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1.
JACC Adv ; 3(8): 101077, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-39135920

RESUMEN

Background: Little is known regarding the characteristics, treatment patterns, and outcomes in patients with adult congenital heart disease (ACHD) admitted to cardiac intensive care units (CICUs). Objectives: The authors sought to better define the contemporary epidemiology, treatment patterns, and outcomes of ACHD admissions in the CICU. Methods: The Critical Care Cardiology Trials Network is a multicenter network of CICUs in North America. Participating centers contributed prospective data from consecutive admissions during 2-month annual snapshots from 2017 to 2022. We analyzed characteristics and outcomes of admissions with ACHD compared with those without ACHD. Multivariable logistic regression was used to assess mortality in ACHD vs non-ACHD admissions. Results: Of 23,299 CICU admissions across 42 sites, there were 441 (1.9%) ACHD admissions. Shunt lesions were most common (46.1%), followed by right-sided lesions (29.5%) and complex lesions (28.7%). ACHD admissions were younger (median age 46 vs 67 years) than non-ACHD admissions. ACHD admissions were more commonly for heart failure (21.3% vs 15.7%, P < 0.001), general medical problems (15.6% vs 6.0%, P < 0.001), and atrial arrhythmias (8.6% vs 4.9%, P < 0.001). ACHD admissions had a higher median presenting Sequential Organ Failure Assessment score (5.0 vs 3.0, P < 0.001). Total hospital stay was longer for ACHD admissions (8.2 vs 5.9 days, P < 0.01), though in-hospital mortality was not different (12.7% vs 13.6%; age- and sex-adjusted OR: 1.19 [95% CI: 0.89-1.59], P = 0.239). Conclusions: This study illustrates the unique aspects of the ACHD CICU admission. Further investigation into the best approach to manage specific ACHD-related CICU admissions, such as cardiogenic shock and acute respiratory failure, is warranted.

2.
Cardiol Clin ; 42(2): 237-252, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38631792

RESUMEN

Within the cardiac intensive care unit, prompt recognition of severe acute valvular lesions is essential because hemodynamic collapse can occur rapidly, especially when cardiac chambers have not had time for compensatory remodeling. Within this context, optimal medical management, considerations for temporary mechanical circulatory support and decisive treatments strategies are addressed. Fundamental concepts include an appreciation for how sudden changes in flow and pressure gradients between cardiac chambers can impact hemodynamic and echocardiographic findings differently compared to similarly severe chronic lesions, as well as understanding the main causes for decompensated heart failure and cardiogenic shock for each valvular abnormality.


Asunto(s)
Insuficiencia Cardíaca , Enfermedades de las Válvulas Cardíacas , Insuficiencia de la Válvula Mitral , Humanos , Enfermedades de las Válvulas Cardíacas/terapia , Urgencias Médicas , Válvulas Cardíacas , Ecocardiografía
3.
Resuscitation ; 191: 109923, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-37597650

RESUMEN

OBJECTIVE: To determine the association between presence of an advanced airway during pediatric cardiopulmonary resuscitation (CPR) and ventilation rates. METHODS: Prospective observational study, January 2017 to June 2020. Patients ≤18 years receiving CC for ≥2 minutes were enrolled. Ventilation rate and type of airway (advanced airway (AA), either endotracheal tube (ETT) or supraglottic airway (SGA); or natural airway (NA)) were collected from video review and analyzed in 'CPR segments' (periods of CPR by individual providers). Ventilation rate (breaths per minute, bpm) was calculated for each segment; hyperventilation was defined as >12 bpm according to 2015 American Heart Association guidelines. Univariate analysis between airway type was done by χ2 testing. Multivariate regression was used to determine the association between the presence of AA with hyperventilation while controlling for within-patient covariance. RESULTS: 779 CPR segments from 94 CPR event were analyzed. The mean ventilation rate per CPR segment across all events was 22 bpm (±16 bpm)). Mean ventilation rates were higher with AA, either ETT (24 ± 17 bpm) or SGA (34 ± 19 bpm), than with NA (17 ± 14, p < 0.001). Hyperventilation occurred more often with AA in place (ETT: 68%; SGA: 96%; NA: 43%; p < 0.001). The presence of AA was independently associated with hyperventilation (AOR 9.3, 95% CI 4.3-20.1). CONCLUSIONS: During pediatric CPR, hyperventilation occurs more often with an AA in place than during CPR with NA. Future research should focus on respiratory physiology during pediatric CPR to determine optimal ventilation rate(s) during pediatric cardiac arrest.


