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OPCML is a highly conserved glycosyl phosphatidylinositol (GPI)-anchored protein belonging to the IgLON family of cell adhesion molecules. OPCML functions as a tumor suppressor and is silenced in over 80% of ovarian cancers by loss of heterozygosity and by epigenetic mechanisms. OPCML inactivation is also observed in many other cancers suggesting a conservation of tumor suppressor function. Although epigenetic silencing and subsequent loss of OPCML expression correlate with poor progression-free and overall patient survival, its mechanism of action is only starting to be fully elucidated. Recent discoveries have demonstrated that OPCML exerts its tumor suppressor effect by inhibiting several cancer hallmark phenotypes in vitro and abrogating tumorigenesis in vivo, by downregulating/inactivating a specific spectrum of Receptor Tyrosine Kinases (RTKs), including EphA2, FGFR1, FGFR3, HER2, HER4, and AXL. This modulation of RTKs can also sensitize ovarian and breast cancers to lapatinib, erlotinib, and anti-AXL therapies. Furthermore, OPCML has also been shown to function in synergy with the tumor suppressor phosphatase PTPRG to inactivate pro-metastatic RTKs such as AXL. Recently, the identification of inactivating point mutations and the elucidation of the crystal structure of OPCML have provided valuable insights into its structure-function relationships, giving rise to its potential as an anti-cancer therapeutic.

OPCML , a tumor suppressor gene, is frequently silenced epigenetically in ovarian and other cancers. Here we report, by analysis of databases of tumor sequences, the observation of OPCML somatic missense mutations from various tumor types and the impact of these mutations on OPCML function, by solving the X-ray crystal structure of this glycoprotein to 2.65 Å resolution. OPCML consists of an extended arrangement of three immunoglobulin-like domains and homodimerizes via a network of contacts between membrane-distal domains. We report the generation of a panel of OPCML variants with representative clinical mutations and demonstrate clear phenotypic effects in vitro and in vivo including changes to anchorage-independent growth, interaction with activated cognate receptor tyrosine kinases, cellular migration, invasion in vitro and tumor growth in vivo. Our results suggest that clinically occurring somatic missense mutations in OPCML have the potential to contribute to tumorigenesis in a variety of cancers. OPCML is a tumour suppressor gene that is epigenetically silenced in ovarian cancer and is somatically mutated in various cancers. Here, the authors solve the X-ray crystal structure of OPCML and model clinically relevant mutations that could contribute to tumorigenesis.

Introduction Depression is a highly prevalent condition in the elderly, with a vast impact on quality of life, life expectancy, and medical outcomes. Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed agents in this condition and, although generally safe, tolerability issues cannot be overlooked. Vortioxetine is an antidepressant with a novel mechanism of action. Based on studies to date, it may have a promising tolerability profile in the elderly, as it does not adversely affect psychomotor or cognitive performance and does not alter cardiovascular and endocrine parameters. The present study aims to assess the tolerability profile of vortioxetine in comparison with the SSRIs considered as a single group in elderly participants with depression. The rate of participants withdrawing from treatment due to adverse events after 6 months of follow up will be the primary outcome. Methods and analysis This is a pragmatic, multicentre, open-label, parallel-group, superiority, randomized trial funded by the Italian Medicines Agency (AIFA - Agenzia Italiana del Farmaco ). Thirteen Italian Community Psychiatric Services will consecutively enrol elderly participants suffering from an episode of major depression over a period of 12 months. Participants will be assessed at baseline and after 1, 3 and 6 months of follow up. At each time point, the following validated rating scales will be administered: Montgomery–Åsberg Depression Rating Scale (MADRS), Antidepressant Side-Effect Checklist (ASEC), EuroQual 5 Dimensions (EQ-5D), Short Blessed Test (SBT), and Charlson Age-Comorbidity Index (CACI). Outcome assessors and the statistician will be masked to treatment allocation. A total of 358 participants (179 in each group) will be enrolled. Ethics and dissemination This study will fully adhere to the ICH E6 Guideline for Good Clinical Practice. Participants’ data will be managed and safeguarded according to the European Data Protection Regulation 2016/679. An external Ethical Advisory Board will help guarantee high ethical standards. Trial registration Clinicaltrials.gov: NCT03779789 , Registered on 19 December 2018. Submitted on 19 December. EudraCT number: 2018–001444-66. Trial status Protocol version 1.5; 09/06/2018. Recruitment started In February 2019 and it is ongoing. It is expected to end approximately on 30 September 2021.

