Publications by authors named "Gonzalo Lopez"

80 Publications

Examining the association between exposome score for schizophrenia and functioning in schizophrenia, siblings, and healthy controls: Results from the EUGEI study.

Eur Psychiatry 2021 Mar 19;64(1):e25. Epub 2021 Mar 19.

Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University Medical Center, Maastricht, The Netherlands.

Background: A cumulative environmental exposure score for schizophrenia (exposome score for schizophrenia [ES-SCZ]) may provide potential utility for risk stratification and outcome prediction. Here, we investigated whether ES-SCZ was associated with functioning in patients with schizophrenia spectrum disorder, unaffected siblings, and healthy controls.

Methods: This cross-sectional sample consisted of 1,261 patients, 1,282 unaffected siblings, and 1,525 healthy controls. The Global Assessment of Functioning (GAF) scale was used to assess functioning. ES-SCZ was calculated based on our previously validated method. The association between ES-SCZ and the GAF dimensions (symptom and disability) was analyzed by applying regression models in each group (patients, siblings, and controls). Additional models included polygenic risk score for schizophrenia (PRS-SCZ) as a covariate.

Results: ES-SCZ was associated with the GAF dimensions in patients (symptom: B = -1.53, p-value = 0.001; disability: B = -1.44, p-value = 0.001), siblings (symptom: B = -3.07, p-value < 0.001; disability: B = -2.52, p-value < 0.001), and healthy controls (symptom: B = -1.50, p-value < 0.001; disability: B = -1.31, p-value < 0.001). The results remained the same after adjusting for PRS-SCZ. The degree of associations of ES-SCZ with both symptom and disability dimensions were higher in unaffected siblings than in patients and controls. By analyzing an independent dataset (the Genetic Risk and Outcome of Psychosis study), we replicated the results observed in the patient group.

Conclusions: Our findings suggest that ES-SCZ shows promise for enhancing risk prediction and stratification in research practice. From a clinical perspective, ES-SCZ may aid in efforts of clinical characterization, operationalizing transdiagnostic clinical staging models, and personalizing clinical management.
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http://dx.doi.org/10.1192/j.eurpsy.2021.19DOI Listing
March 2021

Cross-flow microfiltration for isolation, selective capture and release of liposarcoma extracellular vesicles.

J Extracell Vesicles 2021 Feb 16;10(4):e12062. Epub 2021 Feb 16.

Comprehensive Cancer Center The Ohio State University Columbus Ohio USA.

We present a resource-efficient approach to fabricate and operate a micro-nanofluidic device that uses cross-flow filtration to isolate and capture liposarcoma derived extracellular vesicles (EVs). The isolated extracellular vesicles were captured using EV-specific protein markers to obtain vesicle enriched media, which was then eluted for further analysis. Therefore, the micro-nanofluidic device integrates the unit operations of size-based separation with CD63 antibody immunoaffinity-based capture of extracellular vesicles in the same device to evaluate EV-cargo content for liposarcoma. The eluted media collected showed ∼76% extracellular vesicle recovery from the liposarcoma cell conditioned media and ∼32% extracellular vesicle recovery from dedifferentiated liposarcoma patient serum when compared against state-of-art extracellular vesicle isolation and subsequent quantification by ultracentrifugation. The results reported here also show a five-fold increase in amount of critical liposarcoma-relevant extracellular vesicle cargo obtained in 30 min presenting a significant advance over existing state-of-art.
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http://dx.doi.org/10.1002/jev2.12062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887429PMC
February 2021

Coronary microcirculation damage in anthracycline cardiotoxicity.

Cardiovasc Res 2021 Feb 19. Epub 2021 Feb 19.

Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.

Aims: The aim of this study was to study changes in coronary microcirculation status during and after several cycles of anthracycline treatment.

Methods And Results: Large-White male pigs (n = 40) were included in different experimental protocols (ExPr.) according to anthracycline cumulative exposure (0.45 mg/kg intracoronary (IC) doxorubicin per injection) and follow-up: Control (no doxorubicin); Single injection and sacrifice either at 48 hours (ExPr. 1) or 2 weeks (ExPr. 2); Three injections two weeks apart (low cumulative dose) and sacrifice either 2 weeks (ExPr. 3) or 12 weeks (ExPr. 4) after third injection; Five injections two weeks apart (high cumulative dose) and sacrifice 8 weeks after fifth injection (ExPr. 5). All groups were assessed by serial cardiac magnetic resonance (CMR) to quantify perfusion and invasive measurement of coronary flow reserve (CFR). At the end of each protocol, animals were sacrificed for ex vivo analyses. Vascular function was further evaluated by myography in explanted coronary arteries of pigs undergoing ExPr. 3 and controls.A single doxorubicin injection had no impact on microcirculation status, excluding a direct chemical toxicity. A series of five fortnightly doxorubicin injections (high cumulative dose) triggered a progressive decline in microcirculation status, evidenced by reduced CMR-based myocardial perfusion and CFR-measured impaired functional microcirculation. In the high cumulative dose regime (ExPr. 5), microcirculation changes appeared long before any contractile defect became apparent. Low cumulative doxorubicin dose (3 biweekly injections) was not associated with any contractile defect across long-term follow-up, but provoked persistent microcirculation damage, evident soon after third dose injection. Histological and myograph evaluations confirmed structural damage to arteries of all calibers even in animals undergoing low cumulative dose regimes. Conversely, arteriole damage and capillary bed alteration occurred only after high cumulative dose regime.

Conclusion: Serial in vivo evaluations of microcirculation status using state-of-the-art CMR and invasive CFR show that anthracyclines treatment is associated with progressive and irreversible damage to the microcirculation. This long-persisting damage is present even in low cumulative dose regimes, which are not associated with cardiac contractile deficits. Microcirculation damage might explain some of the increased incidence of cardiovascular events in cancer survivors who received anthracyclines without showing cardiac contractile defects.
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http://dx.doi.org/10.1093/cvr/cvab053DOI Listing
February 2021

GAS7 Deficiency Promotes Metastasis in MYCN-driven Neuroblastoma.

Cancer Res 2021 Feb 18. Epub 2021 Feb 18.

