RESUMEN
While mutations affecting protein-coding regions have been examined across many cancers, structural variants at the genome-wide level are still poorly defined. Through integrative deep whole-genome and -transcriptome analysis of 101 castration-resistant prostate cancer metastases (109X tumor/38X normal coverage), we identified structural variants altering critical regulators of tumorigenesis and progression not detectable by exome approaches. Notably, we observed amplification of an intergenic enhancer region 624 kb upstream of the androgen receptor (AR) in 81% of patients, correlating with increased AR expression. Tandem duplication hotspots also occur near MYC, in lncRNAs associated with post-translational MYC regulation. Classes of structural variations were linked to distinct DNA repair deficiencies, suggesting their etiology, including associations of CDK12 mutation with tandem duplications, TP53 inactivation with inverted rearrangements and chromothripsis, and BRCA2 inactivation with deletions. Together, these observations provide a comprehensive view of how structural variations affect critical regulators in metastatic prostate cancer.
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Variación Estructural del Genoma/genética , Neoplasias de la Próstata/genética , Anciano , Anciano de 80 o más Años , Proteína BRCA2/metabolismo , Quinasas Ciclina-Dependientes/metabolismo , Variaciones en el Número de Copia de ADN , Exoma , Perfilación de la Expresión Génica/métodos , Genómica/métodos , Humanos , Masculino , Persona de Mediana Edad , Mutación , Metástasis de la Neoplasia/genética , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo , Secuencias Repetidas en Tándem/genética , Proteína p53 Supresora de Tumor/metabolismo , Secuenciación Completa del Genoma/métodosRESUMEN
Cytosolic DNA-mediated activation of the transcription factor IRF3 is a key event in host antiviral responses. Here we found that infection with DNA viruses induced interaction of the metabolic checkpoint kinase mTOR downstream effector and kinase S6K1 and the signaling adaptor STING in a manner dependent on the DNA sensor cGAS. We further demonstrated that the kinase domain, but not the kinase function, of S6K1 was required for the S6K1-STING interaction and that the TBK1 critically promoted this process. The formation of a tripartite S6K1-STING-TBK1 complex was necessary for the activation of IRF3, and disruption of this signaling axis impaired the early-phase expression of IRF3 target genes and the induction of T cell responses and mucosal antiviral immunity. Thus, our results have uncovered a fundamental regulatory mechanism for the activation of IRF3 in the cytosolic DNA pathway.
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ADN/inmunología , Factor 3 Regulador del Interferón/inmunología , Proteínas de la Membrana/inmunología , Proteínas Quinasas S6 Ribosómicas 90-kDa/inmunología , Adenoviridae/genética , Adenoviridae/inmunología , Animales , Células de la Médula Ósea/inmunología , Células de la Médula Ósea/metabolismo , Células Cultivadas , Citosol/inmunología , Citosol/metabolismo , Citosol/virología , ADN/genética , ADN/metabolismo , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Células HEK293 , Herpes Simple/inmunología , Herpes Simple/virología , Herpesvirus Humano 1/inmunología , Herpesvirus Humano 1/fisiología , Humanos , Inmunización/métodos , Immunoblotting , Factor 3 Regulador del Interferón/genética , Factor 3 Regulador del Interferón/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Nucleotidiltransferasas/genética , Nucleotidiltransferasas/inmunología , Nucleotidiltransferasas/metabolismo , Ovalbúmina/genética , Ovalbúmina/inmunología , Unión Proteica , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/inmunología , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Quinasas S6 Ribosómicas 90-kDa/genética , Proteínas Quinasas S6 Ribosómicas 90-kDa/metabolismoRESUMEN
Immune checkpoint blockade has revolutionized the field of oncology, inducing durable anti-tumour immunity in solid tumours. In patients with advanced prostate cancer, immunotherapy treatments have largely failed1-5. Androgen deprivation therapy is classically administered in these patients to inhibit tumour cell growth, and we postulated that this therapy also affects tumour-associated T cells. Here we demonstrate that androgen receptor (AR) blockade sensitizes tumour-bearing hosts to effective checkpoint blockade by directly enhancing CD8 T cell function. Inhibition of AR activity in CD8 T cells prevented T cell exhaustion and improved responsiveness to PD-1 targeted therapy via increased IFNγ expression. AR bound directly to Ifng and eviction of AR with a small molecule significantly increased cytokine production in CD8 T cells. Together, our findings establish that T cell intrinsic AR activity represses IFNγ expression and represents a novel mechanism of immunotherapy resistance.