Abstract Introduction: Self-Help Plus (SH+) is a group-based psychological intervention developed by the World Health Organization for managing stress. Objective: To assess the effectiveness of SH+ in preventing mental disorders in refugees and asylum seekers in Western Europe. Methods: We conducted a randomized controlled trial in 5 European countries. Refugees and asylum seekers with psychological distress (General Health Questionnaire score ≥3), but without a Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) or ICD/10 diagnosis of mental disorder, as assessed with the Mini International Neuropsychiatric Interview (MINI), were randomized to SH+ or enhanced treatment as usual (ETAU). The primary outcome was the frequency of mental disorders with the MINI at 6 months. Secondary outcomes included the frequency of mental disorders at postintervention, self-identified problems, psychological symptoms, and other outcomes. Results: Four hundred fifty-nine individuals were randomly assigned to SH+ or ETAU. For the primary outcome, we found no difference in the frequency of mental disorders at 6 months (Cramer V = 0.007, p = 0.90, RR = 0.96; 95% CI 0.52–1.78), while the difference significantly favored SH+ at after the intervention (secondary outcome, measured within 2 weeks from the last session; Cramer V = 0.13, p = 0.01, RR = 0.50; 95% CI 0.29–0.87). Conclusions: This is the first randomized indicated prevention study with the aim of preventing the onset of mental disorders in asylum seekers and refugees in Western Europe. As a prevention effect of SH+ was not observed at 6 months, but rather after the intervention only, modalities to maintain its beneficial effect in the long term need to be identified.

There are clear gaps in our understanding of genes and pathways through which cancer cells facilitate survival strategies as they become chemoresistant. Paclitaxel is used in the treatment of many cancers, but development of drug resistance is common. Along with being an antimitotic agent paclitaxel also activates endoplasmic reticulum (ER) stress. Here, we examine the role of WWOX (WW domain containing oxidoreductase), a gene frequently lost in several cancers, in mediating paclitaxel response. We examine the ER stress-mediated apoptotic response to paclitaxel in WWOX-transfected epithelial ovarian cancer (EOC) cells and following siRNA knockdown of WWOX. We show that WWOX-induced apoptosis following exposure of EOC cells to paclitaxel is related to ER stress and independent of the antimitotic action of taxanes. The apoptotic response to ER stress induced by WWOX re-expression could be reversed by WWOX siRNA in EOC cells. We report that paclitaxel treatment activates both the IRE-1 and PERK kinases and that the increase in paclitaxel-mediated cell death through WWOX is dependent on active ER stress pathway. Log-rank analysis of overall survival (OS) and progression-free survival (PFS) in two prominent EOC microarray data sets (Tothill and The Cancer Genome Atlas), encompassing ~800 patients in total, confirmed clinical relevance to our findings. High WWOX mRNA expression predicted longer OS and PFS in patients treated with paclitaxel, but not in patients who were treated with only cisplatin. The association of WWOX and survival was dependent on the expression level of glucose-related protein 78 (GRP78), a key ER stress marker in paclitaxel-treated patients. We conclude that WWOX sensitises EOC to paclitaxel via ER stress-induced apoptosis, and predicts clinical outcome in patients. Thus, ER stress response mechanisms could be targeted to overcome chemoresistance in cancer.