Department of Biochemistry and Molecular Biology, Mayo Clinic

One of the greatest barriers to curative treatment of neuroblastoma (NB) is its frequent metastatic outgrowth prior to diagnosis, especially in cases driven by amplification of the MYCN oncogene. However, only a limited number of regulatory proteins that contribute to this complex MYCN-mediated process have been elucidated. Here we show that the growth arrest-specific 7 (GAS7) gene, located at chromosome band 17p13.1, is preferentially deleted in high-risk MYCN-driven NB. GAS7 expression was also suppressed in MYCN-amplified NB lacking 17p deletion. GAS7 deficiency led to accelerated metastasis in both zebrafish and mammalian models of NB with overexpression or amplification of MYCN. Analysis of expression profiles and the ultrastructure of zebrafish NB tumors with MYCN overexpression identified that GAS7 deficiency led to (i) downregulation of genes involved in cell-cell interaction, (ii) loss of contact among tumor cells as critical determinants of accelerated metastasis, and (iii) increased levels of MYCN protein. These results provide the first genetic evidence that GAS7 depletion is a critical early step in the cascade of events culminating in NB metastasis in the context of MYCN overexpression.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-1890DOI Listing
February 2021

CAR-T cell-mediated depletion of immunosuppressive tumor-associated macrophages promotes endogenous antitumor immunity and augments adoptive immunotherapy.

Nat Commun 2021 02 9;12(1):877. Epub 2021 Feb 9.

Department of Pathology and Laboratory Medicine, Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

The immunosuppressive tumor microenvironment (TME) represents a major barrier for effective immunotherapy. Tumor-associated macrophages (TAMs) are highly heterogeneous and plastic cell components of the TME which can either promote tumor progression (M2-like) or boost antitumor immunity (M1-like). Here, we demonstrate that a subset of TAMs that express folate receptor β (FRβ) possess an immunosuppressive M2-like profile. In syngeneic tumor mouse models, chimeric antigen receptor (CAR)-T cell-mediated selective elimination of FRβ TAMs in the TME results in an enrichment of pro-inflammatory monocytes, an influx of endogenous tumor-specific CD8 T cells, delayed tumor progression, and prolonged survival. Preconditioning of the TME with FRβ-specific CAR-T cells also improves the effectiveness of tumor-directed anti-mesothelin CAR-T cells, while simultaneous co-administration of both CAR products does not. These results highlight the pro-tumor role of FRβ TAMs in the TME and the therapeutic implications of TAM-depleting agents as preparative adjuncts to conventional immunotherapies that directly target tumor antigens.
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http://dx.doi.org/10.1038/s41467-021-20893-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873057PMC
February 2021

Multi-Layer Micro-Nanofluidic Device for Isolation and Capture of Extracellular Vesicles Derived from Liposarcoma Cell Conditioned Media.

J Microelectromech Syst 2020 Oct 14;29(5):776-782. Epub 2020 Jul 14.

Department of Mechanical and Aerospace Engineering and is also an affiliate of the Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210 USA.

We report on isolation, capture, and subsequent elution for analysis of extracellular vesicles derived from human liposarcoma cell conditioned media, using a multi-layer micro-nanofluidic device operated with tangential flow separation. Our device integrates size-based separation followed by immunoaffinity-based capture of extracellular vesicles in the same device. For liposarcomas, this is the first report on isolating, capturing, and then eluting the extracellular vesicles using a micro-nanofluidic device. The results show a significantly higher yield of the eluted extracellular vesicles (~84%) compared to the current methods of ultracentrifugation (~6%) and ExoQuick-based separations (~16%).
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http://dx.doi.org/10.1109/jmems.2020.3006786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839931PMC
October 2020

Cognitive functioning throughout adulthood and illness stages in individuals with psychotic disorders and their unaffected siblings.

Authors:
Eva Velthorst Josephine Mollon Robin M Murray Lieuwe de Haan Inez Myin Germeys David C Glahn Celso Arango Els van der Ven Marta Di Forti Miguel Bernardo Sinan Guloksuz Philippe Delespaul Gisela Mezquida Silvia Amoretti Julio Bobes Pilar A Saiz María Paz García-Portilla José Luis Santos Estela Jiménez-López Julio Sanjuan Eduardo J Aguilar Manuel Arrojo Angel Carracedo Gonzalo López Javier González-Peñas Mara Parellada Cem Atbaşoğlu Meram Can Saka Alp Üçok Köksal Alptekin Berna Akdede Tolga Binbay Vesile Altınyazar Halis Ulaş Berna Yalınçetin Güvem Gümüş-Akay Burçin Cihan Beyaz Haldun Soygür Eylem Şahin Cankurtaran Semra Ulusoy Kaymak Nadja P Maric Marina M Mihaljevic Sanja Andric Petrovic Tijana Mirjanic Cristina Marta Del-Ben Laura Ferraro Charlotte Gayer-Anderson Peter B Jones Hannah E Jongsma James B Kirkbride Caterina La Cascia Antonio Lasalvia Sarah Tosato Pierre-Michel Llorca Paulo Rossi Menezes Craig Morgan Diego Quattrone Marco Menchetti Jean-Paul Selten Andrei Szöke Ilaria Tarricone Andrea Tortelli Philip McGuire Lucia Valmaggia Matthew J Kempton Mark van der Gaag Anita Riecher-Rössler Rodrigo A Bressan Neus Barrantes-Vidal Barnaby Nelson Patrick McGorry Chris Pantelis Marie-Odile Krebs Stephan Ruhrmann Gabriele Sachs Bart P F Rutten Jim van Os Behrooz Z Alizadeh Therese van Amelsvoort Agna A Bartels-Velthuis Richard Bruggeman Nico J van Beveren Jurjen J Luykx Wiepke Cahn Claudia J P Simons Rene S Kahn Frederike Schirmbeck Ruud van Winkel Abraham Reichenberg

Mol Psychiatry 2021 Jan 7. Epub 2021 Jan 7.

Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Important questions remain about the profile of cognitive impairment in psychotic disorders across adulthood and illness stages. The age-associated profile of familial impairments also remains unclear, as well as the effect of factors, such as symptoms, functioning, and medication. Using cross-sectional data from the EU-GEI and GROUP studies, comprising 8455 participants aged 18 to 65, we examined cognitive functioning across adulthood in patients with psychotic disorders (n = 2883), and their unaffected siblings (n = 2271), compared to controls (n = 3301). An abbreviated WAIS-III measured verbal knowledge, working memory, visuospatial processing, processing speed, and IQ. Patients showed medium to large deficits across all functions (ES range = -0.45 to -0.73, p < 0.001), while siblings showed small deficits on IQ, verbal knowledge, and working memory (ES = -0.14 to -0.33, p < 0.001). Magnitude of impairment was not associated with participant age, such that the size of impairment in older and younger patients did not significantly differ. However, first-episode patients performed worse than prodromal patients (ES range = -0.88 to -0.60, p < 0.001). Adjusting for cannabis use, symptom severity, and global functioning attenuated impairments in siblings, while deficits in patients remained statistically significant, albeit reduced by half (ES range = -0.13 to -0.38, p < 0.01). Antipsychotic medication also accounted for around half of the impairment in patients (ES range = -0.21 to -0.43, p < 0.01). Deficits in verbal knowledge, and working memory may specifically index familial, i.e., shared genetic and/or shared environmental, liability for psychotic disorders. Nevertheless, potentially modifiable illness-related factors account for a significant portion of the cognitive impairment in psychotic disorders.
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http://dx.doi.org/10.1038/s41380-020-00969-zDOI Listing
January 2021

[Limitation of medical liability during the coronavirus pandemic].

