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Previous studies have demonstrated that Eyes Absent 4 (EYA4) influences the proliferation and migration of tumor cells. Notably, studies have established that EYA4 can also limit tumor sensitivity to chemotherapeutic agents. The objective of this study was to investigate the effect of EYA4 in conferring drug resistance in osteosarcoma (OS). Bioinformatics, histological, and cellular analyses revealed that the expression level of EYA4 was higher in OS tissues than in healthy tissues/cells and in resistant tissues/cells compared with sensitive tissues/cells. In vitro and in vivo experiments demonstrated that EYA4 knockdown increased the sensitivity of OS to doxorubicin (DOX). Conversely, overexpression of EYA4 decreased the sensitivity of OS to DOX. Exploration of the resistance mechanism exposed that EYA4 facilitates DNA double-strand break (DSB) repair, a typical mode of DNA damage repair (DDR). Subsequently, our findings indicated that EYA4 could directly interact with histone H2AX to activate the DDR pathway. Taken together, our observations indicated that EYA4 may serve as a target molecule for reversing drug resistance in OS patients.
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Antibióticos Antineoplásicos , Neoplasias Óseas , Daño del ADN , Reparación del ADN , Doxorrubicina , Resistencia a Antineoplásicos , Ratones Desnudos , Osteosarcoma , Doxorrubicina/farmacología , Humanos , Osteosarcoma/tratamiento farmacológico , Osteosarcoma/metabolismo , Osteosarcoma/patología , Osteosarcoma/genética , Resistencia a Antineoplásicos/efectos de los fármacos , Animales , Reparación del ADN/efectos de los fármacos , Reparación del ADN/fisiología , Ratones , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/genética , Neoplasias Óseas/patología , Neoplasias Óseas/metabolismo , Antibióticos Antineoplásicos/farmacología , Línea Celular Tumoral , Daño del ADN/efectos de los fármacos , Transactivadores/genética , Transactivadores/metabolismo , Femenino , Ratones Endogámicos BALB C , Masculino , Ensayos Antitumor por Modelo de Xenoinjerto/métodosRESUMEN
BACKGROUND: Lumbar revision surgery can be performed by simple lumbar nerve decompression or lumbar interbody fusion, including percutaneous endoscopic lumbar discectomy, transforaminal lumbar interbody fusion (TLIF), etc. However, lumbar revision surgery is very difficult in surgical operation. We sought to explore the technique safety and efficacy of microscope-assisted minimally invasive transforaminal lumbar interbody fusion (MI-TLIF) in lumbar revision surgery. METHODS: Cases of postoperative recurrence following lumbar spine surgery (n = 63) treated from December 2016 to July 2021 were retrospectively analyzed, including 24 cases of microscope-assisted MI-TLIF (microscopic group) and 39 cases of naked-eye MI-TLIF (naked-eye group). The operation time, intraoperative blood loss, incision length, postoperative drainage, length of hospital stay, initial operation, and visual analog score (VAS) of low back and leg pain before and at 7 days and 3 months after the operation and the last follow-up were compared between the two groups. The Oswestry Dysfunction Index (ODI) and the Japanese Orthopaedic Association (JOA) scores before and after the operation and the Bridwell interbody fusion grades at 1 year were compared. The independent t tests, Mann-Whitney U tests, and Chi-square tests were used for analysis. RESULTS: All 63 patients were successfully treated by operation and were followed up for an average of 31.5 ± 8.6 months (range 12-48 months). The two groups had no significant difference in sex, age, incision length, initial operation, or operative segment (P > 0.05). There was no significance in operation time, VAS score, ODI score, and JOA score of low back pain or Bridwell interbody fusion grade between the two groups (P > 0.05). Significant differences in intraoperative blood loss, postoperative drainage, and the lengths of hospital stay were observed between the two groups (P < 0.05). Cerebrospinal fluid leakage (n = 2), edema of nerve roots (n = 2), and incision infection (n = 1) were observed in the naked-eye group. There were no complications in the microscopic group, such as cerebrospinal fluid leakage, edema of nerve roots, and incision infection. CONCLUSION: Although microscope-assisted MI-TLIF and naked-eye MI-TLIF are both effective during lumbar revision surgery, microscope-assisted MI-TLIF brings less trauma, less bleeding, shorter postoperative hospital stay, and faster recovery. Unlike traditional surgery, microscope-assisted MI-TLIF provides a clear visual field, adequate hemostasis, and nerve decompression.