Asunto(s)
Reanimación Cardiopulmonar , Paro Cardíaco , Humanos , Niño , Hiperventilación/etiología , Paro Cardíaco/terapia , Intubación Intratraqueal , Estudios Prospectivos
4.
Resuscitation ; 183: 109664, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36521683

RESUMEN

BACKGROUND: Cardiac arrest (CA) is a common reason for admission to the cardiac intensive care unit (CICU), though the relative burden of morbidity, mortality, and resource use between admissions with in-hospital (IH) and out-of-hospital (OH) CA is unknown. We compared characteristics, care patterns, and outcomes of admissions to contemporary CICUs after IHCA or OHCA. METHODS: The Critical Care Cardiology Trials Network is a multicenter network of tertiary CICUs in the US and Canada. Participating centers contributed data from consecutive admissions during 2-month annual snapshots from 2017 to 2021. We analyzed characteristics and outcomes of admissions by IHCA vs OHCA. RESULTS: We analyzed 2,075 admissions across 29 centers (50.3% IHCA, 49.7% OHCA). Admissions with IHCA were older (median 66 vs 62 years), more commonly had coronary disease (38.3% vs 29.7%), atrial fibrillation (26.7% vs 15.6%), and heart failure (36.3% vs 22.1%), and were less commonly comatose on CICU arrival (34.2% vs 71.7%), p < 0.001 for all. IHCA admissions had lower lactate (median 4.3 vs 5.9) but greater utilization of invasive hemodynamics (34.3% vs 23.6%), mechanical circulatory support (28.4% vs 16.8%), and renal replacement therapy (15.5% vs 9.4%); p < 0.001 for all. Comatose IHCA patients underwent targeted temperature management less frequently than OHCA patients (63.3% vs 84.9%, p < 0.001). IHCA admissions had lower unadjusted CICU (30.8% vs 39.0%, p < 0.001) and in-hospital mortality (36.1% vs 44.1%, p < 0.001). CONCLUSION: Despite a greater burden of comorbidities, CICU admissions after IHCA have lower lactate, greater invasive therapy utilization, and lower crude mortality than admissions after OHCA.


Asunto(s)
Cardiología , Reanimación Cardiopulmonar , Paro Cardíaco Extrahospitalario , Humanos , Paro Cardíaco Extrahospitalario/terapia , Coma , Unidades de Cuidados Intensivos , Cuidados Críticos , Hospitales , Estudios Retrospectivos
5.
Anesth Analg ; 135(2): 394-405, 2022 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-35696706

RESUMEN

BACKGROUND: Behavioral pain treatments may improve postsurgical analgesia and recovery; however, effective and scalable options are not widely available. This study tested a digital perioperative behavioral medicine intervention in orthopedic trauma surgery patients for feasibility and efficacy for reducing pain intensity, pain catastrophizing, and opioid cessation up to 3 months after surgery. METHODS: A randomized controlled clinical trial was conducted at an orthopedic trauma surgery unit at a major academic hospital to compare a digital behavioral pain management intervention ("My Surgical Success" [MSS]) to a digital general health education (HE) intervention (HE; no pain management skills). The enrolled sample included 133 patients; 84 patients were randomized (MSS, n = 37; HE, n = 47) and completed study procedures. Most patients received their assigned intervention within 3 days of surgery (85%). The sample was predominantly male (61.5%), White (61.9%), and partnered (65.5%), with at least a bachelor's degree (69.0%). Outcomes were collected at 1-3 months after intervention through self-report e-surveys and electronic medical record review; an intention-to-treat analytic framework was applied. Feasibility was dually determined by the proportion of patients engaging in their assigned treatment and an application of an 80% threshold for patient-reported acceptability. We hypothesized that MSS would result in greater reductions in pain intensity and pain catastrophizing after surgery and earlier opioid cessation compared to the digital HE control group. RESULTS: The engagement rate with assigned interventions was 63% and exceeded commonly reported rates for fully automated Internet-based e-health interventions. Feasibility was demonstrated for the MSS engagers, with >80% reporting treatment acceptability. Overall, both groups improved in the postsurgical months across all study variables. A significant interaction effect was found for treatment group over time on pain intensity, such that the MSS group evidenced greater absolute reductions in pain intensity after surgery and up to 3 months later (treatment × time fixed effects; F [215] = 5.23; P = .024). No statistically significant between-group differences were observed for time to opioid cessation or for reductions in pain catastrophizing ( F [215] = 0.20; P = .653), although the study sample notably had subclinical baseline pain catastrophizing scores (M = 14.10; 95% confidence interval, 11.70-16.49). CONCLUSIONS: Study findings revealed that a fully automated behavioral pain management skills intervention (MSS) may be useful for motivated orthopedic trauma surgery patients and reduce postsurgical pain up to 3 months. MSS was not associated with reduced time to opioid cessation compared to the HE control intervention.