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Linfocitos T CD8-positivos , Inmunoterapia , Neoplasias de la Próstata , Receptores Androgénicos , Antagonistas de Andrógenos/farmacología , Antagonistas de Andrógenos/uso terapéutico , Linfocitos T CD8-positivos/inmunología , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Interferón gamma , Masculino , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/inmunología , Neoplasias de la Próstata/metabolismo , Receptores Androgénicos/metabolismo , Insuficiencia del TratamientoRESUMEN
Ribosomal protein (RP) expression in higher eukaryotes is regulated translationally through the 5'TOP sequence. This mechanism evolved to more rapidly produce RPs on demand in different tissues. Here we show that 40S ribosomes, in a complex with the mRNA binding protein LARP1, selectively stabilize 5'TOP mRNAs, with disruption of this complex leading to induction of the impaired ribosome biogenesis checkpoint (IRBC) and p53 stabilization. The importance of this mechanism is underscored in 5q− syndrome, a macrocytic anemia caused by a large monoallelic deletion, which we found to also encompass the LARP1 gene. Critically, depletion of LARP1 alone in human adult CD34+ bone marrow precursor cells leads to a reduction in 5'TOP mRNAs and the induction of p53. These studies identify a 40S ribosome function independent of those in translation that, with LARP1, mediates the autogenous control of 5'TOP mRNA stability, whose disruption is implicated in the pathophysiology of 5q− syndrome.
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Autoantígenos/metabolismo , Biosíntesis de Proteínas , Secuencia de Oligopirimidina en la Región 5' Terminal del ARN , Estabilidad del ARN , ARN Mensajero/metabolismo , Ribonucleoproteínas/metabolismo , Proteínas Ribosómicas/metabolismo , Ribosomas/metabolismo , Anemia Macrocítica/genética , Anemia Macrocítica/metabolismo , Autoantígenos/genética , Células de la Médula Ósea/metabolismo , Deleción Cromosómica , Cromosomas Humanos Par 5/genética , Cromosomas Humanos Par 5/metabolismo , Células HCT116 , Humanos , Complejos Multiproteicos , Unión Proteica , Interferencia de ARN , ARN Mensajero/genética , Ribonucleoproteínas/genética , Proteínas Ribosómicas/genética , Ribosomas/genética , Factores de Tiempo , Transfección , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Antígeno SS-BRESUMEN
There is limited knowledge about the metabolic reprogramming induced by cancer therapies and how this contributes to therapeutic resistance. Here we show that although inhibition of PI3K-AKT-mTOR signaling markedly decreased glycolysis and restrained tumor growth, these signaling and metabolic restrictions triggered autophagy, which supplied the metabolites required for the maintenance of mitochondrial respiration and redox homeostasis. Specifically, we found that survival of cancer cells was critically dependent on phospholipase A2 (PLA2) to mobilize lysophospholipids and free fatty acids to sustain fatty acid oxidation and oxidative phosphorylation. Consistent with this, we observed significantly increased lipid droplets, with subsequent mobilization to mitochondria. These changes were abrogated in cells deficient for the essential autophagy gene ATG5 Accordingly, inhibition of PLA2 significantly decreased lipid droplets, decreased oxidative phosphorylation, and increased apoptosis. Together, these results describe how treatment-induced autophagy provides nutrients for cancer cell survival and identifies novel cotreatment strategies to override this survival advantage.
