RESUMEN
Objectives: Accelerating demand for patient messaging has impacted the practice of many providers. Messages are not recommended for urgent medical issues, but some do require rapid attention. This presents an opportunity for artificial intelligence (AI) methods to prioritize review of messages. Our study aimed to highlight some patient portal messages for prioritized review using a custom AI system integrated into the electronic health record (EHR). Materials and Methods: We developed a Bidirectional Encoder Representations from Transformers (BERT)-based large language model using 40 132 patient-sent messages to identify patterns involving high acuity topics that warrant an immediate callback. The model was then implemented into 2 shared pools of patient messages managed by dozens of registered nurses. A primary outcome, such as the time before messages were read, was evaluated with a difference-in-difference methodology. Results: Model validation on an expert-reviewed dataset (n = 7260) yielded very promising performance (C-statistic = 97%, average-precision = 72%). A binarized output (precision = 67%, sensitivity = 63%) was integrated into the EHR for 2 years. In a pre-post analysis (n = 396 466), an improvement exceeding the trend was observed in the time high-scoring messages sit unread (21 minutes, 63 vs 42 for messages sent outside business hours). Discussion: Our work shows great promise in improving care when AI is aligned with human workflow. Future work involves audience expansion, aiding users with suggested actions, and drafting responses. Conclusion: Many patients utilize patient portal messages, and while most messages are routine, a small fraction describe alarming symptoms. Our AI-based workflow shortens the turnaround time to get a trained clinician to review these messages to provide safer, higher-quality care.
RESUMEN
BACKGROUND: There is a paucity of data guiding treatment duration of oral vancomycin for Clostridiodes difficile infection (CDI) in patients requiring concomitant systemic antibiotics. OBJECTIVES: To evaluate prescribing practices of vancomycin for CDI in patients that required concurrent systemic antibiotics and to determine whether a prolonged duration of vancomycin (>14 days), compared to a standard duration (10-14 days), decreased CDI recurrence. METHODS: In this retrospective cohort study, we evaluated adult hospitalized patients with an initial episode of CDI who were treated with vancomycin and who received overlapping systemic antibiotics for >72 hours. Outcomes of interest included CDI recurrence and isolation of vancomycin-resistant Enterococcus (VRE). RESULTS: Among the 218 patients included, 36% received a standard duration and 64% received a prolonged duration of treatment for a median of 13 days (11-14) and 20 days (16-26), respectively. Patients who received a prolonged duration had a longer median duration of systemic antibiotic overlap with vancomycin (11 vs 8 days; P < .001) and significantly more carbapenem use and infectious disease consultation. Recurrence at 8 weeks (12% standard duration vs 8% prolonged duration; P = .367), recurrence at 6 months (15% standard duration vs 10% prolonged duration; P = .240), and VRE isolation (3% standard duration vs 9% prolonged duration; P = .083) were not significantly different between groups. Discontinuation of vancomycin prior to completion of antibiotics was an independent predictor of 8-week recurrence on multivariable logistic regression (OR, 4.8; 95% CI, 1.3-18.1). CONCLUSIONS: Oral vancomycin prescribing relative to the systemic antibiotic end date may affect CDI recurrence to a greater extent than total vancomycin duration alone. Further studies are needed to confirm these findings.
