RAF1 facilitates KIT signaling and serves as a potential treatment target for gastrointestinal stromal tumor.

The aberrant activation of RAS/RAF/MEK/ERK signaling is important for KIT mutation-mediated tumorigenesis of gastrointestinal stromal tumor (GIST). In this study, we found that inhibition of RAF1 suppresses the activation of both wild-type KIT and primary KIT mutations in GIST, with primary KIT mutations showing greater sensitivity. This suggests a positive feedback loop between KIT and RAF1, wherein RAF1 facilitates KIT signaling. We further demonstrated that RAF1 associates with KIT and the kinase activity of RAF1 is necessary for its contribution to KIT activation. Accordingly, inhibition of RAF1 suppressed cell survival, proliferation, and cell cycle progression in vitro mediated by both wild-type KIT and primary KIT mutations. Inhibition of RAF1 in vivo suppressed GIST growth in a transgenic mouse model carrying germline KIT/V558A mutation, showing a similar treatment efficiency as imatinib, the first-line targeted therapeutic drug of GIST, while the combination use of imatinib and RAF1 inhibitor further suppressed tumor growth. Acquisition of drug-resistant secondary mutation of KIT is a major cause of treatment failure of GIST following targeted therapy. Like wild-type KIT and primary KIT mutations, inhibition of RAF1 suppressed the activation of secondary KIT mutation, and the cell survival, proliferation, cell cycle progression in vitro, and tumor growth in vivo mediated by secondary KIT mutation. However, the activation of secondary KIT mutation is less dependent on RAF1 compared with that of primary KIT mutations. Taken together, our results revealed that RAF1 facilitates KIT signaling and KIT mutation-mediated tumorigenesis of GIST, providing a rationale for further investigation into the use of RAF1 inhibitors alone or in combination with KIT inhibitor in the treatment of GIST, particularly in cases resistant to KIT inhibitors.

Four and a half LIM domains 2 (FHL2) attenuates tumorigenesis of gastrointestinal stromal tumors (GISTs) by negatively regulating KIT signaling.

Gastrointestinal stromal tumors (GISTs) are predominately induced by KIT mutants. In this study, we found that four and a half LIM domains 2 (FHL2) was highly expressed in GISTs and KIT signaling dramatically increased FHL2 transcription while FHL2 inhibited KIT transcription. In addition, our results showed that FHL2 associated with KIT and increased the ubiquitination of both wild-type KIT and primary KIT mutants in GISTs, leading to decreased expression and activation of KIT although primary KIT mutants were less inhibited by FHL2 than wild-type KIT. In the animal experiments, loss of FHL2 expression in mice carrying germline KIT/V558A mutation which can develop GISTs resulted in increased tumor growth, but increased sensitivity of GISTs to imatinib treatment which is used as the first-line targeted therapy of GISTs, suggesting that FHL2 plays a role in the response of GISTs to KIT inhibitor. Unlike wild-type KIT and primary KIT mutants, we further found that FHL2 didn't alter the expression and activation of drug-resistant secondary KIT mutants. Taken together, our results indicated that FHL2 acts as the negative feedback of KIT signaling in GISTs while primary KIT mutants are less sensitive and secondary KIT mutants are resistant to the inhibition of FHL2.

Spinopelvic morphology impacts on postoperative proximal junctional kyphosis in congenital scoliosis with thoracolumbar hemivertebrae.

