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The ATR kinase protects cells against DNA damage and replication stress and represents a promising anti-cancer drug target. The ATR inhibitors (ATRi) berzosertib and gartisertib are both in clinical trials for the treatment of advanced solid tumors as monotherapy or in combination with genotoxic agents. We carried out quantitative phospho-proteomic screening for ATR biomarkers that are highly sensitive to berzosertib and gartisertib, using an optimized mass spectrometry pipeline. Screening identified a range of novel ATR-dependent phosphorylation events, which were grouped into three broad classes: (i) targets whose phosphorylation is highly sensitive to ATRi and which could be the next generation of ATR biomarkers; (ii) proteins with known genome maintenance roles not previously known to be regulated by ATR; (iii) novel targets whose cellular roles are unclear. Class iii targets represent candidate DNA damage response proteins and, with this in mind, proteins in this class were subjected to secondary screening for recruitment to DNA damage sites. We show that one of the proteins recruited, SCAF1, interacts with RNAPII in a phospho-dependent manner and recruitment requires PARP activity and interaction with RNAPII. We also show that SCAF1 deficiency partly rescues RAD51 loading in cells lacking the BRCA1 tumor suppressor. Taken together these data reveal potential new ATR biomarkers and new genome maintenance factors.
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TP53-mutant blood cancers remain a clinical challenge. BH3-mimetic drugs inhibit BCL-2 pro-survival proteins, inducing cancer cell apoptosis. Despite acting downstream of p53, functional p53 is required for maximal cancer cell killing by BH3-mimetics through an unknown mechanism. Here, we report p53 is activated following BH3-mimetic induced mitochondrial outer membrane permeabilization, leading to BH3-only protein induction and thereby potentiating the pro-apoptotic signal. TP53-deficient lymphomas lack this feedforward loop, providing opportunities for survival and disease relapse after BH3-mimetic treatment. The therapeutic barrier imposed by defects in TP53 can be overcome by direct activation of the cGAS/STING pathway, which promotes apoptosis of blood cancer cells through p53-independent BH3-only protein upregulation. Combining clinically relevant STING agonists with BH3-mimetic drugs efficiently kills TRP53/TP53-mutant mouse B lymphoma, human NK/T lymphoma, and acute myeloid leukemia cells. This represents a promising therapy regime that can be fast-tracked to tackle TP53-mutant blood cancers in the clinic.
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Apoptosis , Proteínas de la Membrana , Proteína p53 Supresora de Tumor , Proteína p53 Supresora de Tumor/genética , Humanos , Animales , Ratones , Proteínas de la Membrana/genética , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Mutación , Neoplasias Hematológicas/tratamiento farmacológico , Neoplasias Hematológicas/genética , Proteínas Proto-Oncogénicas c-bcl-2/genética , Fragmentos de Péptidos/farmacología , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Transducción de Señal/efectos de los fármacos , Proteínas Proto-Oncogénicas/genéticaRESUMEN
Patient-derived xenograft (PDX) modeling is a valuable tool for the study of leukemia pathogenesis, progression, and therapy response. Engraftment of human leukemia cells occurs following injection into the tail vein (or retro-orbital vein) of preconditioned immunocompromised mice. Injected mice are maintained in a sterile and supportive housing environment until leukemia engraftment is observed, at which time studies such as drug treatments or leukemia sampling can occur. Here, we outline a method for generating PDXs from Acute Myeloid Leukemia (AML) patient samples using tail vein injection; however it can also be readily applied to T- and B- Acute Lymphoblastic Leukemia (ALL) samples.