Asunto(s)
Antibacterianos , Clostridioides difficile , Infecciones por Clostridium , Recurrencia , Vancomicina , Humanos , Vancomicina/administración & dosificación , Vancomicina/uso terapéutico , Estudios Retrospectivos , Masculino , Femenino , Antibacterianos/uso terapéutico , Antibacterianos/administración & dosificación , Persona de Mediana Edad , Infecciones por Clostridium/tratamiento farmacológico , Anciano , Administración Oral , Anciano de 80 o más Años , Esquema de Medicación , Enterococos Resistentes a la Vancomicina , AdultoRESUMEN
BACKGROUND: Diffuse gliomas represent over 80% of malignant brain tumors ranging from low-grade to aggressive high-grade lesions. Within isocitrate dehydrogenase (IDH)-mutant gliomas, there is a high variability in survival and a need to more accurately predict outcome. METHODS: To identify and characterize a predictive signature of outcome in gliomas, we utilized an integrative molecular analysis (using methylation, mRNA, copy number variation (CNV), and mutation data), analyzing a total of 729 IDH-mutant samples including a test set of 99 from University Health Network (UHN) and 2 validation cohorts including the German Cancer Research Center (DKFZ) and The Cancer Genome Atlas (TCGA). RESULTS: Cox regression analysis of methylation data from the UHN cohort identified CpG-based signatures that split the glioma cohort into 2 prognostic groups strongly predicting survival that were validated using 2 independent cohorts from TCGA and DKFZ (all P-valuesâ <â .0001). The methylation signatures that predicted poor outcomes also exhibited high CNV instability and hypermethylation of HOX gene probes. Integrated multi-platform analyses using mRNA and methylation (iRM) showed that parallel HOX gene overexpression and simultaneous hypermethylation were significantly associated with increased mutational load, high aneuploidy, and worse survival (P-valueâ <â .0001). A 7-HOX gene signature was developed and validated using the most significantly associated HOX genes with patient outcome in both 1p/19q codeleted and non-codeleted IDHmut gliomas. CONCLUSIONS: HOX gene methylation and expression provide important prognostic information in IDH-mutant gliomas that are not captured by current molecular diagnostics. A 7-HOX gene signature of outcome shows significant survival differences in both 1p/19q codeleted and non-codeleted IDH-mutant gliomas.
Asunto(s)
Neoplasias Encefálicas , Glioma , Humanos , Genes Homeobox , Isocitrato Deshidrogenasa/genética , Variaciones en el Número de Copia de ADN , Glioma/patología , Neoplasias Encefálicas/patología , Mutación , ARN MensajeroRESUMEN
Background: Escherichia coli and Klebsiella pneumoniae with a piperacillin-tazobactam-nonsusceptible/ceftriaxone-susceptible (TZP-NS/CRO-S) phenotype have been increasingly identified, with limited available literature evaluating treatment strategies. Methods: This was a retrospective study of noncritically ill adults hospitalized between 2013 and 2021 and treated at least 48 hours for TZP-NS/CRO-S E coli or K pneumoniae infections. The primary composite endpoint included escalation to intensive care unit, infection- or treatment-related readmission, mortality, and infection recurrence. Outcomes were compared between groups who received carbapenem (CG) versus carbapenem-sparing agents (CSG) as targeted gram-negative therapy. Results: Of 1062 patients screened, 200 were included (CG, n = 51; CSG, n = 149). Baseline characteristics, including Charlson Comorbidity Index (CCI; median [interquartile range], 6 [3-9] vs 6 [4-9]; P = .704), were similar between groups, except for more immunocompromised CG patients (29% vs 11%, P = .001). The most common infection sources were urinary (31% vs 57%, P = .002) and bloodstream (18% vs 17%, P = .887). Eighty-eight percent of the CG received meropenem, while 58% of the CSG received ceftriaxone as targeted therapy. There was no statistical difference in the primary endpoint between overall groups (27% vs 17%, P = .123), nor when stratified by infection source. More patients in the CSG switched to oral therapy (15 [29%] vs 100 [67%], P < .001). In multivariate analysis, CCI was an independent predictor of the primary outcome (odds ratio [OR], 1.199 [95% confidence interval, 1.074-1.340]; P = .001), while treatment with carbapenem-sparing therapy was not. Conclusions: Our study did not find improved clinical outcomes with targeted carbapenem therapy for TZP-NS/CRO-S infections. Carbapenem-sparing agents may be considered to spare carbapenems in noncritically ill patients similar to those included in our cohort.