PURPOSE: It aims to investigate the lumbar and pelvic morphology in congenital scoliosis with thoracolumbar hemivertebrae and its impact on proximal junctional kyphosis (PJK) incidence after hemivertebra resection and short fusion. METHODS: 23 congenital scoliosis patients with thoracolumbar hemivertebra aged between 10 and 18 years were enrolled in the retrospective study. Spinopelvic sagittal parameters were analyzed on whole-spine standing lateral radiographs preoperatively, one-week postoperatively and at the final follow-up. Pearson correlations were calculated for local kyphosis (LK), lumbar and pelvic morphology parameters. Binary logistic regression and receiver operating characteristics (ROC) curve analysis were performed to identify the risk factors for PJK. RESULTS: Thoracolumbar hemivertebra caused LK of 29.2° ± 17.3°, an increased lumbar lordosis (LL) (-64.7° ± 16.3°), lower LL apex (52.2% at L5), and small pelvic incidence (PI) (36.8° ± 6.6°). LK was correlated with lumbar morphology parameters, including LL (r = - 0.837), upper arc of LL (LLUA) (r = - 0.879), thoracolumbar kyphosis (TLK) (r = 0.933), thoracic kyphosis (TK) (r = 0.762) and TK apex (TKA) (r = - 0.749). Surgical treatment improved the lumbar morphology, but not pelvic morphology. At the final follow-up, LL had returned to its preoperative value (p = 0.158). PJK occurred in 30.4% of cases as a compensatory mechanism. Preoperatively, significant differences of parameters between non-PJK and PJK groups were observed in LK and TLK. Binary logistic regression identified three independent risk factors for PJK: preoperative LLA (OR = 0.005, 95%CI = 0.000-0.287, p = 0.011), preoperative TLK (OR = 1.134, 95%CI = 1.001-1.286, p = 0.048), and preoperative lumbar lordosis morphology type (OR = 5.507, 95%CI = 1.202-25.227, p = 0.028). However, residual LK after surgery was not correlated with PJK incidence. ROC curve analysis verified that preoperative TLK > 22.59° was associated with increased PJK incidence after surgery. CONCLUSIONS: Lumbar morphology changes as a compensatory mechanism beneath the thoracolumbar hemivertebra. However, a stable pelvis tends to allow the LL to return to its preoperative value. PJK occurred as a cranial compensatory mechanism for increasing LL and corrected TLK. A larger TLK (> 22.59°) was an independent risk factor for PJK incidence in patients with type 2 and 3A lumbar lordosis morphology.

Erector Spinae Atrophy Correlates with Global Sagittal Imbalance and Postoperative Proximal Junctional Kyphosis Incidence in Lumbar Degenerative Kyphosis.

STUDY DESIGN: Retrospective cohort study. PURPOSE: This study aimed to investigate the relationship between lumbar erector muscle atrophy and global sagittal imbalance in lumbar degenerative kyphosis (LDK) and with postoperative proximal junctional kyphosis. OVERVIEW OF LITERATURE: Lumbar erector muscle atrophy has been studied in LDK. However, its role in the compensatory mechanism is still under intense discussion, and the role of erector spinae (ES) muscle is always overlooked. METHODS: This study enrolled 51 patients with LDK out of 382 patients with adult degenerative spinal deformity. Baseline information was reviewed including demographic data and complications. Sagittal spinopelvic alignments and global imbalance parameters were assessed on full-length X-ray images of the spine. Muscularity and the fatty infiltration area of the ES and multifidus (MF) were measured at the L4/5 level on preoperative magnetic resonance image to evaluate the lumbar erector muscle atrophy. Stratification by sagittal vertical axis (SVA) was performed: group 1 with SVA <100 mm and group 2 with SVA >100 mm, and these groups were compared. Spearman correlation and multivariable logistic regression analyses were performed to analyze and define risk factors of postoperative proximal junctional kyphosis (PJK). RESULTS: Group 2 had lower ES and MF muscularity than group 1. ES muscularity correlated with SVA (r=-0.510, p<0.003), lumbar lordosis (r=-0.415, p<0.018), and postoperative PJK (r=-0.508, p<0.022). MF muscularity did not correlate with the above parameters. Multivariable logistic regression analysis verified ES muscularity (odds ratio [OR], 0.001; p<0.039) and SVA (OR, 1.034; p<0.048) as the risk factors for postoperative PJK. CONCLUSIONS: ES atrophy, besides the MF, is an important predictor in distinguishing decompensated LDK from well-compensated ones. It plays an important role in compensatory mechanism, not only correlates with global sagittal imbalance but also ties to PJK after deformity corrective surgery.

Cell-permeable PI3 kinase competitive peptide inhibits KIT mutant mediated tumorigenesis of gastrointestinal stromal tumor (GIST).

BACKGROUND: Mutations in the receptor tyrosine kinase KIT are the main cause of gastrointestinal stromal tumor (GIST), and the KIT mutants mediated PI3 kinase activation plays a key role in the tumorigenesis of GIST. In this study, we aimed to block PI3 kinase activation by cell-permeable peptide and investigate its possible application in the treatment of GIST. METHODS AND RESULTS: We designed cell-permeable peptides based on the binding domain of PI3 kinase subunit p85 to KIT or PI3 kinase subunit p110, respectively, in order to compete for the binding between p85 and KIT or p110 and therefore inhibit the activation of PI3 kinases mediated by KIT. The results showed that the peptide can penetrate the cells, and inhibit the activation of PI3 kinases, leading to reduced cell survival and cell proliferation mediated by KIT mutants in vitro. Treatment of mice carrying germline KIT/V558A mutation, which can develop GIST, with the peptide that can compete for the binding between p85 and p110, led to reduced tumorigenesis of GIST. The peptide can further enhance the inhibition of the tumor growth by imatinib which is used as the first line targeted therapy of GIST. CONCLUSIONS: Our results showed that cell-permeable PI3 kinase competitive peptide can inhibit KIT-mediated PI3 kinase activation and tumorigenesis of GIST, providing a rationale to further test the peptide in the treatment of GIST and even other tumors with over-activation of PI3 kinases.