IntroductionThis article describes two randomised controlled trials that will evaluate the effectiveness and cost-effectiveness of Self-Help Plus (SH+), a group self-help intervention developed by the WHO to reduce distress. In these trials SH+ is being tested as a preventative intervention to lower the incidence of mental disorders in asylum seekers and refugees with psychological distress resettled in Europe and Turkey.Methods and analysisTwo prospective, multicentre, randomised, rater-blinded, parallel-group studies will follow participants over a period of 12 months. One trial will be conducted in Europe and one in Turkey. In each trial, 600 asylum seekers and refugees screening positive on the General Health Questionnaire (≥3), but without a formal diagnosis of any mental disorders according to the Mini International Neuropsychiatric Interview, will be randomly allocated to SH+or to enhanced treatment-as-usual. The primary outcome will be a lower incidence of mental disorders at 6 month follow-up. Secondary outcomes will include the evaluation of psychological symptoms, functioning, well-being, treatment acceptability and indicators of intervention cost-effectiveness.Ethics and disseminationThe two trials received ethical clearance from the local Ethics Committees of the participating sites (seven sites), as well as from the WHO Ethics Committee. All participants will provide informed consent before screening and before study inclusion (a two-step procedure). The results of the trials will be disseminated in agreement with a dissemination plan that includes publication(s) in peer-reviewed journals and presentations at relevant national and international conferences and meetings.Trials registration numbersNCT03571347, NCT03587896.

The opioid-binding cell adhesion molecule (OPCML) is a glycosylphosphatidylinositol (GPI) anchored protein that was found to be epigenetically inactivated in 83% of ovarian cancers and demonstrated to act as a tumour suppressor gene (TSG), inhibiting tumour cell growth in vitro and severely attenuating tumourigenesis in vivo (Sellar et al., 2003). We subsequently showed that OPCML exerted its suppressor functions by negatively regulating a spectrum of receptor tyrosine kinases (RTKs), such as ErbB2/HER2, FGFR1 and EphA2, attenuating their downstream signalling (McKie et al., 2012). Initial in vitro interaction studies revealed that OPCML physically interacted with this defined group of RTKs as a prerequisite for their downregulation. The aims of this PhD project were to define key interacting regions between OPCML and the extracellular domains of the target RTKs, to work towards elucidating the structure of OPCML and to investigate the therapeutic potential of a recombinant form of OPCML. Here it is described how a comprehensive panel of OPCML constructs was created and how these constructs were utilised for GST- and His-tagged OPCML protein production in E.coli (BL21(DE3)) and insect cells (Sf21). Selected His-tag constructs were used for expression and purification of the protein to attempt initial crystallisation studies. Tagged OPCML proteins were utilised to investigate RTK interacting partners of OPCML from members of the EGFR and FGFR families by pull-down assays initially. We then developed in-house mammalian 2-hybrid expertise in order to investigate in detail the interacting regions between OPCML and members of the EGFR, FGFR and Eph families, identifying regions of the receptors critical for the interaction with OPCML upon creating deletion constructs of their extracellular domain. We identified the importance of the distal Ig domain of OPCML to RTK interaction by virtue of our analysis of a previously identified somatic missense mutation in a primary ovarian tumour, a C-G transversion at nucleotide position 334 resulting in amino acid substitution (P95R) within the first Ig domain (Sellar et al 2003). Expression of the OPCMLP95R elicits clear disruption of cell adhesion phenotypes, in addition to disrupting the interaction of OPCML with EphA2. The FGFR1 interaction with OPCML has appeared more robust compared to the other RTK examples studied and a more precise deletion of specific FGFR1 amino acid motifs is required for loss of interaction to be observed. A His-tagged OPCML was used for the treatment of cancer cells in vitro and of two intraperitoneal models in vivo, demonstrating that exogenous administration of the recombinant protein caused profound anti-tumorigenic effects in several ovarian cancer cell lines as well as in the intraperitoneal models of EOC in mice.

