Stepwise reduction of bone mineral density increases the risk of cage subsidence in oblique lumbar interbody fusion patients biomechanically: an in-silico study.

BACKGROUND: Cage subsidence causes poor prognoses in patients treated by oblique lumbar interbody fusion (OLIF). Deterioration of the biomechanical environment initially triggers cage subsidence, and patients with low bone mineral density (BMD) suffer a higher risk of cage subsidence. However, whether low BMD increases the risk of cage subsidence by deteriorating the local biomechanical environment has not been clearly identified. METHODS: OLIF without additional fixation (stand-alone, S-A) and with different additional fixation devices (AFDs), including anterolateral single rod screws (ALSRs) and bilateral pedicle screws (BPSs) fixation, was simulated in the L4-L5 segment of a well-validated finite element model. The biomechanical effects of different BMDs were investigated by adjusting the material properties of bony structures. Biomechanical indicators related to cage subsidence were computed and recorded under different directional moments. RESULTS: Overall, low BMD triggers stress concentration in surgical segment, the highest equivalent stress can be observed in osteoporosis models under most loading conditions. Compared with the flexion-extension loading condition, this variation tendency was more pronounced under bending and rotation loading conditions. In addition, AFDs obviously reduced the stress concentration on both bony endplates and the OLIF cage, and the maximum stress on ALSRs was evidently higher than that on BPSs under almost all loading conditions. CONCLUSIONS: Stepwise reduction of BMD increases the risk of a poor local biomechanical environment in OLIF patients, and regular anti-osteoporosis therapy should be considered an effective method to biomechanically optimize the prognosis of OLIF patients.

Long non-coding RNA ARHGAP5-AS1 inhibits migration of breast cancer cell via stabilizing SMAD7 protein.

PURPOSE: Tumor metastasis is the main cause of death from breast cancer patients and cell migration plays a critical role in cancer metastasis. Recent studies have shown long non-coding RNAs (lncRNAs) play an essential role in the initiation and progression of cancer. In the present study, the role of an LncRNA, Rho GTPase Activating Protein 5- Antisense 1 (ARHGAP5-AS1) in breast cancer was investigated. METHODS: RNA sequencing was performed to find out dysregulated LncRNAs in MDA-MB-231-LM2 cells. Transwell migration assays and F-actin staining were utilized to estimate cell migration ability. RNA pulldown assays and RNA immunoprecipitation were used to prove the interaction between ARHGAP5-AS1 and SMAD7. Western blot and immunofluorescence imaging were used to examine the protein levels. Dual luciferase reporter assays were performed to evaluate the activation of TGF-ß signaling. RESULTS: We analyzed the RNA-seq data of MDA-MB-231 and its highly metastatic derivative MDA-MB-231-LM2 cell lines (referred to as LM2) and identified a novel lncRNA (NR_027263) named as ARHGAP5-AS1, which expression was significantly downregulated in LM2 cells. Further functional investigation showed ARHGAP5-AS1 could inhibit cell migration via suppression of stress fibers in breast cancer cell lines. Afterwards, SMAD7 was further identified to interact with ARHGAP5-AS1 by its PY motif and thus its ubiquitination and degradation was blocked due to reduced interaction with E3 ligase SMURF1 and SMURF2. Moreover, ARHGAP5-AS1 could inhibit TGF-ß signaling pathway due to its inhibitory role on SMAD7. CONCLUSION: ARHGAP5-AS1 inhibits breast cancer cell migration via stabilization of SMAD7 protein and could serve as a novel biomarker and a potential target for breast cancer in the future.

Hypoxia activated long non-coding RNA HABON regulates the growth and proliferation of hepatocarcinoma cells by binding to and antagonizing HIF-1 alpha.

