Cancer cells experience an increase in oxidative stress. The pentose phosphate pathway (PPP) is a major biochemical pathway that generates antioxidant NADPH. Here, we show that transketolase (TKT), an enzyme in the PPP, is required for cancer growth because of its ability to affect the production of NAPDH to counteract oxidative stress. We show that TKT expression is tightly regulated by the Nuclear Factor, Erythroid 2-Like 2 (NRF2)/Kelch-Like ECHAssociated Protein 1 (KEAP1)/BTB and CNC Homolog 1 (BACH1) oxidative stress sensor pathway in cancers. Disturbing the redox homeostasis of cancer cells by genetic knockdown or pharmacologic inhibition of TKT sensitizes cancer cells to existing targeted therapy (Sorafenib). Our study strengthens the notion that antioxidants are beneficial to cancer growth and highlights the therapeutic benefits of targeting pathways that generate antioxidants.M etabolic reprogramming has recently been recognized as a hallmark of cancer (1). Cancer cells preferentially use glycolysis instead of oxidative phosphorylation to generate energy even in the presence of oxygen (O 2 ). This metabolic shift, named the Warburg Effect, channels glucose intermediates for macromolecule and antioxidant synthesis. A very important metabolic pathway that connects with glycolysis is the pentose phosphate pathway (PPP). The major goal of the PPP is the production of ribose-5-phosphate (R5P) and NADPH. R5P is the major backbone of RNA and is critical to nucleotide synthesis. NADPH is the major antioxidant that maintains the two major redox molecules, glutathione and thioredoxin, in the reduced state. NADPH therefore counteracts reactive oxygen species (ROS), enabling cancer cells to survive oxidative stress.The PPP is composed of the oxidative and nonoxidative arms. The oxidative arm of the PPP produces NADPH and ribose by three irreversible steps. First, glucose-6-phosphate dehydrogenase (G6PD) converts glucose-6-phosphate (G6P) to 6-phospho-gluconolactone and NAPDH. Second, phosphogluconolactonase converts 6-phospho-gluconolactone to 6-phosphogluconate. Third, 6-phosphogluconate dehydrogenase converts 6-phosphogluconate to ribulose-5-phosphate (Ru5P) and NAPDH. Ru5P then enters the nonoxidative arm of the PPP. Ru5P is converted to xylulose-5-phosphate (X5P) and Ru5P by epimerase and isomerase, respectively. The transketolase (TKT) family [transketolase-like 1 (TKTL1) and TKTL2] transfers two-carbon groups from X5P to R5P to generate sedoheptulose-7-phosphate (S7P) to glyceraldehyde-3-phosphate (G3P). Transaldolase (TALDO) transfers three-carbon groups from S7P to G3P to generate erythrose-4-phosphate (E4P) and fructose-6-phosphate (F6P). Finally, TKT transfers two-carbon groups from X5P to E4P to generate G3P and F6P, which reenter glycolysis. All enzymes in the nonoxidative arm of the PPP are reversible, allowing cells to adapt to the dynamic metabolic demands. When cells experience high oxidative stress, metabolites from the nonoxidative arm are rechanneled into glycolysis to refill the oxidative arm for...

BackgroundBracing has been shown to decrease significantly the progression of high-risk curves to the threshold for surgery in patients with adolescent idiopathic scoliosis (AIS), but the treatment failure rate remains high. There is evidence to suggest that Schroth scoliosis-specific exercises can slow progression in mild scoliosis. The aim of this study was to evaluate the efficacy of Schroth exercises in AIS patients with high-risk curves during bracing.MethodsA prospective, historical cohort-matched study was carried out. Patients diagnosed with AIS who fulfilled the Scoliosis Research Society (SRS) criteria for bracing were recruited to receive Schroth exercises during bracing. An outpatient-based Schroth program was given. Data for these patients were compared with a 1:1 matched historical control group who were treated with bracing alone. The assessor and statistician were blinded. Radiographic progression, truncal shift, and SRS-22r scores were compared between cases and controls.ResultsTwenty-four patients (5 males and 19 females, mean age 12.3 ± 1.4 years) were included in the exercise group, and 24 patients (mean age 11.8 ± 1.1 years) were matched in the control group. The mean follow-up period for the exercise group was 18.1 ± 6.2 months. In the exercise group, spinal deformity improved in 17% of patients (Cobb angle improvement of ≥ 6°), worsened in 21% (Cobb angle increases of ≥ 6°), and remained stable in 62%. In the control group, 4% improved, 50% worsened, and 46% remained stable. In the subgroup analysis, 31% of patients who were compliant (13 cases) improved, 69% remained static, and none had worsened, while in the non-compliant group (11 cases), none had improved, 46% worsened, and 46% remained stable. Analysis of the secondary outcomes showed improvement of the truncal shift, angle of trunk rotation, the SRS function domain, and total scores in favor of the exercise group.ConclusionThis is the first study to investigate the effects of Schroth exercises on AIS patients during bracing. Our findings from this preliminary study showed that Schroth exercise during bracing was superior to bracing alone in improving Cobb angles, trunk rotation, and QOL scores. Furthermore, those who were compliant with the exercise program had a higher rate of Cobb angle improvement. The results of this study form the basis for a randomized controlled trial to evaluate the effect of Schroth exercises during bracing in AIS.Trial registration HKUCTR-2226. Registered 22 June 2017 (retrospectively registered)

