Stable Response and Sustained Improvement of Itch and Sleep Symptoms in Patients with Atopic Dermatitis Treated with Lebrikizumab over 52 Weeks.

BACKGROUND: Lebrikizumab demonstrated significant improvement versus placebo for measures of skin clearance and patient-reported outcomes at weeks 16 and 52 in patients with moderate-to-severe atopic dermatitis (AD). We report the sustained impact of lebrikizumab monotherapy, over 52 weeks and between visits, on the frequency of itch and sleep loss symptoms, as assessed by Patient-Oriented Eczema Measure (POEM), in patients with moderate-to-severe AD. METHODS: In ADvocate1 and ADvocate2, Week-16 lebrikizumab responders (EASI75 or IGA 0/1 with ≥ 2-point improvement and without rescue medication) were randomized to lebrikizumab every 2 weeks (Q2W), every 4 weeks (Q4W), or placebo for 36 weeks. This pooled analysis reports improvement from Week 16 to 52 in patients achieving POEM response 0 (no days) or 1 (1-2 days) for Items 1 (itch) and 2 (sleep disturbance) for the lebrikizumab Q2W and Q4W treatment arms. Observed (excluding data collected after treatment discontinuation, rescue medication use, or patient transfer to escape arm) results were reported. RESULTS: At Week 16, for lebrikizumab Q2W and Q4W, 35.9% (n = 37/103) and 39.3% (n = 42/107) of patients responded 0 or 1 to Item 1 of POEM (Itch) and 12.6% (n = 13/103) and 12.1% (n = 13/107) responded 0. A total of 66.0% (n = 68/103) and 72.6% (n = 77/106) of patients responded 0 or 1 to Item 2 of POEM (Sleep) and 37.9% (n = 39/103) and 44.3% (n = 47/106) responded 0, respectively. By Week 52, for lebrikizumab Q2W and Q4W, 44.6% (n = 29/65) and 48.0% (n = 36/75) responded 0 or 1 to Item 1 of POEM (Itch), and 21.5% (n = 14/65) and 18.7% (n = 14/75) of patients responded 0. A total of 83.1% (n = 54/65) and 78.4% (n = 58/74) responded 0 or 1 to Item 2 of POEM (Sleep), and 67.7% (n = 44/65) and 59.5% (n = 44/74) responded 0, respectively. CONCLUSION: Weekly POEM responses for itch and sleep disturbance remained stable between doses and visits, and continued to improve from Week 16 through 52, in lebrikizumab-treated patients, demonstrating consistent improvement over time for key AD symptoms. TRIAL REGISTRATION NUMBERS: ADvocate1 (NCT04146363) and ADvocate2 (NCT04178967).

Investigation on the mechanism of the combination of eremias multiocellata and cisplatin in reducing chemoresistance of gastric cancer based on in vitro and in vivo experiments.

BACKGROUND: Cisplatin (DDP) is one of the important chemotherapy drugs for patients with advanced gastric cancer and metastasis, but its resistance is a bottleneck problem that affects clinical efficacy and patient survival. Eremias multiocellata (EM) is a traditional Chinese herbal medicine, which has been used in the treatment of precancerous lesions, gastric cancer, liver fibrosis, and other digestive diseases. However, the mechanism of reducing chemotherapy resistance to gastric cancer is still unclear. METHODS: We used the MTT assay to evaluate the proliferative viability of gastric cancer parental cell line MKN45 and its drug-resistant cell line MKN45/DDP, and compared their drug-resistance indices. The migration and invasion abilities of MKN45/DDP drug-resistant cells were evaluated using the Transwell assay. Apoptosis in MKN45/DDP drug-resistant cells was detected using flow cytometry. The effect of a combination of EM and cisplatin on the levels of reactive oxygen species (ROS) and lipid peroxides (LPO) in cisplatin-resistant gastric cancer cells was detected using ROS fluorescent probes and a lipid peroxidation assay kit in conjunction with flow cytometry. The effect of EM combined with cisplatin on the level of iron ions was detected by fluorescence probe and confocal laser technique. Hematoxylin-eosin staining (HE staining) was used to detect the histopathologic morphology of drug-resistant gastric cancer in nude mice. Ferroptosis-related proteins were measured using immunohistochemistry. Real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) was used to detect tumor drug resistance-related genes. The NF-κB/Snail pathway-related proteins, PI3K/AKT/mTOR pathway-related proteins, and drug resistance-related proteins were detected by Western blot. RESULTS AND CONCLUSIONS: The results of in vitro and in vivo experiments showed that EM combined with DDP could effectively inhibit the migration and invasive ability of MKN45/DDP cells, as well as induce apoptosis of MKN45/DDP cells; the combination of the two drugs could significantly increase the levels of ROS, lipid peroxidation and divalent ferric ions in MKN45/DDP cells, at the same time reducing the levels of Ferroptosis-related proteins, which could induce Ferroptosis. In addition, EM combined with DDP can also exert the effect of reversing DDP resistance and increasing the sensitivity of gastric cancer drug-resistant cells to DDP by regulating the NF-κB/Snail signaling pathway, PI3K/AKT/mTOR signaling pathway, and the expression of drug resistance-related proteins and genes.

