assisted Minimally Invasive Versus Open Transforaminal Lumbar Interbody Fusion for Lumbar Degenerative Diseases: 5-Year Outcomes.

OBJECTIVE: We sought to evaluate 5-year outcomes between microendoscopy-assisted minimally invasive (MIS) and open transforaminal lumbar interbody fusion (TLIF). METHODS: Sixty single-level MIS and open surgeries were performed (30 patients in either group). Perioperative parameters including operative duration, intraoperative estimated blood loss, fluoroscopy time, postoperative analgesic usage, ambulatory time, and complications were recorded. Visual analog scale (back and leg), Japanese Orthopaedics Association score, and Oswestry Disability Index were obtained. Finally, self-evaluation of surgical outcomes (modified MacNab criteria), interbody fusion rate (Bridwell grade 1), and prevalence of adjacent segment degeneration were assessed. RESULTS: Intraoperative estimated blood loss and postoperative analgesia usage were reduced in the MIS group, and patients undergoing microendoscopy-assisted MIS-TLIF ambulated earlier than those receiving open TLIF postoperatively. Nevertheless, surgical duration and fluoroscopy time were prolonged in the MIS group. Complication incidences were similar in both groups. Visual analog scale (back and leg), Japanese Orthopaedics Association, and Oswestry Disability Index were improved at 1 month, 2 years, and 5 years postoperatively in both groups when compared with preoperative scores. Significant improvements in these scores were found in the MIS group at 1 month postoperatively, while at 2 years and 5 years postoperatively, both groups revealed comparable aforementioned scores. Excellent and perfect scale rating, interbody fusion rate, and adjacent segment degeneration prevalence between the groups were almost similar. CONCLUSIONS: Microendoscopy-assisted MIS-TLIF is comparable with open TLIF in terms of 5-year outcomes with additional benefits of reduced intraoperative iatrogenic injury, decreased initial pain, minimized activity restrictions, and accelerated ambulation recovery after surgery.

Cigarette Smoke Induction of Interleukin-27/WSX-1 Regulates the Differentiation of Th1 and Th17 Cells in a Smoking Mouse Model of Emphysema.

IFN-γ-producing CD4+ T (Th1) cells and IL-17-producing CD4+ T (Th17) cells play a critical role in the pathogenesis of chronic obstructive pulmonary disease (COPD). However, the immune regulation between Th1 and Th17 cells remains unclear. Previous studies have demonstrated that interleukin-27 (IL-27)/WSX-1 exerted pro- or anti-inflammatory effects in many acute inflammatory diseases by modulating T cell-mediated immune response, but little was known about its role in chronic inflammatory disease, especially in smoking-related lung diseases. Considering IL-27 is an important regulator in T lymphocytes immune responses and was found markedly increased in patients with COPD, we hypothesized that IL-27/WSX-1 may exert immuno-regulatory effects on the differentiation of Th1 and Th17 cells in smoking-related COPD. In this study, we aimed to evaluate the expression of IL-27 in patients with COPD and explore the role of IL-27/WSX-1 on Th1 and Th17 cells differentiation in a smoking mouse model of emphysema. We found that elevated expression of IL-27 was associated with increased proportion of Th1 cells and Th17 cells in patients with COPD and demonstrated parallel findings in cigarette smoke-exposed mice. In addition, cigarette smoke exposure upregulated the expression of IL-27R (WSX-1) by naive CD4+ T cells in mice. In vitro, IL-27 significantly augmented the secretion of IFN-γ by naive CD4+ T cells via a T-bet, p-STAT1, and p-STAT3-dependent manner, but inhibited the production of IL-17 by a ROR-γt and p-STAT1-dependent way. Furthermore, anti-IL27 treatment dramatically decreased the expression of IFN-γ-producing CD4+ T cells in cigarette smoke-exposed mice. These findings proposed that IL-27 has functions for promoting the expression of Th1 cells but inhibiting the expression of Th17 cells in vitro and IL-27 neutralization-attenuated Th1-mediated inflammation in vivo, suggesting targeting IL-27/WSX-1 may provide a new therapeutic approach for smoking-related COPD.

Decreased expression of microRNA-124 is an independent unfavorable prognostic factor for patients with breast cancer.

