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Despite much effort to improve treatments, patients with malignant glioma still present a very poor prognosis that has not changed significantly in the last decades. In this context, it is crucial to better understand glioma pathogenesis to identify new molecular prognostic subgroups and therapeutic targets. WNT6 was recently identified as a new oncogenic molecule in glioblastoma (GBM), with prognostic value in patients, but the mechanisms underlying WNT6 aberrant expression in glioma are still unknown. WNT6 was overexpressed in a subset of gliomas independently of IDH mutations, 1p/19q codeletion status, and WNT6 gene copy number. Interestingly, WNT6 expression is associated with the DNA methylation levels of particular CpG regions at both the WNT6 promoter and the gene body in glioma patient samples. HOXA9, a transcription factor previously associated with poorer clinical outcome in GBM, was identified as a novel transcriptional regulator of WNT6, activating the WNT/β‐catenin pathway in vitro and in vivo. In various cohorts of glioma patients, mRNA levels of WNT6 and HOXA9 were significantly correlated, extending our in vitro and in vivo findings into the clinical setting. Interestingly, this novel molecular link between WNT6 and HOXA9 was not limited to glioma, as they were co‐expressed also in patients with other tumor types. Clinically, WNT6 was a prognostic biomarker of shorter survival in GBM, independently of HOXA9 expression. Concomitant high expression of both WNT6 and HOXA9 identified a subgroup of patients with particularly dismal survival. These findings describe novel WNT6 regulatory mechanisms in GBM, establishing particular DNA methylation patterns and HOXA9 as critical regulators of WNT6 expression in glioma. This HOXA9‐WNT6 molecular link supports WNT signaling in GBM cells and is a powerful prognostic biomarker, highlighting the clinical relevance of this axis in patients. Novel therapies targeting WNT6‐HOXA9 signaling may thus be useful for this deadly disease., This work highlights DNA methylation and the homeobox HOXA9 protein as critical regulators of WNT6 expression in malignant glioma. The concomitant expression of HOXA9 and WNT6 results in overactivation of the WNT/β‐catenin signaling pathway in vitro and in vivo, and identifies a subgroup of glioblastoma patients with particularly dismal prognosis, suggesting this HOXA9‐WNT6 link may be an attractive therapeutic target.

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Abnormal expression of the long non-coding RNA HOX transcript antisense intergenic RNA (HOTAIR) is oncogenic in several human cancers, including gliomas. The HOTAIR single nucleotide polymorphisms (SNPs) rs920778 (C > T) and rs12826786 (C > T) present in the intronic enhancer and promoter regions of HOTAIR, respectively, are associated with expression, cancer susceptibility, and patient prognosis in some tumor types. However, the relevance of these HOTAIR SNPs has not been studied in glioma. Here, we report a case-control study comprising 177 Portuguese glioma patients and 199 cancer-free controls. All subjects were genotyped by PCR and restriction fragment length polymorphism (RFLP). No statistically significant differences were found in the genotype or allele distributions of either rs920778 or rs12826786 between glioma patients and controls, suggesting these SNPs are not associated with glioma risk. No significant associations were found between rs920778 variants and HOTAIR expression levels, while rs12826786 CT genotype was associated with increased intratumoral HOTAIR RNA levels when compared to TT genotype (p-value = 0.04). Univariate (Log-rank) and multivariate (Cox proportional) analyses showed both rs920778 CT and rs12826786 CT genotypes were significantly associated with longer overall survival of WHO grade III anaplastic oligodendroglioma patients. Our results suggest that HOTAIR SNPs rs920778 and rs12826786 do not play a significant role in glioma susceptibility, but may be important prognostic factors in anaplastic oligodendroglioma patients. Future studies are warranted to validate and expand these findings, and to further dissect the importance of these SNPs in glioma., Fundação para a Ciência e Tecnologia (PTDC/SAU-GMG/113795/2009 and IF/00601/2012 to B.M.C.; SFRH/BD/88220/2012 to A.X.M.; SFRH/BD/52287/2013 to A.I.O.; SFRH/BD/88121/2012 to J.V.C.; SFRH/BD/81042/2011 to M.P.; SFRH/BD/92786/2013 to C.S.G.; SFRH/BD/51996/2012 to T.L.; SFRH/BPD/104290/2014 to M.V.P.; PTDC/SAU-ONC/115513/2009 to R.M.R., Fundação Calouste Gulbenkian (B.M.C.), Liga Portuguesa Contra o Cancro (B.M.C.) and Inter-University Doctoral Programme in Ageing and Chronic Disease (PhDOC; to A.X.M. and A.I.O.). Project co-financed by Programa Operacional Regional do Norte (ON.2—O Novo Norte), Quadro de Referência Estratégico Nacional (QREN), Fundo Europeu de Desenvolvimento Regional (FEDER)

Indoor environmental conditions in neonatal intensive care units, such noise levels above the recommended, may induce some risks, not only for preterm infants’ development, but also for health care staff. The aim of this work is to summarize some good practices guidelines that can be followed by health care staff in a daily basis, which are intended to promote noise reduction in neonatal intensive care units. It is expected some initial resistance to the implementation of some recommendations, but evidence shows that in general, with training, health care staff should recognize the need of changes.