Visualization of Pulse-Wave Velocity on Arterial Wall of Mice Through High-Frequency Ultrafast Doppler Imaging.

Arterial pulse-wave velocity (PWV) is widely used in clinical applications to assess cardiovascular diseases. Ultrasound methods have been proposed for estimating regional PWV in human arteries. Furthermore, high-frequency ultrasound (HFUS) has been applied to perform preclinical small-animal PWV measurements; however, electrocardiogram (ECG)-gated retrospective imaging is required to achieve high-frame-rate imaging, which might be affected by arrhythmia-related problems. In this article, HFUS PWV mapping based on 40-MHz ultrafast HFUS imaging is proposed to visualize PWV on mouse carotid artery to measure arterial stiffness without ECG gating. In contrast to most other studies that used cross-correlation methods to detect arterial motion, ultrafast Doppler imaging was applied in this study to measure arterial wall velocity for PWV estimations. The performance of the proposed HFUS PWV mapping method was verified using a polyvinyl alcohol (PVA) phantom with various freeze-thaw cycles. Small-animal studies were then performed in wild-type (WT) mice and in apolipoprotein E knockout (ApoE KO) mice that were fed a high-fat diet (for 16 and 24 weeks). The Young's modulus of the PVA phantom measured through HFUS PWV mapping was 15.3 ± 0.81, 20.8 ± 0.32, and 32.2 ± 1.11 kPa for three, four, and five freeze-thaw cycles, respectively, and the corresponding measurement biases (relative to theoretical values) were 1.59%, 6.41%, and 5.73%, respectively. In the mouse study, the average PWVs were 2.0 ± 0.26, 3.3 ± 0.45, and 4.1 ± 0.22 m/s for 16-week WT, 16-week ApoE KO, and 24-week ApoE KO mice, respectively. The PWVs of ApoE KO mice increased during the high-fat diet feeding period. HFUS PWV mapping was used to visualize the regional stiffness of mouse artery, and a histology confirmed that the plaque formation in the bifurcation region increased the regional PWV. All the results indicate that the proposed HFUS PWV mapping method is a convenient tool for investigating arterial properties in preclinical small-animal studies.

The regulation and functions of the matricellular CCN proteins induced by shear stress.

Shear stress is a frictional drag generated by the flow of fluid, such as blood or interstitial fluid, and plays a critical role in regulating cellular gene expression and functional phenotype. The matricellular CCN family proteins are dynamically regulated by shear stress of different flow patterns, and their expression significantly alters the microenvironment of cells. Secreted CCN proteins mainly bind to several cell surface integrin receptors to mediate their diverse functions in regulating cell survival, function, and behavior. Gene-knockout studies indicate major functions of CCN proteins in the cardiovascular and skeletal systems, the two primary systems in which CCN expressions are regulated by shear stress. In the cardiovascular system, the endothelium is directly exposed to vascular shear stress. Unidirectional laminar blood flow generates laminar shear stress, which promotes a mature endothelial phenotype and upregulates anti-inflammatory CCN3 expression. In contrast, disturbed flow generates oscillatory shear stress, which induces endothelial dysfunction through the induction of CCN1 and CCN2. Shear-induced CCN1 binds to integrin α6ß1 and promotes superoxide production, NF-κB activation, and inflammatory gene expression in endothelial cells. Although the interaction between shear stress and CCN4-6 is not clear, CCN 4 exhibits a proinflammatory property and CCN5 inhibits vascular cell growth and migration. The crucial roles of CCN proteins in cardiovascular development, homeostasis, and disease are evident but not fully understood. In the skeletal system, mechanical loading on bone generates shear stress from interstitial fluid in the lacuna-canalicular system and promotes osteoblast differentiation and bone formation. CCN1 and CCN2 are induced and potentially mediate fluid shear stress mechanosensing in osteocytes. However, the exact roles of interstitial shear stress-induced CCN1 and CCN2 in bone are still not clear. In contrast to other CCN family proteins, CCN3 inhibits osteoblast differentiation, although its regulation by interstitial shear stress in osteocytes has not been reported. The induction of CCN proteins by shear stress in bone and their functions remain largely unknown and merit further investigation. This review discusses the expression and functions of CCN proteins regulated by shear stress in physiological conditions, diseases, and cell culture models. The roles between CCN family proteins can be compensatory or counteractive in tissue remodeling and homeostasis.