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Discectomía Percutánea , Desplazamiento del Disco Intervertebral , Fusión Vertebral , Humanos , Resultado del Tratamiento , Reoperación , Vértebras Lumbares/cirugía , Estudios Retrospectivos , Procedimientos Quirúrgicos Mínimamente Invasivos/métodos , Fusión Vertebral/métodos , Desplazamiento del Disco Intervertebral/cirugía , Infección de la Herida Quirúrgica/cirugía , Pérdida de Sangre Quirúrgica , Pérdida de Líquido Cefalorraquídeo/cirugía , EdemaRESUMEN
Neuroinflammation is associated with poor outcomes in patients with spinal cord injury (SCI). Recent studies have demonstrated that stimulator of interferon genes (Sting) plays a key role in inflammatory diseases. However, the role of Sting in SCI remains unclear. In the present study, it is found that increased Sting expression is mainly derived from activated microglia after SCI. Interestingly, knockout of Sting in microglia can improve the recovery of neurological function after SCI. Microglial Sting knockout restrains the polarization of microglia toward the M1 phenotype and alleviates neuronal death. Furthermore, it is found that the downregulation of mitofusin 2 (Mfn2) expression in microglial cells leads to an imbalance in mitochondrial fusion and division, inducing the release of mitochondrial DNA (mtDNA), which mediates the activation of the cGas-Sting signaling pathway and aggravates inflammatory response damage after SCI. A biomimetic microglial nanoparticle strategy to deliver MASM7 (named MSNs-MASM7@MI) is established. In vitro, MSNs-MASM7@MI showed no biological toxicity and effectively delivered MASM7. In vivo, MSNs-MASM7@MI improves nerve function after SCI. The study provides evidence that cGas-Sting signaling senses Mfn2-dependent mtDNA release and that its activation may play a key role in SCI. These findings provide new perspectives and potential therapeutic targets for SCI treatment.
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Microglía , Traumatismos de la Médula Espinal , Humanos , Microglía/metabolismo , ADN Mitocondrial/genética , ADN Mitocondrial/metabolismo , Regulación hacia Abajo , Inflamación/metabolismo , Traumatismos de la Médula Espinal/metabolismo , Nucleotidiltransferasas/metabolismoRESUMEN
Background: There are many pharmaceutical interventions available to prevent osteoporotic vertebral fractures in postmenopausal women, but the efficacy and safety of these drugs are unknown. This study aimed to investigate the efficacy and safety of drugs in the prevention of osteoporotic vertebral fractures. Methods: PubMed, Embase, and the Cochrane Library were comprehensively searched for randomized controlled trials (RCTs) published up to February 15, 2020, including postmenopausal women with osteoporosis. Network meta-analysis was conducted based on the Cochrane Handbook for Systematic Reviews of Interventions and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The relative risk (RR) and 95% confidence interval (CI) were used to report the results. This study was registered with PROSPERO, number CRD42020201167. Main Outcomes were incidences of new vertebral fracture and serious adverse events. Results: Fifty-five RCTs (n = 104 580) evaluating vertebral fractures of sixteen kinds of pharmacologic therapies were included in the network meta-analysis. Abaloparatide (RR, 0.21; [95% CI, 0.09 to 0.51]), alendronate (RR, 0.55; [95% CI, 0.38 to 0.81]), calcitonin (RR, 0.44; [95% CI, 0.25 to 0.78]), denosumab (RR, 0.33; [95% CI, 0.14 to 0.61]), parathyroid hormone (PTH) (RR, 0.32; [95% CI, 0.10 to 0.97]), risedronate (RR, 0.65; [95% CI, 0.42 to 1.00]), romosozumab (RR, 0.31; [95% CI, 0.16 to 0.61]), strontium ranelate (RR, 0.62; [95% CI, 0.42 to 0.93]), teriparatide (RR, 0.27; [95% CI, 0.17 to 0.43]), and zoledronate (RR, 0.41; [95% CI, 0.93]) were associated with lower vertebral fracture risk compared to placebo. PTH was associated with more adverse event rates. For any two drug treatments, the RR of serious adverse events was not statistically significant. Hormone replacement therapy (HRT) and calcitonin may be slower to work because they have only been shown to reduce the risk of vertebral fractures in long-term (>18 months) follow-up. Conclusions: A variety of drugs are safe and effective in preventing osteoporotic vertebral fractures. HRT and calcitonin only reduced the risk of vertebral fractures during a follow-up of 21-72 months.
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Purpose: To evaluate the effects of physical exercise on neck and shoulder muscle strength and pain in military pilots. Method: Embase, PubMed, and Cochrane Library databases were searched studies published up to April 1, 2022. Studies that met the screening criteria were included in the final meta-analysis. We calculated neck and shoulder maximal voluntary isometric contractions (MVICs), prevalence of pain, and pain intensity. Heterogeneity was explored by subgroup and sensitivity analyses. Result: A total of 15 studies with 907 participants were included. In the exercise group, muscle strength was significantly increased in four directions of neck motion: flexion (standardized mean difference (SMD) = 0.45; 95% CI, 0.08-0.82), extension (SMD = 0.63; 95% CI, 0.27-1.00), right lateral flexion (Rtflx) (SMD = 0.53; 95% CI, 0.12-0.94), and left lateral flexion (Ltflx) (SMD = 0.50; 95% CI, 0.09-0.91). Subgroup analysis showed that fighter pilots, strength plus endurance training, and a follow-up period <20 weeks exhibited more significant muscle strength improvements than helicopter pilots, simple strength training, and a follow-up period ≥20 weeks. Overall, the pooled odds ratio (OR) for the effect of physical exercise on the prevalence of neck pain was not statistically significant (I2 = 60%). Sensitivity analysis revealed that the heterogeneity was restored after removing each of two studies (I2 = 47%), and the pooled OR was statistically significant (OR = 0.46; 95% CI, 0.23 to 0.94, or OR = 0.47; 95% CI, 0.24-0.91). Furthermore, compared with observational studies (OS), the reduction in the prevalence of neck pain was more significant in randomized controlled trials (RCTs) (OR = 0.37; 95% CI, 0.18-0.78). No significant differences in the effects of exercise on shoulder muscle strength and neck and shoulder pain intensity were observed. Conclusion: Physical exercise can improve neck muscle strength in military pilots. After removing studies that may be the source of heterogeneity, exercise showed a protective effect on neck pain, especially in RCTs. The conclusion that exercise had no effects on shoulder muscle strength and pain intensity should be taken with caution.