RESUMEN
BACKGROUND: Although a few case reports have shown that immune checkpoint inhibitors (ICIs) are potential inducers of capillary leak syndrome (CLS), an incidental finding cannot be ruled out. The aim of this study was to describe the clinical characteristics of ICI-induced CLS through a systematic review and to assess a potential safety signal. METHODS: Medline/PubMed, Embase, and Reactions Weekly were screened, and a global disproportionality study was performed using the World Health Organization pharmacovigilance database through January 15, 2023. A signal of disproportionate reporting was defined as a Bayesian information component (IC) with a 95% credibility interval (CrI) lower boundary that exceeds 0. RESULTS: A total of 47 cases of ICI-associated CLS were included, 14 from the systematic review (of 61 screened articles) and 33 from VigiBase (of 34,058,481 reports of adverse drug reactions). The median time to CLS onset from the start of ICI was 12 weeks (interquartile range 8-49, n = 24). A total of 57% (8/14) of patients experienced an immune-related adverse event (irAE) before CLS. A fatal outcome was reported in 23% (7/31) of patients. A significant overreporting of CLS was found with ICIs compared with all other drugs (IC 2.4, 95% CrI from 1.8 to 2.8). CONCLUSION: This study showed a significant signal of disproportionality reporting for ICI-induced CLS, characterized by a long time to onset, and compared with the idiopathic form of the disease with a less abrupt onset and a less consistent hemoconcentration pattern.
Asunto(s)
Antineoplásicos Inmunológicos , Síndrome de Fuga Capilar , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Humanos , Inhibidores de Puntos de Control Inmunológico , Farmacovigilancia , Teorema de Bayes , Antineoplásicos Inmunológicos/efectos adversos , Estudios RetrospectivosRESUMEN
INTRODUCTION: A detectable and rising PSA following radical prostatectomy is indicative of recurrent prostate cancer. Salvage radiotherapy (SRT) with/without androgen deprivation therapy represents the main treatment option for these patients and has been historically associated with a biochemical control rate of ~70%. To determine the optimal timing, diagnostic workup, radiotherapy dosefractionation, treatment volume, and use of systemic therapy, several informative studies have been conducted in the last decade. AREAS COVERED: This review examines the recent evidence to guide radiotherapy decision making in the SRT setting. Key topics include adjuvant vs salvage RT, utilization of molecular imaging and genomic classifiers, length of androgen deprivation therapy, inclusion of elective pelvic volume, and emerging role for hypofractionation. EXPERT OPINION: Recently reported trials, conducted in an era prior to the routine use of molecular imaging and genomic classifiers, have been pivotal in establishing the current standard of care for SRT in prostate cancer. However, decisions about radiation treatment and systemic therapy may be tailored based on available prognostic and predictive biomarkers. Data from contemporary clinical trials are awaited to define and establish individualized, biomarker-driven approaches for SRT.
Asunto(s)
Neoplasias de la Próstata , Masculino , Humanos , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/radioterapia , Antígeno Prostático Específico , Antagonistas de Andrógenos , Andrógenos , Recurrencia Local de Neoplasia , Prostatectomía/métodos , Terapia Recuperativa/métodos , Radioterapia AdyuvanteAsunto(s)
Escorbuto , Vasculitis , Humanos , Escorbuto/diagnóstico , Vasculitis/diagnóstico , Diagnóstico Diferencial , Ácido AscórbicoRESUMEN
Collateral lethality occurs when loss of a gene/protein renders cancer cells dependent on its remaining paralog. Combining genome-scale CRISPR/Cas9 loss-of-function screens with RNA sequencing in over 900 cancer cell lines, we found that cancers of nervous system lineage, including adult and pediatric gliomas and neuroblastomas, required the nuclear kinase vaccinia-related kinase 1 (VRK1) for their survival in vivo. VRK1 dependency was inversely correlated with expression of its paralog VRK2. VRK2 knockout sensitized cells to VRK1 loss, and conversely, VRK2 overexpression increased cell fitness in the setting of VRK1 loss. DNA methylation of the VRK2 promoter was associated with low VRK2 expression in human neuroblastomas and adult and pediatric gliomas. Mechanistically, depletion of VRK1 reduced barrier-to-autointegration factor phosphorylation during mitosis, resulting in DNA damage and apoptosis. Together, these studies identify VRK1 as a synthetic lethal target in VRK2 promoter-methylated adult and pediatric gliomas and neuroblastomas.