Estimation of Mouse Carotid Arterial Wall Shear Stress Using High-Frequency Ultrasound Imaging.

Wall shear stress (WSS) is a crucial hemodynamic factor that promotes atherosclerosis (plaque) development in arteries; although the relationship between WSS and arterial atherosclerosis has been explored in many animal studies, it is not fully understood. No suitable tool, however, exists for rapidly estimating dynamic WSS in small-animal studies. This study proposes a 40-MHz high-frequency ultrasound (HFUS) imaging system for dynamic WSS estimation based on mouse carotid artery blood flow velocity gradient measurements by vector Doppler imaging (VDI). Aliasing reduces the accuracy of Doppler measurements, which can be prevented by increasing the imaging frame rate. Conventionally, imaging is performed at two tilted angles by alternating between the angles; in the proposed method, the frame rate was doubled by imaging at each tilted angle sequentially and by then temporally aligning the sequences based on pulsatile flow characteristics. Velocity estimation using this method had low errors for both a steady-flow straight-tube and pulsatile flow 60%-stenosis phantom. The method was tested for wild-type (WT) C57BL/6 mice at 16 weeks old and apolipoprotein E knockout (ApoE KO) mice at 16 and 24 weeks old; differences in time-averaged and oscillatory WSS were observed, and histology confirmed that the 24-week ApoE KO mice with the highest oscillatory WSS had the greatest plaque formation. The proposed HFUS WSS imaging method can predict the location and extent of plaque development; thus, this method is useful for small-animal studies investigating the WSS effect on atherosclerotic plaque development.

Efficacy and safety of baricitinib in combination with topical corticosteroids in patients with moderate-to-severe atopic dermatitis with inadequate response, intolerance or contraindication to ciclosporin: results from a randomized, placebo-controlled, phase III clinical trial (BREEZE-AD4).

BACKGROUND: Baricitinib, an oral selective Janus kinase (JAK)1 and JAK 2 inhibitor, was shown to improve the signs and symptoms of moderate-to-severe atopic dermatitis (AD). OBJECTIVES: To evaluate the efficacy and safety of baricitinib with background topical corticosteroids (TCS) in patients with moderate-to-severe AD and inadequate response, intolerance or contraindication to ciclosporin A (CA). METHODS: In this double-blind, randomized, placebo-controlled, phase III study, patients were randomized 1: 1: 2: 1 to placebo (N = 93), baricitinib 1 mg (N = 93), 2 mg (N = 185) or 4 mg (N = 92) with background TCS. The primary endpoint was the proportion of patients receiving baricitinib 4 mg or 2 mg (+ TCS) vs. placebo + TCS who achieved ≥ 75% improvement from baseline in the Eczema Area and Severity Index (EASI 75) at week 16. RESULTS: Baricitinib 4 mg + TCS was superior to placebo + TCS for EASI 75 (4 mg: 32%, placebo: 17%, P = 0·031) at week 16 and for improvements in itch, skin pain and number of night-time awakenings owing to itch. Improvements were maintained through 52 weeks of treatment. Treatment-emergent adverse events (TEAEs) were more common with baricitinib than placebo (+ TCS); most were mild or moderate. The most frequent TEAEs with baricitinib 4 mg + TCS were nasopharyngitis, herpes simplex, influenza and headache. No deaths or deep vein thromboses were reported. CONCLUSIONS: Baricitinib 4 mg + TCS improved the signs and symptoms of moderate-to-severe AD through 52 weeks of treatment in patients with inadequate response, intolerance or contraindication to CA. The safety profile was consistent with previous studies of baricitinib in moderate-to-severe AD. What is already known about this topic? Ciclosporin A is indicated for the treatment of atopic dermatitis that is refractory to topical therapies. However, its use is limited by safety concerns and it may not provide adequate response for some patients. Baricitinib, an oral selective Janus kinase (JAK)1 and JAK2 inhibitor, has been shown to improve the signs and symptoms of moderate-to-severe atopic dermatitis as a monotherapy or in combination with topical corticosteroids. What does this study add? Baricitinib combined with background low- or moderate-potency topical corticosteroids provided improvements in the signs and symptoms of moderate-to-severe atopic dermatitis through 1 year of treatment in patients with a contraindication, intolerance or failure to respond to ciclosporin A. The most common treatment-emergent adverse events with baricitinib 4 mg were nasopharyngitis, herpes simplex, influenza and headache. The safety profile was consistent with previous studies in patients with moderate-to-severe atopic dermatitis.

