RESUMEN
Leukemia stem cells (LSCs) have the capacity to self-renew and propagate disease upon serial transplantation in animal models, and elimination of this cell population is required for curative therapies. Here, we describe a series of pooled, in vivo RNAi screens to identify essential transcription factors (TFs) in a murine model of acute myeloid leukemia (AML) with genetically and phenotypically defined LSCs. These screens reveal the heterodimeric, circadian rhythm TFs Clock and Bmal1 as genes required for the growth of AML cells in vitro and in vivo. Disruption of canonical circadian pathway components produces anti-leukemic effects, including impaired proliferation, enhanced myeloid differentiation, and depletion of LSCs. We find that both normal and malignant hematopoietic cells harbor an intact clock with robust circadian oscillations, and genetic knockout models reveal a leukemia-specific dependence on the pathway. Our findings establish a role for the core circadian clock genes in AML.
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Factores de Transcripción ARNTL/genética , Proteínas CLOCK/genética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Células Madre Neoplásicas/patología , Animales , Ritmo Circadiano , Modelos Animales de Enfermedad , Técnicas de Inactivación de Genes , Hematopoyesis , Humanos , Leucemia Mieloide Aguda/metabolismo , Ratones , Ratones Endogámicos C57BL , Células Madre Neoplásicas/metabolismo , Interferencia de ARN , ARN Interferente Pequeño/metabolismoRESUMEN
Nuclear hormone receptors (NRs) are ligand-binding transcription factors that are widely targeted therapeutically. Agonist binding triggers NR activation and subsequent degradation by unknown ligand-dependent ubiquitin ligase machinery. NR degradation is critical for therapeutic efficacy in malignancies that are driven by retinoic acid and estrogen receptors. Here, we demonstrate the ubiquitin ligase UBR5 drives degradation of multiple agonist-bound NRs, including the retinoic acid receptor alpha (RARA), retinoid x receptor alpha (RXRA), glucocorticoid, estrogen, liver-X, progesterone, and vitamin D receptors. We present the high-resolution cryo-EMstructure of full-length human UBR5 and a negative stain model representing its interaction with RARA/RXRA. Agonist ligands induce sequential, mutually exclusive recruitment of nuclear coactivators (NCOAs) and UBR5 to chromatin to regulate transcriptional networks. Other pharmacological ligands such as selective estrogen receptor degraders (SERDs) degrade their receptors through differential recruitment of UBR5 or RNF111. We establish the UBR5 transcriptional regulatory hub as a common mediator and regulator of NR-induced transcription.
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Cromatina , Factores de Transcripción , Humanos , Ligandos , Cromatina/genética , Factores de Transcripción/metabolismo , Receptores Citoplasmáticos y Nucleares/genética , Ubiquitinas , Ubiquitina-Proteína Ligasas/genéticaRESUMEN
Effective and sustained inhibition of non-enzymatic oncogenic driver proteins is a major pharmacological challenge. The clinical success of thalidomide analogues demonstrates the therapeutic efficacy of drug-induced degradation of transcription factors and other cancer targets1-3, but a substantial subset of proteins are resistant to targeted degradation using existing approaches4,5. Here we report an alternative mechanism of targeted protein degradation, in which a small molecule induces the highly specific, reversible polymerization of a target protein, followed by its sequestration into cellular foci and subsequent degradation. BI-3802 is a small molecule that binds to the Broad-complex, Tramtrack and Bric-à-brac (BTB) domain of the oncogenic transcription factor B cell lymphoma 6 (BCL6) and leads to the proteasomal degradation of BCL66. We use cryo-electron microscopy to reveal how the solvent-exposed moiety of a BCL6-binding molecule contributes to a composite ligand-protein surface that engages BCL6 homodimers to form a supramolecular structure. Drug-induced formation of BCL6 filaments facilitates ubiquitination by the SIAH1 E3 ubiquitin ligase. Our findings demonstrate that a small molecule such as BI-3802 can induce polymerization coupled to highly specific protein degradation, which in the case of BCL6 leads to increased pharmacological activity compared to the effects induced by other BCL6 inhibitors. These findings open new avenues for the development of therapeutic agents and synthetic biology.