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Background: Falls occur frequently among older individuals, leading to high morbidity and mortality. This study was to assess the efficacy of vitamin D in preventing older individuals from falling. Methods: We searched the PubMed, Cochrane Library, and EMBASE databases systematically using the keywords "vitamin D" and "fall" for randomized controlled trials (RCTs) comparing the effects of vitamin D with or without calcium supplements with those of a placebo or no treatment on fall incidence in adults older than 50 years. A meta-analysis was performed to calculate risk ratios (RRs), absolute risk differences (ARDs) and 95% CIs with random-effects models. Results: A total of 38 RCTs involving 61 350 participants fulfilled the inclusion criteria. Compared with placebo, high-dose vitamin D (≥ 700 IU) can prevent falls [RR, 0.87 (95% CI 0.79 to 0.96); ARD, -0.06 (95% CI, -0.10 to -0.02)]. Low-dose vitamin D (<700 IU) was not significantly associated with falls. Subgroup analysis showed that supplemental calcium, 25(OH) D concentration and frequency influenced the effect of vitamin D in preventing falls. Sensitivity analysis showed that vitamin D prevented falls, which was consistent with the primary analysis. In addition, the active form of vitamin D also prevented falls. Conclusion: In this meta-analysis of RCTs, doses of 700 IU to 2000 IU of supplemental vitamin D per day were associated with a lower risk of falling among ambulatory and institutionalized older adults. However, this conclusion should be cautiously interpreted, given the small differences in outcomes. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42020179390.
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Accidentes por Caídas , Calcio , Accidentes por Caídas/prevención & control , Anciano , Suplementos Dietéticos , Humanos , Vitamina D , VitaminasRESUMEN
Background: Traditionally paired meta-analysis revealed inconsistencies in the safety and effectiveness of surgical interventions. We conducted a network meta-analysis to assess various treatments' clinical efficacy and safety for pure cervical radiculopathy. Methods: The Embase, PubMed, and Cochrane Library databases were searched for randomized controlled trials (RCTs) comparing different treatment options for patients with pure cervical radiculopathy from inception until October 23, 2021. The primary outcomes were postoperative success rates, postoperative complication rates, and postoperative reoperation rates. The pooled data were subjected to a random-effects consistency model. The protocol was published in PROSPERO (CRD42021284819). Results: This study included 23 RCTs (n = 1,844) that evaluated various treatments for patients with pure cervical radiculopathy. There were no statistical differences between treatments in the consistency model in terms of major clinical effectiveness and safety outcomes. Postoperative success rates were higher for anterior cervical foraminotomy (ACF: probability 38%), posterior cervical foraminotomy (PCF: 24%), and anterior cervical discectomy with fusion and additional plating (ACDFP: 21%). Postoperative complication rates ranked from high to low as follows: cervical disc replacement (CDR: probability 32%), physiotherapy (25%), ACF (25%). Autologous bone graft (ABG) had better relief from arm pain (probability 71%) and neck disability (71%). Among the seven surgical interventions with a statistical difference, anterior cervical discectomy with allograft bone graft plus plating (ABGP) had the shortest surgery time. Conclusions: According to current results, all surgical interventions can achieve satisfactory results, and there are no statistically significant differences. As a result, based on their strengths and patient-related factors, surgeons can exercise discretion in determining the appropriate surgical intervention for pure cervical radiculopathy.Systematic Review Registration: CRD42021284819.