Shear-Regulated Extracellular Microenvironments and Endothelial Cell Surface Integrin Receptors Intertwine in Atherosclerosis.

Mechanical forces imposed by blood flow shear stress directly modulate endothelial gene expression and functional phenotype. The production of extracellular matrix proteins and corresponding cell-surface integrin receptors in arterial endothelial cells is intricately regulated by blood flow patterns. Laminar blood flow promotes mature and atheroresistant endothelial phenotype, while disturbed flow induces dysfunctional and atheroprone endothelial responses. Here, we discuss how hemodynamic changes orchestrate the remodeling of extracellular microenvironments and the expression profile of the integrin receptors in endothelial cells leading to oxidative stress and inflammation. Targeting the interaction between matrix proteins and their corresponding integrins is a potential therapeutic approach for atherosclerosis.

Efficacy and Safety of Baricitinib Combined With Topical Corticosteroids for Treatment of Moderate to Severe Atopic Dermatitis: A Randomized Clinical Trial.

Importance: Baricitinib, an oral selective Janus kinase 1 and 2 inhibitor, effectively reduced disease severity in moderate to severe atopic dermatitis (AD) in 2 phase 3 monotherapy studies. Objective: To assess the efficacy and safety of 4 mg and 2 mg of baricitinib in combination with background topical corticosteroid (TCS) therapy in adults with moderate to severe AD who previously had an inadequate response to TCS therapy. Design, Setting, and Participants: This double-blind, placebo-controlled, phase 3 randomized clinical trial, BREEZE-AD7 (Study of Baricitinib [LY3009104] in Combination With Topical Corticosteroids in Adults With Moderate to Severe Atopic Dermatitis) was conducted from November 16, 2018, to August 22, 2019, at 68 centers across 10 countries in Asia, Australia, Europe, and South America. Patients 18 years or older with moderate to severe AD and an inadequate response to TCSs were included. After completing the study, patients were followed up for up to 4 weeks or enrolled in a long-term extension study. Interventions: Patients were randomly assigned (1:1:1) to receive 2 mg of baricitinib once daily (n = 109), 4 mg of baricitinib once daily (n = 111), or placebo (n = 109) for 16 weeks. The use of low-to-moderate potency TCSs was allowed. Main Outcomes and Measures: The primary end point was the proportion of patients achieving a validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) score of 0 (clear) or 1 (almost clear), with a 2-point or greater improvement from baseline at week 16. Results: Among 329 patients (mean [SD] age, 33.8 [12.4] years; 216 [66%] male), at week 16, a vIGA-AD score of 0 (clear) or 1 (almost clear) was achieved by 34 patients (31%) receiving 4 mg of baricitinib and 26 (24%) receiving 2 mg of baricitinib compared with 16 (15%) receiving placebo (odds ratio vs placebo, 2.8 [95% CI, 1.4-5.6]; P = .004 for the 4-mg group; 1.9 [95% CI, 0.9-3.9]; P = .08 for the 2-mg group). Treatment-emergent adverse events were reported in 64 of 111 patients (58%) in the 4-mg group, 61 of 109 patients (56%) in the 2-mg group, and 41 of 108 patients (38%) in the placebo group. Serious adverse events were reported in 4 patients (4%) in the 4-mg group, 2 (2%) in the 2-mg group, and 4 (4%) in the placebo group. The most common adverse events were nasopharyngitis, upper respiratory tract infections, and folliculitis. Conclusions and Relevance: A dose of 4 mg of baricitinib in combination with background TCS therapy significantly improved the signs and symptoms of moderate to severe AD, with a safety profile consistent with previous studies of baricitinib in AD. Trial Registration: ClinicalTrials.gov Identifier: NCT03733301.