Asunto(s)
Analgésicos Opioides , Catastrofización , Analgésicos/uso terapéutico , Analgésicos Opioides/uso terapéutico , Estudios de Factibilidad , Femenino , Humanos , Masculino , Dimensión del Dolor , Dolor Postoperatorio/diagnóstico , Dolor Postoperatorio/tratamiento farmacológico , Dolor Postoperatorio/etiología
6.
JAMA Netw Open ; 4(8): e2113401, 2021 08 02.
Artículo en Inglés | MEDLINE | ID: mdl-34398206

RESUMEN

Importance: Chronic low back pain (CLBP), the most prevalent chronic pain condition, imparts substantial disability and discomfort. Cognitive behavioral therapy (CBT) reduces the effect of CLBP, but access is limited. Objective: To determine whether a single class in evidence-based pain management skills (empowered relief) is noninferior to 8-session CBT and superior to health education at 3 months after treatment for improving pain catastrophizing, pain intensity, pain interference, and other secondary outcomes. Design, Setting, and Participants: This 3-arm randomized clinical trial collected data from May 24, 2017, to March 3, 2020. Participants included individuals in the community with self-reported CLBP for 6 months or more and an average pain intensity of at least 4 (range, 0-10, with 10 indicating worst pain imaginable). Data were analyzed using intention-to-treat and per-protocol approaches. Interventions: Participants were randomized to (1) empowered relief, (2) health education (matched to empowered relief for duration and format), or (3) 8-session CBT. Self-reported data were collected at baseline, before treatment, and at posttreatment months 1, 2, and 3. Main Outcomes and Measures: Group differences in Pain Catastrophizing Scale scores and secondary outcomes at month 3 after treatment. Pain intensity and pain interference were priority secondary outcomes. Results: A total of 263 participants were included in the analysis (131 women [49.8%], 130 men [49.4%], and 2 other [0.8%]; mean [SD] age, 47.9 [13.8] years) and were randomized into 3 groups: empowered relief (n = 87), CBT (n = 88), and health education (n = 88). Empowered relief was noninferior to CBT for pain catastrophizing scores at 3 months (difference from CBT, 1.39 [97.5% CI, -∞ to 4.24]). Empowered relief and CBT were superior to health education for pain catastrophizing scores (empowered relief difference from health education, -5.90 [95% CI, -8.78 to -3.01; P < .001]; CBT difference from health education, -7.29 [95% CI, -10.20 to -4.38; P < .001]). Pain catastrophizing score reductions for empowered relief and CBT at 3 months after treatment were clinically meaningful (empowered relief, -9.12 [95% CI, -11.6 to -6.67; P < .001]; CBT, -10.94 [95% CI, -13.6 to -8.32; P < .001]; health education, -4.60 [95% CI, -7.18 to -2.01; P = .001]). Between-group comparisons for pain catastrophizing at months 1 to 3 were adjusted for baseline pain catastrophizing scores and used intention-to-treat analysis. Empowered relief was noninferior to CBT for pain intensity and pain interference (priority secondary outcomes), sleep disturbance, pain bothersomeness, pain behavior, depression, and anxiety. Empowered relief was inferior to CBT for physical function. Conclusions and Relevance: Among adults with CLBP, a single-session pain management class resulted in clinically significant improvements in pain catastrophizing, pain intensity, pain interference, and other secondary outcomes that were noninferior to 8-session CBT at 3 months. Trial Registration: ClinicalTrials.gov Identifier: NCT03167086.