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Polimerizacion/efectos de los fármacos , Proteolisis/efectos de los fármacos , Proteínas Proto-Oncogénicas c-bcl-6/química , Proteínas Proto-Oncogénicas c-bcl-6/metabolismo , Microscopía por Crioelectrón , Humanos , Técnicas In Vitro , Ligandos , Modelos Moleculares , Proteínas Nucleares/metabolismo , Complejo de la Endopetidasa Proteasomal/efectos de los fármacos , Complejo de la Endopetidasa Proteasomal/metabolismo , Proteínas Proto-Oncogénicas c-bcl-6/ultraestructura , Solventes , Biología Sintética , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitinación/efectos de los fármacosRESUMEN
PPM1D encodes a phosphatase that is recurrently activated across cancer, most notably in therapy-related myeloid neoplasms. However, the function of PPM1D in hematopoiesis and its contribution to tumor cell growth remain incompletely understood. Using conditional mouse models, we uncover a central role for Ppm1d in hematopoiesis and validate its potential as a therapeutic target. We find that Ppm1d regulates the competitive fitness and self-renewal of hematopoietic stem cells (HSCs) with and without exogenous genotoxic stresses. We also show that although Ppm1d activation confers cellular resistance to cytotoxic therapy, it does so to a lesser degree than p53 loss, informing the clonal competition phenotypes often observed in human studies. Notably, loss of Ppm1d sensitizes leukemias to cytotoxic therapies in vitro and in vivo, even in the absence of a Ppm1d mutation. Vulnerability to PPM1D inhibition is observed across many cancer types and dependent on p53 activity. Importantly, organism-wide loss of Ppm1d in adult mice is well tolerated, supporting the tolerability of pharmacologically targeting PPM1D. Our data link PPM1D gain-of-function mutations to the clonal expansion of HSCs, inform human genetic observations, and support the therapeutic targeting of PPM1D in cancer.
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Daño del ADN , Proteína p53 Supresora de Tumor , Adulto , Humanos , Animales , Ratones , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Proteína Fosfatasa 2C , Mutación , Monoéster Fosfórico Hidrolasas/genética , Ciclo CelularRESUMEN
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening inflammatory syndrome that may complicate hematologic malignancies (HMs). The appropriateness of current criteria for diagnosing HLH in the context of HMs is unknown because they were developed for children with familial HLH (HLH-2004) or derived from adult patient cohorts in which HMs were underrepresented (HScore). Moreover, many features of these criteria may directly reflect the underlying HM rather than an abnormal inflammatory state. To improve and potentially simplify HLH diagnosis in patients with HMs, we studied an international cohort of 225 adult patients with various HMs both with and without HLH and for whom HLH-2004 criteria were available. Classification and regression tree and receiver-operating curve analyses were used to identify the most useful diagnostic and prognostic parameters and to optimize laboratory cutoff values. Combined elevation of soluble CD25 (>3900 U/mL) and ferritin (>1000 ng/mL) best identified HLH-2004-defining features (sensitivity, 84%; specificity, 81%). Moreover, this combination, which we term the optimized HLH inflammatory (OHI) index, was highly predictive of mortality (hazard ratio, 4.3; 95% confidence interval, 3.0-6.2) across diverse HMs. Furthermore, the OHI index identified a large group of patients with high mortality risk who were not defined as having HLH according to HLH-2004/HScore. Finally, the OHI index shows diagnostic and prognostic value when used for routine surveillance of patients with newly diagnosed HMs as well as those with clinically suspected HLH. Thus, we conclude that the OHI index identifies patients with HM and an inflammatory state associated with a high mortality risk and warrants further prospective validation.