BDNF reverses aging-related microglial activation.

BACKGROUND: Excessive microglial activation is implicated in the pathogenesis of various age-related neurodegenerative diseases. In addition to neurons, brain-derived neurotrophic factor (BDNF) and its receptor TrkB are also expressed in microglia. However, the direct effect of BDNF on age-related microglial activation has rarely been investigated. METHODS: We began to address this question by examining the effect of age on microglial activation and the BDNF-TrkB pathway in mice. By using pharmacological and genetic approaches, the roles of BDNF and downstream signaling pathways in microglial activation and related neurotoxicity were examined in microglial cell line and primary microglial cells. RESULTS: We showed that microglial activation was evident in the brains of aged mice. The levels of BDNF and TrkB in microglia decreased with age and negatively correlated with their activation statuses in mice during aging. Interestingly, aging-related microglial activation could be reversed by chronic, subcutaneous perfusion of BDNF. Peripheral lipopolysaccharide (LPS) injection-induced microglial activation could be reduced by local supplement of BDNF, while shTrkB induced local microglial activation in naïve mice. In cultured microglial cell line and primary microglial cells, BDNF inhibited LPS-induced microglial activation, including morphological changes, activations of p38, JNK, and NF-кB, and productions of proinflammatory cytokines. These effects were blocked by shTrkB. BDNF induced activations of ErK and CREB which then competed with LPS-induced activation of NF-кB for binding to a common coactivator, CREB-binding protein. CONCLUSIONS: Decreasing BDNF-TrkB signaling during aging favors microglial activation, while upregulation BDNF signaling inhibits microglial activation via the TrkB-Erk-CREB pathway.

Pathological changes from the originating to the peripheral sites of Sinonasal Inverted Papilloma are the underlying mechanisms of preoperative MRI-tumor origin prediction.

BACKGROUND: Our previous study showed that convoluted cerebriform pattern (CCP)-based reverse tracing method in preoperative magnetic resonance imaging (MRI) is a reliable tool in predicting originating site of sinonasal inverted papilloma (SNIP). This study aimed to determine the underlying pathological mechanism of the preoperative MRI-CCP reverse tracing method by assessing the histopathological changes from the origin to the peripheral sites of SNIP. METHODOLOGY: The originating site of SNIP was predicted by preoperative MRI in 30 consecutive patients suspected to have primary SNIP. Samples of SNIP originating and peripheral sites were processed by pathological staining for evaluation of stroma score, micro-vessel density (MVD), and tight junction proteins (claudin-5, zonula occludens (ZO)-1 and occludin) expression. RESULTS: The originating site of SNIP was accurately predicted by preoperative MRI in all patients. Stroma scores, and MVD were significantly greater in the periphery of SNIP than in the originating site. In contrast, Claudin-5 expression in micro-vessels was greater at the originating site than the periphery. CONCLUSIONS: More edematous stroma and intensive micro-vessels with defective tight junction in periphery of SNIP result in more contrast agent diffusing and CCP that can only be observed at the periphery of SNIP on T2 and contrast-enhanced T1 weighted MR images, which may be the mechanisms underlying the CCP reverse tracing method.

Community Treatment Order Outcomes in Quebec: A Unique Jurisdiction.