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Antineoplásicos/farmacología , Neoplasias/metabolismo , Transducción de Señal/efectos de los fármacos , Animales , Apoptosis , Autofagia , Benzamidas/farmacología , Línea Celular Tumoral , Respiración de la Célula/efectos de los fármacos , Supervivencia Celular , Compuestos Heterocíclicos con 3 Anillos/farmacología , Humanos , Gotas Lipídicas/metabolismo , Ratones , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Neoplasias/enzimología , Neoplasias/patología , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Fosfolipasa A2/farmacología , Fosfolípidos/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/metabolismo , Pirimidinas/farmacología , Células Tumorales CultivadasRESUMEN
Elevated ribosome biogenesis in oncogene-driven cancers is commonly targeted by DNA-damaging cytotoxic drugs. Our previous first-in-human trial of CX-5461, a novel, less genotoxic agent that specifically inhibits ribosome biogenesis via suppression of RNA polymerase I (Pol I) transcription, revealed single-agent efficacy in refractory blood cancers. Despite this clinical response, patients were not cured. In parallel, we demonstrated a marked improvement in the in vivo efficacy of CX-5461 in combination with PI3K/AKT/mTORC1 pathway inhibitors. Here, we reveal the molecular basis for this improved efficacy observed in vivo, which is associated with specific suppression of translation of mRNAs encoding regulators of cellular metabolism. Importantly, acquired resistance to this cotreatment is driven by translational rewiring that results in dysregulated cellular metabolism and induction of a cAMP-dependent pathway critical for the survival of blood cancers including lymphoma and acute myeloid leukemia. Our studies thus identify key molecular mechanisms underpinning the response of blood cancers to selective inhibition of ribosome biogenesis and define metabolic vulnerabilities that will facilitate the rational design of more effective regimens for Pol I-directed therapies.
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Neoplasias/metabolismo , Biosíntesis de Proteínas/genética , Biosíntesis de Proteínas/fisiología , Ribosomas/metabolismo , Transcripción Genética/efectos de los fármacos , Animales , Antineoplásicos/farmacología , Benzotiazoles/farmacología , Línea Celular Tumoral , Resistencia a Antineoplásicos , Factores de Intercambio de Guanina Nucleótido/metabolismo , Humanos , Masculino , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Ratones , Ratones Endogámicos C57BL , Naftiridinas/farmacología , Neoplasias/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Biosíntesis de Proteínas/efectos de los fármacos , Inhibidores de Proteínas Quinasas , ARN Polimerasa I/metabolismo , ARN Mensajero/metabolismo , ARN Ribosómico , Ribosomas/efectos de los fármacos , TranscriptomaRESUMEN
Many oncogenes enhance nucleotide usage to increase ribosome content, DNA replication, and cell proliferation, but in parallel trigger p53 activation. Both the impaired ribosome biogenesis checkpoint (IRBC) and the DNA damage response (DDR) have been implicated in p53 activation following nucleotide depletion. However, it is difficult to reconcile the two checkpoints operating together, as the IRBC induces p21-mediated G1 arrest, whereas the DDR requires that cells enter S phase. Gradual inhibition of inosine monophosphate dehydrogenase (IMPDH), an enzyme required for de novo GMP synthesis, reveals a hierarchical organization of these two checkpoints. We find that the IRBC is the primary nucleotide sensor, but increased IMPDH inhibition leads to p21 degradation, compromising IRBC-mediated G1 arrest and allowing S phase entry and DDR activation. Disruption of the IRBC alone is sufficient to elicit the DDR, which is strongly enhanced by IMPDH inhibition, suggesting that the IRBC acts as a barrier against genomic instability.
