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Although the presence of mental health stigma associated with seeking help has been demonstrated in many parts of the world, this work has largely been from an independent perspective (i.e., "I will be perceived as crazy") rather than from an interdependent perspective (i.e., "My family will be viewed negatively"). Interdependent stigma of seeking help (i.e., the extent to which people believe their family would be devalued and shamed if they seek psychological help) may be an important type of stigma that has not been assessed. Based on self-construal theory, the present study sought to develop and evaluate the psychometric properties of an Interdependent Stigma of Seeking Help (ISSH) scale in eight different countries and regions (i.e., Australia, Brazil, Germany, Hong Kong, Taiwan, Türkiye, the UAE, the United States). Findings suggest that the psychometric properties of the eight-item ISSH are adequate for research purposes (a unidimensional scale with full invariance and internal consistency estimates from .84 to .94). The ISSH was moderately related to other measures of stigma and psychological distress. Some differences in the relationship with specific outcomes by country and region were found, and there were notable country differences in the latent mean levels of ISSH, with Hong Kong and Taiwan having the highest means, and Australia, the United States, and Brazil having the lowest levels. Results suggest that the ISSH could be used to help clarify the complex relationships between stigma and other variables of interest and might be useful in developing culturally relevant interventions. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
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BACKGROUND: Catenin (Cadherin-Associated Protein), Beta 1 (CTNNB1) genomic alterations are rare in prostate cancer (PCa). Gain-of-function mutations lead to overexpression of ß-catenin, with consequent hyperactivation of the Wnt/ß-catenin signaling pathway, implicated in PCa progression and treatment resistance. To date, successful targeted treatment options for Wnt/ß-catenin - driven PCa are lacking. METHODS: We report a rare histologic transformation of a CTNNB1 (ß-catenin) mutated metastatic castration resistant prostate cancer (mCRPC), clinically characterized by highly aggressive disease course. We histologically and molecularly characterized the liver metastatic tumor samples, as well as successfully generated patient-derived organoids (PDOs) and patient-derived xenograft (PDX) from a liver metastasis. We used the generated cell models for further molecular characterization and drug response assays. RESULTS: Immunohistochemistry of liver metastatic biopsies and PDX tumor showed lack of expression of typical PCa (e.g., AR, PSA, PSAP, ERG) or neuroendocrine markers (synaptophysin), compatible with double-negative CRPC, but was positive for nuclear ß-catenin expression, keratin 7 and 34ßE12. ERG rearrangement was confirmed by fluorescent in situ hybridization (FISH). Drug response assays confirmed, in line with the clinical disease course, lack of sensitivity to common drugs used in mCRPC (e.g., enzalutamide, docetaxel). The casein kinase 1 (CK1) inhibitor IC261 and the tankyrase 1/2 inhibitor G700-LK showed modest activity. Moreover, despite harbouring a CTNNB1 mutation, PDOs were largely insensitive to SMARCA2/4- targeting PROTAC degraders and inhibitor. CONCLUSIONS: The reported CTNNB1-mutated mCRPC case highlights the potential challenges of double-negative CRPC diagnosis and underlines the relevance of further translational research to enable successful targeted treatment of rare molecular subtypes of mCRPC.
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Mutación , beta Catenina , Humanos , Masculino , beta Catenina/genética , beta Catenina/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/patología , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/patología , Animales , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Anciano , Progresión de la EnfermedadRESUMEN
Prostate cancer is one of the most prevalent and, upon metastasis, deadliest cancers in men. Timely identification is essential for effective treatment. Furthermore, accurate determination of prostatic origin is crucial for personalized therapy once the cancer has spread. However, current prostate cancer screening methods are lacking. A recent article in The Journal of Pathology addresses this issue by utilizing an improved antibody to reevaluate HOXB13 as a lineage marker for prostate cancer. The study's findings support the concept that, despite decreased expression in advanced prostate cancer, HOXB13 remains highly suitable for determining prostatic origin due to its androgen receptor independence, high specificity, and sensitivity. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Neoplasias de la Próstata , Masculino , Humanos , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Antígeno Prostático Específico/metabolismo , Detección Precoz del Cáncer , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Próstata/patología , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , InmunoglobulinasRESUMEN
Alterations in DNA damage response (DDR) and related genes are present in up to 25% of advanced prostate cancers (PCa). Most frequently altered genes are involved in the homologous recombination repair, the Fanconi anemia, and the mismatch repair pathways, and their deficiencies lead to a highly heterogeneous spectrum of DDR-deficient phenotypes. More than half of these alterations concern non- BRCA DDR genes. From a therapeutic perspective, poly-ADP-ribose polymerase inhibitors have demonstrated robust clinical efficacy in tumors with BRCA2 and BRCA1 alterations. Mismatch repair-deficient PCa, and a subset of CDK12-deficient PCa, are vulnerable to immune checkpoint inhibitors. Emerging data point to the efficacy of ATR inhibitors in PCa with ATM deficiencies. Still, therapeutic implications are insufficiently clarified for most of the non- BRCA DDR alterations, and no successful targeted treatment options have been established.
