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1.
Nature ; 615(7950): 158-167, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36634707

RESUMEN

Despite the success of PD-1 blockade in melanoma and other cancers, effective treatment strategies to overcome resistance to cancer immunotherapy are lacking1,2. Here we identify the innate immune kinase TANK-binding kinase 1 (TBK1)3 as a candidate immune-evasion gene in a pooled genetic screen4. Using a suite of genetic and pharmacological tools across multiple experimental model systems, we confirm a role for TBK1 as an immune-evasion gene. Targeting TBK1 enhances responses to PD-1 blockade by decreasing the cytotoxicity threshold to effector cytokines (TNF and IFNγ). TBK1 inhibition in combination with PD-1 blockade also demonstrated efficacy using patient-derived tumour models, with concordant findings in matched patient-derived organotypic tumour spheroids and matched patient-derived organoids. Tumour cells lacking TBK1 are primed to undergo RIPK- and caspase-dependent cell death in response to TNF and IFNγ in a JAK-STAT-dependent manner. Taken together, our results demonstrate that targeting TBK1 is an effective strategy to overcome resistance to cancer immunotherapy.


Asunto(s)
Resistencia a Antineoplásicos , Evasión Inmune , Inmunoterapia , Proteínas Serina-Treonina Quinasas , Humanos , Evasión Inmune/genética , Evasión Inmune/inmunología , Inmunoterapia/métodos , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/genética , Organoides , Factores de Necrosis Tumoral/inmunología , Interferón gamma/inmunología , Esferoides Celulares , Caspasas , Quinasas Janus , Factores de Transcripción STAT
4.
PLoS Med ; 13(12): e1002196, 2016 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-27959922

RESUMEN

In a Perspective, Mack Su and David Fisher discuss the development of immunotherapies for treatment of melanoma and other cancer types.


Asunto(s)
Inmunoterapia/tendencias , Melanoma/terapia , Medicina de Precisión/métodos , Humanos , Medicina de Precisión/tendencias
9.
J Biol Chem ; 288(12): 8433-8444, 2013 Mar 22.
Artículo en Inglés | MEDLINE | ID: mdl-23341446

RESUMEN

Identification of cell type-specific enhancers is important for understanding the regulation of programs controlling cellular development and differentiation. Enhancers are typically marked by the co-transcriptional activator protein p300 or by groups of cell-expressed transcription factors. We hypothesized that a unique set of enhancers regulates gene expression in human erythroid cells, a highly specialized cell type evolved to provide adequate amounts of oxygen throughout the body. Using chromatin immunoprecipitation followed by massively parallel sequencing, genome-wide maps of candidate enhancers were constructed for p300 and four transcription factors, GATA1, NF-E2, KLF1, and SCL, using primary human erythroid cells. These data were combined with gene expression analyses, and candidate enhancers were identified. Consistent with their predicted function as candidate enhancers, there was statistically significant enrichment of p300 and combinations of co-localizing erythroid transcription factors within 1-50 kb of the transcriptional start site (TSS) of genes highly expressed in erythroid cells. Candidate enhancers were also enriched near genes with known erythroid cell function or phenotype. Candidate enhancers exhibited moderate conservation with mouse and minimal conservation with nonplacental vertebrates. Candidate enhancers were mapped to a set of erythroid-associated, biologically relevant, SNPs from the genome-wide association studies (GWAS) catalogue of NHGRI, National Institutes of Health. Fourteen candidate enhancers, representing 10 genetic loci, mapped to sites associated with biologically relevant erythroid traits. Fragments from these loci directed statistically significant expression in reporter gene assays. Identification of enhancers in human erythroid cells will allow a better understanding of erythroid cell development, differentiation, structure, and function and provide insights into inherited and acquired hematologic disease.


Asunto(s)
Elementos de Facilitación Genéticos , Células Eritroides/metabolismo , Regulación de la Expresión Génica , Secuencia de Bases , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/fisiología , Células Cultivadas , Cromatina/genética , Cromatina/metabolismo , Inmunoprecipitación de Cromatina , Secuencia Conservada , Proteína p300 Asociada a E1A/metabolismo , Factor de Transcripción GATA1/metabolismo , Factor de Transcripción GATA1/fisiología , Genes Reporteros , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Factores de Transcripción de Tipo Kruppel/metabolismo , Factores de Transcripción de Tipo Kruppel/fisiología , Luciferasas de Luciérnaga/biosíntesis , Luciferasas de Luciérnaga/genética , Anotación de Secuencia Molecular , Subunidad p45 del Factor de Transcripción NF-E2/metabolismo , Subunidad p45 del Factor de Transcripción NF-E2/fisiología , Análisis de Secuencia por Matrices de Oligonucleótidos , Polimorfismo de Nucleótido Simple , Regiones Promotoras Genéticas , Unión Proteica , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas/fisiología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Análisis de Secuencia de ADN , Proteína 1 de la Leucemia Linfocítica T Aguda , Transcriptoma
10.
Sci Adv ; 7(14)2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33811065

