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Elevated serum concentrations of the vasoactive protein endothelin-1 (ET-1) occur in the setting of systemic inflammatory response syndrome and contribute to distal organ hypoperfusion and pulmonary hypertension. Thus, understanding the cellular source and transcriptional regulation of systemic inflammatory stress-induced ET-1 expression may reveal therapeutic targets. Using a murine model of LPS-induced septic shock, we demonstrate that the hepatic macrophage is the primary source of elevated circulating ET-1, rather than the endothelium as previously proposed. Using pharmacologic inhibitors, ET-1 promoter luciferase assays, and by silencing and overexpressing NF-κB inhibitory protein IκB expression, we demonstrate that LPS-induced ET-1 expression occurs via an NF-κB-dependent pathway. Finally, the specific role of the cRel/p65 inhibitory protein IκBß was evaluated. Although cytoplasmic IκBß inhibits activity of cRel-containing NF-κB dimers, nuclear IκBß stabilizes NF-κB/DNA binding and enhances gene expression. Using targeted pharmacologic therapies to specifically prevent IκBß/NF-κB signaling, as well as mice genetically modified to overexpress IκBß, we show that nuclear IκBß is both necessary and sufficient to drive LPS-induced ET-1 expression. Together, these results mechanistically link the innate immune response mediated by IκBß/NF-κB to ET-1 expression and potentially reveal therapeutic targets for patients with Gram-negative septic shock.
Assuntos
Endotelina-1/imunologia , Endotoxemia/imunologia , Regulação da Expressão Gênica/imunologia , Proteínas I-kappa B/imunologia , Fígado/imunologia , Macrófagos/imunologia , NF-kappa B/imunologia , Transdução de Sinais/imunologia , Animais , Linhagem Celular , Endotelina-1/genética , Endotoxemia/genética , Endotoxemia/patologia , Proteínas I-kappa B/genética , Fígado/patologia , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Camundongos Transgênicos , NF-kappa B/genética , Transdução de Sinais/genéticaRESUMO
OBJECTIVE: The mortality rate of schizophrenia patients is higher than that of the general population; cardiovascular disease (CVD) is their leading cause of death. This issue must be studied since people with schizophrenia are disproportionately burdened with CVD. Therefore, our goal was to identify the prevalence of CVD and other comorbidities, stratified by age and gender, in patients with schizophrenia living in Puerto Rico. METHODS: A retrospective, case-control, descriptive study was conducted. Subjects in this study were admitted to Dr. Federico Trilla's hospital from 2004 through 2014 for both psychiatric- and non psychiatric conditions. The sample populations were stratified by the confounding variables of tobacco use and alcohol abuse, and the resulting stratification was analyzed with the Cochran-Mantel-Haenszel method. RESULTS: A higher frequency of CVDs was noted in the patients with schizophrenia compared to those in the control group. Although hypertension was the most frequent pathology encountered in both groups, ischemic heart disease was approximately four times more frequent in the patients with schizophrenia. CVD represented 58.4% and 52.7% in the schizophrenia and non-schizophrenia groups, respectively, although a statistically significant difference was not observed. The prevalence of malignancies in patients without schizophrenia was higher than in patients with schizophrenia. Moreover, the prevalence of asthma was 10.9% in the control group compared to 5.3% in the schizophrenia group. CONCLUSION: These findings should motivate a systematic approach to prioritizing the aggressive management, early diagnosis, and prevention of comorbid risk factors in patients with schizophrenia.