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Daño del ADN , Neoplasias de la Próstata , Masculino , Humanos , Reparación de la Incompatibilidad de ADN , Reparación del ADN , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéuticoRESUMEN
BACKGROUND: The antidiabetic drug metformin has known anticancer effects related to its antioxidant activity; however, its clinical benefit for prostate cancer (PCa) has thus far been inconclusive. Here, we investigate whether the efficacy of metformin in PCa is related to the expression status of NKX3.1, a prostate-specific homeobox gene that functions in mitochondria to protect the prostate from aberrant oxidative stress. OBJECTIVE: To investigate the relationship of NKX3.1 expression and metformin efficacy in PCa. DESIGN, SETTING, AND PARTICIPANTS: Functional studies were performed in vivo and in vitro in genetically engineered mouse models and human LNCaP cells, and organotypic cultures having normal or reduced/absent levels of NKX3.1. Correlative studies were performed using two independent retrospective tissue microarray cohorts of radical prostatectomies and a retrospective cohort of prostate biopsies from patients on active surveillance. INTERVENTION: Metformin was administered before or after the induction of oxidative stress by treatment with paraquat. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Functional endpoints included analyses of histopathology, tumorigenicity, and mitochondrial function. Correlative endpoints include Kaplan-Meier curves and Cox proportional hazard regression models. RESULTS AND LIMITATIONS: Metformin reversed the adverse consequences of NKX3.1 deficiency following oxidative stress in vivo and in vitro, as evident by reduced tumorigenicity and restored mitochondrial function. Patients with low NKX3.1 expression showed a significant clinical benefit from taking metformin. CONCLUSIONS: Metformin can overcome the adverse consequences of NKX3.1 loss for PCa progression by protecting against oxidative stress and promoting normal mitochondrial function. These functional activities and clinical correlates were observed only with low NKX3.1 expression. Thus, the clinical benefit of metformin in PCa may depend on the status of NKX3.1 expression. PATIENT SUMMARY: Prostate cancer patients with low NKX3.1 are likely to benefit most from metformin treatment to delay disease progression in a precision interception paradigm.
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Metformina , Neoplasias de la Próstata , Masculino , Ratones , Animales , Humanos , Próstata/patología , Estudios Retrospectivos , Metformina/farmacología , Metformina/uso terapéutico , Metformina/metabolismo , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Factores de Transcripción/genética , Neoplasias de la Próstata/genéticaRESUMEN
BACKGROUND: Right to left shunt (RLS), including patent foramen ovale, is a recognized risk factor for stroke. RLS/patent foramen ovale diagnosis is made by transthoracic echocardiography (TTE), which is insensitive, transesophageal echocardiography, which is invasive, and transcranial Doppler (TCD), which is noninvasive and accurate but scarce. METHODS: We conducted a prospective, single-arm device clinical trial of robot-assisted TCD (raTCD) versus TTE for RLS diagnosis at 6 clinical sites in patients who presented with an event suspicious for embolic cerebrovascular ischemia from October 6, 2020 to October 20, 2021. raTCD was performed with standard TCD bubble study technique. TTE bubble study was performed per local standards. The primary outcome was rate of RLS detection by raTCD versus TTE. RESULTS: A total of 154 patients were enrolled, 129 evaluable (intent to scan) and 121 subjects had complete data per protocol. In the intent to scan cohort, mean age was 60±15 years, 47% were women, and all qualifying events were diagnosed as ischemic stroke or transient ischemic attack. raTCD was positive for RLS in 82 subjects (64%) and TTE was positive in 26 (20%; absolute difference 43.4% [95% CI, 35.2%-52.0%]; P<0.001). On prespecified secondary analysis, large RLS was detected by raTCD in 35 subjects (27%) versus 13 (10%) by TTE (absolute difference 17.0% [95% CI, 11.5%-24.5%]; P<0.001). There were no serious adverse events. CONCLUSIONS: raTCD was safe and ≈3 times more likely to diagnose RLS than TTE. TTE completely missed or underdiagnosed two thirds of large shunts diagnosed by raTCD. The raTCD device, used by health professionals with no prior TCD training, may allow providers to achieve the known sensitivity of TCD for RLS and patent foramen ovale detection without the need for an experienced operator to perform the test. Pending confirmatory studies, TCD appears to be the superior screen for RLS compared with TTE (funded by NeuraSignal). REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04604015.