Asunto(s)
Glioma , Neuroblastoma , Vaccinia , Niño , Glioma/genética , Humanos , Péptidos y Proteínas de Señalización Intracelular , Sistema Nervioso , Neuroblastoma/genética , Proteínas Serina-Treonina Quinasas/genética , Virus VacciniaRESUMEN
Receptor tyrosine kinase (RTK)-RAS signalling through the downstream mitogen-activated protein kinase (MAPK) cascade regulates cell proliferation and survival. The SHOC2-MRAS-PP1C holophosphatase complex functions as a key regulator of RTK-RAS signalling by removing an inhibitory phosphorylation event on the RAF family of proteins to potentiate MAPK signalling1. SHOC2 forms a ternary complex with MRAS and PP1C, and human germline gain-of-function mutations in this complex result in congenital RASopathy syndromes2-5. However, the structure and assembly of this complex are poorly understood. Here we use cryo-electron microscopy to resolve the structure of the SHOC2-MRAS-PP1C complex. We define the biophysical principles of holoenzyme interactions, elucidate the assembly order of the complex, and systematically interrogate the functional consequence of nearly all of the possible missense variants of SHOC2 through deep mutational scanning. We show that SHOC2 binds PP1C and MRAS through the concave surface of the leucine-rich repeat region and further engages PP1C through the N-terminal disordered region that contains a cryptic RVXF motif. Complex formation is initially mediated by interactions between SHOC2 and PP1C and is stabilized by the binding of GTP-loaded MRAS. These observations explain how mutant versions of SHOC2 in RASopathies and cancer stabilize the interactions of complex members to enhance holophosphatase activity. Together, this integrative structure-function model comprehensively defines key binding interactions within the SHOC2-MRAS-PP1C holophosphatase complex and will inform therapeutic development .
Asunto(s)
Microscopía por Crioelectrón , Péptidos y Proteínas de Señalización Intracelular , Complejos Multiproteicos , Proteína Fosfatasa 1 , Proteínas ras , Secuencias de Aminoácidos , Sitios de Unión , Guanosina Trifosfato/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intracelular/química , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Sistema de Señalización de MAP Quinasas , Complejos Multiproteicos/química , Complejos Multiproteicos/metabolismo , Complejos Multiproteicos/ultraestructura , Mutación Missense , Fosforilación , Unión Proteica , Proteína Fosfatasa 1/química , Proteína Fosfatasa 1/metabolismo , Proteína Fosfatasa 1/ultraestructura , Estabilidad Proteica , Quinasas raf , Proteínas ras/química , Proteínas ras/metabolismo , Proteínas ras/ultraestructuraRESUMEN
Metastatic castration-resistant prostate cancers (mCRPCs) are treated with therapies that antagonize the androgen receptor (AR). Nearly all patients develop resistance to AR-targeted therapies (ARTs). Our previous work identified CREB5 as an upregulated target gene in human mCRPC that promoted resistance to all clinically approved ART. The mechanisms by which CREB5 promotes progression of mCRPC or other cancers remains elusive. Integrating ChIP-seq and rapid immunoprecipitation and mass spectroscopy of endogenous proteins, we report that cells overexpressing CREB5 demonstrate extensive reprogramming of nuclear protein-protein interactions in response to the ART agent enzalutamide. Specifically, CREB5 physically interacts with AR, the pioneering actor FOXA1, and other known co-factors of AR and FOXA1 at transcription regulatory elements recently found to be active in mCRPC patients. We identified a subset of CREB5/FOXA1 co-interacting nuclear factors that have critical functions for AR transcription (GRHL2, HOXB13) while others (TBX3, NFIC) regulated cell viability and ART resistance and were amplified or overexpressed in mCRPC. Upon examining the nuclear protein interactions and the impact of CREB5 expression on the mCRPC patient transcriptome, we found that CREB5 was associated with Wnt signaling and epithelial to mesenchymal transitions, implicating these pathways in CREB5/FOXA1-mediated ART resistance. Overall, these observations define the molecular interactions among CREB5, FOXA1, and pathways that promote ART resistance.