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Daño del ADN , Puntos de Control de la Fase G1 del Ciclo Celular , Nucleótidos/metabolismo , Ribosomas/metabolismo , Células HCT116 , Humanos , Nucleótidos/genética , Ribosomas/genética , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
BACKGROUND: Dementia is common in Parkinson's disease (PD), but there is wide variation in its timing. A critical gap in PD research is the lack of quantifiable markers of progression, and methods to identify early stages of dementia. Atrophy-based magnetic resonance imaging (MRI) has limited sensitivity in detecting or tracking changes relating to PD dementia, but quantitative susceptibility mapping (QSM), sensitive to brain tissue iron, shows potential for these purposes. OBJECTIVE: The objective of the paper is to study, for the first time, the longitudinal relationship between cognition and QSM in PD in detail. METHODS: We present a longitudinal study of clinical severity in PD using QSM, including 59 PD patients (without dementia at study onset), and 22 controls over 3 years. RESULTS: In PD, increased baseline susceptibility in the right temporal cortex, nucleus basalis of Meynert, and putamen was associated with greater cognitive severity after 3 years; and increased baseline susceptibility in basal ganglia, substantia nigra, red nucleus, insular cortex, and dentate nucleus was associated with greater motor severity after 3 years. Increased follow-up susceptibility in these regions was associated with increased follow-up cognitive and motor severity, with further involvement of hippocampus relating to cognitive severity. However, there were no consistent increases in susceptibility over 3 years. CONCLUSIONS: Our study suggests that QSM may predict changes in cognitive severity many months prior to overt cognitive involvement in PD. However, we did not find robust longitudinal changes in QSM over the course of the study. Additional tissue metrics may be required together with QSM for it to monitor progression in clinical practice and therapeutic trials. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Enfermedad de Alzheimer , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/diagnóstico por imagen , Enfermedad de Parkinson/patología , Estudios Longitudinales , Ganglios Basales/patología , Sustancia Negra/patología , Imagen por Resonancia Magnética/métodosRESUMEN
INTRODUCTION: A major pitfall of many of the established oral epithelial dysplasia (OED) grading criteria is their lack of reproducibility and accuracy to predict malignant transformation. The main objective of this study was to determine whether calibration of practicing oral pathologists on OED grading could improve the reproducibility of the WHO 2017 and the binary OED grading systems. METHODS: A nationwide online exercise was carried out to determine the influence of calibration on the reproducibility of the WHO 2017 and the binary OED grading systems. RESULTS: A significant improvement was observed in the inter-observer agreement for the WHO 2017 OED grading system (K 0.196 vs. 0.448; Kw 0.357 vs. 0.562) after the calibration exercise. The significant difference (p = 0.027) in the level of agreement between those with five or more years and less than 5 years of experience was no more observed (p = 0.426) after the calibration exercise. The percent agreement for binary grading was significantly higher (91.8%) for buccal mucosal lesions as compared to lesions on the tongue after the calibration exercise. CONCLUSION: This study validates the significance of calibration in improving the reproducibility of OED grading. The nationwide exercise resulted in a statistically significant improvement in the inter-observer agreement for the WHO 2017 OED grading system among a large number of oral pathologists. It is highly recommended that similar exercises should be organized periodically by professional bodies responsible for continuing education among oral pathologists to improve the reliability of OED grading for optimal treatment of oral potentially malignant disorders.
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Neoplasias de la Boca , Lesiones Precancerosas , Humanos , Reproducibilidad de los Resultados , Neoplasias de la Boca/patología , Mucosa Bucal/patología , Malasia , Calibración , Lesiones Precancerosas/patología , Hiperplasia/patología , Compuestos OrgánicosRESUMEN
BACKGROUND: Several studies have demonstrated that females have a higher risk of arrhythmia recurrence after pulmonary vein (PV) isolation for atrial fibrillation (AF). There are limited data on sex-based differences in PV reconnection rates at repeat ablation. We aimed to investigate sex-based differences in electrophysiological findings and atrial arrhythmia recurrence after repeat AF ablation METHODS: We conducted a retrospective study of 161 consecutive patients (32% female, age 65 ± 10 years) who underwent repeat AF ablation after index PV isolation between 2010 and 2022. Demographics, procedural characteristics and follow-up data were collected. Recurrent atrial tachycardia (AT)/AF was defined as any atrial arrhythmia ≥30 s in duration. RESULTS: Compared to males, females tended to be older and had a significantly higher prevalence of prior valve surgery (10 vs. 2%; P = .03). At repeat ablation, PV reconnection was found in 119 (74%) patients. Males were more likely to have PV reconnection at repeat ablation compared to females (81 vs. 59%; P = .004). Excluding repeat PV isolation, there were no significant differences in adjunctive ablation strategies performed at repeat ablation between females and males. During follow-up, there were no significant differences in freedom from AT/AF recurrence between females and males after repeat ablation (63 vs. 59% at 2 years, respectively; P = .48). CONCLUSIONS: After initial PV isolation, significantly fewer females have evidence of PV reconnection at the time of repeat ablation for recurrent AF. Despite this difference, long-term freedom from AT/AF was similar between females and males after repeat ablation.