Published: 26 November 2018/ Issue Date: March 2021 This study explores the mediating role of rumination and valued living in the relationship between mindfulness and depressive symptoms in a sample of women with chronic pain. Women with musculoskeletal chronic pain (N = 124) were recruited online through the advertisement of the study in several national associations for individuals with chronic pain. Participants responded a set of questionnaires that aimed to assess mindfulness, rumination, obstructions to and progress in valued living, and depressive symptoms. All variables were significantly associated in the expected directions. Results showed the relationship between mindfulness and depressive symptoms was fully mediated by rumination and experiencing obstructions in valued living, but not by difficulties in moving forward towards valued living. Clinical implications are discussed. Results seem to suggest the potential benefits of explicitly targeting general rumination and internal obstructions to living congruently to personal values, when conducting mindfulness-based interventions for reducing depression in chronic pain.

Aim: Evaluate the impact of the single nucleotide polymorphisms rs920778 and rs12826786 in the long noncoding RNA HOTAIR in the susceptibility and prognosis of prostate cancer (PCa) patients. Patients & methods: HOTAIR single nucleotide polymorphisms were genotyped by restriction fragment length polymorphism in 151 PCa cases and 180 cancer-free controls. Odds ratio, 95% CIs and prognostic significance were calculated. Results: Our data showed no statistically significant associations between HOTAIR polymorphic variants in rs920778 and rs12826786 and PCa susceptibility. However, the CC genotype in rs12826786 was significantly associated with shorter biochemical recurrence-free survival in pT3-stage PCa patients. Conclusion: Our results indicate that HOTAIR rs12826786 CC genotype may be an independent prognostic biomarker in a particular subset of PCa tumors., Fundação para a Ciência e Tecnologia (IF/00601/2012 to BM Costa; SFRH/BD/52287/2013 to AI Oliveira; SFRH/BD/88220/2012 to AX Magalhaes), Fundação Calouste Gulbenkian (BM Costa), Liga Portuguesa Contra o Cancro (BM Costa) and Inter-University Doctoral Programme in Ageing and Chronic Disease (PhDOC; to AI Oliveira and AX Magalhaes). Project co-financed by Programa Operacional Regional do Norte (ON.2-O Novo Norte), Quadro de Referencia Estratégico Nacional (QREN), Fundo Europeu de Desenvolvimento Regional (FEDER) and a grant (74-CI-IPOP) from Research Center of Portuguese Oncology Institute of Porto (C Jeronimo)., info:eu-repo/semantics/publishedVersion

Glioblastoma is the most malignant brain tumor, exhibiting remarkable resistance to treatment. Here we investigated the oncogenic potential of HOXA9 in gliomagenesis, the molecular and cellular mechanisms by which HOXA9 renders glioblastoma more aggressive, and how HOXA9 affects response to chemotherapy and survival. The prognostic value of HOXA9 in glioblastoma patients was validated in two large datasets from TCGA and Rembrandt, where high HOXA9 levels were associated with shorter survival. Transcriptomic analyses identified novel HOXA9-target genes with key roles in cancer-related processes, including cell proliferation, DNA repair, and stem cell maintenance. Functional studies with HOXA9-overexpressing and HOXA9-silenced glioblastoma cell models revealed that HOXA9 promotes cell viability, stemness and invasion, and inhibits apoptosis. Additionally, HOXA9 promoted the malignant transformation of human immortalized astrocytes in an orthotopic in vivo model, and caused tumor-associated death. HOXA9 also mediated resistance to temozolomide treatment in vitro and in vivo via upregulation of BCL2. Importantly, the pharmacological inhibition of BCL2 with the BH3 mimetic ABT-737 reverted temozolomide resistance in HOXA9-positive cells. These data establish HOXA9 as a driver of glioma initiation, aggressiveness and resistance to therapy. In the future, the combination of BH3 mimetics with temozolomide should be further explored as an alternative treatment for glioblastoma., The authors would like to acknowledge the funding agencies that supported this work: Fundação para a Ciência e Tecnologia (PTDC/SAU-GMG/113795/2009 and SFRH/ BPD/33612/2009 to B.M.C.; SFRH/BD/81042/2011 to M.P.; SFRH/BD/88220/2012 to A.X.M.; PTDC/SAUGMG/ 113795/2009 to A.I.O. and C.S.G.), Fundação Calouste Gulbenkian (B.M.C.), and Liga Portuguesa Contra o Cancro (B.M.C.), and Schering-Plough Farma (R.M.R), Portugal. Project co-financed by Programa Operacional Regional do Norte (ON.2—O Novo Norte), Quadro de Referência Estratégico Nacional (QREN), Fundo Europeu de Desenvolvimento Regional (FEDER). The authors would like to extend their appreciation to Dr. Chris Jones and Dr. Sergey Popov (ICR, UK) for helpful assistance regarding histopathological analysis of xenograft tumors, Dr. Russell Pieper for sharing the hTERT/E6/E7 cell line (UCSF, USA), and Dr. Joseph Costello (UCSF, USA) for critical review of the manuscript.