Asunto(s)
Neoplasias de la Próstata Resistentes a la Castración , Receptores Androgénicos , Línea Celular Tumoral , Núcleo Celular/metabolismo , Proteína de Unión al Elemento de Respuesta al AMP Cíclico , Factor Nuclear 3-alfa del Hepatocito/genética , Humanos , Masculino , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismoRESUMEN
The transcriptional co-activator YAP1 oncogene is the downstream effector of the Hippo pathway, which regulates tissue homeostasis, organ size, regeneration, and tumorigenesis. Multiple cancers are dependent on sustained expression of YAP1 for cell proliferation, survival, and tumorigenesis, but the molecular basis of this oncogene dependency is not well understood. To identify genes that can functionally substitute for YAP1, we performed a genome-scale genetic rescue screen in YAP1-dependent colon cancer cells expressing an inducible YAP1-specific shRNA. We found that the transcription factor PRDM14 rescued cell proliferation and tumorigenesis upon YAP1 suppression in YAP1-dependent cells, xenografts, and colon cancer organoids. YAP1 and PRDM14 individually activated the transcription of calmodulin 2 (CALM2) and a glucose transporter SLC2A1 upon YAP1 suppression, and CALM2 or SLC2A1 expression was required for the rescue of YAP1 suppression. Together, these findings implicate PRDM14-mediated transcriptional upregulation of CALM2 and SLC2A1 as key components of oncogenic YAP1 signaling and dependency.
Asunto(s)
Carcinogénesis/genética , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ARN/metabolismo , Factores de Transcripción/metabolismo , Proteínas Señalizadoras YAP/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Calmodulina/genética , Calmodulina/metabolismo , Línea Celular Tumoral , Proliferación Celular/genética , Supervivencia Celular/genética , Neoplasias del Colon/genética , Proteínas de Unión al ADN/genética , Expresión Génica/genética , Regulación Neoplásica de la Expresión Génica/genética , Transportador de Glucosa de Tipo 1/genética , Humanos , Ratones , Ratones Desnudos , Organoides , Fosfoproteínas/metabolismo , Proteínas de Unión al ARN/genética , Transducción de Señal/genética , Factores de Transcripción/genética , Activación Transcripcional , Ensayos Antitumor por Modelo de Xenoinjerto , Proteínas Señalizadoras YAP/genética , Proteínas Señalizadoras YAP/fisiologíaRESUMEN
Tumor biology may play an important role as an effective predictive biomarker that is complementary to functional imaging for metastatic hormone-sensitive prostate cancer.
Asunto(s)
Neoplasias de la Próstata , Biología , Hormonas , Humanos , Masculino , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/patologíaRESUMEN
Bladder cancer is a genetically heterogeneous disease, and novel therapeutic strategies are needed to expand treatment options and improve clinical outcomes. Here, we identified a unique subset of urothelial tumors with focal amplification of the RAF1 (CRAF) kinase gene. RAF1-amplified tumors had activation of the RAF/MEK/ERK signaling pathway and exhibited a luminal gene expression pattern. Genetic studies demonstrated that RAF1-amplified tumors were dependent upon RAF1 activity for survival, and RAF1-activated cell lines and patient-derived models were sensitive to available and emerging RAF inhibitors as well as combined RAF plus MEK inhibition. Furthermore, we found that bladder tumors with HRAS- or NRAS-activating mutations were dependent on RAF1-mediated signaling and were sensitive to RAF1-targeted therapy. Together, these data identified RAF1 activation as a dependency in a subset making up nearly 20% of urothelial tumors and suggested that targeting RAF1-mediated signaling represents a rational therapeutic strategy.