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Fibrilación Atrial , Ablación por Catéter , Venas Pulmonares , Recurrencia , Reoperación , Humanos , Fibrilación Atrial/cirugía , Fibrilación Atrial/fisiopatología , Venas Pulmonares/cirugía , Masculino , Femenino , Ablación por Catéter/métodos , Estudios Retrospectivos , Anciano , Factores Sexuales , Persona de Mediana EdadRESUMEN
This corrects the article DOI: 10.1038/nature22964.
RESUMEN
S6K1 has been implicated in a number of key metabolic responses, which contribute to obesity. Critical among these is the control of a transcriptional program required for the commitment of mesenchymal stem cells to the adipocytic lineage. However, in contrast to its role in the cytosol, the functions and targets of nuclear S6K1 are unknown. Here, we show that adipogenic stimuli trigger nuclear translocation of S6K1, leading to H2BS36 phosphorylation and recruitment of EZH2 to H3, which mediates H3K27 trimethylation. This blocks Wnt gene expression, inducing the upregulation of PPARγ and Cebpa and driving increased adipogenesis. Consistent with this finding, white adipose tissue from S6K1-deficient mice exhibits no detectable H2BS36 phosphorylation or H3K27 trimethylation, whereas both responses are highly elevated in obese humans or in mice fed a high-fat diet. These findings define an S6K1-dependent mechanism in early adipogenesis, contributing to the promotion of obesity.
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Adipocitos/enzimología , Adipogénesis , Tejido Adiposo/enzimología , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Histonas/metabolismo , Obesidad/enzimología , Procesamiento Proteico-Postraduccional , Proteínas Quinasas S6 Ribosómicas 70-kDa/metabolismo , Proteínas Quinasas S6 Ribosómicas 90-kDa/metabolismo , Tejido Adiposo/patología , Adiposidad , Animales , Proteínas Potenciadoras de Unión a CCAAT/metabolismo , Modelos Animales de Enfermedad , Proteína Potenciadora del Homólogo Zeste 2/genética , Epigénesis Genética , Células HeLa , Histonas/genética , Humanos , Masculino , Metilación , Ratones , Obesidad/genética , Obesidad/patología , PPAR gamma/genética , PPAR gamma/metabolismo , Fosforilación , Proteínas Quinasas S6 Ribosómicas 70-kDa/genética , Proteínas Quinasas S6 Ribosómicas 90-kDa/genética , Transcripción Genética , Transfección , Proteínas Wnt/genética , Proteínas Wnt/metabolismo , Vía de Señalización WntRESUMEN
PURPOSE OF REVIEW: A bibliometric analysis was performed to analyze and compare the top 100 articles from the most well-known five pain journals: Pain, Pain Physician, Pain Medicine, Regional Anesthesia & Pain Medicine, and Journal of Pain. A query of the Scopus database was performed to filter the top 200 most cited articles from each journal. CY score was calculated for the top 200 articles from each journal by dividing the total number of citations by the number of years the article has been published. RECENT FINDINGS: All articles had a collective analysis of the top CY scores, the top 100 of which were further analyzed. The pain subtype, type of publication, country of origin, and senior author were extrapolated from these top 100 articles. Frequency tables were organized, revealing Pain Journal as the highest publishing journal out of the top 100 articles. Chronic pain was the most studied subtype of pain and narrative reviews were the most common type of evidence. Studies were also organized in five-year epochs to analyze the frequency of publications in these intervals. Results show that 2010-2014 had the highest frequency of articles published overall. Journal Impact Factor (JIF) is also an objective indicator of the average number of citations per published article from each journal. The journal with the highest JIF was Pain with an impact factor of 7.926. (6).