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Modelos Animales de Enfermedad , Animales , Humanos , Ratones , Ensayos Antitumor por Modelo de Xenoinjerto/métodos , Leucemia Mieloide Aguda/patología , Xenoinjertos , Leucemia/patologíaRESUMEN
PURPOSE: To identify symptoms and their impacts on daily functioning and health-related quality of life (HRQoL) experienced by adult patients with ulcerative colitis (UC) and evaluate patient-reported outcome (PRO) measures for UC clinical studies. METHODS: A conceptual model of symptoms and impacts of UC were developed from a literature review. PRO measures were identified from the literature, clinical trials databases, health technology assessment submissions, and regulatory label claims, and were selected for conceptual analysis based on disease specificity and use across information sources. PRO measures covering the most concepts when mapped against the conceptual model were assessed for gaps in psychometric properties using Food and Drug Administration (FDA) guidance and consensus-based standards for the selection of health measurement instruments (COSMIN) criteria. RESULTS: The conceptual model grouped the 52 symptom concepts and 72 proximal and distal impacts into eight, two, and five dimensions, respectively. Of 65 PRO measures identified, eight underwent conceptual analysis. Measures covering the most concepts and assessed for psychometric properties were the Inflammatory Bowel Disease Questionnaire, Symptoms and Impacts Questionnaire for UC, UC-PRO symptoms modules, UC-PRO impact modules, and Crohn's and UC Questionnaire; all had good or excellent support for content validity. The UC-PRO Signs and Symptoms fully met FDA guidance and COSMIN criteria for content validity and most psychometric properties. CONCLUSION: Existing PRO measures assess concepts relevant to patients with UC, but all PRO measures reviewed require further psychometric evaluation to demonstrate they are fit for purpose.
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Colitis Ulcerosa , Medición de Resultados Informados por el Paciente , Psicometría , Calidad de Vida , Humanos , Colitis Ulcerosa/psicología , Encuestas y Cuestionarios/normasRESUMEN
BACKGROUND: There is increased emphasis on incorporating patient perspectives and patient-relevant endpoints in drug development. We developed a conceptual model of the impact of chronic hepatitis B (CHB) on patients' lives and evaluated the content validity of the Hepatitis B Quality of Life (HBQOL) instrument, a patient-reported outcome tool for use in clinical studies, as a patient-relevant endpoint to measure health-related quality of life in patients with CHB. METHODS: A literature review of qualitative studies of patient experience with CHB and concept elicitation telephone interviews with patients with CHB in the United Kingdom were used to develop a conceptual model of the experience and impact of living with CHB. The content validity of the HBQOL was evaluated using cognitive debriefing techniques. RESULTS: The qualitative literature review (N = 43 publications) showed that patients with CHB experience emotional/psychological impacts. During concept elicitation interviews (N = 24), fatigue was the most commonly reported symptom, and most participants were worried/anxious about virus transmission and disease progression/death. A conceptual model of patients' experiences with CHB was developed. The conceptual relevance and comprehensibility of the HBQOL were supported, though limitations, including the lack of a self-stigma item and recall period, were noted for future improvement. CONCLUSIONS: The conceptual model shows that patients with CHB experience emotional/psychological impacts that affect their lifestyles, relationships, and work/schooling. The cognitive debriefing interviews support the content validity of the HBQOL as a conceptually relevant patient-reported outcome measure of health-related quality of life.
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Hepatitis B Crónica , Hepatitis B , Humanos , Calidad de Vida , Estilo de Vida , AnsiedadRESUMEN
Mantle cell lymphoma (MCL) is an incurable B-cell malignancy with an overall poor prognosis, particularly for patients that progress on targeted therapies. Novel, more durable treatment options are needed for patients with MCL. Protein arginine methyltransferase 5 (PRMT5) is overexpressed in MCL and plays an important oncogenic role in this disease via epigenetic and posttranslational modification of cell cycle regulators, DNA repair genes, components of prosurvival pathways, and RNA splicing regulators. The mechanism of targeting PRMT5 in MCL remains incompletely characterized. Here, we report on the antitumor activity of PRMT5 inhibition in MCL using integrated transcriptomics of in vitro and in vivo models of MCL. Treatment with a selective small-molecule inhibitor of PRMT5, PRT-382, led to growth arrest and cell death and provided a therapeutic benefit in xenografts derived from patients with MCL. Transcriptional reprograming upon PRMT5 inhibition led to restored regulatory activity of the cell cycle (p-RB/E2F), apoptotic cell death (p53-dependent/p53-independent), and activation of negative regulators of B-cell receptor-PI3K/AKT signaling (PHLDA3, PTPROt, and PIK3IP1). We propose pharmacologic inhibition of PRMT5 for patients with relapsed/refractory MCL and identify MTAP/CDKN2A deletion and wild-type TP53 as biomarkers that predict a favorable response. Selective targeting of PRMT5 has significant activity in preclinical models of MCL and warrants further investigation in clinical trials.