PRL2 Phosphatase Promotes Oncogenic KIT Signaling in Leukemia Cells through Modulating CBL Phosphorylation.

Receptor tyrosine kinase KIT is frequently activated in acute myeloid leukemia (AML). While high PRL2 (PTP4A2) expression is correlated with activation of SCF/KIT signaling in AML, the underlying mechanisms are not fully understood. We discovered that inhibition of PRL2 significantly reduces the burden of oncogenic KIT-driven leukemia and extends leukemic mice survival. PRL2 enhances oncogenic KIT signaling in leukemia cells, promoting their proliferation and survival. We found that PRL2 dephosphorylates CBL at tyrosine 371 and inhibits its activity toward KIT, leading to decreased KIT ubiquitination and enhanced AKT and ERK signaling in leukemia cells. IMPLICATIONS: Our studies uncover a novel mechanism that fine-tunes oncogenic KIT signaling in leukemia cells and will likely identify PRL2 as a novel therapeutic target in AML with KIT mutations.

Relationship between Fusion Mass Shift and Postoperative Distal Adding-on in Lenke 1 Adolescent Idiopathic Scoliosis after Selective Thoracic Fusion.

STUDY DESIGN: This is a retrospective cohort study. PURPOSE: This study aims to investigate the risk factors for postoperative distal adding-on in Lenke 1 adolescent idiopathic scoliosis (AIS) and validate the relationship between fusion mass shift (FMS) and postoperative distal adding-on. OVERVIEW OF LITERATURE: Postoperative distal curve adding-on is one of the complications in AIS. FMS has been proposed to prevent postoperative distal adding-on, which requires further validation from different institutions. METHODS: This study included 60 patients with Lenke 1 AIS who underwent selective thoracic fusion surgery. Coronal spinal alignment parameters were analyzed preoperatively, postoperatively, and at the final follow-up. The postoperative FMS was divided into two groups: the balanced group (FMS ≤20 mm) and the unbalanced group (FMS >20 mm). An independent t-test was used to compare quantitative data between groups, and a chi-square test was used for qualitative data. Furthermore, binary logistic regression and receiver operating characteristics curve analyses were used to identify the risk factors for postoperative distal adding-on in AIS. RESULTS: At 2-year follow-up, the unbalanced group was more likely to have adding-on (17 of 24 patients) than the balanced group (six of 36 patients; p<0.001). Twenty-three patients with distal adding-on had significantly greater preoperative and postoperative lower instrumented vertebrae (LIV) rotation, FMS, and FMS angle (FMSA) than those without postoperative distal adding-on. Binary logistic regression analysis selected three independent risk factors for adding-on incidence after surgery: FMS (odds ratio [OR], 1.115; 95% confidence interval [CI], 1.049-1.185; p<0.001), FMSA (OR, 1.590; 95% CI, 1.225-2.064; p<0.001), and postoperative LIV rotation (OR, 6.581; 95% CI, 2.280-19.000; p<0.001). CONCLUSIONS: Achieving a balanced fusion mass intraoperatively is important to avoid postoperative distal adding-on, with FMS of <20 mm and FMS angle of <4.5°. Furthermore, correcting LIV rotation helps to decrease the incidence of postoperative distal addingon.

Predicting thoracic kyphosis morphology and the thoracolumbar inflection point determined by individual lumbar lordosis in asymptomatic adults.