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Biomarcadores de Tumor/sangre , Ferritinas/sangre , Neoplasias Hematológicas/complicaciones , Subunidad alfa del Receptor de Interleucina-2/sangre , Linfohistiocitosis Hemofagocítica/diagnóstico , Linfohistiocitosis Hemofagocítica/mortalidad , Anciano , Femenino , Estudios de Seguimiento , Humanos , Linfohistiocitosis Hemofagocítica/sangre , Linfohistiocitosis Hemofagocítica/etiología , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
Gout is a common inflammatory arthritis caused by precipitation of monosodium urate (MSU) crystals in individuals with hyperuricemia. Acute flares are accompanied by secretion of proinflammatory cytokines, including interleukin-1ß (IL-1ß). Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition predisposing to hematologic cancers and cardiovascular disease. CHIP is associated with elevated IL-1ß, thus we investigated CHIP as a risk factor for gout. To test the clinical association between CHIP and gout, we analyzed whole exome sequencing data from 177 824 individuals in the MGB Biobank (MGBB) and UK Biobank (UKB). In both cohorts, the frequency of gout was higher among individuals with CHIP than without CHIP (MGBB, CHIP with variant allele fraction [VAF] ≥2%: odds ratio [OR], 1.69; 95% CI, 1.09-2.61; P = .0189; UKB, CHIP with VAF ≥10%: OR, 1.25; 95% CI, 1.05-1.50; P = .0133). Moreover, individuals with CHIP and a VAF ≥10% had an increased risk of incident gout (UKB: hazard ratio [HR], 1.28; 95% CI, 1.06-1.55; P = .0107). In murine models of gout pathogenesis, animals with Tet2 knockout hematopoietic cells had exaggerated IL-1ß secretion and paw edema upon administration of MSU crystals. Tet2 knockout macrophages elaborated higher levels of IL-1ß in response to MSU crystals in vitro, which was ameliorated through genetic and pharmacologic Nlrp3 inflammasome inhibition. These studies show that TET2-mutant CHIP is associated with an increased risk of gout in humans and that MSU crystals lead to elevated IL-1ß levels in Tet2 knockout murine models. We identify CHIP as an amplifier of NLRP3-dependent inflammatory responses to MSU crystals in patients with gout.
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Dioxigenasas , Gota , Animales , Hematopoyesis Clonal , Proteínas de Unión al ADN/genética , Dioxigenasas/genética , Gota/genética , Humanos , Inflamasomas/genética , Interleucina-1beta/genética , Ratones , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Ácido Úrico/química , Ácido Úrico/farmacologíaRESUMEN
There is a growing body of evidence that therapy-related myeloid neoplasms (t-MNs) with driver gene mutations arise in the background of clonal hematopoiesis (CH) under the positive selective pressure of chemo- and radiation therapies. Uncovering the exposure relationships that provide selective advantage to specific CH mutations is critical to understanding the pathogenesis and etiology of t-MNs. In a systematic analysis of 416 patients with t-MN and detailed prior exposure history, we found that TP53 mutations were significantly associated with prior treatment with thalidomide analogs, specifically lenalidomide. We demonstrated experimentally that lenalidomide treatment provides a selective advantage to Trp53-mutant hematopoietic stem and progenitor cells (HSPCs) in vitro and in vivo, the effect of which was specific to Trp53-mutant HSPCs and was not observed in HSPCs with other CH mutations. Because of the differences in CK1α degradation, pomalidomide treatment did not provide an equivalent level of selective advantage to Trp53-mutant HSPCs, providing a biological rationale for its use in patients at high risk for t-MN. These findings highlight the role of lenalidomide treatment in promoting TP53-mutated t-MNs and offer a potential alternative strategy to mitigate the risk of t-MN development.
