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1.
Cell Death Differ ; 2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-33953350

RESUMO

Receptor interacting protein kinase 3 (RIP3 or RIPK3), the critical executor of cell programmed necrosis, plays essential roles in maintaining immune responses and appropriate tissue homeostasis. Although the E3 ligases CHIP and PELI1 are reported to promote RIP3 degradation, however, how post-translational modification regulates RIP3 activity and stability is poorly understood. Here, we identify the tripartite motif protein TRIM25 as a negative regulator of RIP3-dependent necrosis. TRIM25 directly interacts with RIP3 through its SPRY domain and mediates the K48-linked polyubiquitination of RIP3 on residue K501. The RING domain of TRIM25 facilitates the polyubiquitination chain on RIP3, thereby promoting proteasomal degradation of RIP3. Also, TRIM25 deficiency inhibited the ubiquitination of RIP3, thus promoting TNF-induced cell necrosis. Our current finding reveals the regulating mechanism of polyubiquitination on RIP3, which might be a potential therapeutic target for the intervention of RIP3-dependent necrosis-related diseases.

2.
Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi ; 35(4): 445-452, 2021 Apr 15.
Artigo em Chinês | MEDLINE | ID: mdl-33855828

RESUMO

Objective: To investigate the effect of modified lateral mass screws implantation strategy on axial symptoms in cervical expansive open-door laminoplasty. Methods: A clinical data of 166 patients, who underwent cervical expansive open-door laminoplasty between August 2011 and July 2016 and met the selection criteria, was retrospective analyzed. Among them, 81 patients were admitted before August 2014 using the traditional mini-plate placement and lateral mass screws implantation strategy (control group), and 85 patients were admitted after August 2014 using modified lateral mass screws implantation strategy (modified group). There was no significant difference in the gender composition, age, clinical diagnosis, disease duration, diseased segment, and preoperative Japanese Orthopaedic Association (JOA) score, pain visual analogue scale (VAS) score, Neck Disability Index (NDI), cervical curvature and range of motion, spinal canal diameter and cross-sectional areas, and Pavlov's value between the two groups ( P>0.05). The operation time, intraoperative blood loss, the number of facet joints penetrated by lateral mass screws, effectiveness evaluation indexes (JOA score and improvement rate, VAS score, NDI), imaging evaluation indexes (cervical curvature and range of motion, spinal canal diameter and cross-sectional areas, Pavlov's value, and lamina open angle), and complications were recorded and compared between the two groups. Results: The modified group had shorter operation time and lower intraoperative blood loss than the control group ( P<0.05). There were 121 (29.9%, 121/405) and 10 (2.4%, 10/417) facet joints penetrated by lateral mass screws in control and modified groups, respectively; and the difference in incidence was significant ( χ 2=115.797, P=0.000). Eighteen patients in control group had 3 or more facet joints penetrated while no patients in modified group suffered 3 or more facet joint penetrated. The difference between the two groups was significant ( P=0.000). All patients were followed up, the follow-up time was (28.7±4.9) months in modified group and (42.4±10.7) months in control group, showing significant difference ( t=10.718, P=0.000). The JOA score, VAS score, and NDI at last follow-up of the two groups were significantly improved compared with preoperative ( P<0.05); there was no significant difference in JOA score and improvement rate and VAS score between the two groups ( P>0.05), but the NDI was significantly lower in modified group than in control group ( P<0.05). There were significant differences in cervical curvature and range of motion, spinal canal diameter, Pavlov's value, and cross-sectional areas at last follow-up when compared with those before operation in both groups ( P<0.05). There was no significant difference in the above indicators and lamina open angle between the two groups ( P>0.05). The modified group has a relative lower axial symptom rate (23/85, 27.1%) than the control group (27/81, 33.3%), but the difference was not significant ( Z=-1.446, P=0.148). There was no significant differences between the two groups in the incidences of C 5 nerve root palsy, cerebrospinal fluid leakage, wound infection, and lung or urinary tract infection ( P>0.05). Conclusion: In the cervical expansive open-door laminoplasty, the modified lateral mass screws implantation strategy can effectively reduce the risk of lateral mass screw penetrated to the cervical facet joints, and thus has a positive significance in avoiding the axial symptoms caused by facet joint destruction.