PURPOSE: The aims of this study were to explore the correlations between thoracic kyphosis (TK) and lumbar lordosis (LL) parameters and to build corresponding linear regressions to predict TK morphology and the thoracolumbar inflection point (IP) determined by individual LL parameters in asymptomatic adults. METHODS: A total of 280 adult healthy volunteers were recruited, and full-spine X-rays were performed for each subject in a standing posture. The following sagittal parameters were measured: cumulative TK, LL, proximal LL (PLL), the apices of TK (TKA) and LL (LLA), the IP and the distance from the plumb line of the thoracic apex (TAPL) and the lumbar apex (LAPL) to the gravity line. The correlations between TK and LL parameters were analyzed, and the corresponding linear regressions were conducted. RESULTS: Extensive variations existed in TK alignment, including angular and morphological parameters. In addition, there were statistical correlations of all cumulative TK angles with LL (r values from - 0.173 to - 0.708) and PLL (r values from - 0.206 to - 0.803), TKA and IP with LLA (rs = 0.359 and 0.582, respectively) and TAPL with LAPL (rs = 0.335). The common predictive formulas employed in ASD surgery could include T10-L1 = - 3.6-0.2*LL (R2 = 0.201), T4-L1 = 3.4-0.5*LL (R2 = 0.457), TKA = - 10.3 + 1.1*LLA (R2 = 0.180) and IP = - 12.7 + 1.6*LLA (R2 = 0.330). CONCLUSION: There were intimate associations between TK and LL parameters in asymptomatic adults. Moreover, predictive models for thoracic alignment, particularly cumulative TK, based on LL parameters were proposed, which could better delineate anatomical relationships, guide thoracic construction during adult spinal deformity surgery and may help preventing proximal junctional failure.

Farnesyltransferase (FTase) Inhibitors Increase Inhibition of KIT Mutants by Imatinib.

Background: Mutations in the receptor tyrosine kinase KIT are the major cause of gastrointestinal stromal tumors. KIT-mediated activation of the RAS/RAF/MEK/ERK and PI3 kinase/AKT pathways plays an important role in KIT mutant-mediated cell transformation. Methods: The frequently seen primary KIT mutations W557K558del and V560D, and the secondary KIT mutations V654A and N822K, in gastrointestinal stromal tumors were stably transfected into Ba/F3 cells. Cell proliferation was examined with a CCK kit, and cell survival and cell cycle were examined by flow cytometry. Cell signaling was examined by western blot. Results: We found that farnesyltransferase inhibitors tipifarnib and lonafarnib, which inhibit RAS activity, inhibited ERK activation mediated by both wild-type and KIT mutants, which often occur in gastrointestinal stromal tumors. Correspondingly, both wild-type and KIT mutant-mediated cell survival and proliferation were inhibited by both inhibitors. Imatinib is used as the first-line targeted therapy for gastrointestinal stromal tumors in the clinic. In our study, both inhibitors increased imatinib-mediated inhibition of cell survival and proliferation induced by both wild-type and KIT mutants. Similar to the primary KIT mutations, secondary mutations of KIT-induced ERK activation and cell response were inhibited by both inhibitors. Conclusions: Our results suggested the potential benefit of farnesyltransferase inhibitors either alone or combined with imatinib in the treatment of gastrointestinal stromal tumors carrying KIT mutations.

BTF3 promotes proliferation and glycolysis in hepatocellular carcinoma by regulating GLUT1.

Hepatocellular carcinoma (HCC) is a grievous tumor with an increasing incidence worldwide. Basic transcription factor 3 (BTF3) is discovered to regulate the expression of glucose transporter 1 (GLUT1), which benefits glycolysis, a momentous signature of tumors, through transactivation of the forkhead box M1 (FOXM1) expression. BTF3 is highly expressed in HCC. However, whether BTF3 promotes GLUT1 expression through FOXM1 to modulate glycolysis in HCC remains unclear. The expression profile of BTF3 were determined by online database, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot. The role and mechanism of BTF3 in the proliferation and glycolysis of HCC cells were examined by cell counting kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU) incorporation, XF96 Extracellular Flux analyzer, spectrophotometry and western blot analysis. In addition, the direct interaction between BTF3 and FOXM1 was verified by dual-luciferase reporter and co-immunoprecipitation assays. Moreover, the role of BTF3 was also explored in a xenografted mice model. The expression of BTF3 was increased in HCC cells and tumor tissues. Knockdown of BTF3 reduced the cell viability, Edu positive cells, extracellular acidification rate (ECAR), glucose consumption and lactate production in both Huh7 and HCCLM3 cells. The expressions of FOXM1 and GLUT1 were increased in HCC tissues, which were positively correlated with the BTF3 expression. Moreover, a direct interaction existed between BTF3 and FOXM1 in HCC cells. Downregulation of BTF3 decreased the relative protein levels of FOXM1 and GLUT1, which were rescued with overexpression of FOXM1 in both cells. More importantly, overexpression of FOXM1 restored the cell viability, ECAR, glucose consumption and lactate production in both Huh7 and HCCLM3 cells transfected with siBTF3#1. Furthermore, inhibition of BTF3 decreased tumor weight and volume, and the relative level of BTF3, FOXM1, GLUT1 and Ki-67 in tumor tissues from mice xenografted with Huh7 cells. BTF3 enhanced the cell proliferation and glycolysis through FOXM1/GLUT1 axis in HCC.