Rev Med Chil 2020 08;148(8):1221-1223

Observatorio de Bioética y Derecho, ICIM, Facultad de Medicina Clínica Alemana Universidad del Desarrollo, Santiago, Chile.

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http://dx.doi.org/10.4067/S0034-98872020000801221DOI Listing
August 2020

Integrated Proteogenomic Characterization across Major Histological Types of Pediatric Brain Cancer.

Cell 2020 Dec 25;183(7):1962-1985.e31. Epub 2020 Nov 25.

Department of Genetics and Genomic Sciences and Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address:

We report a comprehensive proteogenomics analysis, including whole-genome sequencing, RNA sequencing, and proteomics and phosphoproteomics profiling, of 218 tumors across 7 histological types of childhood brain cancer: low-grade glioma (n = 93), ependymoma (32), high-grade glioma (25), medulloblastoma (22), ganglioglioma (18), craniopharyngioma (16), and atypical teratoid rhabdoid tumor (12). Proteomics data identify common biological themes that span histological boundaries, suggesting that treatments used for one histological type may be applied effectively to other tumors sharing similar proteomics features. Immune landscape characterization reveals diverse tumor microenvironments across and within diagnoses. Proteomics data further reveal functional effects of somatic mutations and copy number variations (CNVs) not evident in transcriptomics data. Kinase-substrate association and co-expression network analysis identify important biological mechanisms of tumorigenesis. This is the first large-scale proteogenomics analysis across traditional histological boundaries to uncover foundational pediatric brain tumor biology and inform rational treatment selection.
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http://dx.doi.org/10.1016/j.cell.2020.10.044DOI Listing
December 2020

Evidence, and replication thereof, that molecular-genetic and environmental risks for psychosis impact through an affective pathway.

Psychol Med 2020 Oct 19:1-13. Epub 2020 Oct 19.

Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University Medical Centre, Maastricht, The Netherlands.

Background: There is evidence that environmental and genetic risk factors for schizophrenia spectrum disorders are transdiagnostic and mediated in part through a generic pathway of affective dysregulation.

Methods: We analysed to what degree the impact of schizophrenia polygenic risk (PRS-SZ) and childhood adversity (CA) on psychosis outcomes was contingent on co-presence of affective dysregulation, defined as significant depressive symptoms, in (i) NEMESIS-2 (n = 6646), a representative general population sample, interviewed four times over nine years and (ii) EUGEI (n = 4068) a sample of patients with schizophrenia spectrum disorder, the siblings of these patients and controls.

Results: The impact of PRS-SZ on psychosis showed significant dependence on co-presence of affective dysregulation in NEMESIS-2 [relative excess risk due to interaction (RERI): 1.01, p = 0.037] and in EUGEI (RERI = 3.39, p = 0.048). This was particularly evident for delusional ideation (NEMESIS-2: RERI = 1.74, p = 0.003; EUGEI: RERI = 4.16, p = 0.019) and not for hallucinatory experiences (NEMESIS-2: RERI = 0.65, p = 0.284; EUGEI: -0.37, p = 0.547). A similar and stronger pattern of results was evident for CA (RERI delusions and hallucinations: NEMESIS-2: 3.02, p < 0.001; EUGEI: 6.44, p < 0.001; RERI delusional ideation: NEMESIS-2: 3.79, p < 0.001; EUGEI: 5.43, p = 0.001; RERI hallucinatory experiences: NEMESIS-2: 2.46, p < 0.001; EUGEI: 0.54, p = 0.465).

Conclusions: The results, and internal replication, suggest that the effects of known genetic and non-genetic risk factors for psychosis are mediated in part through an affective pathway, from which early states of delusional meaning may arise.
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http://dx.doi.org/10.1017/S0033291720003748DOI Listing
October 2020

Svpluscnv: analysis and visualization of complex structural variation data.

Bioinformatics 2020 Oct 14. Epub 2020 Oct 14.

Genetics and Genomics Sciences, Icahn School of Medicine, New York, USA.

Motivation: Despite widespread prevalence of somatic structural variations (SV) across most tumor types, understanding of their molecular implications often remains poor. SVs are extremely heterogeneous in size and complexity, hindering the interpretation of their pathogenic role. Tools integrating large SV datasets across platforms are required to fully characterize the cancer's somatic landscape.

Results: svpluscnv R package is a swiss army knife for the integration and interpretation of orthogonal datasets including copy number variant (CNV) segmentation profiles and sequencing-based structural variant calls (SVC). The package implements analysis and visualization tools to evaluate chromosomal instability and ploidy, identify genes harboring recurrent SVs and detects complex rearrangements such as chromothripsis and chromoplexia. Further, it allows systematic identification of hot-spot shattered genomic regions, showing reproducibility across alternative detection methods and datasets.

Availability: https://github.com/ccbiolab/svpluscnv.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btaa878DOI Listing
October 2020

A replication study of JTC bias, genetic liability for psychosis and delusional ideation.

Psychol Med 2020 Oct 13:1-7. Epub 2020 Oct 13.

Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University Medical Centre, Maastricht, the Netherlands.

Background: This study attempted to replicate whether a bias in probabilistic reasoning, or 'jumping to conclusions'(JTC) bias is associated with being a sibling of a patient with schizophrenia spectrum disorder; and if so, whether this association is contingent on subthreshold delusional ideation.

Methods: Data were derived from the EUGEI project, a 25-centre, 15-country effort to study psychosis spectrum disorder. The current analyses included 1261 patients with schizophrenia spectrum disorder, 1282 siblings of patients and 1525 healthy comparison subjects, recruited in Spain (five centres), Turkey (three centres) and Serbia (one centre). The beads task was used to assess JTC bias. Lifetime experience of delusional ideation and hallucinatory experiences was assessed using the Community Assessment of Psychic Experiences. General cognitive abilities were taken into account in the analyses.