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Radiculopatía , Fusión Vertebral , Vértebras Cervicales/cirugía , Humanos , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Radiculopatía/etiología , Radiculopatía/cirugía , Fusión Vertebral/efectos adversos , Fusión Vertebral/métodos , Resultado del TratamientoRESUMEN
Background: Clinically, there are substantive practice variations in surgical management of degenerative lumbar spondylolisthesis. We aimed at evaluating whether decompression alone outcomes for patients with degenerative lumbar spondylolisthesis are comparable to those of decompression with fusion. Methods: In this meta-analysis, the Embase, PubMed, and Cochrane Library databases were searched from inception to February 16th, 2022. Randomised controlled trials (RCTs) and cohort studies comparing decompression alone with decompression and fusion for patients with degenerative lumbar spondylolisthesis were included in this study. There were no language limitations. Odds ratio (OR), mean difference (MD) and 95% confidence interval (CI) were used to report results in the random-effects model. Main outcomes included Oswestry disability index (ODI), pain, clinical satisfaction, complication and reoperation rates. The study protocol was published in PROSPERO (CRD42022310645). Findings: Thirty-three studies (6 RCTs and 27 cohort studies) involving 94 953 participants were included. Differences in post-operative ODI between decompression alone and decompression with fusion were not significant. A small difference for back (MD, 0.13; [95% CI, 0.08 to 0.18]; I 2:0.00%) and leg pain (MD, 0.30; [95% CI, 0.09 to 0.51]; I 2:48.35%) was observed on the 3rd post-operative month. The results did not reveal significant differences in leg pain and back pain between decompression alone and fusion groups on the 6th, 12th, and 24th post-operative months. Difference in clinical satisfaction between decompression alone and decompression with fusion were not significant from RCTs (OR, 0.26; [95% CI, 0.03 to 1.92]; I 2:83.27%). Complications (OR, 1.54; [95% CI, 1.16 to 2.05]; I 2:48.88%), operation time (MD, 83.39; [95% CI, 55.93 to 110.85]; I 2:98.75%), intra-operative blood loss (MD, 264.58; [95% CI, 174.99 to 354.16]; I 2:95.61%) and length of hospital stay (MD, 2.85; [95% CI, 1.60 to 4.10]; I 2:99.49%) were higher with fusion. Interpretation: Clinical effectiveness of decompression alone was comparable to that of decompression with fusion for degenerative lumbar spondylolisthesis. Decompression alone is recommended for patients with degenerative lumbar spondylolisthesis. Funding: This work was supported by grants from the National Natural Science Foundation of China (No. 81871818), Tangdu Hospital Seed Talent Program (Fei-Long Wei), Natural Science Basic Research Plan in Shaanxi Province of China (No.2019JM-265) and Social Talent Fund of Tangdu Hospital (No.2021SHRC034).
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Background: Traditional paired meta-analyses have yielded inconsistent results for the safety and effectiveness of robotic-assisted pedicle screw placement due to the high heterogeneity within studies. This study evaluated the clinical effectiveness and safety of robotic-assisted pedicle screw placement. Methods: The Embase, PubMed, and Cochrane Library databases were searched with no language limitations from inception to Jan 4, 2022. Odds ratio (OR), mean difference (MD), and 95% confidence interval (CI) were used to report results. The main outcomes were accuracy of pedicle screw placement, proximal facet joint violation, and complications. The study protocol was published in PROSPERO (CRD42022301417). Findings: 26 trials including 2046 participants evaluating robotic-assisted pedicle screw placement were included in this study. Our pooled results showed that Renaissance (OR 2.86; [95% CI 1.79 to 4.57]) and TiRobot (OR 3.10; [95% CI 2.19 to 4.40]) yielded higher rates of perfect pedicle screw insertion (Grades A) than the conventional freehand technique. Renaissance (OR 2.82; [95% CI 1.51 to 5.25]) and TiRobot (OR 4.58; [95% CI 2.65 to 7.89]) yielded higher rates of clinically acceptable pedicle screw insertion (Grades A+B). However, ROSA, SpineAssist, and Orthobot were not associated with higher perfect pedicle screw insertion and clinically acceptable pedicle screw insertion rates. Robot-assisted techniques were associated with low rates of proximal facet joint violation (OR 0.18; [95% CI 0.10 to 0.32]; I2:9.55%) and overall complications (OR 0.38; [95% CI 0.23 to 0.63]; I2:27.05%). Moreover, robot-assisted techniques were associated with lower radiation doses (MD -14.38; [95% CI -25.62 to -3.13]; I2:100.00%). Interpretation: Our findings suggest that only Renaissance and TiRobot systems are associated with high accuracy rates of pedicle screw placement. Robotic-assisted techniques hold great promise in spinal surgery due to their safety and effectiveness. Funding: This work was supported by grants from the National Natural Science Foundation of China (No. 81871818), Tangdu Hospital Seed Talent Program (Fei-Long Wei) and Natural Science Basic Research Plan in Shaanxi Province of China (No.2019JM-265).
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Background: Minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) is an effective surgical option for lumbar spinal stenosis (LSS) with spondylolisthesis. However, few studies have discussed oblique lateral interbody fusion (OLIF) with MIS-TLIF. Objective: To evaluate postoperative improvements, complications, and reoperation rates between patients with LSS undergoing OLIF or MIS-TLIF. Methods: We retrospectively studied 113 LLS patients who underwent OLIF (53) or MIS-TLIF (60) with percutaneous pedicle screw fixation between January 2016 and December 2018. We measured estimated blood loss, operative time, hospital stay, reoperation, and complication incidence, visual analog scale (VAS), Oswestry Disability Index (ODI), Japanese Orthopedic Association (JOA), and Short Form-36 (SF-36) scores, discal and foraminal height and lumbar lordotic angle. Results: The mean age was 58.81 ± 0.9 years. The TLIF group had increased operation time, blood loss, and hospital stays (p = 0.007, 0.001, and 0.016, respectively). Postoperatively, VAS and ODI scores significantly decreased while JOA and SF-36 scores significantly increased. The postoperative differences in main outcomes between the groups were insignificant (all p > 0.05). The OLIF group had the lowest rates of overall (9.8% OLIF vs. 12.9% MIS-TLIF), intraoperative (3.9% OLIF vs. 4.8% MIS-TLIF), and postoperative complications (5.9% OLIF vs. 8.1% MIS-TLIF), but the differences were insignificant (p = 0.607, 0.813, and 0.653, respectively). The reoperation rate did not differ significantly (3.8% OLIF vs. 3.3% MIS-TLIF) (p = 0.842). OLIF restored disc height (74.4 vs. 32.0%), foraminal height (27.4 vs. 18.2%), and lumbar lordotic angle (3.5 vs. 1.1%) with greater success than did MIS-TLIF. Conclusion: Patients undergoing OLIF with LSS improved similarly to MIS-TLIF patients. OLIF restored disc height, foraminal height and lumbar lordotic angle more successfully than did MIS-TLIF.