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Foramen Oval Permeable , Robótica , Accidente Cerebrovascular , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Ecocardiografía , Ecocardiografía Transesofágica , Foramen Oval Permeable/complicaciones , Estudios Prospectivos , Accidente Cerebrovascular/etiología , Ultrasonografía Doppler TranscranealRESUMEN
Although recent efforts have led to the development of highly effective androgen receptor (AR)-directed therapies for the treatment of advanced prostate cancer, a significant subset of patients will progress with resistant disease including AR-negative tumors that display neuroendocrine features [neuroendocrine prostate cancer (NEPC)]. On the basis of RNA sequencing (RNA-seq) data from a clinical cohort of tissue from benign prostate, locally advanced prostate cancer, metastatic castration-resistant prostate cancer and NEPC, we developed a multi-step bioinformatics pipeline to identify NEPC-specific, overexpressed gene transcripts that encode cell surface proteins. This included the identification of known NEPC surface protein CEACAM5 as well as other potentially targetable proteins (e.g., HMMR and CESLR3). We further showed that cadherin EGF LAG seven-pass G-type receptor 3 (CELSR3) knockdown results in reduced NEPC tumor cell proliferation and migration in vitro. We provide in vivo data including laser capture microdissection followed by RNA-seq data supporting a causal role of CELSR3 in the development and/or maintenance of the phenotype associated with NEPC. Finally, we provide initial data that suggests CELSR3 is a target for T-cell redirection therapeutics. Further work is now needed to fully evaluate the utility of targeting CELSR3 with T-cell redirection or other similar therapeutics as a potential new strategy for patients with NEPC. Significance: The development of effective treatment for patients with NEPC remains an unmet clinical need. We have identified specific surface proteins, including CELSR3, that may serve as novel biomarkers or therapeutic targets for NEPC.
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Tumores Neuroendocrinos , Neoplasias de la Próstata , Humanos , Masculino , Neoplasias de la Próstata/genética , Tumores Neuroendocrinos/genética , Próstata/metabolismo , Membrana Celular/metabolismo , Cadherinas/genéticaRESUMEN
An important distinction to make when assessing the impact of social media use on mental health is whether the use is passive (e.g., browsing) or active (e.g., posting). Recent research suggests that the connection between passive social media use and mental ill-being is inconsistent, with some research finding a significant negative association, while other research finds no such association. In the present research, we sought to investigate this relationship, as well as two potential moderators of this relationship: the subjective appraisal of social media content social media users consume (i.e., positively or negatively-appraised) and age of users. In a cross-sectional survey of Australian and United States Facebook users (N = 991), there was no direct relationship between passive use and mental ill-being, however user age and positive (but not negative) content appraisal were found to moderate the relationship between passive use and mental ill-being. Specifically, the relationship between passive use and mental ill-being became weaker as subjective positive appraisal increased, and it reversed to become negative at high levels of positive appraisal. Additionally, the positive relationship between passive use and mental ill-being became weaker as age of social media users increased, and the direction of this relationship became negative at the oldest ages of social media users. These results suggest that the relationship between social media use and mental ill-being is more nuanced than previous research suggests. In particular, higher amounts of passive Facebook use may have a less negative, or even a positive effect on social media users' mental health when the content being (passively) consumed is positively appraised, or when users are older.