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Doenças Cardiovasculares , Humanos , Doenças Cardiovasculares/epidemiologia , Porto Rico/epidemiologia , Estudos Retrospectivos , Prevalência , Fatores de RiscoRESUMO
BACKGROUND AND PURPOSE: Stereotactic radiosurgery (SRS) after maximal safe resection is an accepted treatment strategy for patients with cerebral metastatic disease. Despite its high conformality profile, the incidence of radionecrosis (RN) remains high. SRS delivered pre-operatively could be associated with a reduced incidence of RN. We sought to evaluate whether neoadjuvant SRS could reduce radiotherapy doses in a cohort of patients treated with post-operative SRS. METHODS: A cohort of 47 brain metastases (BM) treated at 2 academic institutions was retrospectively analyzed. Subjects underwent surgical extirpation of BMs and subsequent SRS to surgical bed. Post-operative volumetric and dosimetric data was collected from records or recreations of delivered plans; pre-operative data were derived from hypothetical radiotherapy courses and compared using Wilcoxon signed-rank tests. RESULTS: Higher planned tumor volume post-operatively (median[IQR] 12.28 [6.54, 18.69]cc vs 10.20 [4.53, 21.70]cc respectively, pâ¯=â¯0.4150) was observed. The median prescribed radiotherapy dose (DRx) was 16â¯Gy pre-operatively and 24â¯Gy post-operatively (pâ¯<â¯0.0001). Further investigations revealed improved pre-operative conformity index (1.23[1.20, 1.29] vs 1.29[1.23, 1.39], pâ¯=â¯0.0098) and gradient index (2.72[2.59, 2.98] vs 2.94[2.69, 3.47], pâ¯=â¯0.0004). A significant difference was found in normal brain tissue exposed to 10â¯Gy (12.97[6.78, 25.54]cc vs 32.13[19.42, 48.40]cc, pâ¯<â¯0.0001), 12â¯Gy (9.31[4.56, 17.43]cc vs 23.80[14.74, 36.56]cc, pâ¯<â¯0.0001), and 14â¯Gy (5.62[3.23, 11.61]cc vs 17.47[9.00, 28.31]cc, pâ¯<â¯0.0001), favoring pre-operative SRS. CONCLUSIONS: Neoadjuvant SRS is associated reduced DRx, better conformality profile and decreased radiation to normal tissue. These findings could support the use of neoadjuvant SRS for the treatment of BMs.
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Neoplasias Encefálicas , Lesões por Radiação , Radiocirurgia , Neoplasias Supratentoriais , Humanos , Estudos Retrospectivos , Radiocirurgia/efeitos adversos , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/cirurgia , Neoplasias Encefálicas/patologia , Encéfalo/patologia , Lesões por Radiação/etiologia , Resultado do TratamentoRESUMO
PURPOSE: Missense mutated von Hippel Lindau (VHL) protein (pVHL) maintains intrinsic function but undergoes proteasomal degradation and tumor initiation and/or progression in VHL disease. Vorinostat can rescue missense mutated pVHL and arrest tumor growth in preclinical models. We asked whether short-term oral vorinostat could rescue pVHL in central nervous system hemangioblastomas in patients with germline missense VHL. PATIENTS AND METHODS: We administered oral vorinostat to 7 subjects (ages 46.0 ± 14.5 years) and then removed symptomatic hemangioblastomas surgically (ClinicalTrials.gov identifier NCT02108002). RESULTS: Vorinostat was tolerated without serious adverse events by all patients. pVHL expression was elevated in neoplastic stromal cells compared with untreated hemangioblastomas from same patients. We found transcriptional suppression of downstream hypoxia-inducible factor (HIF) effectors. Mechanistically, vorinostat prevented Hsp90 recruitment to mutated pVHL in vitro. The effects of vorinostat on the Hsp90-pVHL interaction, pVHL rescue, and transcriptional repression of downstream HIF effectors was independent of the location of the missense mutation on the VHL locus. We confirmed a neoplastic stromal cell-specific effect in suppression of protumorigenic pathways with single-nucleus transcriptomic profiling. CONCLUSIONS: We found that oral vorinostat treatment in patients with germline missense VHL mutations has a potent biologic effect that warrants further clinical study. These results provide biologic evidence to support the use of proteostasis modulation for the treatment of syndromic solid tumors involving protein misfolding. Proteostasis modulation with vorinostat rescues missense mutated VHL protein. Further clinical trials are needed to demonstrate tumor growth arrest.