Results: JTC bias was positively associated not only with patient status but also with sibling status [adjusted relative risk (aRR) ratio : 4.23 CI 95% 3.46-5.17 for siblings and aRR: 5.07 CI 95% 4.13-6.23 for patients]. The association between JTC bias and sibling status was stronger in those with higher levels of delusional ideation (aRR interaction in siblings: 3.77 CI 95% 1.67-8.51, and in patients: 2.15 CI 95% 0.94-4.92). The association between JTC bias and sibling status was not stronger in those with higher levels of hallucinatory experiences.

Conclusions: These findings replicate earlier findings that JTC bias is associated with familial liability for psychosis and that this is contingent on the degree of delusional ideation but not hallucinations.
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http://dx.doi.org/10.1017/S0033291720003578DOI Listing
October 2020

Somatic structural variation targets neurodevelopmental genes and identifies as a tumor suppressor in neuroblastoma.

Genome Res 2020 09 13;30(9):1228-1242. Epub 2020 Aug 13.

Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.

Neuroblastoma is a malignancy of the developing sympathetic nervous system that accounts for 12% of childhood cancer deaths. Like many childhood cancers, neuroblastoma shows a relative paucity of somatic single-nucleotide variants (SNVs) and small insertions and deletions (indels) compared to adult cancers. Here, we assessed the contribution of somatic structural variation (SV) in neuroblastoma using a combination of whole-genome sequencing (WGS) of tumor-normal pairs ( = 135) and single-nucleotide polymorphism (SNP) genotyping of primary tumors ( = 914). Our study design allowed for orthogonal validation and replication across platforms. SV frequency, type, and localization varied significantly among high-risk tumors. nonamplified high-risk tumors harbored an increased SV burden overall, including a significant excess of tandem duplication events across the genome. Genes disrupted by SV breakpoints were enriched in neuronal lineages and associated with phenotypes such as autism spectrum disorder (ASD). The postsynaptic adapter protein-coding gene, , located on Chromosome 11q13, was disrupted by SVs in 14% of nonamplified high-risk tumors based on WGS and 10% in the SNP array cohort. Expression of was low across human-derived neuroblastoma cell lines and high-risk neuroblastoma tumors. Forced expression of in neuroblastoma cells resulted in significant growth inhibition ( = 2.6 × 10 to 3.4 × 10) and accelerated neuronal differentiation following treatment with all- retinoic acid ( = 3.1 × 10 to 2.4 × 10). These data further define the complex landscape of somatic structural variation in neuroblastoma and suggest that events leading to deregulation of neurodevelopmental processes, such as inactivation of , are key mediators of tumorigenesis in this childhood cancer.
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http://dx.doi.org/10.1101/gr.252106.119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545140PMC
September 2020

β-catenin S45F mutation results in apoptotic resistance.

Oncogene 2020 08 10;39(34):5589-5600. Epub 2020 Jul 10.

Program in Translational Therapeutics, The James Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA.

Wnt/β-catenin signaling is one of the key cascades regulating embryogenesis and tissue homeostasis; it has also been intimately associated with carcinogenesis. This pathway is deregulated in several tumors, including colorectal cancer, breast cancer, and desmoid tumors. It has been shown that CTNNB1 exon 3 mutations are associated with an aggressive phenotype in several of these tumor types and may be associated with therapeutic tolerance. Desmoid tumors typically have a stable genome with β-catenin mutations as a main feature, making these tumors an ideal model to study the changes associated with different types of β-catenin mutations. Here, we show that the apoptosis mechanism is deregulated in β-catenin S45F mutants, resulting in decreased induction of apoptosis in these cells. Our findings also demonstrate that RUNX3 plays a pivotal role in the inhibition of apoptosis found in the β-catenin S45F mutants. Restoration of RUNX3 overcomes this inhibition in the S45F mutants, highlighting it as a potential therapeutic target for malignancies harboring this specific CTNNB1 mutation. While the regulatory effect of RUNX3 in β-catenin is already known, our results suggest the possibility of a feedback loop involving these two genes, with the CTNNB1 S45F mutation downregulating expression of RUNX3, thus providing additional possible novel therapeutic targets for tumors having deregulated Wnt/β-catenin signaling induced by this mutation.
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http://dx.doi.org/10.1038/s41388-020-1382-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7441052PMC
August 2020

Remote ischaemic preconditioning ameliorates anthracycline-induced cardiotoxicity and preserves mitochondrial integrity.

Cardiovasc Res 2021 Mar;117(4):1132-1143

Translational Laboratory for Cardiovascular Imaging and Therapy, Centro Nacional de Investigaciones Cardiovasculares (CNIC), c/Melchor Fernandez Almagro, 3. 28029 Madrid, Spain.

Aims: Anthracycline-induced cardiotoxicity (AIC) is a serious adverse effect among cancer patients. A central mechanism of AIC is irreversible mitochondrial damage. Despite major efforts, there are currently no effective therapies able to prevent AIC.

Methods And Results: Forty Large-White pigs were included. In Study 1, 20 pigs were randomized 1:1 to remote ischaemic preconditioning (RIPC, 3 cycles of 5 min leg ischaemia followed by 5 min reperfusion) or no pretreatment. RIPC was performed immediately before each intracoronary doxorubicin injections (0.45 mg/kg) given at Weeks 0, 2, 4, 6, and 8. A group of 10 pigs with no exposure to doxorubicin served as healthy controls. Pigs underwent serial cardiac magnetic resonance (CMR) exams at baseline and at Weeks 6, 8, 12, and 16, being sacrifice after that. In Study 2, 10 new pigs received 3 doxorubicin injections (with/out preceding RIPC) and were sacrificed at week 6. In Study 1, left ventricular ejection fraction (LVEF) depression was blunted animals receiving RIPC before doxorubicin (RIPC-Doxo), which had a significantly higher LVEF at Week 16 than doxorubicin treated pigs that received no pretreatment (Untreated-Doxo) (41.5 ± 9.1% vs. 32.5 ± 8.7%, P = 0.04). It was mainly due to conserved regional contractile function. In Study 2, transmission electron microscopy (TEM) at Week 6 showed fragmented mitochondria with severe morphological abnormalities in Untreated-Doxo pigs, together with upregulation of fission and autophagy proteins. At the end of the 16-week Study 1 protocol, TEM revealed overt mitochondrial fragmentation with structural fragmentation in Untreated-Doxo pigs, whereas interstitial fibrosis was less severe in RIPC+Doxo pigs.