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The clinical use of potent androgen receptor (AR) inhibitors has promoted the emergence of novel subtypes of metastatic castration-resistant prostate cancer (mCRPC), including neuroendocrine prostate cancer (CRPC-NE), which is highly aggressive and lethal 1 . These mCRPC subtypes display increased lineage plasticity and often lack AR expression 2-5 . Here we show that neuroendocrine differentiation and castration-resistance in CRPC-NE are maintained by the activity of Nuclear Receptor Binding SET Domain Protein 2 (NSD2) 6 , which catalyzes histone H3 lysine 36 dimethylation (H3K36me2). We find that organoid lines established from genetically-engineered mice 7 recapitulate key features of human CRPC-NE, and can display transdifferentiation to neuroendocrine states in culture. CRPC-NE organoids express elevated levels of NSD2 and H3K36me2 marks, but relatively low levels of H3K27me3, consistent with antagonism of EZH2 activity by H3K36me2. Human CRPC-NE but not primary NEPC tumors expresses high levels of NSD2, consistent with a key role for NSD2 in lineage plasticity, and high NSD2 expression in mCRPC correlates with poor survival outcomes. Notably, CRISPR/Cas9 targeting of NSD2 or expression of a dominant-negative oncohistone H3.3K36M mutant results in loss of neuroendocrine phenotypes and restores responsiveness to the AR inhibitor enzalutamide in mouse and human CRPC-NE organoids and grafts. Our findings indicate that NSD2 inhibition can reverse lineage plasticity and castration-resistance, and provide a potential new therapeutic target for CRPC-NE.
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The evolutionarily conserved minor spliceosome (MiS) is required for protein expression of â¼714 minor intron-containing genes (MIGs) crucial for cell-cycle regulation, DNA repair, and MAP-kinase signaling. We explored the role of MIGs and MiS in cancer, taking prostate cancer (PCa) as an exemplar. Both androgen receptor signaling and elevated levels of U6atac, a MiS small nuclear RNA, regulate MiS activity, which is highest in advanced metastatic PCa. siU6atac-mediated MiS inhibition in PCa in vitro model systems resulted in aberrant minor intron splicing leading to cell-cycle G1 arrest. Small interfering RNA knocking down U6atac was â¼50% more efficient in lowering tumor burden in models of advanced therapy-resistant PCa compared with standard antiandrogen therapy. In lethal PCa, siU6atac disrupted the splicing of a crucial lineage dependency factor, the RE1-silencing factor (REST). Taken together, we have nominated MiS as a vulnerability for lethal PCa and potentially other cancers.
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Neoplasias de la Próstata Resistentes a la Castración , Neoplasias de la Próstata , Masculino , Humanos , Intrones/genética , Neoplasias de la Próstata/metabolismo , Empalme del ARN/genética , Empalmosomas/metabolismo , Transducción de Señal , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo , Línea Celular Tumoral , Neoplasias de la Próstata Resistentes a la Castración/genéticaRESUMEN
A substantial body of research indicates that higher education students from lower social class backgrounds tend to have poorer health than those from higher social class backgrounds. To investigate sleep as a potential mediator of this relationship, online survey responses of students from five large Australian universities, one Irish university and one large Australian technical college were analysed in three studies (Study 1 N = 628; Study 2 N = 376; Study 3 N = 446). The results revealed that sleep quality, sleep duration, sleep disturbances, pre-sleep worries and sleep schedule variability mediated the relationship between social class and physical and mental health. Sleep remained a significant mediator when controlling for related variables and other mediators. Thus, the findings suggest that sleep partly explains social class differences in health. We discuss the importance of addressing sleep issues among students from lower social class backgrounds.
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Trastornos del Sueño-Vigilia , Estudiantes , Humanos , Australia , Estudiantes/psicología , Clase Social , Salud Mental , Sueño , UniversidadesRESUMEN
Phosphatidylinositol (PI)regulating enzymes are frequently altered in cancer and have become a focus for drug development. Here, we explore the phosphatidylinositol-5-phosphate 4-kinases (PI5P4K), a family of lipid kinases that regulate pools of intracellular PI, and demonstrate that the PI5P4Kα isoform influences androgen receptor (AR) signaling, which supports prostate cancer (PCa) cell survival. The regulation of PI becomes increasingly important in the setting of metabolic stress adaptation of PCa during androgen deprivation (AD), as we show that AD influences PI abundance and enhances intracellular pools of PI-4,5-P2. We suggest that this PI5P4Kα-AR relationship is mitigated through mTORC1 dysregulation and show that PI5P4Kα colocalizes to the lysosome, the intracellular site of mTORC1 complex activation. Notably, this relationship becomes prominent in mouse prostate tissue following surgical castration. Finally, multiple PCa cell models demonstrate marked survival vulnerability following stable PI5P4Kα inhibition. These results nominate PI5P4Kα as a target to disrupt PCa metabolic adaptation to castrate resistance.