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Produtos Biológicos , Neoplasias do Sistema Nervoso Central , Hemangioblastoma , Doença de von Hippel-Lindau , Humanos , Doença de von Hippel-Lindau/genética , Vorinostat , Proteostase , Proteína Supressora de Tumor Von Hippel-Lindau/genéticaRESUMO
Background: Surgical management of atlantoaxial instability (AAI) in pediatric patients with Down syndrome is associated with high neurological morbidity. Moreover, Down syndrome cognitive impairment coupled to AAI removes traditional verbal communication to relay evolving symptoms and aid in neurologic examination. It is not clear whether surgical adjuncts can alter clinical outcomes in this vulnerable population. Case Description: Herein, we report the case of a 6-year-old patient with significant developmental delay and severe AAI that was successfully managed by stabilization with guidance of neurophysiologic investigations in the perioperative phase. Conclusion: Perioperative neurophysiologic monitoring is safe, useful, and reliable in pediatric patients with trisomy 21 undergoing cervical traction and occipitocervical instrumented fusion for AAI.
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BACKGROUND: Blood pressure monitoring is crucial during neuroendovascular procedures. Intraoperative hemodynamic instability is associated with complications, which underscores the importance of continuous monitoring. Although direct measurement with an intra-arterial catheter is the gold standard for determining arterial pressure, it is costly, time-consuming, and associated with complications. The novel ClearSight system offers a noninvasive technique for monitoring arterial pressure via a finger cuff. This study compared noninvasive arterial pressure measurements with the gold standard method. METHODS: Simultaneous recording of noninvasive and invasive arterial pressure was performed in patients undergoing neuroendovascular interventions. Both techniques were compared employing linear regression, Lin's correlation coefficient, Bland-Altman, and error grid analysis. RESULTS: The study enrolled 24 consecutive patients. The concordance correlation coefficient between both methods was 0.3526 (95% confidence interval [0.3134, 0.3906]) for mean arterial pressure and 0.4680 (95% confidence interval [0.4353, 0.4995]) and for systolic arterial pressure. The mean (SD) of the differences was 0.81 (17.86) mm Hg (95% limits of agreement [-52.52, 54.14]) for mean arterial pressure and 5.38 (14.64) mm Hg (95% limits of agreement [-45.12, 56.08]) for systolic arterial pressure. Error grid analysis demonstrated that the majority of measurements lie in regions with no or low risk for patients (mean arterial pressure, 71.0% and 24.4%; systolic arterial pressure, 59.2% and 25.8%). CONCLUSIONS: The ClearSight system provided accurate measurements of arterial blood pressure compared with invasive methods and within safe clinical parameters. This method may serve as a safe and reliable alternative for invasive blood pressure monitoring during neuroendovascular procedures.
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Pressão Arterial , Monitores de Pressão Arterial , Procedimentos Endovasculares , Monitorização Hemodinâmica/métodos , Monitorização Intraoperatória/métodos , Procedimentos Neurocirúrgicos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Dedos , Monitorização Hemodinâmica/instrumentação , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Monitorização Intraoperatória/instrumentação , Adulto JovemRESUMO
BACKGROUND: Partially thrombosed intracranial aneurysms (PTIA) represent a unique subset of intracranial aneurysms with an ill-defined natural history, posing challenges to standard management strategies. This study aims to assess the efficacy of flow diversion in the treatment of this pathology. METHODS: A retrospective review of patients with flow-diverted PTIA at 6 cerebrovascular centers was performed. Clinical and radiographic data were collected from the medical records, with the primary outcome of aneurysmal occlusion and secondary outcomes of clinical status and complications. RESULTS: Fifty patients with 51 PTIA treated with flow diversion were included. Median age was 56.5 years. Thirty-three (64.7%) aneurysms were saccular and 16 (31.4%) were fusiform/dolichoectatic. The most common location was the internal carotid artery (54.9%) followed by the vertebral and basilar arteries (17.7% and 17.7%, respectively). Last imaging follow-up was performed at a median of 25.1 (interquartile range, 12.8-43) months. Complete occlusion at last radiographic follow-up was achieved in 37 (77.1%) aneurysms. Pretreatment aneurysm thrombosis of >50% was associated with a significantly lower rate of complete aneurysm occlusion (58.8 vs. 87.1%, P = 0.026) with a trend toward better functional outcome (modified Rankin scale <2) at last follow-up in patients with <50% pretreatment aneurysm thrombosis (96.8 vs. 82.4; P = 0.08). Ischemic complications occurred in 5 (9.8%) patients, producing symptoms in 4 (7.8%) and resultant mortality in 2 (4.2%) patients. CONCLUSIONS: Flow diversion treatment of PTIA has adequate efficacy along with a reasonable safety profile. Aneurysms harboring large amounts of pretreatment thrombus were associated with lower rates of complete occlusion.