[Clinical application of neurovascular staghorn flap for repairing of defects in fingertips].

Objective: To evaluate the effectiveness of neurovascular staghorn flap for repairing defects in fingertips. Methods: Between August 2019 and October 2021, a total of 15 fingertips defects were repaired with neurovascular staghorn flap. There were 8 males and 7 females with an average age of 44 years (range, 28-65 years). The causes of injury included 8 cases of machine crush injury, 4 cases of heavy object crush injury, and 3 cases of cutting injury. There were 1 case of thumb, 5 cases of index finger, 6 cases of middle finger, 2 cases of ring finger, and 1 case of little finger. There were 12 cases in emergency, and 3 cases with finger tip necrosis after trauma suture. Bone and tendon exposed in all cases. The range of fingertip defect was 1.2 cm×0.8 cm to 1.8 cm×1.5 cm, and the range of skin flap was 2.0 cm×1.5 cm to 2.5 cm×2.0 cm. The donor site was sutured directly. Results: All flaps survived without infection or necrosis, and the incisions healed by first intention. All patients were followed up 6-12 months, with an average of 10 months. At last follow-up, the appearance of the flap was satisfactory, the wear resistance was good, the color was similar to the skin of the finger pulp, and there was no swelling; the two-point discrimination of the flap was 3-5 mm. One patient had linear scar contracture on the palmar side with slight limitation of flexion and extension, which had little effect on the function; the other patients had no obvious scar contracture, good flexion and extension of the fingers, and no dysfunction. The finger function was evaluated according to the total range of motion (TAM) system of the Hand Surgery Society of Chinese Medical Association, and excellent results were obtained in 13 cases and good results in 2 cases. Conclusion: The neurovascular staghorn flap is a simple and reliable method to repair fingertip defect. The flap has a good fit with the wound without wasting skin. The appearance and function of the finger are satisfactory after operation.

SPRY4 inhibits and sensitizes the primary KIT mutants in gastrointestinal stromal tumors (GISTs) to imatinib.

BACKGROUND: KIT is frequently mutated in gastrointestinal stromal tumors (GISTs), and the treatment of GISTs largely relies on targeting KIT currently. In this study, we aimed to investigate the role of sprouty RTK signaling antagonist 4 (SPRY4) in GISTs and related mechanisms. METHODS: Ba/F3 cells and GIST-T1 cell were used as cell models, and mice carrying germline KIT/V558A mutation were used as animal model. Gene expression was examined by qRT-PCR and western blot. Protein association was examined by immunoprecipitation. RESULTS: Our study revealed that KIT increased the expression of SPRY4 in GISTs. SPRY4 was found to bind to both wild-type KIT and primary KIT mutants in GISTs, and inhibited KIT expression and activation, leading to decreased cell survival and proliferation mediated by KIT. We also observed that inhibition of SPRY4 expression in KITV558A/WT mice led to increased tumorigenesis of GISTs in vivo. Moreover, our results demonstrated that SPRY4 enhanced the inhibitory effect of imatinib on the activation of primary KIT mutants, as well as on cell proliferation and survival mediated by the primary KIT mutants. However, in contrast to this, SPRY4 did not affect the expression and activation of drug-resistant secondary KIT mutants, nor did it affect the sensitivity of secondary KIT mutants to imatinib. These findings suggested that secondary KIT mutants regulate a different downstream signaling cascade than primary KIT mutants. CONCLUSIONS: Our results suggested that SPRY4 acts as negative feedback of primary KIT mutants in GISTs by inhibiting KIT expression and activation. It can increase the sensitivity of primary KIT mutants to imatinib. In contrast, secondary KIT mutants are resistant to the inhibition of SPRY4.

The correlation of sacral table angle to spinopelvic sagittal alignment in healthy adults.