Assuntos
Laminoplastia , Parafusos Ósseos , Vértebras Cervicais/cirurgia , Humanos , Laminectomia , Estudos Retrospectivos , Resultado do Tratamento
3.
Clin Spine Surg ; 2021 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-33929395

RESUMO

STUDY DESIGN: This was a retrospective study. OBJECTIVE: The main question of this study is whether the change of postoperative T1 slope will affect the clinical and imaging recovery of patients with single-level anterior cervical discectomy and fusion (ACDF). SUMMARY OF BACKGROUND DATA: The T1 slope after ACDF is different from that preoperatively, however, the clinical significance of this change has not been reported. MATERIALS AND METHODS: A retrospective analysis was conducted on 87 patients with single-level ACDF. Visual Analogue Scale was used to compare neck and upper limb pain before and after surgery. Neurological improvement was assessed by the Japanese Orthopaedic Association Scores and Neck Disability Index. Preoperative and postoperative T1 slope, occipital-C2 angle, C2-C7 overall curvature and functional spinal unit curvature were measured and analyzed by lateral cervical spine x-ray. RESULTS: All patients were followed up for 23.98±12.17 months. The Japanese Orthopaedic Association, Visual Analogue Scale, and Neck Disability Index scores as well as the overall curvature and change of C2-C7 and functional spinal unit were significantly improved in the last postoperative follow-up. At 12 months after surgery and the last follow-up, patients with increased T1 slope had more severe neck pain symptoms than those with decreased T1 slope (P<0.05). The overall curvature and change of C2-C7 in patients with increased T1 slope were better than those with decreased T1 slope (P<0.05). CONCLUSION: For patients with increased postoperative T1 slope after single-level ACDF, the degree of postoperative neck pain was more severe, suggesting that some clinical intervention is needed.

4.
Glycobiology ; 2021 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-33909026

RESUMO

Mucin-type O-glycosylation is initiated by the UDP-GalNAc polypeptide:N-acetylgalactosaminyltransferase (ppGalNAc-T) family of enzymes, which consists of 20 members in humans. Among them, unlike other ppGalNAc-Ts located in Golgi apparatus, ppGalNAc-T18 distributes primarily in the endoplasmic reticulum (ER) and non-catalytically regulates ER homeostasis and O-glycosylation. Here, we report the mechanism for ppGalNAc-T18 ER localization and the function of each structural domain of ppGalNAc-T18. By using ppGalNAc-T18 truncation mutants, we revealed that the luminal stem region and catalytic domain of ppGalNAc-T18 are essential for ER localization, whereas the lectin domain and N-glycosylation of ppGalNAc-T18 are not required. In the absence of the luminal region (i.e., stem region, catalytic and lectin domains), the conserved Golgi retention motif RKTK within the cytoplasmic tail combined with the transmembrane domain ensure ER export and Golgi retention, as observed for other Golgi resident ppGalNAc-Ts. Results from co-immunoprecipitation assays showed that the luminal region interacts with ER resident proteins UGGT1, PLOD3 and LPCAT1. Furthermore, flow cytometry analysis showed that the entire luminal region is required for the non-catalytic O-GalNAc glycosylation activity of ppGalNAc-T18. The findings reveal a novel subcellular localization mechanism of ppGalNAc-Ts and provide a foundation to further characterize the function of ppGalNAc-T18 in the ER.