The adaptation of tumour cells to hypoxic microenvironment is one of the most significant characteristics of many malignant tumour diseases including hepatocarcinoma. Recently, long non-coding RNAs (lncRNAs) have been reported to play important roles in the various levels of gene regulation thus functioning in growth and survival of tumour cells. Here, new hypoxia-related lncRNAs in hepatocarcinoma cells were screened and validated by lncRNA chip-array as well as real-time RT-PCR. Among them, a hypoxia-activated lncRNA that we identified and termed Hypoxia-Activated BNIP3 Overlapping Non-coding RNA (HABON), was not only regulated by hypoxic-induced factor-1α (HIF-1α) but its expression increased significantly under hypoxia in tumour cells. We deciphered the biological characteristics of HABON including its cell localization, genomic location, as well as its full-length sequence, and proved HABON could promote growth, proliferation and clone-formation of hepatocarcinoma cells under hypoxia. Then, we revealed that HABON was transcriptionally activated by HIF-1α in hypoxic cells, furthermore, it could interact with HIF-1α and promote its protein degradation, thus affecting transcription of HIF-1α's target genes to exert its effects on cells. Besides, the elevated expression of HABON under hypoxia could promote the transcriptional activation of BNIP3 through HIF-1α, and increasing the expression level of BNIP3. This research provides a novel clue for the adaptive survival and growth mechanism of tumour under hypoxia, and gives a way to reveal the nature of tumour cells' resistance characteristics to harsh microenvironment.

Characteristics of Sagittal Alignment in Patients with Severe and Rigid Scoliosis.

OBJECTIVE: There has been increasing concern about the importance of sagittal alignment in the evaluation and treatment of spinal scoliosis. However, recent studies have only focused on patients with mild to moderate scoliosis. To date, little is known about the sagittal alignment in patients with severe and rigid scoliosis (SRS). This study was performed to evaluate the sagittal alignment in patients with SRS, and to analyze how it was altered after corrective surgery. METHODS: In this retrospective cohort study, we included 58 patients with SRS who underwent surgery from January 2015 to April 2020. Preoperative and postoperative radiographs were reviewed, and the sagittal parameters mainly included thoracic kyphosis (TK), lumbar lordosis (LL), pelvic incidence (PI), pelvic tilt (PT), sacrum slope (SS), and sagittal vertical axis (SVA). The sagittal balance state was evaluated according to whether the PI minus the LL (PI-LL) was less than 9°, and the patients were divided into thoracic hyperkyphosis and normal groups based on whether the TK exceeded 40°. The Student's t test, Pearson's test, and Receiver operating characteristic (ROC) curve analysis were used to compare related parameters between the different groups. RESULTS: The mean follow-up duration was 2.8 years. Preoperatively, the mean PI was 43.6 ± 9.4°, and the mean LL was 65.2 ± 13.9°. Sixty-nine percent of patients showed sagittal imbalance, and they showed larger TK and LL values and smaller PI and SVA values than those with sagittal balance. Additionally, most patients (44/58) presented with thoracic hyperkyphosis; this group had smaller PI and SVA values than the normal patients. Patients with syringomyelia-associated scoliosis were more likely to present with thoracic hyperkyphosis. The TK and LL values were significantly decreased, and 45% of patients with preoperative sagittal imbalance recovered after surgery. These patients had a larger PI (46.4 ± 9.0° vs 38.3 ± 8.8°, P = 0.003) and a smaller TK (25.5 ± 5.2° vs 36.3 ± 8.0°, P = 0.000) at the final follow-up. CONCLUSION: Preoperative sagittal imbalance appears in the majority of SRS patients, accounting for approximately 69% of our cohort. Patients with small PI values or syringomyelia-associated scoliosis were more likely to present with thoracic hyperkyphosis. Sagittal imbalance can generally be corrected by surgery, except in patients with a PI less than 39°. To achieve good postoperative sagittal alignment, we recommend controlling the TK to within 31°.

Incomplete insertion of pedicle screws triggers a higher biomechanical risk of screw loosening: mechanical tests and corresponding numerical simulations.

Screw loosening is a widely reported issue after spinal screw fixation and triggers several complications. Biomechanical deterioration initially causes screw loosening. Studies have shown that incomplete insertion of pedicle screws increases the risk of screw breakage by deteriorating the local mechanical environment. However, whether this change has a biomechanical effect on the risk of screw loosening has not been determined. This study conducted comprehensive biomechanical research using polyurethane foam mechanical tests and corresponding numerical simulations to verify this topic. Pedicle screw-fixed polyurethane foam models with screws with four different insertion depths were constructed, and the screw anchoring ability of different models was verified by toggle tests with alternating and constant loads. Moreover, the stress distribution of screw and bone-screw interfaces in different models was computed in corresponding numerical mechanical models. Mechanical tests presented better screw anchoring ability with deeper screw insertion, but parameters presented no significant difference between groups with complete thread insertion. Correspondingly, higher stress values can be recorded in the model without complete thread insertion; the difference in stress values between models with complete thread insertion was relatively slight. Therefore, incomplete thread insertion triggers local stress concentration and the corresponding risk of screw loosening; completely inserting threads could effectively alleviate local stress concentration and result in the prevention of screw loosening.