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Artéria Carótida Interna/cirurgia , Embolização Terapêutica , Procedimentos Endovasculares , Aneurisma Intracraniano/terapia , Idoso , Angiografia Cerebral/métodos , Estudos de Coortes , Embolização Terapêutica/métodos , Procedimentos Endovasculares/métodos , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do TratamentoRESUMO
OBJECTIVEVon Hippel-Lindau disease (VHL) is a tumor predisposition syndrome characterized by CNS hemangioblastomas (HBs) and clear cell renal cell carcinomas (RCCs) due to hypoxia-inducible factor activation (pseudohypoxia). Because of the lack of effective medical therapies for VHL, HBs and RCCs account for significant morbidity and mortality, ultimately necessitating numerous neurological and renal surgeries. Propranolol is an FDA-approved pan-beta adrenergic antagonist with antitumor effects against infantile hemangiomas (IHs) and possibly VHL HBs. Here, the authors investigated the antitumor efficacy of propranolol against pseudohypoxia-driven VHL-HBs and VHL-RCCs.METHODSPatient-derived VHL-associated HBs (VHL-HBs) or 786-O-VHL-/- RCC cells were treated with clinically relevant concentrations of propranolol in vitro and assessed with viability assays, flow cytometry, quantitative real-time polymerase chain reaction, and western blotting. In vivo confirmation of propranolol antitumor activity was confirmed in athymic nude mice bearing 786-O xenograft tumors. Lastly, patients enrolled in a VHL natural history study (NCT00005902) were analyzed for incidental propranolol intake. Propranolol activity against VHL-HBs was assessed retrospectively with volumetric HB growth kinetic analysis.RESULTSPropranolol decreased HB and RCC viability in vitro with IC50 (half maximal inhibitory concentration) values of 50 µM and 200 µM, respectively. Similar to prior reports in infantile hemangiomas, propranolol induced apoptosis and paradoxically increased VEGF-A mRNA expression in patient-derived VHL-HBs and 786-O cells. While intracellular VEGF protein levels were not affected by propranolol treatment, propranolol decreased HIF expression in 786-O cells (7.6-fold reduction, p < 0.005). Propranolol attenuated tumor progression compared with control (33% volume reduction at 7 days, p < 0.005) in 786-O xenografted tumor-bearing mice. Three patients (harboring 25 growing CNS HBs) started propranolol therapy during the longitudinal VHL-HB study. HBs in these patients tended to grow slower (median growth rate 27.1 mm3/year vs 13.3 mm3/year) during propranolol treatment (p < 0.0004).CONCLUSIONSPropranolol decreases VHL-HB and VHL-related RCC viability in vitro likely by modulation of VEGF expression and by inducing apoptosis. Propranolol abrogates 786-O xenograft tumor progression in vivo, and retrospective clinical data suggest that propranolol curtails HB growth. These results suggest that propranolol may play a role in the treatment of VHL-related tumors.