5.
Int Orthop ; 2021 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-33733284

RESUMO

BACKGROUND: The unstable intertrochanteric femur fracture remains a challenge for surgeons. However, few studies have compared the clinical effectiveness of intramedullary nail in combination with a reconstruction plate and intramedullary nail alone in the treatment of patients with unstable intertrochanteric femoral fractures with lateral wall damage. METHODS: This study retrospectively analyzed 16 patients with 31 A3 intertrochanteric fractures treated with the intramedullary nail in combination with reconstruction plate (the study group) and 19 patients with 31 A3 intertrochanteric fractures treated with intramedullary nail alone (the control group) between January 2012 and January 2018. The operation time, intra-operative blood loss, time of fracture healing, and complication rates of post-operative fixation failure were assessed between the two groups. At the follow-up of post-operative six and 12 months, Harris hip score (HHS) and the Parker-Palmer mobility score (PPMS) were used to evaluate the functional states and mobility levels. RESULTS: The distribution of all basic characteristics was similar between the two groups (P ˃ 0.05). The study group had longer operation time and more intra-operative blood loss in comparison with the control group (P < 0.001), while the study group had shorter fracture healing time (P = 0.03) and lower fixation failure rate as compared with the control group. Regarding the functional outcome, the study group had higher HHSs and PPMS than the control group (P = 0.003). CONCLUSIONS: Although intramedullary nails in combination with reconstruction plates had longer operation time and more intra-operative blood loss, it might be superior to intramedullary nail alone in terms of fracture healing time, fixation failure complication rate, and post-operative functional recovery.

6.
Cancer Biol Med ; 2021 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-33733647

RESUMO

OBJECTIVE: The hyperactivated neddylation pathway plays an important role in tumorigenesis and is emerging as a promising anticancer target. We aimed to study whether NEDD8 (neural precursor cell expressed, developmentally down-regulated 8) might serve as a therapeutic target in esophageal squamous cell carcinoma (ESCC). METHODS: The clinical relevance of NEDD8 expression was evaluated by using The Cancer Genome Atlas (TCGA) database and tissue arrays. NEDD8-knockdown ESCC cells generated with the CRISPR/Cas9 system were used to explore the anticancer effects and mechanisms. Quantitative proteomic analysis was used to examine the variations in NEDD8 knockdown-induced biological pathways. The cell cycle and apoptosis were assessed with fluorescence activated cell sorting. A subcutaneous-transplantation mouse tumor model was established to investigate the anticancer potential of NEDD8 silencing in vivo. RESULTS: NEDD8 was upregulated at both the mRNA and protein expression levels in ESCC, and NEDD8 overexpression was associated with poorer overall patient survival (mRNA level: P = 0.028, protein level: P = 0.026, log-rank test). Downregulation of NEDD8 significantly suppressed tumor growth both in vitro and in vivo. Quantitative proteomic analysis revealed that downregulation of NEDD8 induced cell cycle arrest, DNA damage, and apoptosis in ESCC cells. Mechanistic studies demonstrated that NEDD8 knockdown led to the accumulation of cullin-RING E3 ubiquitin ligases (CRLs) substrates through inactivation of CRLs, thus suppressing the malignant phenotype by inducing cell cycle arrest and apoptosis in ESCC. Rescue experiments demonstrated that the induction of apoptosis after NEDD8 silencing was attenuated by DR5 knockdown. CONCLUSIONS: Our study elucidated the anti-ESCC effects and underlying mechanisms of NEDD8 knockdown, and validated NEDD8 as a potential target for ESCC therapy.

7.
World Neurosurg ; 149: 181-189, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33662606

RESUMO

OBJECTIVE: Anterior cervical corpectomy and fusion (ACCF) is employed in patients with localized cervical spinal stenosis (CSS). However, there are some disadvantages such as subsidence of the titanium mesh cage, slow fusion rates, breakage of the plate and screws, and donor-site complications. For patients with small posterior osteophytes, ossified or hypertrophy of the posterior longitudinal ligaments or ligamentum flavum, the range of decompression from the classic anterior cervical discectomy and fusion (ACDF) cannot meet the clinical requirements. However, employing ACCF is controversial. Therefore, it is necessary to seek a novel, safe and effective surgery that can combine the strengths of ACDF and ACCF. Our objective was to describe a novel anterior approach cervical surgery and investigate its clinical outcomes on segmental CSS at the C4-C6 levels 6 months postoperatively. METHODS: A novel anterior cervical X-shape-corpectomy and fusion (ACXF) was performed to correct the CSS. RESULTS: The patient's neurologic function and myodynamia of the extremities were improved significantly 3 and 6 months after surgery with good bony fusion. Neck pain also was relieved. Immediately postoperative and after 6-month images indicated no significant spinal stenosis. The patient's cervical curvature was improved after surgery without significant implant subsidence or loss of adjacent intervertebral height. There were no postoperative complications. CONCLUSIONS: ACXF may be a safe and effective procedure for segmental CSS and an alternative for ACCF, as it has a wide operative field of view, sufficient decompression range, excellent transverse vertebral bony fusion, less internal fixation-related complications, and graft subsidence and no donor-site complications.