Asunto(s)
Dolor Crónico/terapia , Terapia Cognitivo-Conductual/métodos , Dolor de la Región Lumbar/terapia , Manejo del Dolor/métodos , Educación del Paciente como Asunto/métodos , Catastrofización/psicología , Catastrofización/terapia , Dolor Crónico/psicología , Empoderamiento , Femenino , Humanos , Análisis de Intención de Tratar , Dolor de la Región Lumbar/psicología , Masculino , Persona de Mediana Edad , Dimensión del Dolor/psicología , Resultado del Tratamiento
7.
Pediatr Emerg Care ; 37(12): e1122-e1127, 2021 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-31842200

RESUMEN

OBJECTIVES: Effective leadership and teamwork are imperative during pediatric cardiopulmonary resuscitations (CPR). The initial phase of pediatric CPR, termed the "first 5 minutes," has significant care delivery gaps in both leadership and team performance. The aim of the study was to describe the performance data of emergency department (ED) teams who performed CPR in a pediatric ED. METHODS: We conducted a retrospective video review of resuscitations involving pediatric patients younger than 21 years who presented in cardiac arrest to a tertiary pediatric ED. Descriptive statistics were used for data analysis. RESULTS: Twenty events met study inclusion criteria. Prearrival task completion included the following: estimated weight (90%), airway set-up (85%), epinephrine dose prepared (84%), defibrillator ready (75%), and intraosseous kit ready (50%). Median prearrival notification time was 5 minutes 34 seconds (interquartile range = 4:44-7:13) with no significant relationship between prearrival time and task completion. Within the first 5 minutes, the team leader provided a care summary in 84%, prioritized tasks in 95%, and assigned roles for airway management (90%), intravenous/intravenous access (63%), and CPR/pulse check (63%). Most critical tasks were completed within 1 minute; however, only 25% had defibrillator pads placed within the 5-minute window. CONCLUSIONS: Our study of leadership and teamwork during the first 5 minutes of pediatric CPR care noted wide variation in team performance. Opportunities for improvements in CPR readiness can be incorporated into education and quality programs to drive improvements in the care of future pediatric patients experiencing cardiac arrest.


Asunto(s)
Reanimación Cardiopulmonar , Paro Cardíaco , Niño , Servicio de Urgencia en Hospital , Paro Cardíaco/terapia , Humanos , Liderazgo , Estudios Retrospectivos
8.
Resuscitation ; 153: 37-44, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32505613

RESUMEN

OBJECTIVES: To describe chest compression (CC) quality by individual providers in two pediatric emergency departments (EDs) using video review and compression monitor output during pediatric cardiac arrests. METHODS: Prospective observational study. Patients <18 yo receiving CC for >1 min were eligible. Data was collected from video review and CC monitor device in a synchronized fashion and reported in 'segments' by individual providers. Univariate comparison by age (<1 yo, 1-8 yo, >8 yo) was performed by chi-square testing for dichotomous variables ('high-quality' CPR) and nonparametric testing for continuous variables (CC rate and depth). Univariate comparison of ventilation rate (V) was made between segments with an advanced airway versus without. RESULTS: 524 segments had data available; 42/524 (8%) met criteria for 'high-quality CC'. Patients >8 yo had more segments meeting criteria (18% vs. 2% and 0.5%; p < 0.001). Segments compliant for rate were less frequent in <1 yo (17% vs. 24% vs. 27%; p = 0.03). Segments compliant for depth were less frequent in <1 year olds and 1-8 year olds (5% and 9% vs. 20%, p < 0.001.) Mean V for segments with an advanced airway was higher than with a natural airway (24 ±â€¯18 vs. 14 ±â€¯10 bpm, p < 0.001). Hyperventilation was more prevalent in CPR segments with an advanced airway (66% vs. 32%, p < 0.001). CONCLUSIONS: CC depth is rarely guideline compliant in infants. Hyperventilation is more prevalent during CPR periods with an advanced airway in place. Measuring individual provider CPR quality is feasible, allowing future studies to evaluate the impact of CPR training.


Asunto(s)
Reanimación Cardiopulmonar , Paro Cardíaco , Niño , Preescolar , Servicio de Urgencia en Hospital , Paro Cardíaco/terapia , Humanos , Lactante , Monitoreo Fisiológico , Estudios Prospectivos
9.
Resuscitation ; 145: 158-165, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31421191