OBJECTIVE: We study compulsory community treatment orders (CTOs) for patients with severe and persistent mental illness (SPMI). Focusing on a unique jurisdiction in Canada that allows for long duration CTOs with strict enforcement procedures, our objectives are to determine whether extended duration CTOs are effective and to determine whether associated hospitalization costs are reduced. METHOD: A mirror image, naturalistic design was employed using patients as their own controls to enhance external validity. No inclusive or exclusive criteria were employed for the 367 SPMI clinic patients who were studied over a 5-year period. Detailed documentation of the dates of all CTOs, long-acting antipsychotic injections (LAIs), emergency visits, hospitalizations, duration of hospitalizations, crimes and/or police involvement were collected. To study the relation between CTO and injection adherence, we use a mixed-effect linear regression model. To study the effect of injection adherence and hospitalization, we use survival analysis via Kaplan-Meier and Cox survival models. RESULTS: CTO and non-CTO patients did not differ with respect to demographics, but CTO patients were significantly more severely ill. Following a CTO, adherence to LAIs increased over time (P < 0.001). The average time the patients spent in the community, that is, outside the hospital, was significantly longer under a CTO, and the duration of hospitalizations was decreased. CONCLUSIONS: LAI adherence and outpatient office visits were enhanced by extended duration CTOs, as was time out of the hospital. The shorter duration of hospital stays implies cost savings. These must be weighed against their undesirable coercive nature.

CCN1 triggers adaptive autophagy in cardiomyocytes to curb its apoptotic activities.

Autophagy occurs at basal levels for cellular homeostasis under normal conditions and is increased in response to nutrient starvation or stress to ensure cell survival. However, excessive autophagy can be deleterious to cardiomyocytes. CCN1/Cyr61, a matricellular protein, is expressed in the stressed heart to induce cardiomyopathy. The role of autophagy in CCN1-associated cardiotoxicity was not clear. Here, we found that autophagy was induced in the myocardium of the isoproterenol (ISO; 100 mg/kg/day for 5 days; s.c.) treated mice, where CCN1 expression is colocalized. The knock-in mice carrying an integrin α6ß1-binding-defective mutant allele Ccn1-dm were resistant to the ISO-induced cardiac injury and autophagy. Our in vitro studies demonstrated that CCN1 dose- and time-dependently induced GFP-LC3-labeled autophagosome formation in rat cardiomyoblast H9c2 cells. The formation of autolysosomes in response to CCN1 (5 µg/ml; 3 h) treatment was identified by the acridine orange staining. The autophagy induction was confirmed by the elevated protein levels of Beclin 1, Atg5, and LC3-II, and the decrease of p62. Inhibition of autophagy by 3-methyladenine or by silencing Atg5 gene enabled CCN1-induced apoptosis in H9c2 cells, suggesting a protective role of autophagy. CCN1 binds to integrin α6ß1 to induce autophagy through reactive oxygen species, and the activation of ERK and JNK. Furthermore, mitophagy was observed after CCN1 treatment for the clearance of depolarized mitochondria. Together, these results demonstrated that autophagy is induced in response to CCN1/α6ß1 signaling in cardiomyocytes to alleviate CCN1-associated cardiotoxicity.

Shear-Induced CCN1 Promotes Atheroprone Endothelial Phenotypes and Atherosclerosis.

BACKGROUND: Atherosclerosis occurs preferentially at the blood vessels encountering blood flow turbulence. The matricellular protein CCN1 is induced in endothelial cells by disturbed flow, and is expressed in advanced atherosclerotic lesions in patients and in the Apoe-/- mouse model. The role of CCN1 in atherosclerosis remains undefined. METHODS: To assess the function of CCN1 in vivo, knock-in mice carrying the integrin α6ß1-binding-defective mutant allele Ccn1-dm on the Apoe-/- background were tested in an atherosclerosis model generated by carotid artery ligation. Additionally, CCN1-regulated functional phenotypes of human umbilical vein endothelial cells, or primary mouse aortic endothelial cells isolated from wild-type and Ccn1 dm/dm mice, were investigated in the in vitro shear stress experiments under unidirectional laminar shear stress (12 dyn/cm2) versus oscillatory shear stress (±5 dyn/cm2) conditions. RESULTS: We found that Ccn1 expression was upregulated in the arterial endothelium 3 days after ligation before any detectable structural changes, and intensified with the progression of atherosclerotic lesions. Compared with Apoe-/- controls, Ccn1 dm/dm/ Apoe-/- mice were remarkably resistant to ligation-induced plaque formation (n=6). These mice exhibited lower oxidative stress, expression of endothelin-1 and monocyte chemoattractant protein-1, and monocyte homing. CCN1/α6ß1 critically mediated flow-induced activation of the pleiotropic transcription factor nuclear factor-κB and therefore the induction of atheroprone gene expression in the mouse arterial endothelium after ligation (n=6), or in cultured human umbilical vein endothelial cells or primary mouse aortic endothelial cells exposed to oscillatory shear stress (n=3 in triplicate). Interestingly, the activation of nuclear factor-κB by CCN1/α6ß1 signaling prompted more production of CCN1 and α6ß1. Blocking CCN1-α6ß1 binding by the Ccn1-dm mutation or by T1 peptide (derived from an α6ß1-binding sequence of CCN1) disrupted the positive-feedback regulation between CCN1/α6ß1 and nuclear factor-κB, and prevented flow-induced atheroprone phenotypic alterations in endothelial cells or atherosclerosis in mice. CONCLUSIONS: These data demonstrate a causative role of CCN1 in atherosclerosis via modulating endothelial phenotypes. CCN1 binds to its receptor integrin α6ß1 to activate nuclear factor-κB, thereby instigating a vicious circle to persistently promote atherogenesis. T1, a peptide antagonist selectively targeting CCN1-α6ß1, can be further optimized for developing T1-mimetics to treat atherosclerosis.