8.
Future Microbiol ; 16: 305-316, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33635120

RESUMO

Background: Copper stress is an effective host strategy in resisting the opportunistic pathogenic fungus Cryptococcus neoformans. We studied metabolic changes in C. neoformans under copper stress. Materials & methods: Wild-type and metallothionein-null C. neoformans were treated with copper on agar containing glucose, glycerol or ethanol as the carbon source and their metabolites were analyzed by untarget metabolomics strategy using gas chromatography coupled with time-of-flight mass spectrometry. Results: The metabolic profile of C. neoformans varied in the presence and absence of copper. Pathway enrichment analysis showed that the differentially abundant metabolites were related to amino acid and carbohydrate metabolism. C. neoformans grown on glycerol or ethanol resisted copper toxicity better than C. neoformans grown on glucose. Conclusion: Copper stress alters the metabolic profile of C. neoformans.

10.
Emerg Microbes Infect ; 10(1): 342-355, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33555988

RESUMO

The current study aims to develop a safe and highly immunogenic COVID-19 vaccine. The novel combination of a DNA vaccine encoding the full-length Spike (S) protein of SARS-CoV-2 and a recombinant S1 protein vaccine induced high level neutralizing antibody and T cell immune responses in both small and large animal models. More significantly, the co-delivery of DNA and protein components at the same time elicited full protection against intratracheal challenge of SARS-CoV-2 viruses in immunized rhesus macaques. As both DNA and protein vaccines have been proven safe in previous human studies, and DNA vaccines are capable of eliciting germinal center B cell development, which is critical for high-affinity memory B cell responses, the DNA and protein co-delivery vaccine approach has great potential to serve as a safe and effective approach to develop COVID-19 vaccines that provide long-term protection.


Assuntos
/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Vacinas de DNA/imunologia , Vacinas de Subunidades/imunologia , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Linhagem Celular , DNA/imunologia , Células HEK293 , Humanos , Contagem de Linfócitos , Macaca mulatta , Camundongos , Camundongos Endogâmicos C57BL , Plasmídeos/genética , Coelhos , Proteínas Recombinantes/imunologia , /imunologia , Linfócitos T/imunologia
11.
Int Immunopharmacol ; 93: 107402, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33540246

RESUMO

Aberrant expression of long non-coding RNA (lncRNA) H19 is tightly linked to multiple steps of tumorigenesis via the modulation of cell proliferation and apoptosis; however, the pathological significance and regulatory mechanisms of lncRNA H19 in macrophages remain obscure. To investigate whether lncRNA H19 modulates macrophage activation in rheumatoid arthritis (RA), lncRNA H19 levels in PMA-induced PBMC from patients with RA and healthy volunteers were assessed. In addition, the distribution of macrophage subsets, macrophage phenotypic characteristics, and pro-inflammatory gene expression were examined in lncRNA H19 smart silencer- or pcDNA 3.1- H19-transfected macrophages and AAV8-mediated H19 overexpression in a Freund' s complete adjuvant-induced arthritis mouse model. The level of lncRNA H19 was higher in RA patients than in healthy volunteers. Silencing of lncRNA H19 altered lipopolysaccharide plus interferon-induced M1 macrophage polarization and decreased IL-6, CD80, CCL8, and CXCL10 expression in macrophages of RA patients. LncRNA H19 overexpression markedly induced IL-6, CD80, HLA-DR, KDM6A, STAT1, IRF5, CCL8, CXCL9, CXCL10, and CXCL11 expression in macrophages and promoted macrophage migration. AAV8-mediated H19 overexpression aggravated arthritis in mice by promoting M1 macrophage polarization along with iNOS, IL-6, CCL8, CXCL9, CXCL10, CXCL11, MMP3, MMP13 and COX-2 expression in mononuclear cells isolated from the swollen ankle. GSK-J4, an inhibitor of KDM6A, suppressed the activity of lncRNA H19 in macrophages and ameliorated lncRNA H19-aggravated arthritis. In summary, the current study demonstrated that lncRNA H19 is upregulated in RA patients and arthritic mice. LncRNA H19 promotes M1 macrophage polarization and aggravates arthritis by upregulating KDM6A expression.