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INTRODUCTION: Social media has become a ubiquitous part of everyday life; however, evidence suggests patterns of social media use can affect sleep health in children and adolescents. This study aimed to examine the associations of intense and problematic social media use (SMU) with sleep-onset difficulties in adolescence. METHODS: We analysed data from 212,613 adolescents aged 11-15 years (51.1% girls) from 40 European and North American countries that participated in the 2017/2018 Health Behaviour in School-aged Children survey. Intense SMU assessed how often respondents had online contact through social media, and problematic SMU was assessed by symptoms of addiction to social media. Sleep-onset difficulties were assessed using a self-reported item. Multilevel mixed-effects logistic regression was used to obtain the estimates. RESULTS: Sleep-onset difficulties were more common among girls than boys (27.1% vs 20.8%). Intense SMU was significantly associated with sleep-onset difficulties in boys in 17 countries and in girls in 25 countries, while problematic SMU was significantly associated in most of the participating countries. Overall, exposure to problematic SMU alone was highly associated with sleep-onset difficulties both in girls (OR 2.20, 2.04-2.38) and boys (OR 1.88, 1.73-2.04), while the association estimates for intense SMU were smaller and comparable across gender (Girls: OR 1.27, 1.23-1.31; Boys: OR 1.22, 1.18-1.27). Sensitivity analyses supported the above findings. CONCLUSIONS: Intense and/or problematic SMU were associated with sleep-onset difficulties across gender with associations being higher for problematic compared to intense SMU. Prospective research with objective measures is needed to understand the causal mechanisms underlying these relationships.
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Medios de Comunicación Sociales , Humanos , Masculino , Adolescente , Femenino , Medios de Comunicación Sociales/estadística & datos numéricos , Niño , Europa (Continente) , América del Norte/epidemiología , Trastorno de Adicción a Internet/epidemiología , Encuestas y Cuestionarios , Trastornos del Sueño-Vigilia/epidemiología , Trastornos del Sueño-Vigilia/etiología , Conducta del AdolescenteRESUMEN
BACKGROUND: Analysis of industry payments to pediatric orthopaedic surgeons last occurred in 2017. We investigated payments to pediatric orthopaedic surgeons from 2015 to 2021 to understand surgeon characteristics associated with increased industry payments. METHODS: Open Payments Database datasets from 2015 to 2021 were queried for nonresearch payments to pediatric orthopaedic surgeons. Annual aggregates and subcategories were recorded. For surgeons receiving payments in 2021, the Hirsch index (h-index), gender, and US census division were found using the Scopus database, Open Payments Database, and online hospital profiles, respectively. χ 2 , Fisher exact, Mann-Whitney U , and t tests were used to compare surgeons in the top 25%, 10%, and 5% payment percentiles to the bottom 75%, 90%, and 95%, respectively. RESULTS: Payments rose 125% from 2015 to 2021. Education, royalties, and faculty/speaker increased most, while travel/lodging, honoraria, charitable contributions, and ownership interest decreased. Only royalties increased from 2019 to 2021. In 2021, of 419 pediatric orthopaedic surgeons receiving industry payments, men received greater median aggregate payments than women ($379.03 vs. $186.96, P =0.047). There were no differences in gender proportions between the top 75% and bottom 25% ( P =0.054), top 10% and bottom 90% ( P =0.235), and top 5% and bottom 95% ( P =0.280) earning comparison groups. The h-index was weakly positively correlated with industry payments ( rs =0.203, P <0.001). Mean h-indices in the 75th ( P <0.001, 95% CI: 2.62-7.65), 90th ( P =0.001, 95% CI: 3.28-13.03), and 95th ( P =0.005, 95% CI: 4.25-21.11) percentiles were significantly higher. Proportions of surgeons from the Middle Atlantic and West South Central in the 90th ( P =0.025) and 95th percentiles ( P =0.033), respectively, were significantly lower compared to all other regions. A higher proportion of surgeons from the Pacific were placed in the 90th ( P =0.004) and 95th ( P =0.024) percentiles. CONCLUSIONS: Industry payments to pediatric orthopaedic surgeons rose from 2015 to 2021. Most categories fell from 2019 to 2021, which may be related to the SARS-CoV-19 pandemic. In 2021, though gender was not related to aggregate payment percentile, location in select US census divisions and h-index was. LEVEL OF EVIDENCE: Level II-Retrospective study.
