RESUMO
Glial fibrillary acidic protein (GFAP), a proxy of astrocyte reactivity, has been proposed as biomarker of Alzheimer's disease. However, there is limited information about the correlation between blood biomarkers and post-mortem neuropathology. In a single-centre prospective clinicopathological cohort of 139 dementia patients, for which the time-frame between GFAP level determination and neuropathological assessment was exceptionally short (on average 139â days), we analysed this biomarker, measured at three time points, in relation to proxies of disease progression such as cognitive decline and brain weight. Most importantly, we investigated the use of blood GFAP to detect the neuropathological hallmarks of Alzheimer's disease, while accounting for potential influences of the most frequent brain co-pathologies. The main findings demonstrated an association between serum GFAP level and post-mortem tau pathology (ß = 12.85; P < 0.001) that was independent of amyloid deposits (ß = 13.23; P = 0.02). A mediation analysis provided additional support for the role of astrocytic activation as a link between amyloid and tau pathology in Alzheimer's disease. Furthermore, a negative correlation was observed between pre-mortem serum GFAP and brain weight at post-mortem (r = -0.35; P < 0.001). This finding, together with evidence of a negative correlation with cognitive assessments (r = -0.27; P = 0.005), supports the role of GFAP as a biomarker for disease monitoring, even in the late phases of Alzheimer's disease. Moreover, the diagnostic performance of GFAP in advanced dementia patients was explored, and its discriminative power (area under the receiver operator characteristic curve at baseline = 0.91) in differentiating neuropathologically-confirmed Alzheimer's disease dementias from non-Alzheimer's disease dementias was determined, despite the challenging scenario of advanced age and frequent co-pathologies in these patients. Independently of Alzheimer's disease, serum GFAP levels were shown to be associated with two other pathologies targeting the temporal lobes-hippocampal sclerosis (ß = 3.64; P = 0.03) and argyrophilic grain disease (ß = -6.11; P = 0.02). Finally, serum GFAP levels were revealed to be correlated with astrocyte reactivity, using the brain GFAP-immunostained area as a proxy (ρ = 0.21; P = 0.02). Our results contribute to increasing evidence suggesting a role for blood GFAP as an Alzheimer's disease biomarker, and the findings offer mechanistic insights into the relationship between blood GFAP and Alzheimer's disease neuropathology, highlighting its ties with tau burden. Moreover, the data highlighting an independent association between serum GFAP levels and other neuropathological lesions provide information for clinicians to consider when interpreting test results. The longitudinal design and correlation with post-mortem data reinforce the robustness of our findings. However, studies correlating blood biomarkers and neuropathological assessments are still scant, and further research is needed to replicate and validate these results in diverse populations.
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Doença de Alzheimer , Astrócitos , Atrofia , Biomarcadores , Encéfalo , Proteína Glial Fibrilar Ácida , Emaranhados Neurofibrilares , Humanos , Proteína Glial Fibrilar Ácida/sangue , Astrócitos/patologia , Astrócitos/metabolismo , Feminino , Masculino , Emaranhados Neurofibrilares/patologia , Idoso , Atrofia/patologia , Atrofia/sangue , Doença de Alzheimer/sangue , Doença de Alzheimer/patologia , Encéfalo/patologia , Encéfalo/metabolismo , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Autopsia , Proteínas tau/sangue , Estudos Prospectivos , Pessoa de Meia-Idade , Progressão da Doença , Demência/sangue , Demência/patologiaRESUMO
A critical component of gene regulation is recognition of histones and their post-translational modifications by transcription-associated proteins or complexes. Although many histone-binding reader modules have been characterized, the bromo-adjacent homology (BAH) domain family of readers is still poorly characterized. A pre-eminent member of this family is PBRM1 (BAF180), a component of the PBAF chromatin-remodeling complex. PBRM1 contains two adjacent BAH domains of unknown histone-binding potential. We evaluated the tandem BAH domains for their capacity to associate with histones and to contribute to PBAF-mediated gene regulation. The BAH1 and BAH2 domains of human PBRM1 broadly interacted with histone tails, but they showed a preference for unmodified N-termini of histones H3 and H4. Molecular modeling and comparison of the BAH1 and BAH2 domains with other BAH readers pointed to a conserved binding mode via an extended open pocket and, in general, an aromatic cage for histone lysine binding. Point mutants that were predicted to disrupt the interaction between the BAH domains and histones reduced histone binding in vitro and resulted in dysregulation of genes targeted by PBAF in cellulo. Although the BAH domains in PBRM1 were important for PBAF-mediated gene regulation, we found that overall chromatin targeting of PBRM1 was not dependent on BAH-histone interaction. Our findings identify a function of the PBRM1 BAH domains in PBAF activity that is likely mediated by histone tail interaction.