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Linfoma de Células del Manto , Fosfatidilinositol 3-Quinasas , Adulto , Humanos , Línea Celular Tumoral , Linfoma de Células del Manto/tratamiento farmacológico , Linfoma de Células del Manto/genética , Linfoma de Células del Manto/patología , Fosfatidilinositol 3-Quinasas/metabolismo , Proteína-Arginina N-Metiltransferasas/metabolismo , Transducción de Señal , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
The NEK1 kinase controls ciliogenesis, mitosis, and DNA repair, and NEK1 mutations cause human diseases including axial spondylometaphyseal dysplasia and amyotrophic lateral sclerosis. C21ORF2 mutations cause a similar pattern of human diseases, suggesting close functional links with NEK1 Here, we report that endogenous NEK1 and C21ORF2 form a tight complex in human cells. A C21ORF2 interaction domain "CID" at the C-terminus of NEK1 is necessary for its association with C21ORF2 in cells, and pathogenic mutations in this region disrupt the complex. AlphaFold modelling predicts an extended binding interface between a leucine-rich repeat domain in C21ORF2 and the NEK1-CID, and our model may explain why pathogenic mutations perturb the complex. We show that NEK1 mutations that inhibit kinase activity or weaken its association with C21ORF2 severely compromise ciliogenesis, and that C21ORF2, like NEK1 is required for homologous recombination. These data enhance our understanding of how the NEK1 kinase is regulated, and they shed light on NEK1-C21ORF2-associated diseases.
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Reparación del ADN , Osteocondrodisplasias , Humanos , Mutación/genética , Quinasa 1 Relacionada con NIMA/genética , Osteocondrodisplasias/genética , FosforilaciónRESUMEN
Richter's Transformation (RT) is a poorly understood and fatal progression of chronic lymphocytic leukemia (CLL) manifesting histologically as diffuse large B-cell lymphoma. Protein arginine methyltransferase 5 (PRMT5) is implicated in lymphomagenesis, but its role in CLL or RT progression is unknown. We demonstrate herein that tumors uniformly overexpress PRMT5 in patients with progression to RT. Furthermore, mice with B-specific overexpression of hPRMT5 develop a B-lymphoid expansion with increased risk of death, and Eµ-PRMT5/TCL1 double transgenic mice develop a highly aggressive disease with transformation that histologically resembles RT; where large-scale transcriptional profiling identifies oncogenic pathways mediating PRMT5-driven disease progression. Lastly, we report the development of a SAM-competitive PRMT5 inhibitor, PRT382, with exclusive selectivity and optimal in vitro and in vivo activity compared to available PRMT5 inhibitors. Taken together, the discovery that PRMT5 drives oncogenic pathways promoting RT provides a compelling rationale for clinical investigation of PRMT5 inhibitors such as PRT382 in aggressive CLL/RT cases.
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Leucemia Linfocítica Crónica de Células B , Linfoma de Células B Grandes Difuso , Animales , Ratones , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/patología , Linfoma de Células B Grandes Difuso/patologíaRESUMEN
Background: Social distancing has been essential in mitigating the spread of the SARS-CoV-2 virus. Evidence regarding the impact of reduced social contact on mental health during the pandemic has been mixed, however, with studies suggesting that enduring personality traits and affect regulation impairments may together increase risk for suicidal distress during periods of lockdown. The present study utilized experience sampling and longitudinal follow-up methods to evaluate intolerance of aloneness (IA) as a predictor of suicidal ideation (SI) during the pandemic. Methods: A general adult sample (n = 184) recruited online completed an 8-week experience sampling protocol via smartphone between April and September 2020. A subset of n = 69 participants completed a follow-up assessment of SI six months after the initial study period. Results: IA was associated with suicidal ideation both at baseline and prospectively during the experience sampling period. Individuals with greater IA were more likely to report SI in the short-term context of reduced daily in-person social contact. Higher IA at baseline furthermore prospectively predicted the occurrence of SI during the 6-month follow-up period. Limitations: The sample was relatively homogenous in terms of demographic characteristics and excluded individuals with limited access to communication technology. While statistical models accounted for current mental health treatment status, other factors that were not assessed (such as adverse events or psychiatric symptoms in non-treatment-seeking subjects) may have contributed to the development of SI. Conclusions: Findings enhance understanding of how personality-based factors may contribute to suicide risk during periods of social distancing, informing both clinical treatment, risk assessment, and public health intervention approaches.