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Neoplasias Primarias Secundarias , Talidomida , Humanos , Lenalidomida/farmacología , Talidomida/efectos adversos , Células Madre Hematopoyéticas/metabolismo , Genes p53 , Mutación , Neoplasias Primarias Secundarias/etiología , Neoplasias Primarias Secundarias/genética , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Chronic obstructive pulmonary disease (COPD) is associated with age and smoking, but other determinants of the disease are incompletely understood. Clonal hematopoiesis of indeterminate potential (CHIP) is a common, age-related state in which somatic mutations in clonal blood populations induce aberrant inflammatory responses. Patients with CHIP have an elevated risk for cardiovascular disease, but the association of CHIP with COPD remains unclear. We analyzed whole-genome sequencing and whole-exome sequencing data to detect CHIP in 48 835 patients, of whom 8444 had moderate to very severe COPD, from four separate cohorts with COPD phenotyping and smoking history. We measured emphysema in murine models in which Tet2 was deleted in hematopoietic cells. In the COPDGene cohort, individuals with CHIP had risks of moderate-to-severe, severe, or very severe COPD that were 1.6 (adjusted 95% confidence interval [CI], 1.1-2.2) and 2.2 (adjusted 95% CI, 1.5-3.2) times greater than those for noncarriers. These findings were consistently observed in three additional cohorts and meta-analyses of all patients. CHIP was also associated with decreased FEV1% predicted in the COPDGene cohort (mean between-group differences, -5.7%; adjusted 95% CI, -8.8% to -2.6%), a finding replicated in additional cohorts. Smoke exposure was associated with a small but significant increased risk of having CHIP (odds ratio, 1.03 per 10 pack-years; 95% CI, 1.01-1.05 per 10 pack-years) in the meta-analysis of all patients. Inactivation of Tet2 in mouse hematopoietic cells exacerbated the development of emphysema and inflammation in models of cigarette smoke exposure. Somatic mutations in blood cells are associated with the development and severity of COPD, independent of age and cumulative smoke exposure.
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Hematopoyesis Clonal , Enfermedad Pulmonar Obstructiva Crónica/genética , Animales , Femenino , Humanos , Masculino , Ratones , Persona de Mediana Edad , Oportunidad Relativa , Enfermedad Pulmonar Obstructiva Crónica/etiología , Factores de Riesgo , Fumar/efectos adversos , Secuenciación del ExomaRESUMEN
Rationale: Constantly exposed to the external environment and mutagens such as tobacco smoke, human lungs have one of the highest somatic mutation rates among all human organs. However, the relationship of these mutations to lung disease and function is not known. Objectives: To identify the prevalence and significance of clonal somatic mutations in chronic lung diseases. Methods: We analyzed the clonal somatic mutations from 1,251 samples of normal and diseased noncancerous lung tissue RNA sequencing with paired whole-genome sequencing from the Lung Tissue Research Consortium. We examined the associations of somatic mutations with lung function, disease status, and computationally deconvoluted cell types in two of the most common diseases represented in our dataset, chronic obstructive pulmonary disease (COPD; 29%) and idiopathic pulmonary fibrosis (IPF; 13%). Measurements and Main Results: Clonal somatic mutational burden was associated with reduced lung function in both COPD and IPF. We identified an increased prevalence of clonal somatic mutations in individuals with IPF compared with normal control subjects and individuals with COPD independent of age and smoking status. IPF clonal somatic mutations were enriched in disease-related and airway epithelial-expressed genes such as MUC5B in IPF. Patients who were MUC5B risk variant carriers had increased odds of developing somatic mutations of MUC5B that were explained by increased expression of MUC5B. Conclusions: Our identification of an increased prevalence of clonal somatic mutation in diseased lung that correlates with airway epithelial gene expression and disease severity highlights for the first time the role of somatic mutational processes in lung disease genetics.
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Fibrosis Pulmonar Idiopática , Enfermedad Pulmonar Obstructiva Crónica , Humanos , Fibrosis Pulmonar Idiopática/genética , Fibrosis Pulmonar Idiopática/metabolismo , Pulmón/metabolismo , Mutación/genética , Fenómenos Fisiológicos Respiratorios , Enfermedad Pulmonar Obstructiva Crónica/epidemiología , Enfermedad Pulmonar Obstructiva Crónica/genética , Enfermedad Pulmonar Obstructiva Crónica/metabolismoRESUMEN
Adult-onset hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening disease of immune hyperactivation. Unlike pediatric HLH, adult HLH is rarely driven by germline genetic variants. Although numerous precipitating etiologies have been identified, the reason that HLH occurs in only a subset of individuals and how other factors contribute to the disease remains unknown. We hypothesized that clonal hematopoiesis (CH), a state in which somatic mutations in blood cells cause an expanded population of mutant hematopoietic cells and drive an aberrant inflammatory state, could contribute to adult-onset HLH. In a highly annotated cohort of older adults with HLH we found that CH was more prevalent than in control cohorts. Using the adult-onset HLH mouse model in which repeated treatments of the TLR9 agonist, ODN1826, was delivered to the mouse, we observed that macrophages carrying mutations in Tet2, one of the most commonly mutated genes in CH, have an enhanced inflammatory response to TLR9 agonism. Finally, mice carrying Tet2 mutations in the hematopoietic compartment (a common model for CH) displayed an exaggerated response to TLR9 agonism, including worse splenomegaly and anemia. Our data suggest that CH is more common in individuals with adult-onset HLH and can contribute to the pathophysiology of this disease.