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BACKGROUND: The choice of bone substitutes for the treatment of infected bone defects (IBDs) has attracted the attention of surgeons for years. However, single-stage bioabsorbable materials that are used as carriers for antibiotic release, as well as scaffolds for BMSC sheets, need further exploration. Our study was designed to investigate the effect of vancomycin-loaded calcium sulfate hemihydrate/nanohydroxyapatite/carboxymethyl chitosan (CSH/n-HA/CMCS) hydrogels combined with BMSC sheets as bone substitutes for the treatment of IBDs. METHODS: BMSCs were harvested and cultured into cell sheets. After the successful establishment of an animal model with chronic osteomyelitis, 48 New Zealand white rabbits were randomly divided into 4 groups. Animals in Group A were treated with thorough debridement as a control. Group B was treated with BMSC sheets. CSH/n-HA/CMCS hydrogels were implanted in the treatment of Group C, and Group D was treated with CSH/n-HA/CMCS+BMSC sheets. Gross observation and micro-CT 3D reconstruction were performed to assess the osteogenic and infection elimination abilities of the treatment materials. Histological staining (haematoxylin and eosin and Van Gieson) was used to observe inflammatory cell infiltration and the formation of collagen fibres at 4, 8, and 12 weeks after implantation. RESULTS: The bone defects of the control group were not repaired at 12 weeks, as chronic osteomyelitis was still observed. HE staining showed a large amount of inflammatory cell infiltration around the tissue, and VG staining showed no new collagen fibres formation. In the BMSC sheet group, although new bone formation was observed by gross observation and micro-CT scanning, infection was not effectively controlled due to unfilled cavities. Some neutrophils and only a small amount of collagen fibres could be observed. Both the hydrogel and hydrogel/BMSCs groups achieved satisfactory repair effects and infection control. Micro-CT 3D reconstruction at 4 weeks showed that the hydrogel/BMSC sheet group had higher reconstruction efficiency and better bone modelling with normal morphology. HE staining showed little aggregation of inflammatory cells, and VG staining showed a large number of new collagen fibres. CONCLUSIONS: Our preliminary results suggested that compared to a single material, the novel antibiotic-impregnated hydrogels acted as superior scaffolds for BMSC sheets and excellent antibiotic vectors against infection, which provided a basis for applying tissue engineering technology to the treatment of chronic osteomyelitis.
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Sustitutos de Huesos , Quitosano , Osteomielitis , Animales , Conejos , Antibacterianos , Sulfato de Calcio , Colágeno , Hidrogeles , Osteogénesis , Osteomielitis/tratamiento farmacológico , Andamios del Tejido , VancomicinaRESUMEN
BACKGROUND: Osteosarcoma (OS) is a malignant bone tumor mostly occurring in children and adolescents, while chemotherapy resistance often develops and the mechanisms involved remain challenging to be fully investigated. METHODS: Genome-wide CRISPR screening combined with transcriptomic sequencing were used to identify the critical genes of doxorubicin resistance. Analysis of clinical samples and datasets, and in vitro and in vivo experiments (including CCK-8, apoptosis, western blot, qRT-PCR and mouse models) were applied to confirm the function of these genes. The bioinformatics and IP-MS assays were utilized to further verify the downstream pathway. RGD peptide-directed and exosome-delivered siRNA were developed for the novel therapy strategy. RESULTS: We identified that E3 ubiquitin-protein ligase Rad18 (Rad18) contributed to doxorubicin-resistance in OS. Further exploration revealed that Rad18 interact with meiotic recombination 11 (MRE11) to promote the formation of the MRE11-RAD50-NBS1 (MRN) complex, facilitating the activation of the homologous recombination (HR) pathway, which ultimately mediated DNA damage tolerance and leaded to a poor prognosis and chemotherapy response in patients with OS. Rad18-knockout effectively restored the chemotherapy response in vitro and in vivo. Also, RGD-exosome loading chemically modified siRad18 combined with doxorubicin, where exosome and chemical modification guaranteed the stability of siRad18 and the RGD peptide provided prominent targetability, had significantly improved antitumor activity of doxorubicin. CONCLUSIONS: Collectively, our study identifies Rad18 as a driver of OS doxorubicin resistance that promotes the HR pathway and indicates that targeting Rad18 is an effective approach to overcome chemotherapy resistance in OS.
