Correction to: Metabolomic profiling identifies distinct phenotypes for ASS1 positive and negative GBM.

In the original publication of this article [1], published on 8 February 2018, it was noticed that the acknowledgement of the source of the drug ADI-PEG20 was missing.

Metabolomic profiling identifies distinct phenotypes for ASS1 positive and negative GBM.

BACKGROUND: Tumour cells have a high demand for arginine. However, a subset of glioblastomas has a defect in the arginine biosynthetic pathway due to epigenetic silencing of the rate limiting enzyme argininosuccinate synthetase (ASS1). These tumours are auxotrophic for arginine and susceptible to the arginine degrading enzyme, pegylated arginine deiminase (ADI-PEG20). Moreover, ASS1 deficient GBM have a worse prognosis compared to ASS1 positive tumours. Since altered tumour metabolism is one of the hallmarks of cancer we were interested to determine if these two subtypes exhibited different metabolic profiles that could allow for their non-invasive detection as well as unveil additional novel therapeutic opportunities. METHODS: We looked for basal metabolic differences using one and two-dimensional gas chromatography-time-of-flight mass spectrometry (1D/2D GC-TOFMS) followed by targeted analysis of 29 amino acids using liquid chromatography-time-of-flight mass spectrometry (LC-TOFMS). We also looked for differences upon arginine deprivation in a single ASS1 negative and positive cell line (SNB19 and U87 respectively). The acquired data was evaluated by chemometric based bioinformatic methods. RESULTS: Orthogonal partial least squares-discriminant analysis (OPLS-DA) of both the 1D and 2D GC-TOFMS data revealed significant systematic difference in metabolites between the two subgroups with ASS1 positive cells generally exhibiting an overall elevation of identified metabolites, including those involved in the arginine biosynthetic pathway. Pathway and network analysis of the metabolite profile show that ASS1 negative cells have altered arginine and citrulline metabolism as well as altered amino acid metabolism. As expected, we observed significant metabolite perturbations in ASS negative cells in response to ADI-PEG20 treatment. CONCLUSIONS: This study has highlighted significant differences in the metabolome of ASS1 negative and positive GBM which warrants further study to determine their diagnostic and therapeutic potential for the treatment of this devastating disease.

Short-term affective recovery from hip fracture prospectively predicts depression and physical functioning.

OBJECTIVE: The goals of the current study were to determine the average affective experiences in the weeks and months after a hip fracture and assess how these experiences relate to physical and mental health functioning over time. METHOD: Positive and negative affect were assessed over time in a sample of older adults recruited after surgery for hip fracture (n = 500) and a comparison sample of older adults without hip fracture (n = 102) for 1 year longitudinally. RESULTS: For most of the individuals with a hip fracture, positive affect tended to increase over time and negative affect tended to decrease over time, suggesting that most people had at least some recovery of affect. In addition, individuals who showed a slower decrease in negative affect had higher levels of depression 1 year later, and individuals who showed a sharper increase in positive affect had superior physical function 1 year later. CONCLUSION: The current study provides evidence that both positive and negative affect in the first 12 weeks of recovery from hip fracture are potential targets for intervention to maximize psychological and physical recovery in the ensuing year.

Psychological sequelae of surgery in a prospective cohort of patients from three intraoperative awareness prevention trials.

BACKGROUND: Elective surgery can have long-term psychological sequelae, especially for patients who experience intraoperative awareness. However, risk factors, other than awareness, for symptoms of posttraumatic stress disorder (PTSD) after surgery are poorly defined, and practical screening methods have not been applied to a broad population of surgical patients. METHODS: The Psychological Sequelae of Surgery study was a prospective cohort study of patients previously enrolled in the United States and Canada in 3 trials for the prevention of intraoperative awareness. The 68 patients who experienced definite or possible awareness were matched with 418 patients who denied awareness based on age, sex, surgery type, and awareness risk. Participants completed the PTSD Checklist-Specific (PCL-S) and/or a modified Mini-International Neuropsychiatric Interview telephone assessment to identify symptoms of PTSD and symptom complexes consistent with a PTSD diagnosis. We then used structural equation modeling to produce a composite PTSD score and examined potential risk factors. RESULTS: One hundred forty patients were unreachable; of those contacted, 303 (88%) participated a median of 2 years postoperatively. Forty-four of the 219 patients (20.1%) who completed the PCL-S exceeded the civilian screening cutoff score for PTSD symptoms resulting from their surgery (15 of 35 [43%] with awareness and 29 of 184 [16%] without). Nineteen patients (8.7%; 5 of 35 [14%] with awareness and 14 of 184 [7.6%] without) both exceeded the cutoff and endorsed a breadth of symptoms consistent with the Diagnostic and Statistical Manual Fourth Edition diagnosis of PTSD attributable to their surgery. Factors independently associated with PTSD symptoms were poor social support, previous PTSD symptoms, previous mental health treatment, dissociation related to surgery, perceiving that one's life was threatened during surgery, and intraoperative awareness (all P ≤ 0.017). Perioperative dissociation was identified as a potential mediator for perioperative PTSD symptoms. CONCLUSIONS: Events in the perioperative period can precipitate psychological symptoms consistent with subsyndromal and syndromal PTSD. We not only confirmed the high rate of postoperative PTSD in awareness patients but also identified a significant rate in matched nonawareness controls. Screening surgical patients, especially those with potentially mediating risk factors such as intraoperative awareness or perioperative dissociation, for postoperative PTSD symptoms with the PCL-S is practical and could promote early referral, evaluation, and treatment.

ATM and p53 regulate FOXM1 expression via E2F in breast cancer epirubicin treatment and resistance.

In this report, we investigated the role and regulation of forkhead box M1 (FOXM1) in breast cancer and epirubicin resistance. We generated epirubicin-resistant MCF-7 breast carcinoma (MCF-7-EPI(R)) cells and found FOXM1 protein levels to be higher in MCF-7-EPI(R) than in MCF-7 cells and that FOXM1 expression is downregulated by epirubicin in MCF-7 but not in MCF-7-EPI(R) cells. We also established that there is a loss of p53 function in MCF-7-EPI(R) cells and that epirubicin represses FOXM1 expression at transcription and gene promoter levels through activation of p53 and repression of E2F activity in MCF-7 cells. Using p53(-/-) mouse embryo fibroblasts, we showed that p53 is important for epirubicin sensitivity. Moreover, transient promoter transfection assays showed that epirubicin and its cellular effectors p53 and E2F1 modulate FOXM1 transcription through an E2F-binding site located within the proximal promoter region. Chromatin immunoprecipitation analysis also revealed that epirubicin treatment increases pRB (retinoblastoma protein) and decreases E2F1 recruitment to the FOXM1 promoter region containing the E2F site. We also found ataxia-telangiectasia mutated (ATM) protein and mRNA to be overexpressed in the resistant MCF-7-EPI(R) cells compared with MCF-7 cells and that epirubicin could activate ATM to promote E2F activity and FOXM1 expression. Furthermore, inhibition of ATM in U2OS cells with caffeine or depletion of ATM in MCF-7-EPI(R) with short interfering RNAs can resensitize these resistant cells to epirubicin, resulting in downregulation of E2F1 and FOXM1 expression and cell death. In summary, our data show that ATM and p53 coordinately regulate FOXM1 via E2F to modulate epirubicin response and resistance in breast cancer.