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Hematopoyesis Clonal , Linfohistiocitosis Hemofagocítica/metabolismo , Mutación , Adulto , Edad de Inicio , Anciano , Animales , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Dioxigenasas , Femenino , Humanos , Linfohistiocitosis Hemofagocítica/genética , Linfohistiocitosis Hemofagocítica/patología , Masculino , Ratones , Ratones Mutantes , Persona de Mediana Edad , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Receptor Toll-Like 9/agonistas , Receptor Toll-Like 9/genética , Receptor Toll-Like 9/metabolismoRESUMEN
Pharmacologic agents that modulate ubiquitin ligase activity to induce protein degradation are a major new class of therapeutic agents, active in a number of hematologic malignancies. However, we currently have a limited understanding of the determinants of activity of these agents and how resistance develops. We developed and used a novel quantitative, targeted mass spectrometry (MS) assay to determine the relative activities, kinetics, and cell-type specificity of thalidomide and 4 analogs, all but 1 of which are in clinical use or clinical trials for hematologic malignancies. Thalidomide analogs bind the CRL4CRBN ubiquitin ligase and induce degradation of particular proteins, but each of the molecules studied has distinct patterns of substrate specificity that likely underlie the clinical activity and toxicities of each drug. Our results demonstrate that the activity of molecules that induce protein degradation depends on the strength of ligase-substrate interaction in the presence of drug, the levels of the ubiquitin ligase, and the expression level of competing substrates. These findings highlight a novel mechanism of resistance to this class of drugs mediated by competition between substrates for access to a limiting pool of the ubiquitin ligase. We demonstrate that increased expression of a nonessential substrate can lead to decreased degradation of other substrates that are critical for antineoplastic activity of the drug, resulting in drug resistance. These studies provide general rules that govern drug-dependent substrate degradation and key differences between thalidomide analog activity in vitro and in vivo.
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Proteolisis/efectos de los fármacos , Talidomida/análogos & derivados , Talidomida/química , Talidomida/farmacología , Ubiquitina-Proteína Ligasas/química , Neoplasias Hematológicas/enzimología , Humanos , Especificidad por Sustrato , Ubiquitina-Proteína Ligasas/efectos de los fármacosRESUMEN
BACKGROUND: The Northern Territory (NT) has the highest levels of alcohol consumption and harms in Australia. Since the creation of the NT Liquor Act 1978, which came into effect in 1979, numerous legislated alcohol policies have been introduced to attempt to address these harms. We present a narrative historical overview of alcohol policies implemented in the NT from 1979 to 2021. METHODS: Using scoping review methodology, databases were searched from 1979 to 2021. Of 506 articles screened, 34 met inclusion criteria. Reference lists of all included articles were searched, resulting in the inclusion of another 41 articles and reports, totalling 75 final documents. Policies were organised using Babor and colleagues (2010) established framework: 1. pricing/ taxation; 2. regulating physical availability; 3. modifying drinking environments; 4. drink-driving countermeasures; 5. restrictions on marketing; 6. education/persuasion; 7. treatment/early intervention. RESULTS: Two pricing/taxation policies have been implemented, Living With Alcohol (LWA) and Minimum Unit Price, both demonstrating evidence of positive effects on health and consumption outcomes. Eight policies approaches have focused on regulating physical availability, implemented at both individual and local area levels. Several of these policies have varied by location and been amended over time. There is some evidence demonstrating reduction in harms attributable to Liquor Supply Plans, localised restrictions, and General Restricted Areas, although these have been site specific. Of the three policies which targeted modifying the drinking environment; one was evaluated, finding a relocation of social harms, rather than a reduction. The literature outlines a range of controversies, particularly regarding policies in domain 2-3, including racial discrimination and a lack of policy stability. No policies relating to restricting marketing or education/persuasion programs were found. The only drink-driving legislated policy was considered to have contributed to the success of the LWA program. Three policies relating to treatment were described; two were not evaluated and evidence showed no ongoing benefits of Alcohol Mandatory Treatment. DISCUSSION: The NT has implemented a large number of alcohol policies, several of which have evidence of positive effects. However, these policies have often existed in a context of clear politicisation of alcohol policy, frequently with an implicit focus on Aboriginal people's consumption.