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Neoplasias Óseas , Doxorrubicina , Osteosarcoma , Adolescente , Animales , Antibióticos Antineoplásicos/metabolismo , Antibióticos Antineoplásicos/farmacología , Antibióticos Antineoplásicos/uso terapéutico , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/genética , Neoplasias Óseas/patología , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Doxorrubicina/metabolismo , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Humanos , Ratones , Osteosarcoma/tratamiento farmacológico , Osteosarcoma/genética , Osteosarcoma/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/farmacología , Ubiquitina-Proteína Ligasas/uso terapéuticoRESUMEN
Extracellular vesicle (EV) from hypoxic adipose tissue-derived mesenchymal stem cells (AD-MSCs) play critical roles in spinal cord injury (SCI) by transferring miRNAs to target cells through fusion with the cell membrane. However, the role of miR-511-3p within the AD-MSCs -derived EV in SCI is largely unknown. Western blotting results demonstrated the secretion of EVs derived from AD-MSCs under hypoxia (Hyp-EVs) was more than those under normoxia (Nor-EVs), and miR-511-3p expression was more enriched in Hyp-EVs. PC12 cells were stimulated with lipopolysaccharide (LPS) to induce cell damage. AD-MSCs were transfected with miR-511-3p mimic or miR-511-3p inhibitor to induce EVs-miR-511-3p overexpression or silencing. Cells treated with Hyp-EVs-miR-511-3p mimic reduced LPS-induced apoptosis, alleviated inflammation and promoted proliferation, while cells treated with Hyp-EVs-miR-511-3p inhibitor aggravated LPS-induced apoptosis and inflammation, and suppressed proliferation. Luciferase reporter gene assay revealed tumor necrosis factor receptor-associated factor 6 (TRAF6) was a target downstream gene of miR-511-3p. A series of gain- and loss-of-function experiments verified that TRAF6 could antagonize the effects of Hyp-EVs-miR-511-3p on inflammation, cell apoptosis and viability. Furthermore, cells treated with CYM5541, an agonist of sphingosine-1-phosphate receptor 3 (S1PR3), reversed the inhibitory effect of Hyp-EVs-miR-511-3p mimic on S1PR3 expression, inflammation and cell apoptosis. Finally, intravenously injection of Hyp-EVs-miR-511-3p mimic into SCI model rats obviously reduced inflammation and promoted neurological function recovery. In conclusion, EVs-derived miR-511-3p from hypoxia preconditioned AD-MSCs ameliorates SCI via TRAF6/S1P/NF-κB pathway, which indicates that miR-511-3p may be a potential therapeutic target for SCI.
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Tejido Adiposo/fisiología , Vesículas Extracelulares , Hipoxia , Células Madre Mesenquimatosas , MicroARNs/metabolismo , Proproteína Convertasas/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Serina Endopeptidasas/metabolismo , Traumatismos de la Médula Espinal/tratamiento farmacológico , Traumatismos de la Médula Espinal/metabolismo , Factor 6 Asociado a Receptor de TNF/metabolismo , Animales , Modelos Animales de Enfermedad , MicroARNs/farmacología , Células PC12 , Ratas , Quinasa de Factor Nuclear kappa BRESUMEN
BACKGROUND: Electric bicycles related collisions could lead to severe consequences in spine injuries, while no study had comprehensively investigated the epidemiology and demography of spine injuries in electric bicycles related collisions. QUESTIONS/PURPOSES: The aim of this study is to (1) describe the epidemiological characteristics of spine injuries in electric bicycles related collisions, (2) develop clinical guideline of spine injuries in electric bicycles related collisions and (3) support the new road safety policy for electric bicycle riders. METHODS: A retrospective review of spine injuries in electric bicycle related collisions was performed from 86 patients in an urban trauma center between 2018 and 2020. The variables including gender, age, radiographic findings, associated injuries, neurologic injuries, treatment, average length of stay were fully collected. Chi-square test and paired sample mean t-test were used to test for statistically significant differences. All statistical analyses were performed using Statistical Product and Service Solutions 20.0.0 software. A P<0.001 was considered as significant. RESULTS: A total of 86 cases were involved in electric bicycles related collisions lead to spine injuries. The spine injuries victims were predominantly male (79.07%) and middle-aged (41-60years, 44.19%). The most common spine injuries were L1 fractures (10.48%). The most common fracture type was AO Fracture Classification type A (71.40%). Age and multivertebral fractures had significant difference between patients who suffered from an ASOI and from those who did not (P-value: 0.005, 0.005). There was significant difference between patients who suffered from neurologic injuries and from those who did not in AO Classification, multivertebral fractures and ASOI (P-value: 0.0001, 0.001, 0.032). Age, AO Classification, multivertebral fractures, ASOI and neurologic injuries had significant difference to influence patients' ISS and ALOS. CONCLUSIONS: Spine injuries in electric bicycles related collisions may make patients suffer from severe consequences including their potential permanent disability, economic cost, or even life safety. Patients with spine injuries in electric bicycles related collisions should be paid close attention to avoid missed diagnosis and misdiagnosis. Helmet, protective clothing or other safety gear should be required to use to provide greater protection for electric bicycle riders.