RESUMEN

OBJECTIVE: Minimizing pauses in chest compressions during cardiopulmonary resuscitation (CPR) is recommended by the American Heart Association (AHA) and is associated with improved patient outcomes. We studied the quality of pediatric CPR performed in a tertiary pediatric emergency department (ED) with a focus on pauses in chest compressions. METHODS: We conducted an observational study of CPR quality in two pediatric EDs using video review during pediatric cardiac arrest. Events were reviewed for AHA guideline adherence. Parameters of CPR performance were described according to individual compressor segment. Pauses in compressions were analyzed for duration and pause activities. RESULTS: From a 30-month period, 81 cardiac arrests were analyzed, including 1003 individual compressor segments and 900 pauses. Median chest compression fraction was 91%, with a median pause duration of 4 s (IQR 2, 10); 22% of pauses were prolonged (>10 s). Pulse checks occurred in 23% of pauses; 62% were prolonged. Checking a single pulse site (p < 0.001) and having fingers ready pre-pause (p = 0. 001) were associated with significantly shorter pause duration. Pause duration was correlated with the number of pause tasks (r = 0.559, p < 0.001). "Coordinated pauses" (pulse check, rhythm check and compressor change) were rare (6%) and long in duration (19 s; IQR 11, 30). CONCLUSIONS: Prolonged pauses in chest compressions occurred frequently during CPR and were associated with pulse checks and multiple simultaneous tasks. Checking a single pulse site with fingers ready on the pulse site pre-pause could decrease pause duration and improve CPR quality.


Asunto(s)
Reanimación Cardiopulmonar/normas , Masaje Cardíaco/normas , Paro Cardíaco Extrahospitalario/terapia , Adolescente , Reanimación Cardiopulmonar/métodos , Reanimación Cardiopulmonar/mortalidad , Niño , Preescolar , Servicio de Urgencia en Hospital/estadística & datos numéricos , Femenino , Adhesión a Directriz , Masaje Cardíaco/métodos , Humanos , Lactante , Recién Nacido , Masculino , Mejoramiento de la Calidad , Factores de Tiempo , Grabación en Video
10.
Prehosp Emerg Care ; 23(1): 15-21, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30118642

RESUMEN

BACKGROUND: The National Association of Emergency Medical Services (EMS) Physicians emphasizes the importance of high quality communication between EMS providers and emergency department (ED) staff for providing safe, effective care. The Joint Commission has identified ineffective handoff communication as a contributing factor in 80% of serious medical errors. The quality of handoff communication from EMS to ED teams for critically ill pediatric patients needs further exploration. OBJECTIVE: This study assessed the quality of handoff communication between EMS and ED staff during pediatric medical resuscitations. METHODS/DESIGN: We conducted a retrospective review of video recordings of pediatric patients who required critical care ("resuscitation") in the ED between January 2014 and February 2016 at a Level 1 pediatric trauma center. Handoff quality between EMS and emergency department teams was assessed for completeness, timeliness, and efficiency. Institutional review board approval was obtained. RESULTS: Sixty-eight resuscitations were reviewed; 28% presented in cardiac arrest, requiring cardiopulmonary resuscitation (CPR). Completeness of information communicated was variable and included chief complaint (88%), prehospital interventions (81%), physical exam findings (63%), medical history (59%), age (56%), and weight (20%). Completeness of specific vital sign reporting included: respiratory rate (53%), heart rate (43%), oxygen saturation (39%), and blood pressure (31%). Timeliness of communication included median patient handoff and report times of 50 seconds [IQR 30,74] and 108 seconds [IQR 62,252], respectively. Inefficient communication occurred in 87% of handoffs, including interruptions by ED staff (51%), questions from the ED physician team leader asking for information already communicated (40%), and questions by ED physician team leader requesting information not yet communicated (65%). When comparing non-CPR to CPR cases, only timeliness of patient handoff was significantly different for those patients receiving prehospital CPR. CONCLUSION: Handoff communication between EMS and ED teams during pediatric resuscitation was frequently incomplete and inefficient. Future educational and quality improvement interventions could aim to improve the quality of handoff communication for this patient population.


Asunto(s)
Reanimación Cardiopulmonar , Comunicación , Servicios Médicos de Urgencia , Servicio de Urgencia en Hospital , Paro Cardíaco , Pase de Guardia/normas , Grabación en Video , Niño , Cuidados Críticos , Femenino , Humanos , Masculino , Estudios Retrospectivos , Estados Unidos
11.
Microbiology (Reading) ; 162(1): 1-11, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-26518442

RESUMEN

Myxococcus xanthus is a predatory bacterium and a model system for social behaviour in bacteria. Myx. xanthus forms thin biofilms, where cells work together to colonize new territory, invade prey colonies and lyse prey cells. Prey-cell lysis occurs at close proximity, and utilizes antibiotics such as myxovirescin, hydrolytic enzymes such as the protease MepA and extracellular outer-membrane vesicles that may facilitate delivery. Many questions about the mechanism of prey lysis remain, as well as a complete understanding of the vast hydrolytic and secondary metabolite potential present in the Myx. xanthus genome. However, it is clear that predation presents unique challenges for this bacterium, which are solved, in part, through the social behaviours at the disposal of Myx. xanthus. Here, we discuss the life cycle of Myx. xanthus, and the hypothesis that multicellular behaviour in this organism is critical to, and derives from, the challenges of growth as a bacterial predator.