Aims The purpose of this study was to evaluate the incidence and analyze the trends of surgeon-reported complications following surgery for adolescent idiopathic scoliosis (AIS) over a 13-year period from the Scoliosis Research Society (SRS) Morbidity and Mortality database. Methods All patients with AIS between ten and 18 years of age, entered into the SRS Morbidity and Mortality database between 2004 and 2016, were analyzed. All perioperative complications were evaluated for correlations with associated factors. Complication trends were analyzed by comparing the cohorts between 2004 to 2007 and 2013 to 2016. Results Between 2004 and 2016, a total of 84,320 patients were entered into the database. There were 1,268 patients associated with complications, giving an overall complication rate of 1.5%. Death occurred in 12 patients (0.014%). The three most commonly reported complications were surgical site infection (SSI) (441 patients; 0.52%), new neurological deficit (293; 0.35%), and implant-related complications (172; 0.20%). There was a statistically significant but weak correlation between the occurrence of a SSI and the magnitude of the primary curve ( r = 0.227; p < 0.001), and blood loss in surgery ( r = 0.111; p = 0.038), while the occurrence of a new neurological deficit was correlated statistically significantly but weakly with age at surgery ( r = 0.147; p = 0.004) and magnitude of the primary curve ( r = 0.258; p < 0.001). The overall complication rate decreased from 4.95% during 2004 to 2007 to 0.98% during 2013 to 2016 (p = 0.023). Conclusion An overall complication rate of 1.5% was found in our series after surgery for AIS, with a reduction of complication rates found in the second period of the analysis. Cite this article: Bone Joint J 2020;102-B(4):519–523.

Background: Although scoliosis is a 3-dimensional (3D) deformity, little research has been performed on the use of 3D imaging in brace curve correction. The purpose of the present study was to determine the effect of axial-plane parameters on the outcomes of bracing with a thoracolumbosacral orthosis for adolescent idiopathic scoliosis. Methods: This prospective longitudinal cohort study included patients with adolescent idiopathic scoliosis who fulfilled the criteria for bracing according to the Scoliosis Research Society, and was conducted from the time the patient began wearing the brace through a minimum follow-up of 2 years or until a surgical procedure was performed. Radiographs made with use of an EOS Imaging System were used to reconstruct 3D images of the spine at the pre-brace, immediate in-brace, 1-year in-brace, and latest follow-up out-of-brace stages. Univariate and multiple linear regressions were performed to determine the association between axial rotation correction and curve progression at the time of the latest follow-up. Logistic regressions were performed to model the probability of risk of progression. Results: Fifty-three patients were enrolled, and 46 patients were included in the analysis. At the time of the latest follow-up, 30 patients did not experience curve progression and 16 patients had curve progression. There was no difference in baseline demographic characteristics between groups. For the transverse-plane parameters, there was a significant difference between non-progression and progression groups in pre-brace apical vertebral rotation (4.5° ± 11.2° compared with −2.4° ± 9.8°, respectively; p = 0.044) and in 1-year in-brace apical vertebral rotation correction velocity (2.0° ± 5.0°/year compared with −1.7° ± 4.4°/year, respectively; p = 0.016). Logistic regression analysis showed that pre-brace apical vertebral rotation (odds ratio, 1.063; 95% confidence interval, 1.000 to 1.131; p = 0.049) and 1-year in-brace apical vertebral rotation correction velocity (odds ratio, 1.19; 95% confidence interval, 1.021 to 1.38; p = 0.026) were associated with an increased risk of curve progression. There was no difference in Scoliosis Research Society 22-Item scores between patients who experienced curve progression and those who did not. Conclusions: In this prospective study, we demonstrated that axial-plane parameters and the correction of these parameters during bracing are related to the successful use of the brace. Level of Evidence: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.