Conclusion: In a translatable large-animal model of AIC, RIPC applied immediately before each doxorubicin injection resulted in preserved cardiac contractility with significantly higher long-term LVEF and less cardiac fibrosis. RIPC prevented mitochondrial fragmentation and dysregulated autophagy from AIC early stages. RIPC is a promising intervention for testing in clinical trials in AIC.
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http://dx.doi.org/10.1093/cvr/cvaa181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983009PMC
March 2021

Intrauterine therapy with ozone reduces subclinical endometritis and improves reproductive performance in postpartum dairy cows managed in pasture-based systems.

Trop Anim Health Prod 2020 Sep 22;52(5):2523-2528. Epub 2020 May 22.

Instituto Nacional de Investigación Agropecuaria (INIA), Ruta 50 km 11.5, Colonia del Sacramento, Uruguay.

New postpartum strategies have been developed in dairy cows to ameliorate uterine health and reproductive performance, especially the first service conception rates. This study aimed to assess the effect of intrauterine therapy with ozone (IUTO) in early postpartum on subclinical endometritis prevalence and reproductive parameters in dairy cows under commercial farm conditions. For this purpose, eighty clinically healthy cows with a body condition score between 3.0 and 3.5, from four dairy farms, were randomly allocated into two groups: ozone therapy group (OG, n = 40), which were subjected to IUTO, and control group (CG, n = 40). Content of uterine polymorphonuclear (PMN) leukocytes and subclinical endometritis (SE) percentage were assessed at 35 days after calving by uterine cytology. A second cytology was performed 72 h after IUTO. Reproductive parameters such as interval calving to first service (IFS), number of services per conception (nSC), interval calving to conception (ICC) and first service conception rate (FSCR) were analysed. The second endometrial cytology demonstrated that IUTO reduced (P < 0.01) both PMN (3.7 ± 1.4 vs. 7.6 ± 1.1%) and SE (5.0 vs. 50.0%) percentages compared with CG. Likewise, after ozone treatment, both nSC (2.1 ± 0.3 vs. 3.1 ± 0.2; P < 0.01) and ICC (126.2 ± 9.7 vs. 149.0 ± 9.0; P = 0.0672) decreased, and FSCR increased (50.0 vs. 16.2%; P < 0.01) compared with CG. In conclusion, intrauterine ozone therapy applied at 35 days after calving reduced subclinical endometritis prevalence and improved reproductive performance in postpartum dairy cows managed in a pasture-based system.
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http://dx.doi.org/10.1007/s11250-020-02298-3DOI Listing
September 2020

Enhancing Antitumor Efficacy of Heavily Vascularized Tumors by RAMBO Virus through Decreased Tumor Endothelial Cell Activation.

Cancers (Basel) 2020 Apr 23;12(4). Epub 2020 Apr 23.

Department of Neurosurgery, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.

Vascularization is a common pathology for many solid tumors, and therefore anti-angiogenic strategies are being investigated as a therapeutic target for treatment. Numerous studies are also being conducted regarding the effects of oncolytic viruses, including Imlygic, an FDA approved oncolytic herpes simplex virus-1 (oHSV) for the treatment of highly vascularized tumors such as Kaposi sarcoma (NCT04065152), and brain tumors. To our knowledge, the effects of combining oncolytic HSV with angiogenesis inhibition on endothelial cell activation has not been previously described. Here, we tested the effects of Rapid Antiangiogenesis Mediated By Oncolytic Virus (RAMBO), an oHSV which expresses a potent anti-angiogenic gene on endothelial cell activation in heavily vascularized solid tumors. oHSV treatment induces endothelial cell activation, which inhibits virus propagation and oncolysis in adjacent tumor cells in vitro. Consistently, this was also observed in intravital imaging of intracranial tumor-bearing mice in vivo where infected tumor endothelial cells could efficiently clear the virus without cell lysis. Quantitative real-time PCR (Q-PCR), leukocyte adhesion assay, and fluorescent microscopy imaging data, however, revealed that RAMBO virus significantly decreased expression of endothelial cell activation markers and leukocyte adhesion, which in turn increased virus replication and cytotoxicity in endothelial cells. In vivo RAMBO treatment of subcutaneously implanted sarcoma tumors significantly reduced tumor growth in mice bearing sarcoma compared to rHSVQ. In addition, histological analysis of RAMBO-treated tumor tissues revealed large areas of necrosis and a statistically significant reduction in microvessel density (MVD). This study provides strong preclinical evidence of the therapeutic benefit for the use of RAMBO virus as a treatment option for highly vascularized tumors.
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http://dx.doi.org/10.3390/cancers12041040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7225935PMC
April 2020

Novel Indices of Coronary Physiology: Do We Need Alternatives to Fractional Flow Reserve?

Circ Cardiovasc Interv 2020 04 16;13(4):e008487. Epub 2020 Apr 16.

MedStar Washington Hospital Centre, Interventional Cardiology Department, Washington, DC (Y.O., H.M.G.-G., A.H.-K., E.S., K.D., R.W.).

Fractional flow reserve is the current invasive gold standard for assessing the ischemic potential of an angiographically intermediate coronary stenosis. Procedural cost and time, the need for coronary vessel instrumentation, and the need to administer adenosine to achieve maximal hyperemia remain integral components of invasive fractional flow reserve. The number of new alternatives to fractional flow reserve has proliferated over the last ten years using techniques ranging from alternative pressure wire metrics to anatomic simulation via angiography or intravascular imaging. This review article provides a critical description of the currently available or under-development alternatives to fractional flow reserve with a special focus on the available evidence, pros, and cons for each with a view towards their clinical application in the near future for the functional assessment of coronary artery disease.
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http://dx.doi.org/10.1161/CIRCINTERVENTIONS.119.008487DOI Listing
April 2020

Translational large animal model of hibernating myocardium: characterization by serial multimodal imaging.

Basic Res Cardiol 2020 04 14;115(3):33. Epub 2020 Apr 14.

Translational Laboratory for Cardiovascular Imaging and Therapy, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), C/ Melchor Fernandez Almagro 3, Madrid, 28029, Spain.