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Ciclismo , Traumatismos Vertebrales , Accidentes de Tránsito , Ciclismo/lesiones , Dispositivos de Protección de la Cabeza , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Traumatismos Vertebrales/epidemiologíaRESUMEN
Objective: Therapeutic options for lumbar disc surgery (LDH) have been rapidly evolved worldwide. Conventional pair meta-analysis has shown inconsistent results of the safety of different surgical interventions for LDH. A network pooling evaluation of randomized controlled trials (RCT) was conducted to compare eight surgical interventions on complications for patients with LDH. Methods: PubMed, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched for RCT from inception to June 2020, with registration in PROSPERO (CRD42020176821). This study is conducted in accordance with Cochrane guidelines. Primary outcomes include intraoperative, post-operative, and overall complications, reoperation, operation time, and blood loss. Results: A total of 27 RCT with 2,948 participants and eight interventions, including automated percutaneous lumbar discectomy (APLD), chemonucleolysis (CN), microdiscectomy (MD), micro-endoscopic discectomy (MED), open discectomy (OD), percutaneous endoscopic lumbar discectomy (PELD), percutaneous laser disc decompression (PLDD), and tubular discectomy (TD) were enrolled. The pooling results suggested that PELD and PLDD are with lower intraoperative and post-operative complication rates, respectively. TD, PELD, PLDD, and MED were the safest procedures for LDH according to complications, reoperation, operation time, and blood loss. Conclusion: The results of this study provided evidence that PELD and PLDD were with lower intraoperative and post-operative complication rates, respectively. TD, PELD, PLDD, and MED were the safest procedures for LDH according to complications, reoperation, operation time, and blood loss. Systematic Review Registration: PROSPERO, identifier CRD42020176821.
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Background: Percutaneous endoscopic decompression (PED) is a minimally invasive surgical technique that is now used for not only disc herniation but also lumbar spinal stenosis (LSS). However, few studies have reported endoscopic surgery for LSS. Therefore, we conducted this study to evaluate the outcomes and safety of large channel endoscopic decompression. Methods: Forty-one patients diagnosed with LSS who underwent PED surgery were included in the study. The estimated blood loss, operative time, length of hospital stay, hospital costs, reoperations, complications, visual analogue scale (VAS) score, Oswestry Disability Index (ODI) score, Japanese Orthopaedic Association (JOA) score and SF-36 physical-component summary scores were assessed. Preoperative and postoperative continuous data were compared through paired-samples t-tests. The significance level for all analyses was defined as p < 0.05. Results: A total of 41 consecutive patients underwent PED, including 21 (51.2%) males and 20 (48.8%) females. The VAS and ODI scores decreased from preoperatively to postoperatively, but the JOA and SF-36 physical component summary scores significantly increased. The VAS (lumbar) score decreased from 5.05 ± 2.33 to 0.45 ± 0.71 (P = 0.000); the VAS (leg) score decreased from 5.51 ± 2.82 to 0.53 ± 0.72 (P = 0.000); the ODI score decreased from 52.80 ± 20.41 to 4.84 ± 3.98 (P = 0.000), and the JOA score increased from 11.73 ± 4.99 to 25.32 ± 2.12 (P = 0.000). Only 1 patient experienced an intraoperative complication (2.4%; dural tear), and 1 patient required reoperation (2.4%). Conclusions: Surgical treatment for LSS is to sufficiently decompress and minimize the trauma and complications caused by surgery. This study did not reveal any obvious shortcomings of PED and suggested PED is a safe and effective treatment for LSS.
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BACKGROUND: New approaches and technologies can be beneficial for patients but also bring corresponding complications. Traditional pairwise meta-analyses cannot be used to comprehensively rank all surgical approaches. OBJECTIVES: The purpose of this systematic review and network meta-analysis (NMA) was to compare the outcomes of different surgical approaches for lumbar disc herniation (LDH). STUDY DESIGN: NMA of randomized controlled trials (RCTs) for multiple treatment comparisons of LDH. METHODS: The PubMed, Embase, MEDLINE, Ovid, and Cochrane Library databases were searched for RCTs comparing different surgical approaches for patients with LDH from inception to February 10, 2020. The Markov chain Monte Carlo methods were used to perform a hierarchical Bayesian NMA in WinBUGS version 1.4.3 using a random effects consistency model. The primary outcomes were disability and pain intensity. The secondary outcomes were complications and reoperation. The PROSPERO number was CRD42020179406. RESULTS: A total of 22 trials including 2529 patients and all 5 different approaches (open discectomy or microdiscectomy [OD/MD], microendoscopic discectomy [MED], percutaneous endoscopic discectomy [PED], percutaneous discectomy [PD], and tubular discectomy [TD]) were retrospectively retrieved. PED had the best efficacy in improving patients' dysfunction with no statistical significance (probability = 50%). PD was significantly worse than OD/MD, MED, and PED in relieving patients' pain (standardized mean differences: 0.87 [0.03, 1.76], 0.94 [0.06, 1.88], and 1.02 [0.13, 1.94], respectively). There was no statistically significant difference between any 2 surgical approaches in dural tear; intraoperative, postoperative, and overall complications; or reoperation rate. PED had the lowest dural tear rate and the lowest intraoperative and overall complication rates (probability = 51%, 67%, and 33%, respectively). TD had the lowest postoperative complication and reoperation rates (probability = 35% and 39%, respectively). LIMITATIONS: The limitations of this NMA include the inconsistent follow-up times, the criteria for complications, and the reasons for reoperation. CONCLUSIONS: Compared with other approaches used to treat LDH, PED had the best safety and efficacy in general, and TD had the lowest reoperation rate. Finally, we recommended PED for LDH.