Introduction. Depression is a highly prevalent condition in the elderly, with a vast impact on quality of life, life expectancy, and medical outcomes. Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed agents in this condition and, although generally safe, tolerability issues cannot be overlooked. Vortioxetine is an antidepressant with a novel mechanism of action. Based on available studies, it may have a promising tolerability profile in the elderly, as it does not adversely affect psychomotor or cognitive performance, and does not alter cardiovascular and endocrine parameters. The present study aims to assess the tolerability profile of vortioxetine in comparison with the SSRIs considered as a single group in elderly participants with depression. The rate of participants withdrawing from treatment due to adverse events after six months of follow-up will be the primary outcome. Methods and analysis. This is a pragmatic, multicentre, open-label, parallel-group, superiority, randomized trial funded by the Italian Medicines Agency (AIFA - Agenzia Italiana del Farmaco ). Thirteen Italian Community Psychiatric Services will consecutively enrol elderly participants suffering from an episode of major depression over a period of 12 months. Participants will be assessed at baseline and after 1, 3 and 6 months of follow-up. At each time point, the following validated rating scales will be administered: Montgomery–Åsberg Depression Rating Scale (MADRS), Antidepressant Side-Effect Checklist (ASEC), EuroQual 5 Dimensions (EQ-5D), Short Blessed Test (SBT), and Charlson Age-Comorbidity Index (CACI). Outcome assessors and the statistician will be masked to treatment allocation. A total of 358 participants (179 in each group) will be enrolled. Ethics and dissemination. This study will fully adhere to the ICH E6 Guideline for Good Clinical Practice. Participants’ data will be managed and safeguarded according to the European Data Protection Regulation 2016/679. An external Ethical Advisory Board will help guarantee high ethical standards. Trial registration number. EudraCT number: 2018-001444-66; Clinicaltrials.gov: NCT03779789, first submitted on December 12, 2018 and first posted on December 19 th trial status: protocol version 1.5; 09/06/2018. Recruitment started on February 2019 and it is ongoing. It is expected to end approximately on September 30 th 2021.

One-third of all Neotropical forests are secondary forests that regrow naturally after agricultural use through secondary succession. We need to understand better how and why succession varies across environmental gradients and broad geographic scales. Here, we analyze functional recovery using community data on seven plant characteristics (traits) of 1,016 forest plots from 30 chronosequence sites across the Neotropics. By analyzing communities in terms of their traits, we enhance understanding of the mechanisms of succession, assess ecosystem recovery, and use these insights to propose successful forest restoration strategies. Wet and dry forests diverged markedly for several traits that increase growth rate in wet forests but come at the expense of reduced drought tolerance, delay, or avoidance, which is important in seasonally dry forests. Dry and wet forests showed different successional pathways for several traits. In dry forests, species turnover is driven by drought tolerance traits that are important early in succession and in wet forests by shade tolerance traits that are important later in succession. In both forests, deciduous and compound-leaved trees decreased with forest age, probably because microclimatic conditions became less hot and dry. Our results suggest that climatic water availability drives functional recovery by influencing the start and trajectory of succession, resulting in a convergence of community trait values with forest age when vegetation cover builds up. Within plots, the range in functional trait values increased with age. Based on the observed successional trait changes, we indicate the consequences for carbon and nutrient cycling and propose an ecologically sound strategy to improve forest restoration success.

Olfactory and gustatory dysfunction have been reported in mild and major neurocognitive disorders (NCDs), with variable results. While olfactory dysfunction has been consistently explored, reports on gustatory alterations are limited. We systematically reviewed case-control studies evaluating gustatory function in NCDs with various etiologies and different neuropathology. Eighteen studies were included in the systematic review, and eight were included in the meta-analysis. Most studies were on Alzheimer’s disease (AD) and Parkinson’s disease (PD). Pooled analyses showed worse global taste threshold and identification (sour in particular) scores in AD than controls and worse global, sweet, and sour scores in AD compared to mild cognitive impairment (MCI). PD with MCI showed worse global, sweet, salty, and sour scores than controls and cognitively unimpaired PD. Taste dysfunction was differentially associated with the severity of cognitive deficits. Gustatory dysfunction may represent a potential cross-disease chemosensory biomarker of NCD. Whether gustatory alterations may be a pre-clinical biomarker of NCD requires further studies.