14.
Theranostics ; 11(1): 361-378, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33391480

RESUMO

Rationale: As the central hallmark of liver fibrosis, transdifferentiation of hepatic stellate cells (HSCs), the predominant contributor to fibrogenic hepatic myofibroblast responsible for extracellular matrix (ECM) deposition, is characterized with transcriptional and epigenetic remodeling. We aimed to characterize the roles of H3K27 methyltransferase EZH2 and demethylase JMJD3 and identify their effective pathways and novel target genes in HSCs activation and liver fibrosis. Methods: In primary HSCs, we analyzed effects of pharmacological inhibitions and genetic manipulations of EZH2 and JMJD3 on HSCs activation. In HSCs cell lines, we evaluated effects of EZH2 inhibition by DZNep on proliferation, cell cycling, senescence and apoptosis. In CCl4 and BDL murine models of liver fibrosis, we assessed in vivo effects of DZNep administration and Ezh2 silencing. We profiled rat primary HSCs transcriptomes with RNA-seq, screened the pathways and genes associated with DZNep treatment, analyzed EZH2 and JMJD3 regulation towards target genes by ChIP-qPCR. Results: EZH2 inhibition by DZNep resulted in retarded growth, lowered cell viability, cell cycle arrest in S and G2 phases, strengthened senescence, and enhanced apoptosis of HSCs, decreased hepatic collagen deposition and rescued the elevated serum ALT and AST activities of diseased mice, and downregulated cellular and hepatic expressions of H3K27me3, EZH2, α-SMA and COL1A. Ezh2 silencing by RNA interference in vitro and in vivo showed similar effects. JMJD3 inhibition by GSK-J4 and overexpression of wild-type but not mutant Jmjd3 enhanced or repressed HSCs activation respectively. EZH2 inhibition by DZNep transcriptionally inactivated TGF-ß1 pathway, cell cycle pathways and vast ECM components in primary HSCs. EZH2 inhibition decreased H3K27me3 recruitment at target genes encoding TGF-ß1 pseudoreceptor BAMBI, anti-inflammatory cytokine IL10 and cell cycle regulators CDKN1A, GADD45A and GADD45B, and increased their expressions, while Jmjd3 overexpression manifested alike effects. Conclusions: EZH2 and JMJD3 antagonistically modulate HSCs activation. The therapeutic effects of DZNep as epigenetic drug in liver fibrosis are associated with the regulation of EZH2 towards direct target genes encoding TGF-ß1 pseudoreceptor BAMBI, anti-inflammatory cytokine IL10 and cell cycle regulators CDKN1A, GADD45A and GADD45B, which are also regulated by JMJD3. Our present study provides new mechanistic insight into the epigenetic modulation of EZH2 and JMJD3 in HSCs biology and hepatic fibrogenesis.