BACKGROUND: The sacrum plays an important role in sagittal balance of the spine, whereas the exact association between sacral parameters, specifically the sacral table angle (STA) and spinopelvic parameters has been only scarcely assessed. It aims to investigate the correlations between the sacral parameters and spinopelvic sagittal alignment parameters in healthy adults. METHODS: A cohort of 142 Northern Chinese healthy adults between 18 and 45 years old were recruited between April 2019 and March 2021. Full-spine standing X-ray films were performed for every volunteer. The sacral parameters were measured: sacral table angle (STA), sacral inclination (SI) and sacral slope (SS). The spinopelvic sagittal alignment parameters included: pelvic incidence (PI), pelvic tilt (PT), lumbar lordosis (LL), thoracic kyphosis and the apex of lumbar lordosis (LLA). The correlations analysis, as well as the linear regression analysis, were performed between STA, SI and the spinopelvic parameters. RESULTS: An equation 'STA = SI + 90 - SS' was revealed to represent the interrelationships between STA, SI and SS. STA was statistically correlated with PI (rs = - 0.693), PT (rs = - 0.342), SS (rs = - 0.530), LL (rs = 0.454), and LLA (rs = 0.438). SI correlated with STA (rs = 0.329), PT (rs = - 0.562), SS (rs = - 0.612) and LL (rs = 0.476). Simple linear regression analysis also verified the correlation between STA and PI (y = - 1.047x + 149.4), SS (y = - 0.631x + 96.9), LL (y = 0.660x - 117.7), LLA (y = 0.032x + 0.535), and SI (y = 0.359x + 8.23). CONCLUSION: The equation 'STA = SI + 90 - SS' indicates the exact geometric relationship between STA, SI and SS. The sacral parameters, both STA and SI, correlate to the spinopelvic sagittal alignment parameters in healthy adults. The linear regression analysis results also give predictive models for spinopelvic sagittal alignment parameters based on the invariant parameter STA, which are helpful for surgeons in designing an ideal therapeutic plan.

A Novel Method for Predicting Ideal Postoperative Upper Instrumented Vertebra Tilt to Prevent Lateral Shoulder Imbalance after Scoliosis Correction Surgery.

Lateral shoulder imbalance (LSI) is reflected radiologically by the clavicle angle (CA). How to achieve postoperative lateral shoulder balance (LSB) after scoliosis correction surgery remains unclear. In the current study, by using the preoperative upper instrumented vertebra (UIV) tilt, the CA, the flexibility between T1 and the UIV, and the ideal postoperative UIV tilt was predicted based on the following formula: ideal postoperative UIV tilt = preoperative UIV tilt-the flexibility between T1 and UIV-preoperative CA. The reliability of the formula was verified through a retrospective analysis, and 76 scoliosis patients were enrolled. The feasibility of this method was verified through a prospective analysis, and 13 scoliosis patients were enrolled. In the retrospective study, there was a significant correlation between the difference in the actual and ideal postoperative UIV tilt values and the postoperative CA, with correlation coefficients in the whole, LSI, and LSB groups of 0.981, 0.982, and 0.953, respectively (p < 0.001). In the prospective study, all patients achieved satisfactory LSB. Using the formula preoperatively to predict an ideal postoperative UIV tilt and controlling the intraoperative UIV tilt with the improved crossbar technique may be an effective digital method for achieving postoperative LSB and has important clinical significance.

Specific foraminal changes originate from degenerative spondylolisthesis on computed tomographic images.

PURPOSE: Operative treatment for degenerative spondylolisthesis (DS) is accompanied by the high incidence of nerve injury. Foraminal structures, especially the hypertrophied facet joints, have significant impacts on the adjacent nerve. This study aims to identify the specific foraminal changes relating to DS and nerve injury. METHODS: The CT images of 70 patients with DS and 50 patients without lumbar disease were collected. The length and height of the foraminal structure were measured horizontally and vertically on sagittally reconstructed images. Horizontal stenosis, meaning to pending compression to nerve root after complete reduction, was evaluated on the image located to the middle of the foramen. Chi-square test or T-test were carried out using SPSS 26.0. RESULTS: The hyperplasia of the superior articular process (SAP) and articular capsule (Ac) incidence rates in DS group was significantly more common than that of the control group (9.2 vs 0.0%, 42.9 vs 2.0%). The height and width of the SAP and Ac in vertical and horizontal directions were significantly greater than those in the control group (4.95 mm vs - 0.47 mm, P < 0.0001; 3.28 vs 0.02 mm, P < 0.0001; 5.27 vs3.44 mm, P < 0.0001; 2.60 vs 0.37 mm, P < 0.0001). In the DS group, hyperplasia of the SAP and Ac accounted for 9 and 43% respectively, 85 and 45% of which were accompanied by horizontal stenosis of the intervertebral foramen. CONCLUSION: DS is usually characterized of excessive hyperplasia of the SAP and Ac, both of which are possible elements of nerve root injury after complete reduction in operation and should be focused on during surgery.