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Cromatina , Histonas , Humanos , Histonas/metabolismo , Cromatina/genética , Regulação da Expressão Gênica , Ligação ProteicaRESUMO
OBJECTIVE: To study the serological response (SR) and tolerability of COVID-19 vaccine in patients with inflammatory bowel disease (IBD) and its relation with IBD treatment and type of vaccine. METHODS: Observational, cross-sectional study in patients with IBD vaccinated against COVID-19 without known previous infection. SR was analyzed by the determination of IgG antibodies against the S1 subunit. Safety was studied using a questionnaire to identify adverse effects (AE). RESULTS: 280 patients with IBD were included. Type of vaccines: Comirnaty® 68.8%; Spikevax® 10.8%, Vaxzevria® 18.3%, Ad26.COV2-S® 2.2%. 51.3% had AE, being 100% mild. 65% developed IgG antibodies after vaccination. The SR was higher for vaccines with mRNA technology (100% Spikevax®, 68.5% Comirnaty®) compared to those based on adenovirus vector (38.0% Vaxzevria®, 33.3% Ad26.COV2-S®) (P<.001). In the multivariate analysis, SR was related to age (<60 years; OR: 3.8, 95% CI 1.9-7.0; P<.001). The SR in patients with aminosalicylates was 65.4%, 61.4% with immunosuppressants, 65.8% with anti-TNF, and 68.7% with non-anti-TNF biologicals (P=.9). CONCLUSIONS: One third of patients with IBD did not develop antibodies with the initial vaccination against SARS-CoV-2. The SR to vaccines based on mRNA technology was higher, and it was related to age (higher in younger patients). Immunosuppressants and biologicals did not decrease SR. More than half of the patients presented AD, being mild in all cases.
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Vacinas contra COVID-19 , COVID-19 , Doenças Inflamatórias Intestinais , Vacinas , Humanos , Pessoa de Meia-Idade , Vacina de mRNA-1273 contra 2019-nCoV , Anticorpos Antivirais , Vacina BNT162 , ChAdOx1 nCoV-19 , COVID-19/prevenção & controle , Vacinas contra COVID-19/efeitos adversos , Estudos Transversais , Imunoglobulina G , Imunossupressores , Doenças Inflamatórias Intestinais/tratamento farmacológico , RNA Mensageiro , SARS-CoV-2 , VacinaçãoRESUMO
Novel Janus nanoparticles based on Au colloids anisotropically modified with polyamidoamine dendrons were prepared though a masking/toposelective modification approach. These nanomaterials were further functionalized with horseradish peroxidase on the dendritic face and provided on the opposite metal surface with a ssDNA aptamer for C-reactive protein (CRP). The resulting nanoparticles were employed as biorecognition/signaling elements to construct an amperometric aptasensor with sandwich-type architecture for the specific detection of this cardiac biomarker. To do this, screen-printed carbon electrodes modified with electrodeposited Au nanoparticles and functionalized with anti-CRP aptamers were used as transduction interface. The aptasensor was employed for the amperometric detection of CRP (working potential: - 200 mV vs pseudo-Ag/AgCl) in the broad range from 10 pg·mL-1 to 1.0 ng·mL-1 with a detection limit of 3.1 pg·mL-1. This electroanalytical device also showed good specificity, reproducibility (RSD = 9.8%, n = 10), and stability and was useful to quantify CRP in reconstituted human serum samples, with a RSD of 13.3%.