Nonrevascularizable coronary artery disease is a frequent cause of hibernating myocardium leading to heart failure (HF). Currently, there is a paucity of therapeutic options for patients with this condition. There is a lack of animal models resembling clinical features of hibernating myocardium. Here we present a large animal model of hibernating myocardium characterized by serial multimodality imaging. Yucatan minipigs underwent a surgical casein ameroid implant around the proximal left anterior descending coronary artery (LAD), resulting in a progressive obstruction of the vessel. Pigs underwent serial multimodality imaging including invasive coronary angiography, cardiac magnetic resonance (CMR), and hybrid F-Fluorodeoxyglucose positron emission tomography-computed tomography (FDG-PET/CT). A total of 43 pigs were operated on and were followed for 120 ± 37 days with monthly multimodality imaging. 24 pigs (56%) died during the follow-up. Severe LAD luminal stenosis was documented in all survivors. In the group of 19 long-term survivors, 17 (90%) developed left ventricular systolic dysfunction [median LVEF of 35% (IQR 32.5-40.5%)]. In 17/17, at-risk territory was viable on CMR and 14 showed an increased glucose uptake in the at-risk myocardium on FDG-PET/CT. The present pig model resembles most of the human hibernated myocardium characteristics and associated heart failure (systolic dysfunction, viable myocardium, and metabolic switch to glucose). This human-like model might be used to test novel interventions for nonrevascularizable coronary artery disease and ischemia heart failure as a previous stage to clinical trials.
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http://dx.doi.org/10.1007/s00395-020-0788-0DOI Listing
April 2020

Telomere Maintenance Mechanisms Define Clinical Outcome in High-Risk Neuroblastoma.

Cancer Res 2020 06 14;80(12):2663-2675. Epub 2020 Apr 14.

Cancer Center and Department of Pediatrics, School of Medicine, Texas Tech University Health Sciences Center School of Medicine, Texas.

Neuroblastoma is a childhood cancer with heterogeneous clinical outcomes. To comprehensively assess the impact of telomere maintenance mechanism (TMM) on clinical outcomes in high-risk neuroblastoma, we integrated the C-circle assay [a marker for alternative lengthening of telomeres (ALT)], TERT mRNA expression by RNA-sequencing, whole-genome/exome sequencing, and clinical covariates in 134 neuroblastoma patient samples at diagnosis. In addition, we assessed TMM in neuroblastoma cell lines ( = 104) and patient-derived xenografts ( = 28). ALT was identified in 23.4% of high-risk neuroblastoma tumors and genomic alterations in were detected in 60% of ALT tumors; 40% of ALT tumors lacked genomic alterations in known ALT-associated genes. Patients with high-risk neuroblastoma were classified into three subgroups (TERT-high, ALT, and TERT-low/non-ALT) based on presence of C-circles and TERT mRNA expression (above or below median TERT expression). Event-free survival was similar among TERT-high, ALT, or TERT-low/non-ALT patients. However, overall survival (OS) for TERT-low/non-ALT patients was significantly higher relative to TERT-high or ALT patients (log-rank test; < 0.01) independent of current clinical and molecular prognostic markers. Consistent with the observed higher OS in patients with TERT-low/non-ALT tumors, continuous shortening of telomeres and decreasing viability occurred in low TERT-expressing, non-ALT patient-derived high-risk neuroblastoma cell lines. These findings demonstrate that assaying TMM with TERT mRNA expression and C-circles provides precise stratification of high-risk neuroblastoma into three subgroups with substantially different OS: a previously undescribed TERT-low/non-ALT cohort with superior OS (even after relapse) and two cohorts of patients with poor survival that have distinct molecular therapeutic targets. SIGNIFICANCE: These findings assess telomere maintenance mechanisms with TERT mRNA and the ALT DNA biomarker C-circles to stratify neuroblastoma into three groups, with distinct overall survival independent of currently used clinical risk classifiers.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-3068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7313726PMC
June 2020

R2 prime (R2') magnetic resonance imaging for post-myocardial infarction intramyocardial haemorrhage quantification.

Eur Heart J Cardiovasc Imaging 2020 09;21(9):1031-1038

Translational Laboratory for Cardiovascular Imaging and Therapy, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.

Aims: To assess whether R2* is more accurate than T2* for the detection of intramyocardial haemorrhage (IMH) and to evaluate whether T2' (or R2') is less affected by oedema than T2* (R2*), and thus more suitable for the accurate identification of post-myocardial infarction (MI) IMH.

Methods And Results: Reperfused anterior MI was performed in 20 pigs, which were sacrificed at 120 min, 24 h, 4 days, and 7 days. At each time point, cardiac magnetic resonance (CMR) T2- and T2*-mapping scans were recorded, and myocardial tissue samples were collected to quantify IMH and myocardial water content. After normalization by the number of red blood cells in remote tissue, histological IMH increased 5.2-fold, 10.7-fold, and 4.1-fold at Days 1, 4, and 7, respectively. The presence of IMH was correlated more strongly with R2* (r = 0.69; P = 0.013) than with T2* (r = -0.50; P = 0.085). The correlation with IMH was even stronger for R2' (r = 0.72; P = 0.008). For myocardial oedema, the correlation was stronger for R2* (r = -0.63; P = 0.029) than for R2' (r = -0.50; P = 0.100). Multivariate linear regressions confirmed that R2* values were significantly explained by both IMH and oedema, whereas R2' values were mostly explained by histological IMH (P = 0.024) and were little influenced by myocardial oedema (P = 0.262).

Conclusion: Using CMR mapping with histological validation in a pig model of reperfused MI, R2'more accurately detected IMH and was less influenced by oedema than R2* (and T2*). Further studies are needed to elucidate whether R2' is also better suited for the characterization of post-MI IMH in the clinical setting.
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http://dx.doi.org/10.1093/ehjci/jez306DOI Listing
September 2020

Role of Tau Protein in Remodeling of Circadian Neuronal Circuits and Sleep.

Front Aging Neurosci 2019 21;11:320. Epub 2019 Nov 21.

Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, United States.

Multiple neurological, physiological, and behavioral functions are synchronized by circadian clocks into daily rhythms. Neurodegenerative diseases such as Alzheimer's disease and related tauopathies are associated with a decay of circadian rhythms, disruption of sleep patterns, and impaired cognitive function but the mechanisms underlying these alterations are still unclear. Traditional approaches in neurodegeneration research have focused on understanding how pathology impinges on circadian function. Since in Alzheimer's disease and related tauopathies tau proteostasis is compromised, here we sought to understand the role of tau protein in neuronal circadian biology and related behavior. Considering molecular mechanisms underlying circadian rhythms are conserved from to humans, here we took advantage of a recently developed tau-deficient line to show that loss of tau promotes dysregulation of daily circadian rhythms and sleep patterns. Strikingly, tau deficiency dysregulates the structural plasticity of the small ventral lateral circadian pacemaker neurons by disrupting the temporal cytoskeletal remodeling of its dorsal axonal projections and by inducing a slight increase in the cytoplasmic accumulation of core clock proteins. Taken together, these results suggest that loss of tau function participates in the regulation of circadian rhythms by modulating the correct operation and connectivity of core circadian networks and related behavior.
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http://dx.doi.org/10.3389/fnagi.2019.00320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6881280PMC
November 2019

A longitudinal comparison of two neurocognitive test batteries in patients with schizophrenia and healthy volunteers: Time effects on neuropsychological performance and their relation to functional outcome.