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Bebidas Alcohólicas , Política Pública , Consumo de Bebidas Alcohólicas/epidemiología , Consumo de Bebidas Alcohólicas/prevención & control , Política de Salud , Humanos , Northern Territory/epidemiología , ImpuestosRESUMEN
Effectiveness of interventions for violent behaviour may be undermined by the presence of neurocognitive impairment, which is known to be common among alcohol and other drug (AOD) users and violent offenders. The current study aimed to examine whether the cognitive functioning of individuals with AOD histories presenting to a specialist addiction neuropsychology service differed according to their offending history (i.e. non-offending, non-violent offending and violent offending), using a retrospective case file audit design. Data were extracted from 190 clients. Tests assessed a breadth of cognitive domains. Violent offenders demonstrated the lowest premorbid IQ out of the three groups, and a significantly higher proportion of violent offenders presented with impaired divided attention and impaired cognitive inhibition compared to non-violent offenders. Rates of impairment across groups were well beyond those expected within the general population. Delivery of both AOD and violence interventions should be adapted to accommodate individuals' cognitive difficulties.
RESUMEN
Truncating mutations in the terminal exon of protein phosphatase Mg2+/Mn2+ 1D (PPM1D) have been identified in clonal hematopoiesis and myeloid neoplasms, with a striking enrichment in patients previously exposed to chemotherapy. In this study, we demonstrate that truncating PPM1D mutations confer a chemoresistance phenotype, resulting in the selective expansion of PPM1D-mutant hematopoietic cells in the presence of chemotherapy in vitro and in vivo. Clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein-9 nuclease mutational profiling of PPM1D in the presence of chemotherapy selected for the same exon 6 mutations identified in patient samples. These exon 6 mutations encode for a truncated protein that displays elevated expression and activity due to loss of a C-terminal degradation domain. Global phosphoproteomic profiling revealed altered phosphorylation of target proteins in the presence of the mutation, highlighting multiple pathways including the DNA damage response (DDR). In the presence of chemotherapy, PPM1D-mutant cells have an abrogated DDR resulting in altered cell cycle progression, decreased apoptosis, and reduced mitochondrial priming. We demonstrate that treatment with an allosteric, small molecule inhibitor of PPM1D reverts the phosphoproteomic, DDR, apoptotic, and mitochondrial priming changes observed in PPM1D-mutant cells. Finally, we show that the inhibitor preferentially kills PPM1D-mutant cells, sensitizes the cells to chemotherapy, and reverses the chemoresistance phenotype. These results provide an explanation for the enrichment of truncating PPM1D mutations in the blood of patients exposed to chemotherapy and in therapy-related myeloid neoplasms, and demonstrate that PPM1D can be a targeted in the prevention of clonal expansion of PPM1D-mutant cells and the treatment of PPM1D-mutant disease.