RESUMEN

Humans and mice with natural red hair have elevated basal pain thresholds and an increased sensitivity to opioid analgesics. We investigated the mechanisms responsible for higher nociceptive thresholds in red-haired mice resulting from a loss of melanocortin 1 receptor (MC1R) function and found that the increased thresholds are melanocyte dependent but melanin independent. MC1R loss of function decreases melanocytic proopiomelanocortin transcription and systemic melanocyte-stimulating hormone (MSH) levels in the plasma of red-haired (Mc1re/e ) mice. Decreased peripheral α-MSH derepresses the central opioid tone mediated by the opioid receptor OPRM1, resulting in increased nociceptive thresholds. We identified MC4R as the MSH-responsive receptor that opposes OPRM1 signaling and the periaqueductal gray area in the brainstem as a central area of opioid/melanocortin antagonism. This work highlights the physiologic role of melanocytic MC1R and circulating melanocortins in the regulation of nociception and provides a mechanistic framework for altered opioid signaling and pain sensitivity in red-haired individuals.


Asunto(s)
Analgésicos Opioides , Nocicepción , Animales , Cabello , Hormonas Estimuladoras de los Melanocitos/farmacología , Ratones , Receptor de Melanocortina Tipo 1/genética , Receptor de Melanocortina Tipo 4/genética
11.
Sci Adv ; 7(24)2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-34117054

RESUMEN

The current opioid epidemic warrants a better understanding of genetic and environmental factors that contribute to opioid addiction. Here we report an increased prevalence of vitamin D (VitD) deficiency in patients diagnosed with opioid use disorder and an inverse and dose-dependent association of VitD levels with self-reported opioid use. We used multiple pharmacologic approaches and genetic mouse models and found that deficiencies in VitD signaling amplify exogenous opioid responses that are normalized upon restoration of VitD signaling. Similarly, physiologic endogenous opioid analgesia and reward responses triggered by ultraviolet (UV) radiation are repressed by VitD signaling, suggesting that a feedback loop exists whereby VitD deficiency produces increased UV/endorphin-seeking behavior until VitD levels are restored by cutaneous VitD synthesis. This feedback may carry the evolutionary advantage of maximizing VitD synthesis. However, unlike UV exposure, exogenous opioid use is not followed by VitD synthesis (and its opioid suppressive effects), contributing to maladaptive addictive behavior.


Asunto(s)
Endorfinas , Trastornos Relacionados con Opioides , Deficiencia de Vitamina D , Analgésicos Opioides/farmacología , Animales , Humanos , Ratones , Vitamina D/farmacología , Deficiencia de Vitamina D/complicaciones , Deficiencia de Vitamina D/epidemiología , Vitaminas
12.
Sci Transl Med ; 13(581)2021 02 17.
Artículo en Inglés | MEDLINE | ID: mdl-33597266

RESUMEN

Although immune checkpoint inhibitors (ICIs), such as anti-programmed cell death protein-1 (PD-1), can deliver durable antitumor effects, most patients with cancer fail to respond. Recent studies suggest that ICI efficacy correlates with a higher load of tumor-specific neoantigens and development of vitiligo in patients with melanoma. Here, we report that patients with low melanoma neoantigen burdens who responded to ICI had tumors with higher expression of pigmentation-related genes. Moreover, expansion of peripheral blood CD8+ T cell populations specific for melanocyte antigens was observed only in patients who responded to anti-PD-1 therapy, suggesting that ICI can promote breakdown of tolerance toward tumor-lineage self-antigens. In a mouse model of poorly immunogenic melanomas, spreading of epitope recognition toward wild-type melanocyte antigens was associated with markedly improved anti-PD-1 efficacy in two independent approaches: introduction of neoantigens by ultraviolet (UV) B radiation mutagenesis or the therapeutic combination of ablative fractional photothermolysis plus imiquimod. Complete responses against UV mutation-bearing tumors after anti-PD-1 resulted in protection from subsequent engraftment of melanomas lacking any shared neoantigens, as well as pancreatic adenocarcinomas forcibly overexpressing melanocyte-lineage antigens. Our data demonstrate that somatic mutations are sufficient to provoke strong antitumor responses after checkpoint blockade, but long-term responses are not restricted to these putative neoantigens. Epitope spreading toward T cell recognition of wild-type tumor-lineage self-antigens represents a common pathway for successful response to ICI, which can be evoked in neoantigen-deficient tumors by combination therapy with ablative fractional photothermolysis and imiquimod.