Asunto(s)
Amplificación de Genes , Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-raf/genética , Neoplasias de la Vejiga Urinaria/genética , Animales , Línea Celular Tumoral , Femenino , GTP Fosfohidrolasas/genética , Humanos , Proteínas de la Membrana/genética , Ratones , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas c-raf/antagonistas & inhibidores , Proteínas Proto-Oncogénicas p21(ras)/genética , Neoplasias de la Vejiga Urinaria/tratamiento farmacológicoRESUMEN
BACKGROUND: Aberrant androgen receptor (AR) signaling is a major driver of castration-resistant prostate cancer (CRPC). Tumor hypoxia increases AR signaling and is associated with treatment resistance in prostate cancer. Heat shock protein 27 (Hsp27) is a molecular chaperone that is activated in response to heat shock and hypoxia. Hsp27 has previously been reported to facilitate AR nuclear translocation in a p38 mitogen-activated protein kinase (MAPK) dependent manner in castration-sensitive prostate cancer cell lines. Here, we evaluated the potential for inhibiting p38 MAPK/Hsp27 mediated AR signaling under normoxia and hypoxia in experimental models of CRPC. METHODS: We inhibited p38 MAPK with SB203580 in prostate cancer cell lines and measured Hsp27 phosphorylation, AR activity, cell proliferation, and clonogenicity under normoxia and hypoxia. AR activity was measured using an androgen response element driven reporter assay and qPCR to measure expression of AR target genes. Xenograft-bearing mice were treated with SB203580 to measure tumor growth and serum prostate specific antigen (PSA). RESULTS: Our results indicate that p38 MAPK and Hsp27 are activated under normoxia and hypoxia in response to androgens in CRPC cells. p38 MAPK inhibition diminished Hsp27 activation and the hypoxia-mediated increase in AR activity. Additionally, inhibition of p38 MAPK activity decreased proliferation and survival of CRPC cells in vitro and prolonged the survival of tumor-bearing mice. CONCLUSIONS: These results suggest that p38 MAPK inhibition may represent a therapeutic strategy to disrupt AR signaling in the heterogeneous CRPC tumor microenvironment.
RESUMEN
BACKGROUND: Recent international sequencing efforts have allowed for the molecular taxonomy of lower-grade gliomas (LGG). We sought to analyze The Cancer Genome Atlas (TCGA, 2015) gene expression datasets on molecularly defined oligodendrogliomas (IDH-mutated and 1p/19q-codeleted) patients treated with adjuvant radiation or those observed to discover prognostic markers and pathways. METHODS: mRNA expression and clinical information of patients with oligodendroglioma were taken from the TCGA "Brain Lower Grade Glioma" provisional dataset. Transcription factor network reconstruction and analysis were performed using the R packages "RTN" and "RTNsurvival." Elastic net regularization and survival modeling were performed using the "biospear," "plsRCox," "survival" packages. RESULTS: From our cohort of 137 patients, 65 received adjuvant radiation and 72 were observed. In the cohort that received adjuvant radiotherapy, a transcription factor activity signature, that correlated with hypoxia, was associated with shorter disease-free survival (DFS) (median = 45 months vs 108 months, P < .001). This increased risk was not seen in patients who were observed (P = .2). Within the observation cohort, a transcription factor activity signature was generated that was associated with poor DFS (median = 72 months. vs 143 months., P < .01). CONCLUSIONS: We identified a transcription factor activity signature associated with poor prognosis in patients with molecular oligodendroglioma treated with adjuvant radiotherapy. These patients would be potential candidates for treatment intensification. A second signature was generated for patients who were more likely to progress on observation. This potentially identifies a cohort who would benefit from upfront adjuvant radiotherapy.