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Limited information exists about the cellular distribution of mutations which persist in remission in acute myeloid leukemia (AML) (variably considered pre-leukemic mutations). We hypothesized that mutations detectable in all cell compartments may be less pathogenic than those that are myeloid-restricted. Here, we describe the cellular compartments that have IDH mutations in five patients with IDH-mutated AML in morphologic remission. Unlike pre-leukemic clones harboring the more common DNMT3A, TET2 and ASXL1 (DTA) mutations, we show that IDH mutations are myeloid-restricted. This finding provides an explanation for the reports that IDH mutations carry a higher risk for relapse than DTA mutations. Detailed analysis of one case also shows acquisition of additional mutations in distinct cellular compartments, illustrating subclonal complexity associated with therapeutics.
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ADN (Citosina-5-)-Metiltransferasas , Leucemia Mieloide Aguda , Humanos , ADN (Citosina-5-)-Metiltransferasas/genética , ADN Metiltransferasa 3A , Nucleofosmina , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , MutaciónRESUMEN
Venetoclax is an effective treatment for certain blood cancers, such as chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). However, most patients relapse while on venetoclax and further treatment options are limited. Combining venetoclax with immunotherapies is an attractive approach; however, a detailed understanding of how venetoclax treatment impacts normal immune cells in patients is lacking. In this study, we performed deep profiling of peripheral blood (PB) cells from patients with CLL and AML before and after short-term treatment with venetoclax using mass cytometry (cytometry by time of flight) and found no impact on the concentrations of key T-cell subsets or their expression of checkpoint molecules. We also analyzed PB from patients with breast cancer receiving venetoclax long-term using a single-cell multiomics approach (cellular indexing of transcriptomes and epitopes by sequencing) and functional assays. We found significant depletion of B-cell populations with low expression of MCL-1 relative to other immune cells, attended by extensive transcriptomic changes. By contrast, there was less impact on circulating T cells and natural killer (NK) cells, with no changes in their subset composition, transcriptome, or function following venetoclax treatment. Our data indicate that venetoclax has minimal impact on circulating T or NK cells, supporting the rationale of combining this BH3 mimetic drug with cancer immunotherapies for more durable antitumor responses.
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Leucemia Linfocítica Crónica de Células B , Leucemia Mieloide Aguda , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Células Asesinas Naturales , Leucemia Mieloide Aguda/tratamiento farmacológico , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéuticoRESUMEN
Livestock keeping can positively influence the nutritional status of populations and households through increased consumption of animal-source foods (ASF) and other indirect pathways, but can also adversely affect health by increasing the risk of diseases. We conducted a systematic review synthesising the current state of knowledge on the associations among livestock keeping, infectious disease and the nutritional status of children under 5 years and women of reproductive age in low- and lower-middle-income countries (LMICs). A comprehensive search of 12 electronic databases and grey literature sources published from 1991 to the end of December 2020 was conducted. Investigations exploring relationships between livestock keeping and risk of infectious disease transmission and nutritional status were selected using pre-defined inclusion criteria. After screening and filtering of 34,402 unique references, 176 references were included in the final synthesis. Most (160/176, 90.1%) of the references included in the final synthesis were from sub-Saharan Africa (SSA) and Asia. About two out of every five (42%) studies reviewed showed that livestock production is associated with improved height-for-age Z scores (HAZ) and weight-for-length/height Z scores (WHZ), while close to a third (30.7%) with improved weight-for-age Z scores (WAZ). Similarly, livestock production showed a positive or neutral relationship with women's nutritional status in almost all the references that reported on the topic. Conversely, four-fifths (66/81, 79.5%) of the references reporting on infection and morbidity outcomes indicated that livestock keeping is linked to a wide range of infectious disease outcomes, which are spread primarily through water, food and insects. In conclusion, in many LMIC settings, livestock production is associated with better nutritional outcomes but also a higher risk of disease transmission or morbidity among women and children.This review was prospectively registered on PROSPERO 2020 [CRD42020193622].
