TANK-binding kinase 1 (TBK1), a core kinase of antiviral pathways, activates the production of interferons (IFNs). It has been reported that deacetylation activates TBK1; however, the precise mechanism still remains to be uncovered. We show here that during the early stage of viral infection, the acetylation of TBK1 was increased, and the acetylation of TBK1 at Lys241 enhanced the recruitment of IRF3 to TBK1. HDAC3 directly deacetylated TBK1 at Lys241 and Lys692, which resulted in the activation of TBK1. Deacetylation at Lys241 and Lys692 was critical for the kinase activity and dimerization of TBK1 respectively. Using knockout cell lines and transgenic mice, we confirmed that a HDAC3 null mutant exhibited enhanced susceptibility to viral challenge via impaired production of type I IFNs. Furthermore, activated TBK1 phosphorylated HDAC3, which promoted the deacetylation activity of HDAC3 and formed a feedback loop. In this study, we illustrated the roles the acetylated and deacetylated forms of TBK1 play in antiviral innate responses and clarified the post-translational modulations involved in the interaction between TBK1 and HDAC3.

OBJECTIVE: Plant-derived cytotoxic transgene expression, such as trichosanthin (tcs), regulated by recombinant adeno-associated virus (rAAV) vector is a promising cancer gene therapy. However, the cytotoxic transgene can hamper the vector production in the rAAV producer cell line, human embryonic kidney (HEK293) cells. Here, we explored microRNA-122 (miR122) and its target sequence to limit the expression of the cytotoxic gene in the rAAV producer cells. METHODS: A miR122 target (122T) sequence was incorporated into the 3' untranslated region of the tcs cDNA sequence. The firefly luciferase (fluc) transgene was used as an appropriate control. Cell line HEK293-mir122 was generated by the lentiviral vector-mediated genome integration of the mir122 gene in parental HEK293 cells. The effects of miR122 overexpression on cell growth, transgene expression, and rAAV production were determined. RESULTS: The presence of 122T sequence significantly reduced transgene expression in the miR122-enriched Huh7 cell line (in vitro), fresh human hepatocytes (ex vivo), and mouse liver (in vivo). Also, the normal liver physiology was unaffected by delivery of 122T sequence by rAAV vectors. Compared with the parental cells, the miR122-overexpressing HEK293-mir122 cell line showed similar cell growth rate and expression of transgene without 122T, as well as the ability to produce liver-targeting rAAV vectors. Fascinatingly, the yield of rAAV vectors carrying the tcs-122T gene was increased by 77.7-fold in HEK293-mir122 cells. Moreover, the tcs-122T-containing rAAV vectors significantly reduced the proliferation of hepatocellular carcinoma cells without affecting the normal liver cells. CONCLUSION HEK293-mir122 cells along with the 122T sequence provide a potential tool to attenuate the cytotoxic transgene expression, such as tcs, during rAAV vector production.
Animals ; Dependovirus/genetics* ; Genetic Therapy ; Genetic Vectors/genetics* ; HEK293 Cells ; Humans ; Mice ; MicroRNAs/genetics* ; Trichosanthin

OBJECTIVETo summarize the clinical characteristics of peripheral blood, immune phenotypes, fusion genes and cytogenetics of patients with t(8;21) acute myeloid leukemia(AML) through the retrospective analysis of 586 patients with t(8;21) AML from 15 blood disease research centers in Northern area of China.

METHODSThe factors affecting prognosis of patients with t(8;21) AML were investigated by using univariate and multivariate COX regression.

RESULTSThe immune type of t(8;21) AML patients was mainly with HLA-DR, CD117, CD34, MPO, CD38, CD13and CD33(>95%), part of them with CD19and CD56; the most common accompanied mutation of t(8;21) AML patients was C-KIT mutation (37.8%); in addition to t(8;21) ectopic, the most common chromosomal abnormality was sex chromosome deletions (38.9%). The univariate analysis revealed a significant survival superiority of OS and PFS in t(8;21) AML patients of WBC≤3.5×10/L without C-KIT mutation, the newly diagnosed ones achieved HSCT(P<0.05), only survival superiority on OS in t(8;21) AML patients with extramedullary infiltration and CD19 positive; the results of multivariate analysis showed a significant survival superiority on OS and PFS in t(8;21) AML patients with WBC≤3.5×10/L(P<0.05).

CONCLUSIONThe clinical features of t(8;21) AML patients in China are similar to those in other countries, WBC≤3.5×10/L is a good prognostic factor while the C-KIT mutation is a poor one in t(8;21) AML patients.