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BACKGROUND: Pre-operative detection of corticotropin (ACTH) secreting microadenomas causing Cushing's disease (CD) improves surgical outcomes. Current best magnetic resonance imaging fails to detect up to 40% of these microadenomas. 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) is specific, but not sensitive in detecting corticotropinomas. Theoretically, secretagogue stimulation with corticotropin releasing hormone (CRH) could improve detection of adenomas with 18F-FDG PET. Previous attempts with simultaneous CRH stimulation have failed to demonstrate increased 18F-FDG uptake in corticotropinomas. We hypothesized that CRH stimulation leads to a delayed elevation in glucose uptake in corticotropinomas. METHODS: Clinical data was analyzed for efficacy of CRH in improving 18FDG-PET detection of corticotropinomas in CD. Glucose transporter 1 (GLUT1) immunoreactivity was performed on surgical specimens. Ex-vivo, viable cells from these tumors were tested for secretagogue effects (colorimetric glucose uptake), and for fate of intracellular glucose (glycolysis stress analysis). Validation of ex-vivo findings was performed with AtT-20 cells. RESULTS: CRH increased glucose uptake in human-derived corticotroph tumor cells and AtT-20, but not in normal murine or human corticotrophs (p < 0.0001). Continuous and intermittent (1 h) CRH exposure increased glucose uptake in AtT-20 with maximal effect at 4 h (p = 0.001). Similarly, CRH and 8-Br-cAMP led to robust GLUT1 upregulation and increased membrane translocation at 2 h, while fasentin suppressed baseline (p < 0.0001) and CRH-mediated glucose uptake. Expectedly, intra-operatively collected corticotropinomas demonstrated GLUT1 overexpression. Lastly, human derived corticotroph tumor cells demonstrated increased glycolysis and low glucose oxidation. CONCLUSION: Increased and delayed CRH-mediated glucose uptake differentially occurs in adenomatous corticotrophs. Delayed secretagogue-stimulated 18F-FDG PET could improve microadenoma detection.
Assuntos
Adenoma Hipofisário Secretor de ACT/metabolismo , Hormônio Liberador da Corticotropina/farmacologia , Transportador de Glucose Tipo 1/metabolismo , Glucose/metabolismo , Animais , Arginina Vasopressina/farmacologia , Linhagem Celular Tumoral , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Corticotrofos/metabolismo , Dexametasona/farmacologia , Transportador de Glucose Tipo 1/genética , Glicólise/efeitos dos fármacos , Humanos , Camundongos , Transporte Proteico/efeitos dos fármacos , Ovinos , Transcrição Gênica/efeitos dos fármacosRESUMO
Context: Remission failure following transsphenoidal surgery in Cushing disease (CD) from pituitary corticotroph tumors (CtTs) remains clinically challenging. Histone deacetylase inhibitors (HDACis) are antitumor drugs approved for clinical use, with the potential to affect adrenocorticotropin hormone (ACTH) hypersecretion by inhibiting pro-opiomelanocortin (POMC) transcription. Objective: Testing the efficacy of suberoylanilide hydroxamic acid (SAHA) on human and murine ACTH-secreting tumor (AtT-20) cells. Design: Cell viability, ACTH secretion (enzyme-linked immunosorbent assay), apoptosis, and gene expression profile were investigated on AtT-20 cells. In vivo efficacy was examined in an athymic nude mouse AtT-20 xenograft model. SAHA efficacy against human-derived corticotroph tumor (hCtT) (n = 8) was tested in vitro. Setting: National Institutes of Health. Intervention: SAHA (0.5 to 8 µM). Main Outcome Measures: AtT-20 and hCtT cell survival, in vitro/invivo ACTH measurements. Results: SAHA (1 µM) reduced AtT-20 viability to 75% at 24 hours, 43% at 48 hours (analysis of variance; P = 0.002). Apoptosis was confirmed with elevated BAX/Bcl2 ratio and FACS. Intriguingly, early (3-hour) significant decline (70%; P < 0.0001) of secreted ACTH and diminished POMC transcription was observed with SAHA (1 µM). Microarray analysis revealed a direct association between liver X receptor alpha (LXRα) and POMC expression. Accordingly, SAHA reduced LXRα in AtT-20 cells but not in normal murine corticotrophs. Xenografted nude-mice tumor involution (126 ± 33/160 ± 35 vs 337 ± 49 mm3; P = 0.0005) was observed with 5-day intraperitoneal SAHA, with reversal of elevated ACTH (P < 0.0001). SAHA did not affect serum ACTH in nontumor mice. Lastly, we confirmed that SAHA (1 µM/24 h) decreased hCtT survival (78.92%; P = 0.0007) and ACTH secretion (83.64%; P = 0.03). Conclusion: Our findings demonstrate SAHA's efficacy in reducing survival and ACTH secretion in AtT-20 and hCtT cells, providing a potential intervention for recurrent/unremitting CD.