Seven genes for the prognostic prediction in patients with glioma.

PURPOSE: Glioma is a common malignant tumor of the central nervous system, which is characterized by a low cure rate, high morbidity, and high recurrence rate. Consequently, it is imperative to explore some indicators for prognostic prediction in glioma. METHODS: We obtained glioma data from The Cancer Genome Atlas (TCGA). Differentially expressed genes (DEGs) were obtained by R software from TCGA data sets. Through Cox regression analysis, risk scores were obtained to assess the weighted gene-expression levels, which could predict the prognosis of patients with glioma. The validity and the prognostic value of this model in glioma were confirmed by the manifestation of receiver-operating characteristic (ROC) curves, area under the curve (AUC), and 5-year overall survival (OS). RESULTS: In total, 920 DEGs of transcriptome genes in glioma were extracted from the TCGA database. We identified a novel seven-gene signature associated with glioma. Among them, AL118505.1 and SMOC1 were positively related to the 5-year OS of patients with glioma, showing a better prognosis for glioma; however, RAB42, SHOX2, IGFBP2, HIST1H3G, and IGF2BP3 were negatively related to 5-year OS, displaying a worse prognosis. In addition, according to risk scores, AL118505.1 was also a protective factor, while others were risk factors. Furthermore, the expression levels of SHOX2, IGFBP2, and IGF2BP3 were significantly positively correlated with glioma grades. Receiver-operating characteristic (ROC) curve assessed the accuracy and sensitivity of the gene signature. Each of the seven genes for patients with the distribution of the risk score was presented in the heat map. CONCLUSION: We identified a novel seven-gene signature in patients with glioma, which could be used as a predictor for the prognosis of patients with glioma in the future.

Neural stem cell transplantation inhibits glial cell proliferation and P2X receptor-mediated neuropathic pain in spinal cord injury rats.

P2X4 and P2X7 receptors play an important role in neuropathic pain after spinal cord injury. Regulation of P2X4 and P2X7 receptors can obviously reduce pain hypersensitivity after injury. To investigate the role of neural stem cell transplantation on P2X receptor-mediated neuropathic pain and explore related mechanisms, a rat model of spinal cord injury was prepared using the free-falling heavy body method with spinal cord segment 10 as the center. Neural stem cells were injected into the injured spinal cord segment using a micro-syringe. Expression levels of P2X4 and P2X7 receptors, neurofilament protein, and glial fibrillary acidic protein were determined by immunohistochemistry and western blot assay. In addition, sensory function was quantitatively assessed by current perception threshold. The Basso-Beattie-Bresnahan locomotor rating scale was used to assess neuropathological pain. The results showed that 4 weeks after neural stem cell transplantation, expression of neurofilament protein in the injured segment was markedly increased, while expression of glial fibrillary acidic protein and P2X4 and P2X7 receptors was decreased. At this time point, motor and sensory functions of rats were obviously improved, and neuropathic pain was alleviated. These findings demonstrated that neural stem cell transplantation reduced overexpression of P2X4 and P2X7 receptors, activated locomotor and sensory function reconstruction, and played an important role in neuropathic pain regulation after spinal cord injury. Therefore, neural stem cell transplantation is one potential option for relieving neuropathic pain mediated by P2X receptors.