Hotspot mutations in the promoter region of the Telomerase Reverse Transcriptase (TERT) gene are the third most common recurrent mutation in cancer and occur in over 80% of IDH-wild type glioblastomas (GBMs). These single point mutations reactivate the telomerase complex, enabling cellular immortalization through the indefinite maintenance of telomere length. The transcription factor-binding site created by these point mutations specifically recruits the multimeric transcription factor GABP to the mutant TERT promoter. GABP is composed of the DNA-binding GABPα subunit and the trans-activating GABPβ subunit. GABP can form two transcription factor species – a dimer or a tetramer – depending on which of the structurally distinct GABPβ isoforms is incorporated into the complex. In this study, we show that depletion of the GABP tetramer-forming isoform GABPβ1L silences mutant TERT promoter in GBM cells. TERT promoter mutant cells lacking GABPβ1L fail to express TERT at levels sufficient for immortalization, thus leading to telomere shortening, DNA damage accumulation, and cell death in vitro. Additionally, mice bearing orthotopically xenografted TERT promoter mutant tumors lacking GABPβ1L had reduced tumor burden and prolonged survival in comparison to mice bearing GABPβ1L wild-type tumors. Importantly, loss of GABPβ1L has minimal phenotypic effects in a panel of TERT promoter wild-type cell lines, including a transformed human astrocyte line expressing TERT from its endogenous promoter. Exogenous expression of GABPB1L or TERT is sufficient to halt telomere degradation and loss of cell viability in GABPβ1L-deficient lines bearing the mutant TERT promoter. We have now begun to investigate upstream pathways that regulate GABP tetramer formation as well as co-factors required for GABP-mediated regulation of TERT as targets to reverse immortality in TERT promoter mutant GBM. Together, these results highlight the potentially widespread role of the GABP tetramer in enabling replicative immortality of TERT promoter mutant GBM.

Gliomas account for the majority of primary tumors of the CNS, of which glioblastoma (GBM) is the most common and malignant, and for which survival is very poor. Despite significant inter- and intra-tumor heterogeneity, all patients are treated with a standardized therapeutic approach. While some clinical features of GBM patients have already been established as classic prognostic factors (e.g., patient age at diagnosis and Karnofsky performance status), one of the most important research fields in neuro-oncology today is the identification of novel molecular determinants of patient survival and tumor response to therapy. Here, we aim to review and discuss some of the most relevant and novel prognostic biomarkers in adult and pediatric GBM patients that may aid in stratifying subgroups of GBMs and rationalizing treatment decisions., (undefined)

Glioblastoma (GBM) is the most prevalent and most malignant (WHO grade IV) type of brain tumor in adults [1, 2]. In the United States, there are ~10,000 new cases diagnosed annually, and >50,000 patients living with the disease [2, 3]. The clinical responses of patients are particularly poor and vary greatly among individuals [4], and ~32% of all diagnosed cases survive less than a year [3]. This highly aggressive tumor develops either de novo (primary GBM), or as the result of the malignant progression from a lower-grade glioma (secondary GBM). In both cases, prognosis is very poor, and the median survival when radiotherapy and chemotherapy are combined is approximately 15 months [5]. Importantly, GBM is also characterized by extensive heterogeneity at the cellular and molecular levels. These tumors are highly diffuse, with extensive dissemination of tumor cells within the brain, which hinders complete surgical resection. These aggressive characteristics are associated with a remarkable resistance to therapies available today [6], which unfortunately are mostly palliative. In the context of their highest incidence of all malignant brain tumors in adults, their highly aggres‐ sive behavior and therapy-insensitive nature, which together account for a very poor prognosis of GBM patients, this chapter will focus specifically on GBM. In particular, it will review the different hypotheses of glioma/GBM-initiating cells, the major alterations at the levels of gene expression and signaling pathways found in GBM, as well as putative biomarkers of GBM prognosis, and current therapies currently available or under investigation for dealing with these tumors.