Focusing on the amount of immediate changes in spinopelvic radiographic parameters to predict the amount of mid-term improvement of quality of life in adult degenerative scoliosis patients with surgery.

INTRODUCTION: Surgery is still an effective treatment option for adult degenerative scoliosis (ADS), but how to predict patients' significant amount of the improvement in quality of life remains unclear. The previous studies included an inhomogeneous population. This study aimed to report the results about concentrating on the amount of immediate changes in spinopelvic radiographic parameters to predict the amount of mid-term improvement in quality of life in ADS patients. MATERIALS AND METHODS: Pre-operative and immediately post-operative radiographic parameters included Cobb angle, coronal vertical axis (CVA), sagittal vertical axis (SVA), lumbar lordosis (LL), thoracic kyphosis (TK), pelvic tilt (PT), sacral slope (SS), pelvic incidence (PI) and LL/PI matching (PI-LL). Quality of life scores were evaluated pre-operatively and at the final follow-up using Oswestry Disability Index (ODI) and visual analogue scale (VAS). The amount of immediate changes in spinopelvic radiographic parameters (Δ) and the amount of mid-term improvement in quality of life (Δ) were defined, respectively. RESULTS: Patients showed significant change in radiographic parameters, ODI and VAS pre- and post-surgery, except CVA and PI. Univariate analysis showed a significant correlation between ΔTK, ΔLL, ΔCVA and the amount of mid-term improvement in quality of life, but multivariate analysis did not get a significant result. Univariate and multivariate analyses showed that ΔSVA was still a significant predictor of ΔVAS and ΔODI. The changes in the other radiographic parameters were not significant. The equations were developed by linear regression: ΔODI = 0.162 × ΔSVA - 21.592, ΔVAS = 0.034 × ΔSVA - 2.828. In the ROC curve for ΔSVA in the detection of a strong ΔODI or ΔVAS, the cut-off value of ΔSVA was - 19.855 mm and - 15.405 mm, respectively. CONCLUSIONS: This study shows that ΔSVA can predict the amount of mid-term improvement in quality of life in ADS patients. The changes in the other radiographic parameters were not significant. Two equations were yielded to estimate ΔODI and ΔVAS. ΔSVA has respective cut-off value to predict ΔODI and ΔVAS.

MiR-19a-3p Promotes Aerobic Glycolysis in Ovarian Cancer Cells via IGFBP3/PI3K/AKT Pathway.

Aerobic glycolysis is a prominent feature of cancer. Here, we reported that miR-19a-3p promotes aerobic glycolysis in ovarian cancer cells SKVO3 and ES-2 by increased production of ATP, lactic acid, extracellular acidification (ECAR), and increased expression of PKM2, LDHA, GLUT1 and GLUT3. Further study showed that over-expression of IGFBP3, the target of miR-19a-3p, decreases aerobic glycolysis in ovarian cancer cells, while knockdown of IGFBP3 expression increases aerobic glycolysis. The rescue assay suggested that miR-19a-3p promotes aerobic glycolysis in ovarian cancer cells through targeting IGFBP3. Moreover, over-expression of miR-19a-3p or silencing of IGFBP3 expression promoted activation of AKT, which is important for aerobic glycolysis in cancer cells, indicating that miR-19a-3p promotes aerobic glycolysis in ovarian cancer cells through the IGFBP3/PI3K/AKT pathway. This suggests that miR-19a-3p and IGFBP3 may serve as potential treatment targets of ovarian cancer.

Inhibition of PI3 kinase isoform p110α suppresses neuroblastoma growth and induces the reduction of Anaplastic Lymphoma Kinase.

BACKGROUND: In neuroblastoma, hyperactivation of the PI3K signaling pathway has been correlated with aggressive neuroblastomas, suggesting PI3Ks as promising targets for the treatment of neuroblastoma. However, the oncogenic roles of individual PI3K isoforms in neuroblastoma remain elusive. RESULTS: We found that PI3K isoform p110α was expressed at higher levels in neuroblastoma tissues compared with normal tissues, and its high expression was correlated with an unfavorable prognosis of neuroblastoma. Accordingly, PI3K activation in neuroblastoma cells was predominantly mediated by p110α but not by p110ß or p110δ. Suppression of p110α inhibited the growth of neuroblastoma cells both in vitro and in vivo, suggesting a crucial role of p110α in the tumorigenesis of neuroblastoma. Mechanistically, inhibition of p110α decreased anaplastic lymphoma kinase (ALK) in neuroblastoma cells by decreasing its protein stability. CONCLUSIONS: In this study, we investigated the oncogenic roles of PI3K isoforms in neuroblastoma. Our data shed light on PI3K isoform p110α in the tumorigenesis of neuroblastoma, and strongly suggest the p110α inhibitors as potential drugs in treating neuroblastoma.