15.
J Pathol ; 254(1): 57-69, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33512716

RESUMO

Hepatic cysts are found in heterogeneous disorders with different pathogeneses, of which simple hepatic cysts and polycystic liver diseases are two major types. The process of hepatic cytogenesis for these two diseases is caused by defects in remodelling of the ductal plate during biliary tract development, which is called ductal plate malformation. SOX9 is a transcription factor participating in the process of bile duct development, and thus, its dysregulation may play important roles in hepatic cystogenesis. SEC63 encodes an endoplasmic reticulum membrane protein that is mutated in human autosomal dominant polycystic liver disease. However, the transcriptional regulation of SEC63 is largely unknown. In the present study, a liver-specific Sox9 knockout (Sox9LKO ) mouse was generated to investigate the roles and underlying mechanism of SOX9 in hepatic cystogenesis. We found that hepatic cysts began to be observed in Sox9LKO mice at 6 months of age. The number and size of cysts increased with age in Sox9LKO mice. In addition, the characteristics of hepatic cytogenesis, including the activation of proliferation, absence of primary cilium, and disorder of polarity in biliary epithelial cells, were detected in the livers of Sox9LKO mice. RNAi silencing of SOX9 in human intrahepatic biliary epithelial cells (HIBEpic) resulted in increased proliferation and reduced formation of the primary cilium. Moreover, Sec63 was downregulated in primary biliary epithelial cells from Sox9LKO mice and SEC63 in HIBEpic transfected with siSOX9. Chromatin immunoprecipitation assays and luciferase reporter assays further demonstrated that SOX9 transcriptionally regulated the expression of SEC63 in biliary epithelial cells. Importantly, the overexpression of SEC63 in HIBEpic partially reversed the effects of SOX9 depletion on the formation of primary cilia and cell proliferation. These findings highlight the biological significance of SOX9 in hepatic cytogenesis and elucidate a novel molecular mechanism underlying hepatic cytogenesis. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

16.
Dysphagia ; 2021 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-33387002

RESUMO

To investigate whether dysphagia differs between one-level and two-level anterior cervical discectomy and fusion (ACDF) with the Zero Profile (Zero-P) Implant System. A retrospective analysis of 208 patients who underwent ACDF with the Zero-P Implant System and had at least one year of follow-up was performed from January 2013 to December 2018. The patients were divided into two groups based on the number of operated levels (one-level group, N = 86; two-level group, N = 122). Dysphagia was assessed based on the Bazaz grading system. The incidence of dysphagia and the severity of dysphagia at each follow-up were compared between the two groups. The patients were divided into two groups (nondysphagia group, N = 160; dysphagia group, N = 48), and covariates were obtained for multivariate analysis, including demographic parameters, surgical parameters, and radiographic parameters. The results showed that the incidence and severity of postoperative dysphagia in the two-level group were significantly greater at 1 week, 1 month and 3 months postoperatively than those in the one-level group. The results of ordinal logistic regression showed that older age, two-level surgery, greater prevertebral soft tissue swelling (PSTS) and the difference between the postoperative and preoperative C2-7 angle (dC2-7A) were significantly associated with a higher incidence of dysphagia after ACDF with the Zero-P. Two-level ACDF with the Zero-P can result in a significantly greater incidence and severity of transient postoperative dysphagia. Older age, greater PSTS and the dC2-7A were also associated with postoperative dysphagia after ACDF with the Zero-P.

17.
Global Spine J ; : 2192568220986144, 2021 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-33511887

RESUMO

STUDY DESIGN: Retrospective analysis. OBJECTIVES: Cervical disc arthroplasty (CDA) was designed to replace the degenerated disc with the prosthesis to preserve cervical motion. The commonly used artificial discs are designed symmetric, whereas the facet joints were reported to be asymmetric in many people. This study aimed to evaluate the effect of facet tropism on the cervical range of motion (ROM) after single-level CDA using Prestige LP. METHODS: A total of 90 patients who underwent single-level CDA using Prestige LP from 2012 to 2017 were retrospectively reviewed. Radiographs were taken at each time point to measure the C2-C7 ROM and the ROM at the surgical segment. The pre-operation CT scans were utilized to reconstruct and calculate the angular direction of facet joints with respect to transverse, coronal, and sagittal reference planes. Facet tropism above 7° was defined as facet joint asymmetry. RESULTS: No significant difference was found in flexion-extension C2-C7 ROM or ROM at the surgical segment between patients with symmetric and asymmetric fact joints regarding the sagittal plane. Patients with coronal asymmetric facet joints had lower flexion-extension ROM at the surgical level. Patients with transverse asymmetric facet joints had both lower flexion-extension C2-C7 ROM and ROM at the surgical level. After CDA surgery, patients obtained good clinical outcomes including increased Japanese Orthopedic Association (JOA) and decreased Neck Disability Index (NDI) as well as Visual Analogue Scale (VAS). CONCLUSION: The coronal and transverse tropism seemed to be correlated with decreased flexion-extension ROM after CDA using Prestige LP.