Asunto(s)
Inhibidores de Puntos de Control Inmunológico , Melanoma , Animales , Antígenos de Neoplasias , Epítopos , Humanos , Melanocitos , Melanoma/terapia , Ratones
13.
Appl Clin Inform ; 11(5): 792-801, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-33241547

RESUMEN

OBJECTIVE: We deployed a Remote Patient Monitoring (RPM) program to monitor patients with coronavirus disease 2019 (COVID-19) upon hospital discharge. We describe the patient characteristics, program characteristics, and clinical outcomes of patients in our RPM program. METHODS: We enrolled COVID-19 patients being discharged home from the hospital. Enrolled patients had an app, and were provided with a pulse oximeter and thermometer. Patients self-reported symptoms, O2 saturation, and temperature daily. Abnormal symptoms or vital signs were flagged and assessed by a pool of nurses. Descriptive statistics were used to describe patient and program characteristics. A mixed-effects logistic regression model was used to determine the odds of a combined endpoint of emergency department (ED) or hospital readmission. RESULTS: A total of 295 patients were referred for RPM from five participating hospitals, and 225 patients were enrolled. A majority of enrolled patients (66%) completed the monitoring period without triggering an abnormal alert. Enrollment was associated with a decreased odds of ED or hospital readmission (adjusted odds ratio: 0.54; 95% confidence interval: 0.3-0.97; p = 0.039). Referral without enrollment was not associated with a reduced odds of ED or hospital readmission. CONCLUSION: RPM for COVID-19 provides a mechanism to monitor patients in their home environment and reduce hospital utilization. Our work suggests that RPM reduces readmissions for patients with COVID-19 and provides scalable remote monitoring capabilities upon hospital discharge. RPM for postdischarge patients with COVID-19 was associated with a decreased risk of readmission to the ED or hospital, and provided a scalable mechanism to monitor patients in their home environment.


Asunto(s)
Cuidados Posteriores/métodos , COVID-19 , Alta del Paciente , Adulto , Anciano , COVID-19/epidemiología , COVID-19/terapia , Servicio de Urgencia en Hospital/estadística & datos numéricos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pandemias , Readmisión del Paciente/estadística & datos numéricos
14.
Exp Hematol ; 44(3): 161-5.e4, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26607597

RESUMEN

The retinoblastoma gene (RB1) has been implicated as a tumor suppressor in multiple myeloma (MM), yet its role remains unclear because in the majority of cases with 13q14 deletions, un-mutated RB1 remains expressed from the retained allele. To explore the role of Rb1 in MM, we examined the functional consequences of single- and double-copy Rb1 loss in germinal center B cells, the cells of origin of MM. We generated mice without Rb1 function in germinal center B cells by crossing Rb1(Flox/Flox) with C-γ-1-Cre (Cγ1) mice expressing the Cre recombinase in class-switched B cells in a p107(-/-) background to prevent p107 from compensating for Rb1 loss (Cγ1-Rb1(F/F)-p107(-/-)). All mice developed normally, but B cells with two copies of Rb1 deleted (Cγ1-Rb1(F/F)-p107(-/-)) exhibited increased proliferation and cell death compared with Cγ1-Rb1(+/+)-p107(-/-) controls ex vivo. In vivo, Cγ1-Rb1(F/F)-p107(-/-) mice had a lower percentage of splenic B220+ cells and reduced numbers of bone marrow antigen-specific secreting cells compared with control mice. Our data indicate that Rb1 loss induces both cell proliferation and death in germinal center B cells. Because no B-cell malignancies developed after 1 year of observation, our data also suggest that Rb1 loss is not sufficient to transform post-germinal center B cells and that additional, specific mutations are likely required to cooperate with Rb1 loss to induce malignant transformation.


Asunto(s)
Linfocitos B/metabolismo , Proliferación Celular , Transformación Celular Neoplásica/metabolismo , Centro Germinal/metabolismo , Mutación , Proteína de Retinoblastoma/deficiencia , Animales , Linfocitos B/patología , Muerte Celular , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , Centro Germinal/patología , Ratones , Ratones Noqueados
15.
Neuron ; 87(6): 1215-1233, 2015 Sep 23.
Artículo en Inglés | MEDLINE | ID: mdl-26402605

RESUMEN

Analysis of de novo CNVs (dnCNVs) from the full Simons Simplex Collection (SSC) (N = 2,591 families) replicates prior findings of strong association with autism spectrum disorders (ASDs) and confirms six risk loci (1q21.1, 3q29, 7q11.23, 16p11.2, 15q11.2-13, and 22q11.2). The addition of published CNV data from the Autism Genome Project (AGP) and exome sequencing data from the SSC and the Autism Sequencing Consortium (ASC) shows that genes within small de novo deletions, but not within large dnCNVs, significantly overlap the high-effect risk genes identified by sequencing. Alternatively, large dnCNVs are found likely to contain multiple modest-effect risk genes. Overall, we find strong evidence that de novo mutations are associated with ASD apart from the risk for intellectual disability. Extending the transmission and de novo association test (TADA) to include small de novo deletions reveals 71 ASD risk loci, including 6 CNV regions (noted above) and 65 risk genes (FDR ≤ 0.1).