Objective To establish the three-dimensional finite element model of human lower cervical spine C3-7 motion segments after anterior cervical corpectomy and fusion (ACCF) surgery with titanium mesh and bone graft, and to analyze the stability of cervical spine and stress distribution of internal fixation devices after ACCF surgery. Methods The finite element model of cervical spine C3-7 segments after ACCF of C5 segment with titanium mesh, bone graft, plate and screw fixation was established，and C3-7 segment intact model of cervical vertebra was also constructed. The torque moment of 0.5, 1.0, 1.5, 2.0 N﹒m was applied to the ACCF surgery model. The ROM, maximum stress in facet joint and stress distributions on internal fixation devices under flexion, extension, lateral bending and torsion movement were analyzed. Results ROM of reconstructed C5 segment increased with the torque moment increasing after ACCF surgery. In the case of 1.0 N﹒m torque moment and 50 N preload, the ROM of reconstructed C5, C3-4, C6-7 and C3-7 segment was reduced by 81%, 62%, 58% and 80% compared with the intact model. The maximum stress in facet joint of reconstructed C5 segment reduced and the stress in adjacent segments significantly increased. The stress of titanium mesh was mainly distributed on the compression side of movement, and high stress was located in the roots of screws. Conclusions ACCF surgery can promote the stability of cervical spine, decrease the stress in facet joint of operation segment, and has better treatment effect on easing compression from spinal cord caused by cervical spondylotic myelopathy. The research results will provide some theoretical basis for clinical application of ACCF.

Objective To establish the three-dimensional finite element model of human lower cervical spine C3-7 motion segments after anterior cervical corpectomy and fusion (ACCF) surgery with titanium mesh and bone graft,and to analyze the stability of cervical spine and stress distribution of internal fixation devices after ACCF surgery.Methods The finite element model of cervical spine C3-7 segments after ACCF of C5 segment with titanium mesh,bone graft,plate and screw fixation was established,and C3-7 segment intact model of cervical vertebra was also constructed.The torque moment of 0.5,1.0,1.5,2.0 N · m was applied to the ACCF surgery model.The ROM,maximum stress in facet joint and stress distributions on internal fixation devices under flexion,extension,lateral bending and axial rotation movement were analyzed.Results ROM of reconstructed C5 segment increased with the torque moment increasing after ACCF surgery.In the case of 1.0 N · m tomue moment and 50 N preload,the ROM of reconstructed C5,C3-4,C6-7 and C3-7 segment was reduced by 81％,62％,58％ and 80％ compared with the intact model.The maximum stress in facet joint of reconstructed C5 segment reduced and the stress in adjacent segments significantly increased.The stress of titanium mesh was mainly distributed on the compression side of movement,and high stress was located in the roots of screws.Conclusions ACCF surgery can promote the stability of cewical spine,decrease the stress in facet joint of operation segment,and has better treatment effect on easing compression from spinal cord caused by cervical spondylotic myelopathy.The research results will provide some theoretical basis for clinical application of ACCF surgery.

OBJECTIVETo investigate the effect of premature rupture of the membrane (PROM) on neonatal complications in premature infants.

METHODSThe registration information of 7684 preterm infants with gestational age <37 weeks were collected from the cooperative units in the task group between January 1, 2014 to December 31, 2014. Specially trained personnel from each cooperative units filled in the unified form in a standardized format to record the gender, gestational age, birth weight, PROM, placental abruption, antenatal corticosteroid, Apgar score, amniotic fluid pollution, and complications of the infants. The data were analyzed comparatively between the cases with PROM and those without (control).

RESULTSThe preterm mortality rate was significantly lower but the incidences of ICH, NEC, ROP and BPD were significantly higher in PROM group than in the control group (P<0.05). The 95% confidence interval of the OR value was <1 for mortality, and was >1 for ICH, NEC, ROP and BPD. After adjustment for gestational age, birth weight, gender, mode of delivery, placental abruption, placenta previa, prenatal hormones, gestational diabetes mellitus (GDM), gestational period hypertension and 5-min Apgar score <7, the incidences of NEC, ROP and BPD were significantly different between the two groups (P<0.05) with 95% confidence interval of OR value >1, but the mortality rate and incidence of ICH were not significantly different between the two groups (P>0.05).

CONCLUSIONPROM is a risk factor for NEC, ROP and BPD in preterm infants, and adequate intervention of PROM can reduce the incidences of such complications as NEC, ROP and BPD in the infants.