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Neoplasias de la Próstata Resistentes a la Castración , Receptores Androgénicos , Animales , Humanos , Masculino , Ratones , Antagonistas de Andrógenos , Andrógenos/metabolismo , Línea Celular Tumoral , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Receptores Androgénicos/metabolismo , Transducción de SeñalAsunto(s)
Neoplasias , Humanos , Neoplasias/genética , Neoplasias/terapia , Medicina de Precisión , Oncología Médica , Genómica , Atención a la SaludRESUMEN
Metastases from primary prostate cancers to rare locations, such as the brain, are becoming more common due to longer life expectancy resulting from improved treatments. Epigenetic dysregulation is a feature of primary prostate cancer, and distinct DNA methylation profiles have been shown to be associated with the mutually exclusive SPOP-mutant or TMPRSS2-ERG fusion genetic backgrounds. Using a cohort of prostate cancer brain metastases (PCBM) from 42 patients, with matched primary tumors for 17 patients, we carried out a DNA methylation analysis to examine the epigenetic distinction between primary prostate cancer and PCBM, the association between epigenetic alterations and mutational background, and particular epigenetic alterations that may be associated with PCBM. Multiregion sampling of PCBM revealed epigenetic stability within metastases. Aberrant methylation in PCBM was associated with mutational background and PRC2 complex activity, an effect that is particularly pronounced in SPOP-mutant PCBM. While PCBM displayed a CpG island hypermethylator phenotype, hypomethylation at the promoters of genes involved in neuroactive ligand-receptor interaction and cell adhesion molecules such as GABRB3, CLDN8, and CLDN4 was also observed, suggesting that cells from primary tumors may require specific reprogramming to form brain metastasis. This study revealed the DNA methylation landscapes of PCBM and the potential mechanisms and effects of PCBM-associated aberrant DNA methylation. SIGNIFICANCE: DNA methylation analysis reveals the molecular characteristics of PCBM and may serve as a starting point for efforts to identify and target susceptibilities of these rare metastases.
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Neoplasias Encefálicas , Neoplasias de la Próstata , Humanos , Masculino , Metilación de ADN , Neoplasias de la Próstata/patología , Islas de CpG/genética , Epigenómica , Neoplasias Encefálicas/genética , Proteínas Nucleares/metabolismo , Proteínas Represoras/genéticaRESUMEN
Defects in homologous recombination repair (HRR) in tumors correlate with poor prognosis and metastases development. Determining HRR deficiency (HRD) is of major clinical relevance as it is associated with therapeutic vulnerabilities and remains poorly investigated in sarcoma. Here, we show that specific sarcoma entities exhibit high levels of genomic instability signatures and molecular alterations in HRR genes, while harboring a complex pattern of chromosomal instability. Furthermore, sarcomas carrying HRDness traits exhibit a distinct SARC-HRD transcriptional signature that predicts PARP inhibitor sensitivity in patient-derived sarcoma cells. Concomitantly, HRDhigh sarcoma cells lack RAD51 nuclear foci formation upon DNA damage, further evidencing defects in HRR. We further identify the WEE1 kinase as a therapeutic vulnerability for sarcomas with HRDness and demonstrate the clinical benefit of combining DNA damaging agents and inhibitors of DNA repair pathways ex vivo and in the clinic. In summary, we provide a personalized oncological approach to treat sarcoma patients successfully.
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Antineoplásicos , Neoplasias Óseas , Osteosarcoma , Sarcoma , Humanos , Reparación del ADN por Recombinación , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacología , Sarcoma/terapia , Sarcoma/tratamiento farmacológico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Recombinación HomólogaRESUMEN
Precision oncology relies on the accurate identification of somatic mutations in cancer patients. While the sequencing of the tumoral tissue is frequently part of routine clinical care, the healthy counterparts are rarely sequenced. We previously published PipeIT, a somatic variant calling workflow specific for Ion Torrent sequencing data enclosed in a Singularity container. PipeIT combines user-friendly execution, reproducibility and reliable mutation identification, but relies on matched germline sequencing data to exclude germline variants. Expanding on the original PipeIT, here we describe PipeIT2 to address the clinical need to define somatic mutations in the absence of germline control. We show that PipeIT2 achieves a > 95% recall for variants with variant allele fraction >10%, reliably detects driver and actionable mutations and filters out most of the germline mutations and sequencing artifacts. With its performance, reproducibility, and ease of execution, PipeIT2 is a valuable addition to molecular diagnostics laboratories.