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Secuencia de Bases , Resistencia a Antineoplásicos , Inhibidores Enzimáticos/farmacología , Neoplasias Hematológicas , Células Madre Hematopoyéticas/enzimología , Trastornos Mieloproliferativos , Proteínas de Neoplasias , Células Madre Neoplásicas/enzimología , Proteína Fosfatasa 2C , Eliminación de Secuencia , Sistemas CRISPR-Cas , Línea Celular Tumoral , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Neoplasias Hematológicas/tratamiento farmacológico , Neoplasias Hematológicas/enzimología , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/patología , Células Madre Hematopoyéticas/patología , Humanos , Trastornos Mieloproliferativos/tratamiento farmacológico , Trastornos Mieloproliferativos/enzimología , Trastornos Mieloproliferativos/genética , Trastornos Mieloproliferativos/patología , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Células Madre Neoplásicas/patología , Proteína Fosfatasa 2C/antagonistas & inhibidores , Proteína Fosfatasa 2C/genética , Proteína Fosfatasa 2C/metabolismoRESUMEN
Monitoring levels of alcohol-related harm in populations requires indicators that are robust to extraneous influence. We investigated the validity of an indicator for police-attributed alcohol-related assault. We summarized offence records from Queensland Police, investigated patterns of missing data, and considered the utility of a surrogate for alcohol-related assault. Of 242 107 assaults from 2004-2014, in 35% of cases the drug used by the offender was recorded as 'unknown'. Under various assumptions about non-random missingness the proportion of assaults judged to be alcohol-related varied from 30%-65%. We found a sharp increase in missing data from 2007 suggesting the downward trend from that point is artefactual. Conversely, we found a stable and increasing trend using a time-based surrogate. The volume of missing data and other limitations preclude valid estimation of trends using the police indicator, and demonstrate how misleading results can be produced. Our analysis supports the use of an empirically-based surrogate indicator.
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Consumo de Bebidas Alcohólicas/efectos adversos , Víctimas de Crimen/estadística & datos numéricos , Policia/estadística & datos numéricos , Violencia/estadística & datos numéricos , Femenino , Humanos , Masculino , Queensland , Registros/estadística & datos numéricosRESUMEN
Importance: Data sets linking comprehensive genomic profiling (CGP) to clinical outcomes may accelerate precision medicine. Objective: To assess whether a database that combines EHR-derived clinical data with CGP can identify and extend associations in non-small cell lung cancer (NSCLC). Design, Setting, and Participants: Clinical data from EHRs were linked with CGP results for 28â¯998 patients from 275 US oncology practices. Among 4064 patients with NSCLC, exploratory associations between tumor genomics and patient characteristics with clinical outcomes were conducted, with data obtained between January 1, 2011, and January 1, 2018. Exposures: Tumor CGP, including presence of a driver alteration (a pathogenic or likely pathogenic alteration in a gene shown to drive tumor growth); tumor mutation burden (TMB), defined as the number of mutations per megabase; and clinical characteristics gathered from EHRs. Main Outcomes and Measures: Overall survival (OS), time receiving therapy, maximal therapy response (as documented by the treating physician in the EHR), and clinical benefit rate (fraction of patients with stable disease, partial response, or complete response) to therapy. Results: Among 4064 patients with NSCLC (median age, 66.0 years; 51.9% female), 3183 (78.3%) had a history of smoking, 3153 (77.6%) had nonsquamous cancer, and 871 (21.4%) had an alteration in EGFR, ALK, or ROS1 (701 [17.2%] with EGFR, 128 [3.1%] with ALK, and 42 [1.0%] with ROS1 alterations). There were 1946 deaths in 7 years. For patients with a driver alteration, improved OS was observed among those treated with (n = 575) vs not treated with (n = 560) targeted therapies (median, 18.6 months [95% CI, 15.2-21.7] vs 11.4 months [95% CI, 9.7-12.5] from advanced diagnosis; P < .001). TMB (in mutations/Mb) was significantly higher among smokers vs nonsmokers (8.7 [IQR, 4.4-14.8] vs 2.6 [IQR, 1.7-5.2]; P < .001) and significantly lower among patients with vs without an alteration in EGFR (3.5 [IQR, 1.76-6.1] vs 7.8 [IQR, 3.5-13.9]; P < .001), ALK (2.1 [IQR, 0.9-4.0] vs 7.0 [IQR, 3.5-13.0]; P < .001), RET (4.6 [IQR, 1.7-8.7] vs 7.0 [IQR, 2.6-13.0]; P = .004), or ROS1 (4.0 [IQR, 1.2-9.6] vs 7.0 [IQR, 2.6-13.0]; P = .03). In patients treated with anti-PD-1/PD-L1 therapies (n = 1290, 31.7%), TMB of 20 or more was significantly associated with improved OS from therapy initiation (16.8 months [95% CI, 11.6-24.9] vs 8.5 months [95% CI, 7.6-9.7]; P < .001), longer time receiving therapy (7.8 months [95% CI, 5.5-11.1] vs 3.3 months [95% CI, 2.8-3.7]; P < .001), and increased clinical benefit rate (80.7% vs 56.7%; P < .001) vs TMB less than 20. Conclusions and Relevance: Among patients with NSCLC included in a longitudinal database of clinical data linked to CGP results from routine care, exploratory analyses replicated previously described associations between clinical and genomic characteristics, between driver mutations and response to targeted therapy, and between TMB and response to immunotherapy. These findings demonstrate the feasibility of creating a clinicogenomic database derived from routine clinical experience and provide support for further research and discovery evaluating this approach in oncology.