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Aptâmeros de Nucleotídeos , Técnicas Biossensoriais , Nanopartículas Metálicas , Aptâmeros de Nucleotídeos/metabolismo , Técnicas Biossensoriais/métodos , Proteína C-Reativa , Técnicas Eletroquímicas/métodos , Ouro , Humanos , Limite de Detecção , Reprodutibilidade dos TestesRESUMO
We present the case of a 74-year-old man, with a history of residual schizophrenia, who underwent abdominal-pelvic CT with intravenous contrast, due to abdominal acute pain, that showed a stenosis at the origin of the celiac trunk and a large aneurysm of the hepatic artery, secondary to a mediam arcuate ligament syndrome, of the diaphragm was observed.
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Aneurisma , Síndrome do Ligamento Arqueado Mediano , Dor Abdominal , Idoso , Aneurisma/complicações , Aneurisma/diagnóstico por imagem , Artéria Celíaca/diagnóstico por imagem , Constrição Patológica/diagnóstico por imagem , Constrição Patológica/etiologia , Artéria Hepática/diagnóstico por imagem , Humanos , Masculino , Síndrome do Ligamento Arqueado Mediano/diagnóstico por imagemRESUMO
INTRODUCTION: Stability of a diagnosis over time represents the best evidence to validate psychiatric diagnoses and helps to predict the course of a disorder. The diagnosis of bipolar disorder shows large variability over time and only a few numbers of investigations have evaluated the impact of the diagnostic stability vs the change. MATERIAL AND METHODS: A systematic review was made through a literature search in Pubmed, Medline and Web of Science of the articles published in the last 10 years (2008- 2018). We used the following key words; "stability diagnosis", AND "bipolar disorders", AND "mood disorders". We selected those studies conducted in patients who presented affective and/or psychotic clinic where the stability of the diagnosis was studied over time. RESULTS: The initial search showed a total of 140 articles, 13 of which met inclusion criteria. In this review we have found that, compared to other mental disorders, Bipolar Disorder has in its favor a greater construct validity and longterm stability. CONCLUSIONS: Initial phases of Bipolar Disorder constitute a real diagnostic and therapeutic challenge. Despite this, it is considered, added to schizophrenia as one of the most stable diagnostic categories (60% of patients who receive this initial diagnosis remain it during time). The absence of reliable and valid instruments for diagnosis is considered as a limitation so it would be convenient that in the next classifications of mental disorders they continue striving so that the nosological entities have greater construct validity possible.
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Transtorno Bipolar/diagnóstico , Humanos , Transtornos do Humor/diagnóstico , Esquizofrenia/diagnóstico , Fatores de TempoRESUMO
This work reports a new gated nanodevice for acetylcholine-triggered cargo delivery. We prepared and characterized Janus Au-mesoporous silica nanoparticles functionalized with acetylcholinesterase on the Au face and with supramolecular ß-cyclodextrin:benzimidazole inclusion complexes as caps on the mesoporous silica face. The nanodevice is able to selectively deliver the cargo in the presence of acetylcholine via enzyme-mediated acetylcholine hydrolysis, locally lowering the pH and opening the supramolecular gate. Given the key role played by ACh and its relation with Parkinson's disease and other nervous system diseases, we believe that these findings could help design new therapeutic strategies.
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Acetilcolinesterase/metabolismo , Portadores de Fármacos/química , Ouro/química , Nanopartículas/química , Dióxido de Silício/química , Acetilcolina/metabolismo , Acetilcolinesterase/química , Benzimidazóis/química , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/química , Doxorrubicina/metabolismo , Doxorrubicina/toxicidade , Enzimas Imobilizadas/química , Enzimas Imobilizadas/metabolismo , Células HeLa , Humanos , Concentração de Íons de Hidrogênio , Hidrólise , Compostos Organometálicos/química , Compostos Organometálicos/metabolismo , Porosidade , beta-Ciclodextrinas/químicaRESUMO
Crohn´s disease is an inflammatory disease that can involve any portion of the gastrointestinal tract, although terminal ileum is the most commonly affected portion. It is characterized by a transmural and discontinuous distribution pattern, with alternating periods of active disease and remission. We present the case of a 23-year-old patient diagnosed with Crohn´s disease, in treatment with extended release Mesalazine and corticoids. The CT Enterography showed activity signs and a great dilatation of medium ileum with lots of Mesalazine pills accumulated inside. Pill accumulation occurred because of stenosis, which did not let the pills at this level progress to distal ileum, and be absorbed.
Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Doença de Crohn/complicações , Doença de Crohn/diagnóstico por imagem , Ílio/diagnóstico por imagem , Mesalamina/efeitos adversos , Preparações de Ação Retardada/efeitos adversos , Humanos , Masculino , Tomografia Computadorizada por Raios X , Adulto JovemRESUMO
A novel water-soluble graphene derivative was prepared from graphene oxide via a two-step modification approach. Graphene oxide was first functionalised with reactive epoxy groups by covalent modification with (3-glycidyloxypropyl)trimethoxysilane and further cross-linked with glycol chitosan. This graphene derivative was characterized using different microscopy and physicochemical methods and employed as a coating material for a glassy carbon electrode. The nanostructured surface was used as a support for the covalent immobilization of the enzyme laccase through cross-linking with glutaraldehyde. The enzyme electrode was tested for the amperometric detection of different phenolic compounds, which displayed excellent analytical behaviour toward catechol with a linear range of response from 200 nM to 15 µM, sensitivity of 93 mA M(-1) cm(-2), and low detection limit of 76 nM. The enzyme biosensor showed high stability when stored at 4 °C under dry conditions and was successfully employed to quantify the total phenolic compounds in commercial herbal tea samples.
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Técnicas Biossensoriais , Quitosana , Enzimas Imobilizadas/química , Glicóis , Grafite , Nanopartículas/química , Fenóis/análise , Eletrodos , ÓxidosRESUMO
We report herein the design of a smart delivery system in which cargo delivery from capped mesoporous silica (MS) nanoparticles is controlled by an integrated enzyme-based "control unit". The system consists of Janus-type nanoparticles having opposing Au and MS faces, functionalized with a pH-responsive ß-cyclodextrin-based supramolecular nanovalve on the MS surface and two effectors, glucose oxidase and esterase, immobilized on the Au face. The nanodevice behaves as an enzymatic logical OR operator which is selectively fueled by the presence of D-glucose and ethyl butyrate.
Assuntos
Sistemas de Liberação de Medicamentos , Esterases/metabolismo , Glucose Oxidase/metabolismo , Ouro/metabolismo , Nanopartículas/química , Dióxido de Silício/metabolismo , Enzimas Imobilizadas/química , Enzimas Imobilizadas/metabolismo , Esterases/química , Glucose Oxidase/química , Ouro/química , Concentração de Íons de Hidrogênio , Cinética , Modelos Moleculares , Estrutura Molecular , Tamanho da Partícula , Porosidade , Dióxido de Silício/química , Propriedades de SuperfícieRESUMO
Somatic genome editing in mouse models has increased our understanding of the in vivo effects of genetic alterations in areas ranging from neuroscience to cancer biology and beyond. However, existing models are limited in their ability to create multiple targeted edits. Thus, our understanding of the complex genetic interactions that underlie development, homeostasis, and disease remains incomplete. Cas12a is an RNA-guided endonuclease with unique attributes that enable simple targeting of multiple genes with crRNA arrays containing tandem guides. To accelerate and expand the generation of complex genotypes in somatic cells, we generated transgenic mice with Cre-regulated and constitutive expression of enhanced Acidaminococcus sp. Cas12a (enAsCas12a). In these mice, enAsCas12a-mediated somatic genome editing robustly generated compound genotypes, as exemplified by the initiation of diverse cancer types driven by homozygous inactivation of trios of tumor suppressor genes. We further integrated these modular crRNA arrays with clonal barcoding to quantify the size and number of tumors with each array, as well as the efficiency of each crRNA. These Cas12a alleles will enable the rapid generation of disease models and broadly facilitate the high-throughput investigation of coincident genomic alterations in somatic cells in vivo .