BACKGROUND: MicroRNA-124 (miR-124) has been reported to be downregulated in breast cancer. However, its clinical significance and prognostic value in breast cancer have not been extensively studied. METHODS: The tissue expression levels of miR-124 were measured using quantitative real-time PCR in 133 breast cancer patients. The correlation between the miR-124 levels and the clinicopathological factors of the patients was also analyzed. Survival and Cox proportional-hazards regression analyses were performed to determine the correlation between miR-124 expression levels and prognosis in the patients. RESULTS: Quantitative real-time PCR analysis showed that miR-124 had lower expression in breast cancer specimens than that in matched adjacent normal breast tissues (0.39 ± 0.16 vs. 1.00 ± 0.39; P < 0.05). Low miR-124 expression level was significantly associated with advanced TNM stage (P = 0.011), lymph node metastasis (P = 0.012), and poorer pathological differentiation (P = 0.023). A significant difference was found that breast cancer patients with low miR-124 expression level had distinctly shorter overall survival than patients with high miR-124 expression level (63.8% vs. 35.2%, P = 0.03). Furthermore, multivariate analysis of the prognosis factors with a Cox proportional hazards model confirmed that low miR-124 expression was a significant independent predictor of poor survival in breast cancer (HR = 3.16, 95% CI: 1.79-9.13, P = 0.017). CONCLUSION: These findings proved that the decreased expression of miR-124 might be associated with tumor progression and poor prognosis in patients with breast cancer. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/3752603721493544.

Disturbed Th17/Treg Balance in Patients with Non-small Cell Lung Cancer.

The fine balance of T help-17 (Th17)/regulatory T(Treg) cells is crucial for maintenance of immune homeostasis. However, there is little information concerning the role played in non-small cell lung cancer (NSCLC) by Th17/Treg cells. The objective of this study was to investigate the variation of Th17 and Treg cells in the peripheral blood of patients with NSCLC. Blood samples were collected from 19 patients with NSCLC and 19 healthy donors. Samples were processed to detect CD4(+)IL-17(+) Th17 cells and CD4(+)CD25(+)Foxp3(+) Treg cells by flow cytometry, and related gene expressions were assessed by real-time quantitative polymerase chain reaction. The concentrations of interleukin (IL)-1ß, IL-6, IL-10, IL-17, IL-23, and transforming growth factor-beta (TGF-ß1) were also measured by enzyme-linked immunosorbent assay analysis (ELISA). The frequency of circulating Th17 cells and Treg cells was increased in samples derived from patients with NSCLC, accompanied by the upregulation of Foxp3 and RORγt. However, a negative correlation between Treg cells and Th17 cells was found in patients with NSCLC. Additionally, the Th17/Treg ratio and the related cytokines were also significantly higher in patients with NSCLC than in healthy controls. Furthermore, the frequency of Th17 cells was positively correlated with IL-1ß, IL-6, and IL-23 in patients with NSCLC, and the frequency of Treg cells was positively correlated with TGF-ß1 and IL-10. More importantly, the Th17/Treg ratio was positively correlated with the CEA concentrations in patients with NSCLC. Our data indicated that Th17 and Treg subset are involved in the immunopathology of NSCLC. Distinct cytokine environment might play a key role in the differentiation of the Th17 and Treg cells in NSCLC. Reconstituting an adequate balance between Th17 and Treg may be beneficial in the treatment of NSCLC.

Prospective evaluation of preoperative concerns for Chinese patients with spinal degenerative disease.

Objective of this study is to analyze preoperative concerns of patients suffering from spinal degenerative disease in a Chinese population. A total of 94 patients with spinal degenerative disease were included, and they were divided into four groups: male and female group, older (≥60 year-old) and younger group (<60 year-old). Questionnaire was designed through patients counseling, preliminary formulation, pilot test and final revision. Each patient was required to select three items of greatest concern. "Attention rate" (AR) was defined as ratio of selected times of one item upon case number within the group. AR of three most concerned items between male and female group, as well as older and younger group were compared and analyzed. All participants selected "recurrence of symptoms following operation" (41/94), "clinical outcome" (35/94) and "postoperative rehabilitation and daily activity" (30/94) as their three top items of concern. Both male and female groups selected "recurrence of symptoms following operation" (22/47, 19/47), "clinical outcome" (21/47, 14/47), "postoperative rehabilitation and daily activity" (15/47, 15/47) and "limb paralysis" (13/47, 14/47) as their most concerned items, revealing no statistical difference (P>0.05). Older group chose "clinical outcome" (17/46) as their most concerned item, followed by "limb paralysis" (14/46), "postoperative rehabilitation and daily activity" (14/46) and "recurrence of symptoms following operation" (12/46). Younger group chose "recurrence of symptoms following operation" (29/48), "clinical outcome" (18/48) and "postoperative rehabilitation and daily activity" (16/48) as their three top concerned items. AR of "recurrence of symptoms following operation" between older and younger group demonstrated statistical difference (P<0.001), while AR of remaining items of greatest concern between both groups were not statistically different (P>0.05). For Chinese patients, high level concerns are associated with surgical outcome and most of them reveal no gender-associated or age-associated difference. Assessing preoperative concerns empowers better preoperative counseling between surgeons and patients and more informed decision for patients.

