Aurora kinase A inhibition reverses the Warburg effect and elicits unique metabolic vulnerabilities in glioblastoma

Aurora kinase A (AURKA) has emerged as a drug target for glioblastoma (GBM). However, resistance to therapy remains a critical issue. By integration of transcriptome, chromatin immunoprecipitation sequencing (CHIP-seq), Assay for Transposase-Accessible Chromatin sequencing (ATAC-seq), proteomic and metabolite screening followed by carbon tracing and extracellular flux analyses we show that genetic and pharmacological AURKA inhibition elicits metabolic reprogramming mediated by inhibition of MYC targets and concomitant activation of Peroxisome Proliferator Activated Receptor Alpha (PPARA) signaling. While glycolysis is suppressed by AURKA inhibition, we note an increase in the oxygen consumption rate fueled by enhanced fatty acid oxidation (FAO), which was accompanied by an increase of Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α). Combining AURKA inhibitors with inhibitors of FAO extends overall survival in orthotopic GBM PDX models. Taken together, these data suggest that simultaneous targeting of oxidative metabolism and AURKAi might be a potential novel therapy against recalcitrant malignancies

Evaluation of hyaluronic matrix efficacy in sinus augmentation: a randomized-controlled histomorphometric and micro-computed tomography analysis

The objective of the present study was to test the hypothesis that the addition of hyaluronic acid-based matrix to collagenated heterologous bone graft for sinus augmentation would enhance bone formation compared to collagenated heterologous bone graft alone in the early healing period, by micro-computed tomography and histomorphometry. Thirteen systemically healthy patients requiring bilateral two-stage maxillary sinus augmentation (residual crest height <= 4 mm) were enrolled in this split-mouth prospective randomized controlled study. One sinus side as a control group was grafted with only collagenated heterologous bone graft; the other region as a test group was grafted with hyaluronic matrix and collagenated heterologous bone graft. Bone biopsy samples were taken after 4 months during the dental implant surgery and analyzed using micro-computed tomography and histomorphometric parameters. According to the micro-computed tomography and histomorphometric results, a significantly higher percentage of new bone was observed in the test group when compared to the control group after 4 months of healing

A myopathy with unusual features caused by PNPLA2 gene mutations

Introduction: The PNPLA2 gene encodes the enzyme adipose triglyceride lipase (ATGL), which catalyzes the first step of triglyceride hydrolysis. Mutations in this gene are associated with an autosomal recessive lipid-storage myopathy, neutral lipid-storage disease with myopathy (NLSD-M). Results: A 72-year-old woman had late-onset myopathy, with mild weakness, cramps, and exercise intolerance. Electromyography showed myotonic discharges. A few leukocytes showed lipid droplets (Jordan anomaly). Deltoid and quadriceps muscle biopsies showed no lipid storage. Genetic analysis of PNPLA2 detected 2 heterozygous mutations: c.497A&gt;G (p.Asp166Gly) in exon 5 and c.1442C&gt;T (p.Pro481Leu) in exon 10. Expression of mutant PNPLA2 plasmids in HeLa cells resulted in impaired enzyme activity, confirming the pathological effects of the mutations. Conclusions: In this case of NLSD-M, the myopathy may be due to a metabolic defect rather than to a mechanical effect of lipid storage. This suggests that more than 1 mechanism contributes to muscle damage in NLSD-M

Alleviation of a polyglucosan storage disorder by enhancement of autophagic glycogen catabolism

Abstract This work employs adult polyglucosan body disease (APBD) models to explore the efficacy and mechanism of action of the polyglucosan‐reducing compound 144DG11. APBD is a glycogen storage disorder (GSD) caused by glycogen branching enzyme (GBE) deficiency causing accumulation of poorly branched glycogen inclusions called polyglucosans. 144DG11 improved survival and motor parameters in a GBE knockin (Gbeys/ys) APBD mouse model. 144DG11 reduced polyglucosan and glycogen in brain, liver, heart, and peripheral nerve. Indirect calorimetry experiments revealed that 144DG11 increases carbohydrate burn at the expense of fat burn, suggesting metabolic mobilization of pathogenic polyglucosan. At the cellular level, 144DG11 increased glycolytic, mitochondrial, and total ATP production. The molecular target of 144DG11 is the lysosomal membrane protein LAMP1, whose interaction with the compound, similar to LAMP1 knockdown, enhanced autolysosomal degradation of glycogen and lysosomal acidification. 144DG11 also enhanced mitochondrial activity and modulated lysosomal features as revealed by bioenergetic, image‐based phenotyping and proteomics analyses. As an effective lysosomal targeting therapy in a GSD model, 144DG11 could be developed into a safe and efficacious glycogen and lysosomal storage disease therapy

The correlates of benefit from neoadjuvant chemotherapy before surgery in non-small-cell lung cancer: a metaregression analysis

Background: Although neoadjuvant chemotherapy (NCT) is widely used, it is not clear which subgroup of locally advanced non-small-cell lung cancer (NSCLC) patients should be treated with this approach, and if a particular benefit associated with NCT exists. In this study, we aimed to investigate the potential correlates of benefit from NCT in patients with NSCLC.Methods: All randomized clinical trials (RCTs) utilizing a NCT arm (without radiotherapy) versus a control arm before surgery were included for metaregression analysis. All regression analyses were weighed for trial size. Separate analyses were conducted for trials recruiting patients with different stages of disease. Previously published measures of treatment efficacy were used for the purpose of this study, regardless of being published in full text or abstract form.Results: A total of 14 RCTs, consisting of 3,615 patients, were selected. Histology, stage, various characteristics of the NCT protocol, and different trial features including trial quality score were not associated with the benefit of NCT. However, in trials of stage 3 disease only, there was a greater benefit in terms of reduction in mortality from NCT, if protocols with three chemotherapeutics were used (B = -0.18, t = -5.25, P = 0.006).Conclusions: We think that patients with stage 3 NSCLC are served better with NCT before surgery if protocols with three chemotherapy agents or equally effective combinations are used. In addition, the effect of neoadjuvant chemotherapy is consistent with regard to disease and patient characteristics. This finding should be tested in future RCTs or individual patient data meta-analyses. © 2012 Bozcuk et al.; licensee BioMed Central Ltd