RESUMO
BACKGROUND: There is heterogeneity in the long-term trajectories of depressive symptoms among patients. To date, there has been little effort to inform the long-term trajectory of symptom change and the factors associated with different trajectories. Such knowledge is key to treatment decision-making in primary care, where depression is a common reason for consultation. We aimed to identify distinct long-term trajectories of depressive symptoms and explore pre-treatment characteristics associated with them. METHODS: A total of 483 patients from the PsicAP clinical trial were included. Growth mixture modeling was used to identify long-term distinct trajectories of depressive symptoms, and multinomial logistic regression models to explore associations between pre-treatment characteristics and trajectories. RESULTS: Four trajectories were identified that best explained the observed response patterns: "recovery" (64.18%), "late recovery" (10.15%), "relapse" (13.67%), and "chronicity" (12%). There was a higher likelihood of following the recovery trajectory for patients who had received psychological treatment in addition to the treatment as usual. Chronicity was associated with higher depressive severity, comorbidity (generalized anxiety, panic, and somatic symptoms), taking antidepressants, higher emotional suppression, lower levels on life quality, and being older. Relapse was associated with higher depressive severity, somatic symptoms, and having basic education, and late recovery was associated with higher depressive severity, generalized anxiety symptoms, greater disability, and rumination. CONCLUSIONS: There were different trajectories of depressive course and related prognostic factors among the patients. However, further research is needed before these findings can significantly influence care decisions.
Assuntos
Depressão , Sintomas Inexplicáveis , Humanos , Ansiedade , Transtornos de Ansiedade/psicologia , Depressão/psicologia , Estudos Longitudinais , Atenção Primária à SaúdeRESUMO
Here, we report the preparation of a novel Janus nanoparticle with opposite Ir and mesoporous silica nanoparticles through a partial surface masking with toposelective modification method. This nanomaterial was employed to construct an enzyme-powered nanomachine with self-propulsion properties for on-command delivery. The cargo-loaded nanoparticle was provided with a pH-sensitive gate and unit control at the mesoporous face by first attaching boronic acid residues and further immobilization of glucose oxidase through reversible boronic acid esters with the carbohydrate residues of the glycoenzyme. Addition of glucose leads to the enzymatic production of H2O2 and gluconic acid, being the first compound catalytically decomposed at the Ir nanoparticle face producing O2 and causing the nanomachine propulsion. Gluconic acid leads to a pH reduction at the nanomachine microenvironment causing the disruption of the gating mechanism with the subsequent cargo release. This work demonstrates that enzyme-mediated self-propulsion improved release efficiency being this nanomotor successfully employed for the smart release of Doxorubicin in HeLa cancer cells.
Assuntos
Doxorrubicina , Enzimas Imobilizadas , Glucose Oxidase , Nanopartículas , Dióxido de Silício , Dióxido de Silício/química , Humanos , Glucose Oxidase/química , Glucose Oxidase/metabolismo , Células HeLa , Doxorrubicina/farmacologia , Doxorrubicina/química , Porosidade , Nanopartículas/química , Enzimas Imobilizadas/química , Enzimas Imobilizadas/metabolismo , Propriedades de Superfície , Concentração de Íons de Hidrogênio , Tamanho da Partícula , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Portadores de Fármacos/química , Gluconatos/química , Raios Infravermelhos , Peróxido de Hidrogênio/químicaRESUMO
A novel strategy for the construction of disposable amperometric affinity biosensors is described in this work. The approach uses a recombinant bacterial penicillin binding protein (PBP) tagged by an N-terminal hexahistidine tail which was immobilized onto Co(2+)-tetradentate nitrilotriacetic acid (NTA)-modified screen-printed carbon electrodes (SPCEs). The biosensor was employed for the specific detection and quantification of ß-lactam antibiotics residues in milk, which was accomplished by means of a direct competitive assay using a tracer with horseradish peroxidase (HRP) for the enzymatic labeling. The amperometric response measured at -0.20 V versus the Ag pseudoreference electrode of the SPCE upon the addition of H2O2 in the presence of hydroquinone (HQ) as redox mediator was used as the transduction signal. The developed affinity sensor allowed limits of detection to be obtained in the low part-per-billion level for the antibiotics tested in untreated milk samples. Moreover, the biosensor exhibited a good selectivity against other antibiotics residues frequently detected in milk and dairy products. The analysis time was of approximately 30 min.