Incidence and Risk Factors for Postoperative Ileus after Posterior Surgery in Adolescent Idiopathic Scoliosis.

OBJECTIVE: Postoperative ileus (POI) is a relatively common complication after spinal fusion surgery, which can lead to delayed recovery, prolonged length of stay and increased medical costs. However, little is known about the incidence and risk factors of POI after corrective surgery for patients with adolescent idiopathic scoliosis (AIS). This study was performed to report the incidence of POI and identify the independent risk factors for POI after postoperative corrective surgery. METHODS: In this retrospective cohort study, A total of 318 patients with AIS who underwent corrective surgery from April 2015 to February 2021 were enrolled and divided into two groups: those with POI and those without POI. The Student's t test, Mann-Whitney U test, and Pearson's chi-square test were used to compare the two groups regarding patient demographics and preoperative characteristics (age, sex and the major curve type), intraoperative and postoperative parameters (lowest instrumented vertebra [LIV], number of screws, and length of stay), radiographic parameters (T5-12 thoracic kyphosis [TK], T10-L2 thoracolumbar kyphosis and height [TLK and T10-L2 height], L1-S1 lumbar lordosis [LL], and L1-5 height). Then, a multivariate logistic regression analysis was used to identify independent risk factors for POI, and a receiver operating characteristic (ROC) curve was performed to assess the predictive values of these risk factors. RESULTS: Forty-two (13.2%) of 318 patients who developed POI following corrective surgery were identified. The group with POI had a significantly longer length of stay, more lumbar screws, higher proportions of a major lumbar curve and lumbar anterior screw breech, and a lower LIV. Among radiographic parameters, the mean lumbar Cobb angle at baseline, the changes in the lumbar Cobb angle, and T10-L2 and L1-5 height from before to after surgery were significantly larger in the group with POI than in the group without POI. Multivariate logistic regression analysis showed that large changes in T10-L2 (odds ratio [OR] =2.846, P = 0.007) and L1-5 height (OR = 31.294, p = 0.000) and lumbar anterior screw breech (OR = 5.561, P = 0.006) were independent risk factors for POI. The cutoff values for the changes in T10-L2 and L1-5 height were 1.885 cm and 1.195 cm, respectively. CONCLUSION: In this study, we identified that large changes in T10-L2 and L1-5 height and lumbar anterior screw breech were independent risk factors for POI after corrective surgery. Improving the accuracy of pedicle screw placement might reduce the incidence of POI, and greater attention should be given to patients who are likely to have large changes in T10-L2 and L1-5 height after corrective surgery.

The Mismatch Between Bony Endplates and Grafted Bone Increases Screw Loosening Risk for OLIF Patients With ALSR Fixation Biomechanically.

The mismatch between bony endplates (BEPs) and grafted bone (GB) triggers several complications biomechanically. However, no published study has identified whether this factor increases the risk of screw loosening by deteriorating the local stress levels. This study aimed to illustrate the biomechanical effects of the mismatch between BEP and GB and the related risk of screw loosening. In this study, radiographic and demographic data of 56 patients treated by single segment oblique lumbar interbody fusion (OLIF) with anterior lateral single rod (ALSR) fixation were collected retrospectively, and the match sufficiency between BEP and GB was measured and presented as the grafted bony occupancy rate (GBOR). Data in patients with and without screw loosening were compared; regression analyses identified independent risk factors. OLIF with different GBORs was simulated in a previously constructed and validated lumbosacral model, and biomechanical indicators related to screw loosening were computed in surgical models. The radiographic review and numerical simulations showed that the coronal plane's GBOR was significantly lower in screw loosening patients both in the cranial and caudal vertebral bodies; the decrease in the coronal plane's GBOR has been proven to be an independent risk factor for screw loosening. In addition, numerical mechanical simulations showed that the poor match between BEP and GB will lead to stress concentration on both screws and bone-screw interfaces. Therefore, we can conclude that the mismatch between the BEP and GB will increase the risk of screw loosening by deteriorating local stress levels, and the increase in the GBOR by modifying the OLIF cage's design may be an effective method to optimize the patient's prognosis.