Asunto(s)
Myxococcus xanthus/crecimiento & desarrollo , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Myxococcus xanthus/genética , Myxococcus xanthus/fisiología , Esporas Fúngicas/genética , Esporas Fúngicas/crecimiento & desarrollo , Esporas Fúngicas/fisiología
12.
J Hepatol ; 63(6): 1502-10, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26256437

RESUMEN

Studies examining the mechanisms by which the liver incurs injury and then regenerates usually focus on factors and pathways directly within the liver, neglecting the signaling derived from the gut-liver axis. The intestinal content is rich in microorganisms as well as metabolites generated from both the host and colonizing bacteria. Through the gut-liver axis, this complex "soup" exerts an immense impact on liver integrity and function. This review article summarizes data published in the past 30 years demonstrating the signaling derived from the gut-liver axis in relation to liver injury and regeneration. Due to the intricate networks of implicated pathways as well as scarcity of available mechanistic data, it seems that nutrigenomic, metabolomics, and microbiota profiling approaches are warranted to provide a better understanding regarding the interplay and impact between nutrition, bacteria, and host response in influencing liver function and healing. Therefore elucidating the possible molecular mechanisms that link microbiota alteration to host physiological response and vice versa.


Asunto(s)
Ácidos y Sales Biliares/metabolismo , Regeneración Hepática/fisiología , Hígado/lesiones , Hígado/microbiología , Microbiota/fisiología , Endotoxinas/fisiología , Microbioma Gastrointestinal/fisiología , Humanos , Mucosa Intestinal/microbiología , Mucosa Intestinal/fisiopatología , Hígado/fisiología , Modelos Biológicos , Probióticos/uso terapéutico , Transducción de Señal
13.
Mol Cancer Res ; 13(2): 281-92, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25232032

RESUMEN

UNLABELLED: Bile acids (BA) are endogenous agents capable of causing cancer throughout the gastrointestinal (GI) tract. To uncover the mechanism by which BAs exert carcinogenic effects, both human liver and colon cancer cells as well as mouse primary hepatocytes were treated with BAs and assayed for viability, genotoxic stress, and transcriptional response. BAs induced both Nur77 (NR4A1) and proinflammatory gene expression. The intracellular location of BA-induced Nur77 was time dependent; short-term (1-3 hours) exposure induced nuclear Nur77, whereas longer (1-2 days) exposure also increased cytosolic Nur77 expression and apoptosis. Inhibiting Nur77 nuclear export with leptomycin B decreased lithocholic acid (LCA)-induced apoptosis. Extended (7 days) treatment with BA generated resistance to BA with increased nuclear Nur77, viability, and mobility. While, knockdown of Nur77 in BA-resistant cells increased cellular susceptibility to LCA-induced apoptosis. Moreover, in vivo mouse xenograft experiments demonstrated that BA-resistant cells form larger tumors with elevated Nur77 expression compared with parental controls. DNA-binding and gene expression assays identified multiple survival genes (CDK4, CCND2, MAP4K5, STAT5A, and RBBP8) and a proapoptosis gene (BID) as Nur77 targets. Consistently, BA-induced upregulation of the aforementioned genes was abrogated by a lack of Nur77. Importantly, Nur77 was overexpressed in high percentage of human colon and liver cancer specimens, and the intracellular location of Nur77 correlated with elevated serum total BA levels in patients with colon cancer. These data show for the first time that BAs via Nur77 have a dual role in modulating cell survival and death. IMPLICATIONS: These findings establish a direct link between Nur77 and the carcinogenic effect of BAs.


Asunto(s)
Ácidos y Sales Biliares/metabolismo , Neoplasias Colorrectales/patología , Hepatocitos/efectos de los fármacos , Neoplasias Hepáticas/patología , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares/metabolismo , Animales , Apoptosis , Ácidos y Sales Biliares/sangre , Línea Celular Tumoral , Proliferación Celular , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Células HCT116 , Células HT29 , Hepatocitos/citología , Hepatocitos/metabolismo , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Ratones , Trasplante de Neoplasias , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares/genética
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