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Enfermedades Transmisibles , Estado Nutricional , Animales , Humanos , Niño , Femenino , Preescolar , Países en Desarrollo , Ganado , MorbilidadRESUMEN
Randomized trials in acute myeloid leukemia (AML) have demonstrated improved survival by the BCL-2 inhibitor venetoclax combined with azacitidine in older patients, and clinical trials are actively exploring the role of venetoclax in combination with intensive chemotherapy in fitter patients with AML. As most patients still develop recurrent disease, improved understanding of relapse mechanisms is needed. We find that 17% of patients relapsing after venetoclax-based therapy for AML have acquired inactivating missense or frameshift/nonsense mutations in the apoptosis effector gene BAX. In contrast, such variants were rare after genotoxic chemotherapy. BAX variants arose within either leukemic or preleukemic compartments, with multiple mutations observed in some patients. In vitro, AML cells with mutated BAX were competitively selected during prolonged exposure to BCL-2 antagonists. In model systems, AML cells rendered deficient for BAX, but not its close relative BAK, displayed resistance to BCL-2 targeting, whereas sensitivity to conventional chemotherapy was variable. Acquired mutations in BAX during venetoclax-based therapy represent a novel mechanism of resistance to BH3-mimetics and a potential barrier to the long-term efficacy of drugs targeting BCL-2 in AML.
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Leucemia Mieloide Aguda , Proteínas Proto-Oncogénicas c-bcl-2 , Humanos , Anciano , Proteína X Asociada a bcl-2/genética , Línea Celular Tumoral , Proteínas Proto-Oncogénicas c-bcl-2/genética , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Apoptosis , MutaciónRESUMEN
INTRODUCTION: Concerns about the impact of the COVID-19 pandemic on mental health have led to efforts to understand how pandemic-specific factors, such as decreased social contact during periods of social distancing, may relate to suicide risk. The present study evaluated personality-based risk factors and frequency of social contact as prospective predictors of suicidal ideation (SI) during the pandemic. METHODS: We tested a relational diathesis-stress model of suicide focusing on insecure attachment, trait loneliness, and social contact as predictors of SI, using twice-weekly survey data collected via smartphone from a community sample (n = 184) over 8 weeks. RESULTS: Multilevel modeling showed that both trait loneliness and anxious attachment predicted the prospective development of SI during the study period. Reduced in-person contact, but not remote contact, was proximally associated with increased SI. Participants with high attachment avoidance were more likely to develop SI in the context of reduced daily in-person contact compared to participants without these traits. CONCLUSION: Findings support a relational diathesis-stress model of suicide risk during the pandemic, showing that dispositional traits related to emotional connection with others predicted the relative salience of reduced social contact as a proximal risk factor for SI.
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COVID-19 , Ideación Suicida , Humanos , Soledad/psicología , Pandemias , Susceptibilidad a Enfermedades , Evaluación Ecológica Momentánea , Factores de RiesgoRESUMEN
There is increasing recognition of the prognostic significance of tumor cell major histocompatibility complex (MHC) class II expression in anti-cancer immunity. Relapse of acute myeloid leukemia (AML) following allogeneic stem cell transplantation (alloSCT) has recently been linked to MHC class II silencing in leukemic blasts; however, the regulation of MHC class II expression remains incompletely understood. Utilizing unbiased CRISPR-Cas9 screens, we identify that the C-terminal binding protein (CtBP) complex transcriptionally represses MHC class II pathway genes, while the E3 ubiquitin ligase complex component FBXO11 mediates degradation of CIITA, the principal transcription factor regulating MHC class II expression. Targeting these repressive mechanisms selectively induces MHC class II upregulation across a range of AML cell lines. Functionally, MHC class II+ leukemic blasts stimulate antigen-dependent CD4+ T cell activation and potent anti-tumor immune responses, providing fundamental insights into the graft-versus-leukemia effect. These findings establish the rationale for therapeutic strategies aimed at restoring tumor-specific MHC class II expression to salvage AML relapse post-alloSCT and also potentially to enhance immunotherapy outcomes in non-myeloid malignancies.