Schizophr Res 2020 02 6;216:347-356. Epub 2019 Dec 6.

Department of Child and Adolescent Psychiatry, Institute of Psychiatry and Mental Health, Hospital General Universitario Gregorio Marañón, School of Medicine, Universidad Complutense, IiSGM, CIBERSAM, Madrid, Spain; Melbourne Neuropsychiatry Centre, Department of Psychiatry, University of Melbourne & Melbourne Health, Victoria, Australia.

Cognitive impairment is a major unmet need in the treatment of schizophrenia. Over the last decade, the MATRICS Consensus Cognitive Battery (MCCB) has been used to assess the effects of novel treatments for cognitive impairment in schizophrenia. However, other cognitive-neuroscience-based cognitive batteries, such as the Cambridge Neuropsychological Test Automated Battery (CANTAB) have been suggested as an alternative to the MCCB. Although both batteries purport to assess cognitive function in psychosis, no previous study has attempted to examine their validity longitudinally and the potential overlap between the two batteries over time. The aim of the current study was to assess the relationship between the MCCB and the CANTAB in the longitudinal assessment of cognitive impairment in schizophrenia. A sample of 39 stable schizophrenia outpatients and 18 controls completed the MCCB and the CANTAB battery at baseline, and at 2, 4 and 8-weeks follow-up. Correlation analyses and a mixed-model repeated measures approach were used. We found no significant effect of time in the MCCB. In contrast, for the CANTAB a significant effect of time consistent with practice effects for the attention domain in the control group and for the visual learning, reasoning and problem-solving, and social cognition domains in patients, with subjects performing better at follow-up. In particular, a significant time ∗ battery interaction was found for those cognitive domains. These findings suggest there are specific differences across cognitive tests to assess cognitive impairments in schizophrenia and that measures derived from the CANTAB appear to be more prone to practice effects in these patients.
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http://dx.doi.org/10.1016/j.schres.2019.11.018DOI Listing
February 2020

Genomic Profiling of Childhood Tumor Patient-Derived Xenograft Models to Enable Rational Clinical Trial Design.

Cell Rep 2019 11;29(6):1675-1689.e9

Division of Oncology, Children's Hospital of Philadelphia, and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104-4318, USA. Electronic address:

Accelerating cures for children with cancer remains an immediate challenge as a result of extensive oncogenic heterogeneity between and within histologies, distinct molecular mechanisms evolving between diagnosis and relapsed disease, and limited therapeutic options. To systematically prioritize and rationally test novel agents in preclinical murine models, researchers within the Pediatric Preclinical Testing Consortium are continuously developing patient-derived xenografts (PDXs)-many of which are refractory to current standard-of-care treatments-from high-risk childhood cancers. Here, we genomically characterize 261 PDX models from 37 unique pediatric cancers; demonstrate faithful recapitulation of histologies and subtypes; and refine our understanding of relapsed disease. In addition, we use expression signatures to classify tumors for TP53 and NF1 pathway inactivation. We anticipate that these data will serve as a resource for pediatric oncology drug development and will guide rational clinical trial design for children with cancer.
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http://dx.doi.org/10.1016/j.celrep.2019.09.071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6880934PMC
November 2019

White Noise Speech Illusions: A Trait-Dependent Risk Marker for Psychotic Disorder?

Front Psychiatry 2019 25;10:676. Epub 2019 Sep 25.

Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University Medical Center, Maastricht, Netherlands.

White noise speech illusions index liability for psychotic disorder in case-control comparisons. In the current study, we examined i) the rate of white noise speech illusions in siblings of patients with psychotic disorder and ii) to what degree this rate would be contingent on exposure to known environmental risk factors (childhood adversity and recent life events) and level of known endophenotypic dimensions of psychotic disorder [psychotic experiences assessed with the Community Assessment of Psychic Experiences (CAPE) scale and cognitive ability]. The white noise task was used as an experimental paradigm to elicit and measure speech illusions in 1,014 patients with psychotic disorders, 1,157 siblings, and 1,507 healthy participants. We examined associations between speech illusions and increasing familial risk (control -> sibling -> patient), modeled as both a linear and a categorical effect, and associations between speech illusions and level of childhood adversities and life events as well as with CAPE scores and cognitive ability scores. While a positive association was found between white noise speech illusions across hypothesized increasing levels of familial risk (controls -> siblings -> patients) [odds ratio (OR) linear 1.11, 95% confidence interval (CI) 1.02-1.21, = 0.019], there was no evidence for a categorical association with sibling status (OR 0.93, 95% CI 0.79-1.09, = 0.360). The association between speech illusions and linear familial risk was greater if scores on the CAPE positive scale were higher ( interaction = 0.003; OR 0.96, 95% CI 0.85-1.07; OR 1.26, 95% CI 1.09-1.46); cognitive ability was lower ( interaction < 0.001; OR 0.94, 95% CI 0.84-1.05; OR 1.43, 95% CI 1.23-1.68); and exposure to childhood adversity was higher ( interaction < 0.001; OR 0.92, 95% CI 0.82-1.04; OR 1.31, 95% CI 1.13-1.52). A similar, although less marked, pattern was seen for categorical patient-control and sibling-control comparisons. Exposure to recent life events did not modify the association between white noise and familial risk ( interaction = 0.232). The association between white noise speech illusions and familial risk is contingent on additional evidence of endophenotypic expression and of exposure to childhood adversity. Therefore, speech illusions may represent a trait-dependent risk marker.
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http://dx.doi.org/10.3389/fpsyt.2019.00676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6774265PMC
September 2019

Estimating Exposome Score for Schizophrenia Using Predictive Modeling Approach in Two Independent Samples: The Results From the EUGEI Study.

Schizophr Bull 2019 09;45(5):960-965

Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University Medical Center, Maastricht, The Netherlands.