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Cirujanos Ortopédicos , Ortopedia , Cirujanos , Masculino , Humanos , Femenino , Niño , Estados Unidos , Estudios Retrospectivos , Industrias , Bases de Datos Factuales , Conflicto de InteresesRESUMEN
BACKGROUND: Percutaneous endocardial left atrial appendage occlusion (LAAO) is an alternative therapy for stroke prevention in patients with atrial fibrillation who are poor candidates for oral anticoagulants. Oral anticoagulation is generally discontinued 45 days following successful LAAO. Real-world data on early stroke and mortality following LAAO are lacking. METHODS: Using International Classification of Diseases, Tenth Revision, Clinical-Modification codes, we performed a retrospective observational registry analysis to examine the rates and predictors of stroke, mortality, and procedural complications during index hospitalization and 90-day readmission among 42 114 admissions in the Nationwide Readmissions Database for LAAO between 2016 and 2019. Early stroke and mortality were defined as events occurring during index admission or 90-day readmission. Data on timing of early strokes post-LAAO were collected. Multivariable logistic regression modeling was used to ascertain predictors of early stroke and major adverse events. RESULTS: LAAO was associated with low rates of early stroke (0.63%), early mortality (0.53%), and procedural complications (2.59%). Among patients who had readmissions with strokes after LAAO, the median time from implant to readmission was 35 days (interquartile range, 9-57 days); 67% of readmissions with strokes occurred <45 days postimplant. Between 2016 and 2019, the rates of early stroke after LAAO significantly decreased (0.64% versus 0.46% P-for-trend <0.001), while early mortality and major adverse event rates were unchanged. Peripheral vascular disease and a history of prior stroke were independently associated with early stroke after LAAO. Early post-LAAO stroke rates were similar between low, medium, and high LAAO volume tertile centers. CONCLUSIONS: In this contemporary real-world analysis, the early stroke rate after LAAO was low, with the majority occurring within 45 days of device implantation. Despite an increase in LAAO procedures between 2016 and 2019, there with a significant decline in early strokes after LAAO during that period.
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Apéndice Atrial , Fibrilación Atrial , Accidente Cerebrovascular , Humanos , Anticoagulantes , Apéndice Atrial/cirugía , Fibrilación Atrial/complicaciones , Fibrilación Atrial/cirugía , Estudios Retrospectivos , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/complicaciones , Resultado del TratamientoRESUMEN
INTRODUCTION: Left bundle branch area pacing (LBBP) has emerged as an alternative method for conduction system pacing. While initial experience with delivery systems for stylet-driven and lumenless lead implantation for LBBP has been described, data comparing outcomes of stylet-driven versus lumenless lead implantation for LBBP are limited. In this study, we compare success rates and outcomes of LBBP with stylet-driven versus lumenless lead delivery systems. METHODS: Eighty-three consecutive patients (mean age 74.1 ± 11.2 years; 56 [68%] male) undergoing attempted LBBP at a single institution were identified. Cases were grouped by lead delivery systems used: stylet-driven (n = 53) or lumenless (n = 30). Baseline characteristics and procedural findings were recorded and compared between the cohorts. Intermediate term follow-up data on ventricular lead parameters were also compared. RESULTS: Baseline characteristics were similar between groups. Successful LBBP was achieved in 77% of patients, with similar success rates between groups (76% in stylet-driven, 80% in lumenless, p = 0.79), and rates of adjudicated LBB capture and other paced QRS parameters were also similar. Compared with the lumenless group, the stylet-driven group had significantly shorter procedure times (90 ± 4 vs. 112 ± 31 min, p = 0.004) and fluoroscopy times (10 ± 5 vs. 15 ± 6 min, p = 0.003). Ventricular lead parameters at follow-up were similar, and rates of procedural complications and need for lead revision were low in both groups. CONCLUSION: Delivery systems for stylet-driven and for lumenless leads for LBBP have comparable acute success rates. Long-term follow-up of lead performance following use of the various delivery systems is warranted.