Apgar Score ; Birth Weight ; Female ; Fetal Membranes, Premature Rupture ; pathology ; Gestational Age ; Humans ; Incidence ; Infant, Newborn ; Infant, Newborn, Diseases ; etiology ; Infant, Premature ; Pregnancy ; Risk Factors

Abstract? AIM: To evaluate the characteristic of choroidal thickness ( CT ) in highly myopic glaucoma eyes, and investigate the factors that affect the CT in various regions of the macula.?METHODS: Thirty -two highly myopic eyes of 18 patients with primary open angle glaucoma ( POAG ) , 36 non-highly myopic eyes of 20 patients with POAG, and 33 non -glaucoma highly myopic eyes of 21 matched volunteers were enrolled.CT at subfoveal, and 1mm and 3mm nasal, temporal, superior, and inferior to the fovea was measured using enhanced depth imaging coherence tomography. Multiple linear regression analyses were performed to detect the effects of diagnosis, spherical equivalent ( SE) , age, intraocular pressure ( IOP) , central corneal thickness ( CCT ) , and mean deviation ( MD ) of visual field defect on CT at all measured points.?RESULTS:The choroid of highly myopic glaucoma eyes was statistically thinner than non -highly myopic glaucoma eyes at various locations (all P<0.05), while there was no significant difference between highly myopic glaucoma and non-glaucoma high myopia eyes at all locations ( all P >0.05 ). Multiple regression analysis showed that SE was the most influential factor on CT in all regions of the macula, and CT varied significantly with age in 3mm superior to fovea ( S3CT ), but not with diagnosis, MD of visual field defect, IOP, or CCT.? CONCLUSION: CT in highly myopic glaucoma is equivalent in comparison with non -glaucoma highly myopia, although it's thinner than that in glaucoma eyes without high myopia.This implies the lack of association between CT and progression of glaucomatous optic neuropathy.

Objective To study biomechanical properties such as range of motion (ROM), intervertebral disc stress, ligament tension of inferior cervical spinal segment after the treatment of Discover, Prodisc-C artificial intervertebral disc replacement, and anterior cervical discectomy and fusion (ACDF), as well as mechanical property changes of the prosthesis after implantation. Methods Three kinds of operation plan on C5-6 cervical disc degeneration were established: Discover model, Prodisc-C model and ACDF model, as well as C4-7 segment original model of cervical vertebra. Biomechanical property changes after operation in cervical spine C4-7 segment in sagittal, coronal and transverse section were analyzed. Results ROM changes of cervical segment C5-C6 were as following: in Discover model it increased by 12.7%-73.1%, Prodisc-C model increased by 74%-98%, ACDF decreased by 55.8%-71.8%. The stress of C4-5 intervertebral disc after Discover artificial disc replacement showed no obvious increase, while the stress of C6-7 intervertebral disc decreased by 33.2%-54.2% under flexion, extension and axial rotation conditions. The amplification of ligament tension in Discover model decreased by 30%-40% as compared to that in Prodisc-C model. The maximum stress of Discover model (36.72 MPa) appeared under flexion condition, which was smaller than that in Prodisc-C model. Conclusions Artificial disc replacement can help to keep movement performance for segment after surgery. As a newly developed artificial intervertebral disc prosthesis, Discover makes some progress in the aspect of decreasing ligament stress and maintaining spinal stability. The research findings will provide theoretical basis for the clinical study on ACDF and artificial cervical intervertebral disc replacement surgeries.

OBJECTIVETo compare the long-term outcomes of patients receiving percutaneous coronary intervention (PCI), coronary artery bypass grafting (CABG), or medical therapy for treatment of chronic total coronary occlusion (CTO).

METHODSThe patients with CTO were selected from a consecutive cohort of patients who underwent coronary angiography (CAG) between 2008 and 2009. The patients with multiple CAG were excluded. The patients received treatments with PCI, CABG, or conservative medication therapy and were followed for major adverse cardiovascular events (MACE) within 5 years.

RESULTSA total of 253 patients were enrolled in this study, including 192 receiving PCI, 48 receiving CABG, and 13 treated conservatively with medications. The baseline clinical characteristics were similar among the 3 groups except for increased low-density lipoprotein (LDL) and total cholesterol (TC) in the medication group, and increased Syndax score in CABG group. During the follow-up, the incidences of MACE, AMI, death, stroke or heart failure did not differ significantly among the 3 groups (P>0.05). However, CABG group showed a higher incidence of the stroke than the other two groups although this difference did not reach a statistically significantly level (P=0.06).

CONCLUSIONOur study did not demonstrate that recanalization offers greater long-term benefits than medications for treatment of CTO, and the patients receiving CABG appeared to have a higher incidence of stroke.

Chronic Disease ; Cohort Studies ; Coronary Angiography ; Coronary Artery Bypass ; Coronary Occlusion ; surgery ; therapy ; Humans ; Incidence ; Percutaneous Coronary Intervention ; Stroke ; epidemiology ; Treatment Outcome