Exposures constitute a dense network of the environment: exposome. Here, we argue for embracing the exposome paradigm to investigate the sum of nongenetic "risk" and show how predictive modeling approaches can be used to construct an exposome score (ES; an aggregated score of exposures) for schizophrenia. The training dataset consisted of patients with schizophrenia and controls, whereas the independent validation dataset consisted of patients, their unaffected siblings, and controls. Binary exposures were cannabis use, hearing impairment, winter birth, bullying, and emotional, physical, and sexual abuse along with physical and emotional neglect. We applied logistic regression (LR), Gaussian Naive Bayes (GNB), the least absolute shrinkage and selection operator (LASSO), and Ridge penalized classification models to the training dataset. ESs, the sum of weighted exposures based on coefficients from each model, were calculated in the validation dataset. In addition, we estimated ES based on meta-analyses and a simple sum score of exposures. Accuracy, sensitivity, specificity, area under the receiver operating characteristic, and Nagelkerke's R2 were compared. The ESMeta-analyses performed the worst, whereas the sum score and the ESGNB were worse than the ESLR that performed similar to the ESLASSO and ESRIDGE. The ESLR distinguished patients from controls (odds ratio [OR] = 1.94, P < .001), patients from siblings (OR = 1.58, P < .001), and siblings from controls (OR = 1.21, P = .001). An increase in ESLR was associated with a gradient increase of schizophrenia risk. In reference to the remaining fractions, the ESLR at top 30%, 20%, and 10% of the control distribution yielded ORs of 3.72, 3.74, and 4.77, respectively. Our findings demonstrate that predictive modeling approaches can be harnessed to evaluate the exposome.
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http://dx.doi.org/10.1093/schbul/sbz054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6737483PMC
September 2019

Germline 16p11.2 Microdeletion Predisposes to Neuroblastoma.

Am J Hum Genet 2019 09 29;105(3):658-668. Epub 2019 Aug 29.

Cell and Molecular Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Division of Oncology, Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Genomics and Computational Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address:

Neuroblastoma is a cancer of the developing sympathetic nervous system. It is diagnosed in 600-700 children per year in the United States and accounts for 12% of pediatric cancer deaths. Despite recent advances in our understanding of this malignancy's complex genetic architecture, the contribution of rare germline variants remains undefined. Here, we conducted a genome-wide analysis of large (>500 kb), rare (<1%) germline copy number variants (CNVs) in two independent, multi-ethnic cohorts totaling 5,585 children with neuroblastoma and 23,505 cancer-free control children. We identified a 550-kb deletion on chromosome 16p11.2 significantly enriched in neuroblastoma cases (0.39% of cases and 0.03% of controls; p = 3.34 × 10). Notably, this CNV corresponds to a known microdeletion syndrome that affects approximately one in 3,000 children and confers risk for diverse developmental phenotypes including autism spectrum disorder and other neurodevelopmental disorders. The CNV had a substantial impact on neuroblastoma risk, with an odds ratio of 13.9 (95% confidence interval = 5.8-33.4). The association remained significant when we restricted our analysis to individuals of European ancestry in order to mitigate potential confounding by population stratification (0.42% of cases and 0.03% of controls; p = 4.10 × 10). We used whole-genome sequencing (WGS) to validate the deletion in paired germline and tumor DNA from 12 cases. Finally, WGS of four parent-child trios revealed that the deletion primarily arose de novo without maternal or paternal bias. This finding expands the clinical phenotypes associated with 16p11.2 microdeletion syndrome to include cancer, and it suggests that disruption of the 16p11.2 region may dysregulate neurodevelopmental pathways that influence both neurological phenotypes and neuroblastoma.
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http://dx.doi.org/10.1016/j.ajhg.2019.07.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6731370PMC
September 2019

Replicated evidence that endophenotypic expression of schizophrenia polygenic risk is greater in healthy siblings of patients compared to controls, suggesting gene-environment interaction. The EUGEI study.

Psychol Med 2020 08 15;50(11):1884-1897. Epub 2019 Aug 15.

Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University Medical Center, Maastricht, the Netherlands.

Background: First-degree relatives of patients with psychotic disorder have higher levels of polygenic risk (PRS) for schizophrenia and higher levels of intermediate phenotypes.

Methods: We conducted, using two different samples for discovery (n = 336 controls and 649 siblings of patients with psychotic disorder) and replication (n = 1208 controls and 1106 siblings), an analysis of association between PRS on the one hand and psychopathological and cognitive intermediate phenotypes of schizophrenia on the other in a sample at average genetic risk (healthy controls) and a sample at higher than average risk (healthy siblings of patients). Two subthreshold psychosis phenotypes, as well as a standardised measure of cognitive ability, based on a short version of the WAIS-III short form, were used. In addition, a measure of jumping to conclusion bias (replication sample only) was tested for association with PRS.

Results: In both discovery and replication sample, evidence for an association between PRS and subthreshold psychosis phenotypes was observed in the relatives of patients, whereas in the controls no association was observed. Jumping to conclusion bias was similarly only associated with PRS in the sibling group. Cognitive ability was weakly negatively and non-significantly associated with PRS in both the sibling and the control group.

Conclusions: The degree of endophenotypic expression of schizophrenia polygenic risk depends on having a sibling with psychotic disorder, suggestive of underlying gene-environment interaction. Cognitive biases may better index genetic risk of disorder than traditional measures of neurocognition, which instead may reflect the population distribution of cognitive ability impacting the prognosis of psychotic disorder.
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http://dx.doi.org/10.1017/S003329171900196XDOI Listing
August 2020

Derived from Dedifferentiated Liposarcoma Extracellular Vesicles Induces MMP2 Production from Preadipocytes.

Cancer Res 2019 10 6;79(19):4911-4922. Epub 2019 Aug 6.

Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center, Columbus, Ohio.

Dedifferentiated liposarcoma (DDLPS) is frequently diagnosed late, and patients typically respond poorly to treatments. DDLPS is molecularly characterized by wild-type p53 and amplification of the gene, which results in overexpression of MDM2 protein, a key oncogenic process in DDLPS. In this study, we demonstrate that extracellular vesicles derived from patients with DDLPS or from DDLPS cell lines are carriers of MDM2 DNA that can be transferred to preadipocytes, a major and ubiquitous cellular component of the DDLPS tumor microenvironment, leading to impaired p53 activity in preadipocytes and increased proliferation, migration, and production of matrix metalloproteinase 2; treatment with MDM2 inhibitors repressed these effects. Overall, these findings indicate that MDM2 plays a crucial role in DDLPS by enabling cross-talk between tumor cells and the surrounding microenvironment and that targeting vesicular MDM2 could represent a therapeutic option for treating DDLPS. SIGNIFICANCE: Extracellular vesicles derived from dedifferentiated liposarcoma cells induce oncogenic properties in preadipocytes.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-0203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6774856PMC
October 2019