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Carcinoma de Pulmón de Células no Pequeñas/genética , Bases de Datos Genéticas , Registros Electrónicos de Salud , Inmunoterapia , Neoplasias Pulmonares/genética , Mutación , Anciano , Biomarcadores de Tumor/análisis , Carcinoma de Pulmón de Células no Pequeñas/terapia , Conjuntos de Datos como Asunto , Femenino , Perfilación de la Expresión Génica , Genómica , Genotipo , Humanos , Masculino , Registro Médico Coordinado , Persona de Mediana Edad , Medicina de Precisión , Receptor de Muerte Celular Programada 1/análisisAsunto(s)
Ácido Ascórbico , Leucemia , Humanos , Neoplasias , Células Madre Neoplásicas , Células Madre , VitaminasRESUMEN
BACKGROUND: Alcohol-related harm is a substantial burden on the community in Australia and internationally, particularly harm related to risky drinking practices of young people in the night-time economy. This protocol paper describes a study that will report on the changes in a wide range of health and justice outcome measures associated with major policy changes in the state of Queensland, Australia. A key element includes trading hours restrictions for licensed premises to 2 am for the state and 3 am in Safe Night Precincts (SNPs). Other measures introduced include drinks restrictions after midnight, increased patron banning measures for repeat offenders, mandatory ID scanning of patrons in late-night venues, and education campaigns. METHODS: The primary aim of the study is to evaluate change in the levels of harm due to these policy changes using administrative data (e.g., police, hospital, ambulance, and court data). Other study elements will investigate the impact of the Policy by measuring foot traffic volume in SNPs, using ID scanner data to quantify the volume of people entering venues and measure the effectiveness of banning notices, using patron interviews to quantify the levels of pre-drinking, intoxication and illicit drug use within night-time economy districts, and to explore the impacts of the Policy on business and live music, and costs to the community. DISCUSSION: The information gathered through this project aims to evaluate the effectiveness of the Policy and to draw on these findings to inform future prevention and enforcement approaches by policy makers, police, and venue staff.
Asunto(s)
Consumo de Bebidas Alcohólicas/legislación & jurisprudencia , Comercio/legislación & jurisprudencia , Concesión de Licencias/legislación & jurisprudencia , Política Pública , Violencia/prevención & control , Consumo de Bebidas Alcohólicas/efectos adversos , Consumo de Bebidas Alcohólicas/psicología , Comercio/economía , Estudios de Seguimiento , Humanos , Queensland , Factores de Tiempo , Violencia/estadística & datos numéricosRESUMEN
Access to the supply of alcohol is an important factor influencing adolescent alcohol consumption. Although alcohol sales outlets are prohibited from selling alcohol to underage youth, there has been limited research investigating compliance. The present study sought to estimate the extent to which adolescents that appeared underage were successfully able to purchase alcohol from packaged liquor outlets in Australia; and to identify store and sales characteristics associated with illegal purchasing. In 2012, purchase surveys were conducted (n= 310) at packaged liquor outlets in 28 urban and rural communities across three states of Australia: Western Australia, Queensland and Victoria. Confederates successfully purchased alcohol at 60% (95% CI: 55-66) of outlets. The density of general alcohol outlets in the surrounding area and the type of liquor outlet were predictors of successful alcohol purchases; however, this was moderated by the state in which the purchase was made. Regional geographical location was also found to predict underage alcohol purchase. The majority of alcohol sales outlets in Australia breach regulations prohibiting sales to underage youth. Consistent enforcement of policies across the states of Australia, and reducing the number of alcohol outlets, will help prevent alcohol outlets illegally selling alcohol to underage adolescents.