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Fascículo Atrioventricular , Estimulación Cardíaca Artificial , Humanos , Masculino , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Femenino , Estimulación Cardíaca Artificial/métodos , Electrocardiografía/métodos , Sistema de Conducción Cardíaco , Trastorno del Sistema de Conducción CardíacoRESUMEN
MYC-driven B-cell lymphomas are addicted to increased levels of ribosome biogenesis (RiBi), offering the potential for therapeutic intervention. However, it is unclear whether inhibition of RiBi suppresses lymphomagenesis by decreasing translational capacity and/or by p53 activation mediated by the impaired RiBi checkpoint (IRBC). Here we generated Eµ-Myc lymphoma cells expressing inducible short hairpin RNAs to either ribosomal protein L7a (RPL7a) or RPL11, the latter an essential component of the IRBC. The loss of either protein reduced RiBi, protein synthesis, and cell proliferation to similar extents. However, only RPL7a depletion induced p53-mediated apoptosis through the selective proteasomal degradation of antiapoptotic MCL-1, indicating the critical role of the IRBC in this mechanism. Strikingly, low concentrations of the US Food and Drug Administration-approved anticancer RNA polymerase I inhibitor Actinomycin D (ActD) dramatically prolonged the survival of mice harboring Trp53+/+;Eµ-Myc but not Trp53-/-;Eµ-Myc lymphomas, which provides a rationale for treating MYC-driven B-cell lymphomas with ActD. Importantly, the molecular effects of ActD on Eµ-Myc cells were recapitulated in human B-cell lymphoma cell lines, highlighting the potential for ActD as a therapeutic avenue for p53 wild-type lymphoma.
Asunto(s)
Puntos de Control del Ciclo Celular/efectos de los fármacos , Dactinomicina/farmacología , Linfoma de Células B , Proteína 1 de la Secuencia de Leucemia de Células Mieloides , Proteolisis/efectos de los fármacos , Proteínas Proto-Oncogénicas c-myc , Ribosomas , Proteína p53 Supresora de Tumor , Animales , Puntos de Control del Ciclo Celular/genética , Línea Celular Tumoral , Linfoma de Células B/tratamiento farmacológico , Linfoma de Células B/genética , Linfoma de Células B/metabolismo , Masculino , Ratones , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/genética , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , ARN Neoplásico/genética , ARN Neoplásico/metabolismo , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Proteínas Ribosómicas/antagonistas & inhibidores , Proteínas Ribosómicas/genética , Proteínas Ribosómicas/metabolismo , Ribosomas/genética , Ribosomas/metabolismo , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
PURPOSE OF REVIEW: To review recent structural and functional MRI studies of visual hallucinations in Parkinson's disease. RECENT FINDINGS: Previously, neuroimaging had shown inconsistent findings in patients with Parkinson's hallucinations, especially in studies examining grey matter volume. However, recent advances in structural and functional MRI techniques allow better estimates of structural connections, as well as the direction of connectivity in functional MRI. These provide more sensitive measures of changes in structural connectivity and allow models of the changes in directional functional connectivity to be tested. We identified 27 relevant studies and found that grey matter imaging continues to show heterogeneous findings in Parkinson's patients with visual hallucinations. Newer approaches in diffusion imaging and functional MRI are consistent with emerging models of Parkinson's hallucinations, suggesting shifts in attentional networks. In particular, reduced bottom-up, incoming sensory information, and over-weighting of top-down signals appear to be important drivers of visual hallucinations in Parkinson's disease.