Assuntos
Técnicas Biossensoriais/métodos , Carbono/química , Cobalto/química , Equipamentos Descartáveis , Ácido Nitrilotriacético/química , beta-Lactamas/análise , EletrodosRESUMO
Cysteamine core polyamidoamine G-4 dendron branched with ß-cyclodextrins was chemisorbed on the surface of Au electrodes and further coated with Pt nanoparticles. Adamantane-modified glucose oxidase was subsequently immobilized on the nanostructured electrode surface by supramolecular association. This enzyme electrode was used to construct a reagentless amperometric biosensor for glucose, making use of the electrochemical oxidation of H2O2 generated in the enzyme reaction. The amperometric response of the biosensor was rapid (6 s) and a linear function of glucose concentration between 5 and 705 µmol L(-1). The biosensor had a low detection limit of 2.0 µmol L(-1), sensitivity of 197 mA mol(-1) L cm(-2), and retained 94% of its initial response after storage for nine days at 4 °C.
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Técnicas Biossensoriais/instrumentação , Cisteamina/química , Dendrímeros/química , Enzimas Imobilizadas/química , Glucose Oxidase/química , Glucose/análise , beta-Ciclodextrinas/química , Eletrodos , Ouro/química , Limite de Detecção , Modelos Moleculares , Nanopartículas/química , Platina/química , Sensibilidade e EspecificidadeRESUMO
Portopulmonary hypertension is an uncommon disease associated with high morbidity and mortality, so its early diagnosis and treatment are essential. We report here the case of a 57-year-old man with portopulmonary hypertension caused by chronic hepatosplenic schistosomiasis and also liver cirrhosis due to hepatitis C and alcoholism. As well as treating both diseases, portopulmonary hypertension was successfully managed with tadalafil and macitentan as maintenance therapy. This case reminds clinicians that pulmonary hypertension can be multifactorial, a good diagnosis and a multidisciplinary treatment can lead to improved prognosis.
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Here, we describe the design of a novel particle-to-particle intercommunicated nanosystem for dual delivery, triggered by physical and chemical inputs. The nanosystem was composed of an Au-mesoporous silica Janus nanoparticle loaded with paracetamol, mechanized with light-sensitive supramolecular gates at the mesoporous face and functionalized on the metal surface with the enzyme acetylcholinesterase. The second component was a mesoporous silica nanoparticle loaded with rhodamine B and gated with thiol-sensitive ensembles. Upon irradiation of this nanosystem with a near-UV light laser, an analgesic drug was released from the Janus nanomachine due to disassembling of the photosensitive gating mechanism. Further addition of N-acetylthiocholine leads to the enzymatic production of thiocholine at the Janus nanomachine, thus acting as a "chemical messenger" causing the disruption of the gating mechanism at the second mesoporous silica nanoparticle with the subsequent dye release.
Assuntos
Nanopartículas Multifuncionais , Nanopartículas , Acetilcolinesterase , Doxorrubicina/química , Nanopartículas/química , Dióxido de Silício/químicaRESUMO
The paradigm of cancer-targeted therapies has focused largely on inhibition of critical pathways in cancer. Conversely, conditional activation of signaling pathways as a new source of selective cancer vulnerabilities has not been deeply characterized. In this study, we sought to systematically identify context-specific gene-activation-induced lethalities in cancer. To this end, we developed a method for gain-of-function genetic perturbations simultaneously across ~500 barcoded cancer cell lines. Using this approach, we queried the pan-cancer vulnerability landscape upon activating ten key pathway nodes, revealing selective activation dependencies of MAPK and PI3K pathways associated with specific biomarkers. Notably, we discovered new pathway hyperactivation dependencies in subsets of APC-mutant colorectal cancers where further activation of the WNT pathway by APC knockdown or direct ß-catenin overexpression led to robust antitumor effects in xenograft and patient-derived organoid models. Together, this study reveals a new class of conditional gene-activation dependencies in cancer.