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Discectomía Percutánea , Degeneración del Disco Intervertebral , Desplazamiento del Disco Intervertebral , Humanos , Degeneración del Disco Intervertebral/cirugía , Desplazamiento del Disco Intervertebral/cirugía , Vértebras Lumbares/cirugía , Metaanálisis en RedRESUMEN
Background: The symptoms of sciatic herpes zoster are sometimes difficult to distinguish from sciatica caused by lumbar disc herniation. We describe a case of suspected lumbar disc herniation with sciatic herpes zoster to reduce the rate of misdiagnosis. Case Report: A 55-year old man, male, developed low back pain after carrying heavy items 20 years ago. Characteristics of symptoms: 1. Symptoms were aggravated in the upright lumbar forward flexion position; 2. The VAS (leg) score was 8-9 points and the VSA (lumbar) score was 0 point; 3. It can be relieved when rested in the supine position; 4. It came on intermittently with radiation pain in the right lower limb. There were several attacks every year. One month ago, there was radiating pain in the right lower limb. The pain was from the back of the right hip, behind the thigh, in lateral crural region, to the back of the foot. And Symptoms worsened for 10 days. The VAS score was 8 points. Pain could not be relieved by rest or changing posture. There was no back pain, no lower limbs, weak walking, no claudication and other symptoms. Analgesics and neurotrophic drugs are ineffective. After the application of antiviral drugs, the radiation pain in the right lower extremity was significantly relieved. Conclusion: We describe this case in detail and discuss how to make an authentic diagnosis, with a concomitant literature review.
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BACKGROUND: Conventional paired meta-analyses have shown inconsistent results regarding the safety and efficacy of different interventions. OBJECTIVE: To perform a network meta-analysis (NMA) and systematic review based on randomized controlled trials (RCTs) evaluating the efficacies of different interventions for lumbar spinal stenosis (LSS). METHODS: We searched PubMed, Embase, Cochrane Library, Web of Science, and major scientific websites from inception to October 10, 2019, for randomized controlled trials comparing the nine most commonly used interventions for LSS. The main outcomes were disability and pain intensity. The PROSPERO number was CRD42020154247. RESULTS: First, laminotomy was better in improving patients' short- and long-term dysfunction (probability 49% and 25%, respectively). Second, decompression, decompression plus fusion, endoscopic decompression, interspinous process spacer device implantation, laminectomy, laminotomy and minimally invasive decompression were significantly more efficacious in relieving pain than non-surgical interventions (mean difference in the short-term -21.82, -22.00, -16.68, -17.47, -17.75, -17.61 and -18.86; in the long-term -37.14, -34.04, -34.07, -39.79, -36.14, -32.75 and -39.14, respectively). Third, endoscopic decompression had a lower complication rate (probability 51%). In addition, laminotomy had a lower reoperation rate (probability 45%). Fourth, decompression plus fusion resulted in more blood loss than any other surgical intervention (probability 96%). Finally, endoscopic decompression had the shortest hospitalization time (probability 96%). CONCLUSIONS: There were no significant differences among the different interventions in improving patient function. Surgical interventions were associated with better pain relief but a higher incidence of complications. Decompression plus fusion is not necessary for patients. In addition, endoscopic decompression as a novel and less invasive surgical approach may be a good choice for LSS patients.
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Descompresión Quirúrgica/métodos , Laminectomía/métodos , Vértebras Lumbares/cirugía , Metaanálisis en Red , Estenosis Espinal/cirugía , Descompresión Quirúrgica/efectos adversos , Humanos , Laminectomía/efectos adversos , Manejo del DolorRESUMEN
INTRODUCTION: Lumbar spinal stenosis (LSS) is caused by structural changes of the spine, which lead to several severe symptoms, including back pain, leg pain, numbness and tingling in the legs, as well as reduced physical function. However, there is little evidence suggesting whether a patient with LSS should be treated with surgery. If surgery is recommended, which type of surgery benefits the patient most? To answer these questions, we will conduct a network meta-analysis and a systematic review to compare surgical and nonsurgical interventions in terms of efficacy as well as safety in adult patients with LSS. METHODS AND ANALYSIS: We will search the PubMed, Cochrane library, and EMBASE databases for articles published prior to October 10, 2019. We will search for randomized controlled trials assessing surgical and nonsurgical interventions for adult patients with degenerative LSS without any language restrictions. The primary outcome measures will be pain and disability. The secondary outcomes will include adverse events (number of events or number of people with each type of adverse event), reoperations, complications, blood loss and operation time. We will obtain the full texts of the potentially relevant studies and independently assess them. The quality of evidence will be evaluated according to the Grading of Recommendations Assessment, Development and Evaluation framework. A random-effects network meta-analysis will be performed to analyze all the evidence under the frequentist framework, and the ranking results will be presented. We will generate plots depicting the network geometry using Stata. The network meta-analysis will be performed according to the Bayesian framework. Ethics and dissemination Ethics approval is not required. The research will be published in a peer-reviewed journal.