18.
Cell Death Differ ; 2021 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-33504946

RESUMO

Protein Preferentially Expressed Antigen in Melanoma (Prame), a tumor-associated antigen, has been found to frequently overexpress in various cancers, which indicates advanced cancer stages and poor clinical prognosis. Moreover, previous reports noted that Prame functions as a substrate recognizing receptor protein of Cullin RING E3 ligases (CRLs) to mediate potential substrates degradation through Ubiquitin Proteasome System (UPS). However, none of the Prame specific substrate has been identified so far. In this study, proteomic analysis of RBX1-interacting proteins revealed p14/ARF, a well-known tumor suppressor, as a novel ubiquitin target of RBX1. Subsequently, immunoprecipitation and in vivo ubiquitination assay determined Cullin2-RBX1-Transcription Elongation Factor B Subunit 2 (EloB) assembled CRL2 E3 ligase complex to regulate the ubiquitination and subsequent degradation of p14/ARF. Finally, through siRNA screening, Prame was identified as the specific receptor protein responsible for recognizing p14/ARF to be degraded. Additionally, via bioinformatics analysis of TCGA database and clinical samples, Prame was determined to overexpress in tumor tissues vs. paired adjacent tissues and associated with poor prognosis of cancer patients. As such, downregulation of Prame expression significantly restrained cancer cell growth by inducing G2/M phase cell cycle arrest, which could be rescued by simultaneously knocking down of p14/ARF. Altogether, targeting overexpressed Prame in cancer cells inactivated RBX1-Cullin2-EloB-Prame E3 ligase (CRL2Prame) and halted p14/ARF degradation to restrain tumor growth by inducing G2/M phase cell cycle arrest.

19.
Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi ; 35(1): 26-32, 2021 Jan 15.
Artigo em Chinês | MEDLINE | ID: mdl-33448195