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Proteínas F-Box , Leucemia Mieloide Aguda , Oxidorreductasas de Alcohol , Proteínas de Unión al ADN , Proteínas F-Box/genética , Antígenos HLA/genética , Antígenos de Histocompatibilidad Clase II/genética , Antígenos de Histocompatibilidad Clase II/metabolismo , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Activación de Linfocitos , Proteína-Arginina N-Metiltransferasas/metabolismo , Recurrencia , Factores de Transcripción/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
Introduction: Peritoneal dialysis (PD)-related peritonitis is one of the leading causes of discontinuation of PD and is considered a critically important outcome for patients on PD. However, there is no universally accepted method of measuring this outcome in clinical trials. Methods: We convened an online consensus workshop to establish a core outcome measure for PD-related peritonitis in clinical trials. Results: A total of 53 participants, including 18 patients and caregivers, from 12 countries engaged in breakout discussions in this workshop. Transcripts were analyzed thematically. We identified the following 3 themes: (i) feasibility and applicability across diverse settings, which reflected the difficulty with implementing laboratory-based measures in resource-limited environments; (ii) ensuring validity, which included minimizing false positives and considering the specificity of symptoms; and (iii) being meaningful and tangible to patients, which meant that the measure should be easy to interpret, reflect the impact that symptoms have on patients, and promote transparency by standardizing the reporting of peritonitis among dialysis units. Conclusion: A core outcome measure for PD-related peritonitis should include both symptom-based and laboratory-based criteria. Thus, the International Society for Peritoneal Dialysis (ISPD) definition of peritonitis is acceptable. However, there should be consideration of reporting suspected peritonitis in cases where laboratory confirmation is not possible. The measure should include all infections from the time of catheter insertion and capture both the rate of infection and the number of patients who remain peritonitis free. A core outcome measure with these features would increase the impact of clinical trials on the care and decision-making of patients receiving PD.
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The mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) catalyzes one of the rate-limiting steps in de novo pyrimidine biosynthesis, a pathway that provides essential metabolic precursors for nucleic acids, glycoproteins, and phospholipids. DHODH inhibitors (DHODHi) are clinically used for autoimmune diseases and are emerging as a novel class of anticancer agents, especially in acute myeloid leukemia (AML) where pyrimidine starvation was recently shown to reverse the characteristic differentiation block in AML cells. Herein, we show that DHODH blockade rapidly shuts down protein translation in leukemic stem cells (LSCs) and has potent and selective activity against multiple AML subtypes. Moreover, we find that ablation of CDK5, a gene that is recurrently deleted in AML and related disorders, increases the sensitivity of AML cells to DHODHi. Our studies provide important molecular insights and identify a potential biomarker for an emerging strategy to target AML.
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Leucemia Mieloide Aguda , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH , Dihidroorotato Deshidrogenasa , Inhibidores Enzimáticos/farmacología , Humanos , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/metabolismo , Biosíntesis de Proteínas , Pirimidinas/farmacologíaRESUMEN
The impact of reduced social contact on mental health during the COVID-19 pandemic has been identified as a major public health concern. While personality factors such as attachment style have been associated with psychological distress during the pandemic, the longitudinal relevance of these factors and the role of daily social contact in mitigating distress remains poorly understood. This study evaluated the impact of social contact and attachment style on changes in loneliness over an 8-week experience sampling period during the COVID-19 pandemic. A general adult sample (n = 184) recruited online completed measures of psychological distress, attachment, and loneliness via smartphone. Loneliness and daily social contact were assessed twice per week for eight weeks, yielding 1124 unique observations. During the experience sampling period, proximal increases in loneliness were associated with decreased daily in-person contact. In contrast, participants who described themselves as having fewer interactions via text, phone, or videoconferencing, as well as those with higher anxious and avoidant attachment traits, reported greater experiences of loneliness over time. These findings suggest the relevance of both enduring personality characteristics and daily social behaviors as risk factors for loneliness during the pandemic, pointing to potential targets for clinical intervention and future empirical study.
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Cancer cell metabolism is increasingly recognized as providing an exciting therapeutic opportunity. However, a drug that directly couples targeting of a metabolic dependency with the induction of cell death in cancer cells has largely remained elusive. Here we report that the drug-like small-molecule ironomycin reduces the mitochondrial iron load, resulting in the potent disruption of mitochondrial metabolism. Ironomycin promotes the recruitment and activation of BAX/BAK, but the resulting mitochondrial outer membrane permeabilization (MOMP) does not lead to potent activation of the apoptotic caspases, nor is the ensuing cell death prevented by inhibiting the previously established pathways of programmed cell death. Consistent with the fact that ironomycin and BH3 mimetics induce MOMP through independent nonredundant pathways, we find that ironomycin exhibits marked in vitro and in vivo synergy with venetoclax and overcomes venetoclax resistance in primary patient samples. SIGNIFICANCE: Ironomycin couples targeting of cellular metabolism with cell death by reducing mitochondrial iron, resulting in the alteration of mitochondrial metabolism and the activation of BAX/BAK. Ironomycin induces MOMP through a different mechanism to BH3 mimetics, and consequently combination therapy has marked synergy in cancers such as acute myeloid leukemia. This article is highlighted in the In This Issue feature, p. 587.