Asunto(s)
Neoplasias Encefálicas , Oligodendroglioma , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/radioterapia , Cromosomas Humanos Par 1 , Cromosomas Humanos Par 19 , Humanos , Isocitrato Deshidrogenasa/genética , Mutación , Oligodendroglioma/genética , Oligodendroglioma/radioterapia , Pronóstico , Radioterapia Adyuvante , Factores de TranscripciónRESUMEN
Sarcomere and cytoskeleton genes, or actomyosin genes, regulate cell biology including mechanical stress, cell motility, and cell division. While actomyosin genes are recurrently dysregulated in cancers, their oncogenic roles have not been examined in a lineage-specific fashion. In this report, we investigated dysregulation of nine sarcomeric and cytoskeletal genes across 20 cancer lineages. We found that uterine cancers harbored the highest frequencies of amplification and overexpression of the gamma actin gene, ACTG1. Each of the four subtypes of uterine cancers, mixed endometrial carcinomas, serous carcinomas, endometroid carcinomas, and carcinosarcomas harbored between 5~20% of ACTG1 gene amplification or overexpression. Clinically, patients with ACTG1 gains had a poor prognosis. ACTG1 gains showed transcriptional patterns that reflect activation of oncogenic signals, repressed response to innate immunity, or immunotherapy. Functionally, the CRISPR-CAS9 gene deletion of ACTG1 had the most robust and consistent effects in uterine cancer cells relative to 20 other lineages. Overall, we propose that ACTG1 regulates the fitness of uterine cancer cells by modulating cell-intrinsic properties and the tumor microenvironment. In summary, the ACTG1 functions relative to other actomyosin genes support the notion that it is a potential biomarker and a target gene in uterine cancer precision therapies.
Asunto(s)
Actinas , Biomarcadores de Tumor , Amplificación de Genes , Proteínas de Neoplasias , Neoplasias Uterinas , Actinas/genética , Actinas/metabolismo , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Línea Celular Tumoral , Supervivencia sin Enfermedad , Femenino , Humanos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Tasa de Supervivencia , Neoplasias Uterinas/genética , Neoplasias Uterinas/metabolismo , Neoplasias Uterinas/mortalidad , Neoplasias Uterinas/patologíaRESUMEN
The initial management of potentially oligometastatic hormone sensitive prostate cancer has been complicated by rapid advances in the field. Clinically, subgroup analyses of two randomized control trials have suggested that a specific synchronous oligometastatic prostate cancer state may be predictive for benefit from radiation to the primary. Further exploration of metastasis-directed therapy has been supported for various prostate cancer populations among three phase II clinical trials. There are numerous caveats in applying this evidence, a dilemma being addressed by present and upcoming clinical trials. Despite existing clinical equipoise and an avenue to address this uncertainty, the temptation to combine this evidence off-trial exists. Matters have become more complex as our ability to evaluate metastatic disease and tumour biology have also matured. This paper synthesizes our understanding of prostate cancer's natural history into a model which rationalizes both the theoretical benefits and limitations of metastasis directed therapy. We postulate that a metastatic prostate cancer's total disease activity is primarily driven by the combination of its burden of disease and underlying biology, namely genomic instability, then highlight the numerous remaining questions that challenge this hypothesis. This review focuses on harmonizing the language used to describe the disease, the current efforts exploring this hypothesis, and the need for clinical trial participation to appropriately advance patient care.
Asunto(s)
Neoplasias de la Próstata , Radiocirugia , Humanos , Masculino , Metástasis de la Neoplasia , Neoplasias de la Próstata/cirugíaRESUMEN
Androgen-receptor (AR) inhibitors, including enzalutamide, are used for treatment of all metastatic castration-resistant prostate cancers (mCRPCs). However, some patients develop resistance or never respond. We find that the transcription factor CREB5 confers enzalutamide resistance in an open reading frame (ORF) expression screen and in tumor xenografts. CREB5 overexpression is essential for an enzalutamide-resistant patient-derived organoid. In AR-expressing prostate cancer cells, CREB5 interactions enhance AR activity at a subset of promoters and enhancers upon enzalutamide treatment, including MYC and genes involved in the cell cycle. In mCRPC, we found recurrent amplification and overexpression of CREB5. Our observations identify CREB5 as one mechanism that drives resistance to AR antagonists in prostate cancers.