Deterioration of the fixation segment's stress distribution and the strength reduction of screw holding position together cause screw loosening in ALSR fixed OLIF patients with poor BMD.

The vertebral body's Hounsfield unit (HU) value can credibly reflect patients' bone mineral density (BMD). Given that poor bone-screw integration initially triggers screw loosening and regional differences in BMD and strength in the vertebral body exist, HU in screw holding planes should better predict screw loosening. According to the stress shielding effect, the stress distribution changes in the fixation segment with BMD reduction should be related to screw loosening, but this has not been identified. We retrospectively collected the radiographic and demographic data of 56 patients treated by single-level oblique lumbar interbody fusion (OLIF) with anterior lateral single rod (ALSR) screw fixation. BMD was identified by measuring HU values in vertebral bodies and screw holding planes. Regression analyses identified independent risk factors for cranial and caudal screw loosening separately. Meanwhile, OLIF with ALSR fixation was numerically simulated; the elastic modulus of bony structures was adjusted to simulate different grades of BMD reduction. Stress distribution changes were judged by computing stress distribution in screws, bone-screw interfaces, and cancellous bones in the fixation segment. The results showed that HU reduction in vertebral bodies and screw holding planes were independent risk factors for screw loosening. The predictive performance of screw holding plane HU is better than the mean HU of vertebral bodies. Cranial screws suffer a higher risk of screw loosening, but HU was not significantly different between cranial and caudal sides. The poor BMD led to stress concentrations on both the screw and bone-screw interfaces. Biomechanical deterioration was more severe in the cranial screws than in the caudal screws. Additionally, lower stress can also be observed in fixation segments' cancellous bone. Therefore, a higher proportion of ALSR load transmission triggers stress concentration on the screw and bone-screw interfaces in patients with poor BMD. This, together with decreased bony strength in the screw holding position, contributes to screw loosening in osteoporotic patients biomechanically. The trajectory optimization of ALSR screws based on preoperative HU measurement and regular anti-osteoporosis therapy may effectively reduce the risk of screw loosening.

Poor bone mineral density aggravates adjacent segment's motility compensation in patients with oblique lumbar interbody fusion with and without pedicle screw fixation: An in silico study.

Objective: Motility compensation increases the risk of adjacent segment diseases (ASDs). Previous studies have demonstrated that patients with ASD have a poor bone mineral density (BMD), and changes in BMD affect the biomechanical environment of bones and tissues, possibly leading to an increase in ASD incidence. However, whether poor BMD increases the risk of ASD by aggravating the motility compensation of the adjacent segment remains unclear. The present study aimed to clarify this relationship in oblique lumbar interbody fusion (OLIF) models with different BMDs and additional fixation methods. Methods: Stand-alone (S-A) OLIF and OLIF fixed with bilateral pedicle screws (BPS) were simulated in the L4-L5 segment of our well-validated lumbosacral model. Range of motions (ROMs) and stiffness in the surgical segment and at the cranial and caudal sides' adjacent segments were computed under flexion, extension, and unilateral bending and axial rotation loading conditions. Results: Under most loading conditions, the motility compensation of both cranial and caudal segments adjacent to the OLIF segment steeply aggravated with BMD reduction in S-A and BPS OLIF models. More severe motility compensation of the adjacent segment was observed in BPS models than in S-A models. Correspondingly, the surgical segment's stiffness of S-A models was apparently lower than that of BPS models (S-A models showed higher ROMs and lower stiffness in the surgical segment). Conclusion: Poor BMD aggravates the motility compensation of adjacent segments after both S-A OLIF and OLIF with BPS fixation. This variation may cause a higher risk of ASD in OLIF patients with poor BMD. S-A OLIF cannot provide instant postoperative stability; therefore, the daily motions of patients with S-A OLIF should be restricted before ideal interbody fusion to avoid surgical segment complications.