International audience; BACKGROUND: The case-hospitalization ratio (CHR) is a key quantity for the management of emerging pathogens such as pandemic influenza. Yet, few running surveillance systems prospectively monitor the CHR during influenza epidemics. Here, we analyze the proportion of recommended hospitalizations (PRH) among influenza-like illness (ILI) patients attended in general practice in France and compare the PRH observed during the 2009-2010 A(H1N1) pandemic with the one of the twelve previous seasons. METHODS: ILI cases were recorded by general practitioners (GPs) involved in surveillance, who indicated for each case whether they recommended hospitalization. We stratify the analysis by age, sex, and viral subtype. We investigate the reasons why GPs recommended hospitalization and the presence of risk factors for pandemic A(H1N1) complications. RESULTS: The average PRH over the seasons 1997-1998 to 2008-2009 was 3*4‰ (3-3*9). It was three times higher during the 2009-2010 pandemic than during seasonal influenza epidemics (OR = 2*89, 95% CI: 2*28-3*64). The highest increase was among 20-39-year-old women: OR = 11*8 (5*04-29*59). Overall, the principal reasons for recommending hospitalization were "respiratory problems" and "bad general condition." However, during the pandemic, "age" (mainly associated with infants), "pregnancy," and "diagnostic" became more frequent than before (P < 0*001). Finally, pregnancy was the reported risk factor for pandemic A(H1N1) complications that had the largest impact on hospitalization recommendation during the pandemic (OR = 38*62, P < 0*001). CONCLUSION: Easily implemented in surveillance systems, this protocol has the potential to reveal changes in hospitalization recommendation by GPs. Moreover, if the right data are collected alongside, it could give timely insights into epidemic severity.

IntroductionIn recent years, researchers and clinicians have shown an increasing interest in self-compassion. Indeed, several studies have suggested that self-compassion is a positive factor for mental and physical health. The Self-Compassion Scale (SCS; Neff, 2003) has been widely used to assess six dimensions of self-compassion (self-kindness, self-judgment, common humanity, isolation, mindfulness and over-identification) among diverse populations. Recently, it has also been used in perinatal samples but its psychometric properties in pregnant women is still unexplored.ObjectiveThis study aims was to investigate the reliability and the validity of the SCS using Confirmatory Factor Analysis in a sample of Portuguese pregnant women.MethodsParticipants were 417 pregnant women with a mean age of 33 years old (SD = 4.74) in their second trimester of pregnancy (M = 17.26, SD = 4.78, weeks of gestation). Participants completed the Portuguese version of the SCS while waiting for the routine prenatal consultation in Maternity Hospital, Portugal.ResultsA was tested and results showed that the six-factor model had a good fit to the data (TLI = 0.93, CFI = 0.94, RMSEA = 0.06). The total SCS presented a good internal reliability (α = 0.91) and their subscales showed Cronbach's alphas ranging between adequate (α = 0.77) and good (α = 0.87).ConclusionsOverall, these findings suggest that the Portuguese version of the SCS is a valid and reliable measure to assess self-compassion among pregnant women. Thus, SCS could be useful in diverse settings in the perinatal period.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Evidence indicates that exposure to high levels of noise adversely affects human health, and these effects are dependent upon various factors. In hospitals, there are many sources of noise, and high levels exert an impact on patients and staff, increasing both recovery time and stress, respectively. The goal of this pilot study was to develop, implement, and evaluate the effectiveness of a training program (TP) on noise reduction in a neonatal intensive care unit (NICU) by comparing the noise levels before and after the implementation of the program. In total, 79 health professionals participated in the study. The measurements of sound pressure levels took into account the layout of the unit and locations of the main sources of noise. General results indicated that LAeq levels before implementation of the training program were often excessive, ranging from 48.7 ± 2.94 dBA to 71.7 ± 4.74 dBA, exceeding international guidelines. Similarly, following implementation of the training program, noise levels remained unchanged (54.5 ± 0.49 dBA to 63.9 ± 4.37 dBA), despite a decrease in some locations. There was no significant difference before and after the implementation of TP. However, a significant difference was found for Lp,Cpeak, before and after training staff, suggesting greater care by health care professionals performing their tasks. Even recognizing that a TP is quite important to change behaviors, this needs to be considered in a broader context to effectively control noise in the NICU.