Asunto(s)
Trastorno del Espectro Autista/diagnóstico , Trastorno del Espectro Autista/genética , Sitios Genéticos/genética , Variación Genética/genética , Mapas de Interacción de Proteínas/genética , Femenino , Humanos , Masculino
16.
PLoS One ; 8(6): e67941, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23825691

RESUMEN

Activating mutations in Ras (N- and K-) are the most common point mutations found in patients with multiple myeloma (MM) and are associated with poor clinical outcome. We sought to directly examine the role of Ras activation in MM pathogenesis and used two different tissue-specific Cre recombinase mouse lines (Cγ1-Cre and AID-Cre), to generate mice with mutant Kras (Kras(G12D) ) activated specifically in germinal center B-cells. We also generated mice with activation of the Kras(G12D) allele in a tumor-prone Arf-null genetic background. Surprisingly, we observed no significant disruption in B-cell homeostasis in any of these models by serum immunoglobulin ELISA, SPEP, flow cytometry and histological examination. We observed development of non-overlapping tumor types due to off-target Cre expression, but despite successful recombination in germinal center and later B-cell populations, we observed no B-cell phenotype. Together, these data demonstrate that Ras activation is not sufficient to transform primary germinal center B-cells, even in an Arf-null context, and that the temporal order of mutation acquisition may be critical for myeloma development. Specific pathways, yet to be identified, are required before Kras can contribute to the development of MM.


Asunto(s)
Linfocitos B/patología , Transformación Celular Neoplásica , Inhibidor p16 de la Quinasa Dependiente de Ciclina/deficiencia , Eliminación de Gen , Centro Germinal/inmunología , Proteínas Proto-Oncogénicas/genética , Proteínas Supresoras de Tumor/deficiencia , Proteínas ras/genética , Animales , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Linfoma/patología , Ratones , Ratones Transgénicos , Papiloma/patología , Proteínas Proto-Oncogénicas p21(ras) , Neoplasias Cutáneas/patología , Timoma/patología , Proteínas Supresoras de Tumor/genética
17.
J Clin Invest ; 122(8): 2793-806, 2012 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-22751105

RESUMEN

The histone methyltransferase WHSC1 (also known as MMSET) is overexpressed in multiple myeloma (MM) as a result of the t(4;14) chromosomal translocation and in a broad variety of other cancers by unclear mechanisms. Overexpression of WHSC1 did not transform wild-type or tumor-prone primary hematopoietic cells. We found that ACA11, an orphan box H/ACA class small nucleolar RNA (snoRNA) encoded within an intron of WHSC1, was highly expressed in t(4;14)-positive MM and other cancers. ACA11 localized to nucleoli and bound what we believe to be a novel small nuclear ribonucleoprotein (snRNP) complex composed of several proteins involved in postsplicing intron complexes. RNA targets of this uncharacterized snRNP included snoRNA intermediates hosted within ribosomal protein (RP) genes, and an RP gene signature was strongly associated with t(4;14) in patients with MM. Expression of ACA11 was sufficient to downregulate RP genes and other snoRNAs implicated in the control of oxidative stress. ACA11 suppressed oxidative stress, afforded resistance to chemotherapy, and increased the proliferation of MM cells, demonstrating that ACA11 is a critical target of the t(4;14) translocation in MM and suggesting an oncogenic role in other cancers as well.


Asunto(s)
N-Metiltransferasa de Histona-Lisina/metabolismo , Mieloma Múltiple/genética , Mieloma Múltiple/metabolismo , ARN Nucleolar Pequeño/genética , ARN Nucleolar Pequeño/metabolismo , Proteínas Represoras/metabolismo , Translocación Genética , Animales , Secuencia de Bases , Proliferación Celular , Transformación Celular Neoplásica , Cromosomas Humanos Par 14/genética , Cromosomas Humanos Par 4/genética , ADN Complementario/genética , ADN de Neoplasias/genética , Perfilación de la Expresión Génica , Humanos , Intrones , Ratones , Datos de Secuencia Molecular , Mieloma Múltiple/patología , Conformación de Ácido Nucleico , Estrés Oxidativo , ARN Neoplásico/química , ARN Neoplásico/genética , ARN Neoplásico/metabolismo , ARN Nucleolar Pequeño/química , Proteínas Ribosómicas/genética , Proteínas Ribosómicas/metabolismo
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