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Neoplasias , Humanos , Neoplasias/diagnóstico , Neoplasias/genética , Patología Molecular , Flujo de Trabajo , Reproducibilidad de los Resultados , Medicina de Precisión , Mutación , Secuenciación de Nucleótidos de Alto RendimientoRESUMEN
Diagnostic tests usually need to operate at a high sensitivity or specificity level in practice. Accordingly, specificity at the controlled sensitivity, or vice versa, is a clinically sensible performance metric for evaluating continuous biomarkers. Meanwhile, the performance of a biomarker may vary across sub-populations as defined by covariates, and covariate-specific evaluation can be informative. In this article, we develop a novel modeling and estimation method for covariate-specific specificity at a controlled sensitivity level. Unlike existing methods which typically adopt elaborate models of covariate effects over the entire biomarker distribution, our approach models covariate effects locally at a specific sensitivity level of interest. We also extend our proposed model to handle the whole continuum of sensitivities via dynamic regression and derive covariate-specific ROC curves. We provide the variance estimation through bootstrapping. The asymptotic properties are established. We conduct extensive simulation studies to evaluate the performance of our proposed methods in comparison with existing methods, and further illustrate the applications in two clinical studies for aggressive prostate cancer.
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Modelos Estadísticos , Neoplasias de la Próstata , Masculino , Humanos , Simulación por Computador , Curva ROC , BiomarcadoresRESUMEN
Members of disadvantaged groups sometimes support societal systems that enable the very inequalities that disadvantaged them. Is it possible to explain this puzzling system-justifying orientation in terms of rational group-interested motives, without recourse to a separate system motive? The social identity model of system attitudes (SIMSA) claims that it is. SIMSA proposes that the system justification shown by a disadvantaged group (e.g., African American women) can sometimes support identity needs that are tied to a more inclusive (superordinate) in-group (e.g., Americans). There is already some supportive evidence for this proposition, but it is not yet clear whether: (1) such trends are visible in a wider range of disadvantaged contexts, and (2) this explanation also applies to those who are strongly invested in their subgroup (e.g., feminists). In two waves of a large nationally representative survey from 21 to 23 European states (Ntotal = 84,572) and two controlled experiments (Ntotal = 290 women), we found that: (a) system justification was positively associated with superordinate ingroup identification across multiple cases of disadvantage (Studies 1-3), (b) system justification increased when this inclusive identity was made more salient (Studies 2 & 3), and (c) system justification was visible even amongst feminists when they activated their superordinate (Italian) identity (Study 3).
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Actitud , Identificación Social , Humanos , Femenino , Estados Unidos , Cognición , Italia , Grupo SocialRESUMEN
BACKGROUND: Adult-type diffuse gliomas, CNS WHO grade 4 are the most aggressive primary brain tumors and represent a particular challenge for therapeutic intervention. METHODS: In a single-center retrospective study of matched pairs of initial and post-therapeutic glioma cases with a recurrence period greater than 1 year, we performed whole exome sequencing combined with mRNA and microRNA expression profiling to identify processes that are altered in recurrent gliomas. RESULTS: Mutational analysis of recurrent gliomas revealed early branching evolution in 75% of the patients. High plasticity was confirmed at the mRNA and miRNA levels. SBS1 signature was reduced and SBS11 was elevated, demonstrating the effect of alkylating agent therapy on the mutational landscape. There was no evidence for secondary genomic alterations driving therapy resistance. ALK7/ACVR1C and LTBP1 were upregulated, whereas LEFTY2 was downregulated, pointing towards enhanced Tumor Growth Factor ß (TGF-ß) signaling in recurrent gliomas. Consistently, altered microRNA expression profiles pointed towards enhanced Nuclear Factor Kappa B and Wnt signaling that, cooperatively with TGF-ß, induces epithelial to mesenchymal transition (EMT), migration, and stemness. TGF-ß-induced expression of pro-apoptotic proteins and repression of antiapoptotic proteins were uncoupled in the recurrent tumor. CONCLUSIONS: Our results suggest an important role of TGF-ß signaling in recurrent gliomas. This may have clinical implications since TGF-ß inhibitors have entered clinical phase studies and may potentially be used in combination therapy to interfere with chemoradiation resistance. Recurrent gliomas show high incidence of early branching evolution. High tumor plasticity is confirmed at the level of microRNA and mRNA expression profiles.