RESUMO

Objective: To explore the influence factors of anterior bone loss (ABL) after cervical disc arthroplasty (CDA) and effects of ABL on the clinical and radiographic outcomes. Methods: One hundred and fifty-five patients who underwent single-level Prestige-LP CDA between January 2008 and December 2017 and met the inclusive criteria were enrolled in the study. Perioperative data of patients were collected. The Japanese Orthopaedic Association (JOA) score, Neck Disability Index (NDI), and the visual analogue scale (VAS) score were used for clinical outcomes evaluation. Radiographic parameters including cervical lordosis, C 2-7 range of motion (ROM), disc angle, segmental ROM, and the lengths of the upper and lower endplates were assessed on the X-ray films. Device-related complications, including ABL, subsidence, radiographic adjacent segment pathology, and heterotopic ossification, were recorded. Univariate analysis was used to analyze the related factors, and logistic regression analysis was used to screen the influence factors. Patients were grouped according to whether ABL occurred after operation, and the differences in clinical and imaging evaluation parameters were compared. Results: There were 94 cases (60.6%) in the ABL group and 61 cases (39.4%) in the non-ABL group. Univariate analysis showed the significant differences in age, body mass index (BMI), and intraoperative blood loss between the two groups ( P<0.05). However, there was no significant difference in gender, bone mineral density (T value), preoperative blood calcium level, preoperative blood phosphorus level, preoperative alkaline phosphatase level, operative segment, operative time, and follow-up time between the two groups ( P>0.05). Multivariate analysis showed that the age and BMI were influence factors for ABL after CDA ( P<0.05). The JOA score, NDI, and VAS score significantly improved in both groups at 3 months after operation ( P<0.05), and the scores were further improved at last follow-up ( P<0.05). There was no significant difference in JOA score, NDI, and VAS score between the two groups before and after operation ( P>0.05). The preoperative cervical lordosis was significantly smaller in the ABL group than in the non-ABL group ( t=-2.402, P=0.018). At last follow-up, the segmental ROM was significantly greater in the ABL group than in the non-ABL group ( P<0.05), and the lengths of the upper and lower endplates were less in the ABL group than in the non-ABL group ( P<0.05). No significant difference in the other radiographic parameters between the two groups were found ( P>0.05). Prosthesis subsidence occurred in 5 cases (3.2%), including 3 cases in the ABL group and 2 cases in the non-ABL group; the difference between the two groups was not significant ( P=1.000). Heterotopic ossification occurred in 67 cases (43.2%), including 32 cases in the ABL group and 35 cases in the non-ABL group; the difference between the two groups was significant ( χ 2=8.208, P=0.004). High-grade heterotopic ossification was detected in 26 cases (13 cases in the ABL group and 13 cases in the non-ABL group). Twenty-nine cases (18.7%) had radiographic adjacent segment pathology, including 15 cases in the ABL group and 14 cases in non-ABL group; the difference between the two groups was not significant ( χ 2=1.190, P=0.276). Conclusion: The incidence of ABL after CDA was relatively high, which mainly occurred within 3 months after operation, and no longer progressing with stable radiographic features after the first 12 months. Age and BMI were independent influence factors for ABL. ABL does not affect the clinical outcomes but may preserve more ROM of prostheses.


Assuntos
Degeneração do Disco Intervertebral , Substituição Total de Disco , Artroplastia , Vértebras Cervicais/diagnóstico por imagem , Vértebras Cervicais/cirurgia , Seguimentos , Humanos , Degeneração do Disco Intervertebral/cirurgia , Amplitude de Movimento Articular , Estudos Retrospectivos , Resultado do Tratamento
20.
Cancer Res ; 81(4): 860-872, 2021 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-33361394

RESUMO

Targeting epigenetics in cancer has emerged as a promising anticancer strategy. p300/CBP is a central regulator of epigenetics and plays an important role in hepatocellular carcinoma (HCC) progression. Tumor-associated metabolic alterations contribute to the establishment and maintenance of the tumorigenic state. In this study, we used a novel p300 inhibitor, B029-2, to investigate the effect of targeting p300/CBP in HCC and tumor metabolism. p300/CBP-mediated acetylation of H3K18 and H3K27 increased in HCC tissues compared with surrounding noncancerous tissues. Conversely, treatment with B029-2 specifically decreased H3K18Ac and H3K27Ac and displayed significant antitumor effects in HCC cells in vitro and in vivo. Importantly, ATAC-seq and RNA-seq integrated analysis revealed that B029-2 disturbed metabolic reprogramming in HCC cells. Moreover, B029-2 decreased glycolytic function and nucleotide synthesis in Huh7 cells by reducing H3K18Ac and H3K27Ac levels at the promoter regions of amino acid metabolism and nucleotide synthesis enzyme genes, including PSPH, PSAT1, ALDH18A1, TALDO1, ATIC, and DTYMK. Overexpression of PSPH and DTYMK partially reversed the inhibitory effect of B029-2 on HCC cells. These findings suggested that p300/CBP epigenetically regulates the expression of glycolysis-related metabolic enzymes through modulation of histone acetylation in HCC and highlights the value of targeting the histone acetyltransferase activity of p300/CBP for HCC therapy. SIGNIFICANCE: This study demonstrates p300/CBP as a critical epigenetic regulator of glycolysis-related metabolic enzymes in HCC and identifies the p300/CBP inhibitor B029-2 as a potential therapeutic strategy in this disease.

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