Financial toxicity and psychological distress in adults with cancer: A treatment-based analysis.

Objective: To evaluate disparities in financial toxicity and psychological distress in patients with cancer as a function of treatment and reveal the relationship between financial toxicity and psychological distress. Methods: This was a multicenter cross-sectional study. Patients were recruited from March 2017 to October 2018, and questionnaires were completed regarding their demographics, financial toxicity, and psychological distress. A multiple linear regression model was used to examine factors associated with financial and psychological distress. Results: Significant financial toxicity and psychological distress occurred in 47.9% and 56.5% of patients, respectively. Financial toxicity (P â€‹= â€‹0.032) and psychological distress (P â€‹< â€‹0.001) were statistically different among the single chemotherapy, adjuvant therapy, and surgery groups. Multivariable analysis revealed that patients aged 50-59 years (P â€‹= â€‹0.035), 60-69 years (P â€‹= â€‹0.007), and 70 years or older (P â€‹= â€‹0.002) had higher the Comprehensive Score for financial Toxicity (COST) scores compared with patients less than 50 years old. Patients with personal annual income > 40,000 CNY reported higher COST scores than those who had < 20,000 CNY (P â€‹< â€‹0.001). Patients who had Urban Resident Basic Medical Insurance (URBMI) (P â€‹= â€‹0.030) or New Rural Cooperative Medical Scheme (NRCMS) (P â€‹= â€‹0.006) compared with Urban Employee Basic Medical Insurance (UEBMI) presented lower COST scores than patients with UEBMI. The multiple analysis model of psychological distress showed that an age of more than 70 years (P â€‹= â€‹0.010) was significantly associated with low the Distress Thermometer (DT) scores, and patients with colorectal cancer (P â€‹= â€‹0.009), the surgery group (P â€‹< â€‹0.001) and adjuvant therapy group (P â€‹< â€‹0.001) were significantly associated with high DT scores. The correlations between financial toxicity and psychological distress were mild but statistically significant in the chemotherapy-related treatment groups. Conclusions: The research highlights the high rates of financial and psychological distress in adult patients. Multidimensional distress screening and psychosocial interventions should be provided for patients with cancer according to related factors.

A Comparative Study of Bone Tissue Morphology and Bone Turnover Markers in Different Stages of Kümmell's Disease.

Although the incidence of Kümmell's disease (KD) has increased significantly in recent years, its pathological mechanism is still unclear. The aim of this study is to investigate the histomorphological characteristics and the kinetics of bone turnover markers following KD. This study involves 82 patients with KD, and fasting blood samples were collected to detect the serum concentration of bone turnover markers. A transpedicular bone biopsy was performed to collect bone biopsy specimens during vertebroplasty surgery. According to Li's staging system for KD, all cases were divided into 3 stages. Comparisons of the 3 stages and their kinetics were conducted. 19 (23.2%) patients were classified as Stage I, 39 (47.5%) as Stage II, 24 (29.2%) as Stage III. Bone histomorphological analysis showed that the ratios of WBV and FV reached a peak value (14.23 ± 0.62 and 54.63% ± 3.52%; p = 0.001 and 0.001) at Stage I. The ratios of NBV remained low (4.81% ± 2.61%) in Stage I, but reached a peak value (18.50% ± 2.77%; p = 0.001) in Stage III. Bone metabolism index level showed that the serum concentration of OST and ß-CTX continued to rise after fracture, reaching a peak value of (38.15 ± 3.84 and 1.31 ± 0.16 ng/Ml; p = 0.073 and 0.026), while PINP reached its valley value (48.57 ± 7.25 ng/Ml; p = 0.069) in Stage III. A significant and negative correlation was found between the ratio of ß-CTX and EBV/TV (p= 0.0194, r = -0.2037), and FV/TV (p= 0.0001, r = -0.5368). At the same time, ß-CTX had a positive significant correlation with the NBV/TV (p= 0.0001, r = 0.6218). Bone histomorphometric analysis and bone turnover markers showed that KD has a possibility of healing in the early stage.