Microendoscopy-assisted minimally invasive transforaminal lumbar interbody fusion for lumbar degenerative disease: short-term and medium-term outcomes.

OBJECTIVE: To evaluate short-term and medium-term outcomes of microendoscopy-assisted minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) and open TLIF for lumbar degenerative disease. METHODS: In this prospective, randomized control study, 50 cases received microendoscopy-assisted MIS-TLIF (MIS group), while another well-matched 50 cases accepted open TLIF (open group). Parameters between both groups, including surgical duration, intraoperative blood loss and radiologic exposure, postoperative analgesic usage and ambulatory time, visual analogue scale (VAS) for back and leg, functional scores, self-evaluation of surgical outcome (modified MacNab criteria), interbody fusion rate, adjacent segment degeneration (ASD) rate, as well as complication incidence were compared at 1 month and 24 months postoperatively. RESULTS: Intraoperative blood loss and postoperative analgesic usage were significantly reduced in MIS group (P<0.05). Patients undergoing microendoscopy-assisted MIS-TLIF were able to ambulate earlier postoperatively than those receiving open TLIF (P<0.05). However, it showed prolonged surgical duration and enhanced radiologic exposure in MIS group (P<0.05). At 1 month postoperatively, MIS group was associated with more improvement of VAS and functional scores compared with open group (P<0.05). While at 24 months postoperatively, both groups revealed similar VAS and functional scores (P>0.05). Excellent and perfect scale rating by modified MacNab criteria, interbody fusion rate, ASD rate and complication incidence between both groups were nearly the same (P>0.05). CONCLUSIONS: Microendoscopy-assisted MIS-TLIF owns advantages of less iatrogenic injury, decreased blood loss, reduced analgesic usage and earlier rehabilitation, while it has drawbacks of more surgical duration and radiologic exposure. It is superior than open TLIF in terms of short-term clinical outcomes and has similar medium-term clinical outcomes.

Clinicopathologic characteristics and prognostic factors in patients with operable HER-2 overexpressing breast cancer.

OBJECTIVE: To study the relationship between clinical pathologic characteristics, treatment modalities and prognostic factors in HER-2 (Human Epidermal growth factor Receptor-2) overexpressed breast carcinoma. MATERIALS AND METHODS: Major clinico-pathological factors including therapeutic modalities and survival status of 371 breast cancer patients with HER2 over-expression, teated at Yantai Yuhuangding Hospital from March of 2002 to December of 2010 were retrospectively studied, with special attention focused on survival-related factors. RESULTS: The median age of the total 371 patients in this study was 48 years at time of diagnosis, among which, the leading pathological type was infiltrating ductal carcinoma (92.5%); 62.8% presented with a primary tomor larger than 2 cm in diameter at diagnosis, 51.0% had axillary lymph node (ALN) metastases; ER (Estrogen receptor) /PR (Progesterone receptor) double negative occured in 52.8% of cases, and PCNA (proliferation cell nuclear antigen) (+ + +) was found in 55.1%. HER-2 overexpressed patients were usually in advanced stage when the diagnosis was made (72.8% at stages IIA~IIIC). The prognosis and survival were assessed in 259 patients with complete follow-up data. 5-year DFS (disease-free survival) and OS (overall survival) rate was 68.0% and 78.0% respectively. Univariate analysis revealed that age, tumor size, ALN metastases, LVSI (lymph-vascular space involvement), PCNA status, hormonal therapy, chemotherapy cycles, and HER-2 overexpression, correlated closely with the prognosis. ALN metastases, LVSI, PCNA status and chemotherapy cycles were independent predictors of survival. CONCLUSIONS: HER-2 overexpressed breast cancer has special clinical and pathological characteristics, with advanced clinical stages and high rate of ER/PR double negative. Lymph node metastases, LVSI, PCNA and chemotherapy cycles are independent predictors of prognosis.