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1.
Vasa ; 53(1): 61-67, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37965700

RESUMO

Background: Acute kidney injury (AKI) after open thoracoabdominal aortic aneurysm repairs (TAAA) is a common postoperative complication, associated with increased mortality and morbidity. Early detection and management of the kidney tissue damage remains of paramount importance. The aim of this prospectively conducted, observational trial was to evaluate the clinical applicability of Proenkephalin A 119-159 (penKid) for the detection of postoperative AKI. Patients and methods: Thirty-six patients, planned for elective open TAAA repairs from January 2019 to December 2022, were recruited in two German centres (University Hospital Aachen and Charité - University Hospital Berlin). Blood samples were collected pre-surgery (baseline), directly postoperatively and at 12, 24 and 48 hours after surgery. The penKid concentration in plasma was measured using the immunoluminometric sphingotest® assay kit and they were statistically tested for association with AKI and other clinical parameters. Results: Twenty-four patients (62%) developed moderate or severe AKI postoperatively (Stage 2 or 3 of the KDIGO classification) and they had a significantly increased risk for the development of acute respiratory distress syndrome (p=.023) or a fatal outcome (p=.035). Starting from the 12th hour after surgery, we found penKid correlating with AKI stage 2/3 (12 hour penKid mean in pmol/L: 93.9 vs. 43.1; c index .776, p=.0037) and renal replacement therapy (12 hour c index .779, p=.0035). Patients with multi-organ dysfunction syndrome had significantly increased penKid levels at all timepoints. Conclusions: We found penKid to be a promising biomarker for the early detection of postoperative AKI and in-hospital mortality after open TAAA repair, which may enable the early initiation of organ-protective strategies and reduction of further complications associated with AKI.


Assuntos
Injúria Renal Aguda , Aneurisma da Aorta Torácica , Humanos , Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/etiologia , Aorta , Biomarcadores , Estudos Retrospectivos , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/etiologia , Resultado do Tratamento , Fatores de Risco , Aneurisma da Aorta Torácica/cirurgia
2.
Crit Care ; 27(1): 276, 2023 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-37430375

RESUMO

INTRODUCTION: Recent evidence suggests an association of plasma Proenkephalin A 119-159 (penKid) with early and successful liberation from continuous renal replacement therapy (CRRT) in critically ill patients with acute kidney injury. However, these exploratory results are derived from a monocentric trial and therefore require external validation in a multicenter cohort. METHODS: Data and plasma samples from the "Effect of Regional Citrate Anticoagulation versus Systemic Heparin Anticoagulation During Continuous Kidney Replacement Therapy on Dialysis Filter Life Span and Mortality Among Critically Ill Patients With Acute Kidney Injury-A Randomized Clinical Trial" (RICH Trial) were used for this validation study. PenKid was measured in all plasma samples available at CRRT initiation and at day 3 of CRRT. Patients were categorized into low and high penKid groups with a cutoff at 100 pmol/l. Competing-risk time-to-event analyses were performed. Competing risk endpoints were successful and unsuccessful liberation from CRRT, the latter meaning death or initiation of a new RRT within one week of discontinuation of primary CRRT. Then penKid was compared to urinary output. RESULTS: Low pre-CRRT penKid levels at CRRT initiation were not associated with early and successful liberation from CRRT compared to patients with high pre-CRRT penKid levels [subdistribution hazard ratio (sHR) 1.01, 95% CI 0.73-1.40, p = 0.945]. However, the landmark analysis on day 3 of ongoing CRRT demonstrated an association between low penKid levels and successful liberation from CRRT (sHR 2.35, 95% CI 1.45-3.81, p < 0.001) and an association between high penKid levels and unsuccessful liberation (sHR 0.46, 95% CI 0.26-0.80, p = 0.007). High daily urinary output (> 436 ml/d) was even stronger associated with successful liberation (sHR 2.91, 95% CI 1.80-4.73, p < 0.001) compared to penKid. DISCUSSION: This study suggests that penKid may be a competent biomarker to monitor the recovery of kidney function during CRRT. This is in line with previous findings and investigated this concept in a multicenter cohort. Again, low penKid was associated with early and successful CRRT liberation, but was outperformed by high daily urinary output. The findings of this study now warrant further evaluation in prospective studies or a randomized controlled trial. Trial registration The RICH Trial was registered at clinicaltrials.gov: NCT02669589. Registered 01 February 2016.


Assuntos
Injúria Renal Aguda , Terapia de Substituição Renal Contínua , Humanos , Estado Terminal/terapia , Projetos Piloto , Estudos Prospectivos , Diálise Renal , Terapia de Substituição Renal , Injúria Renal Aguda/terapia , Anticoagulantes
3.
Int J Cancer ; 148(5): 1219-1232, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33284994

RESUMO

Here we sought metabolic alterations specifically associated with MYCN amplification as nodes to indirectly target the MYCN oncogene. Liquid chromatography-mass spectrometry-based proteomics identified seven proteins consistently correlated with MYCN in proteomes from 49 neuroblastoma biopsies and 13 cell lines. Among these was phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme in de novo serine synthesis. MYCN associated with two regions in the PHGDH promoter, supporting transcriptional PHGDH regulation by MYCN. Pulsed stable isotope-resolved metabolomics utilizing 13 C-glucose labeling demonstrated higher de novo serine synthesis in MYCN-amplified cells compared to cells with diploid MYCN. An independence of MYCN-amplified cells from exogenous serine and glycine was demonstrated by serine and glycine starvation, which attenuated nucleotide pools and proliferation only in cells with diploid MYCN but did not diminish these endpoints in MYCN-amplified cells. Proliferation was attenuated in MYCN-amplified cells by CRISPR/Cas9-mediated PHGDH knockout or treatment with PHGDH small molecule inhibitors without affecting cell viability. PHGDH inhibitors administered as single-agent therapy to NOG mice harboring patient-derived MYCN-amplified neuroblastoma xenografts slowed tumor growth. However, combining a PHGDH inhibitor with the standard-of-care chemotherapy drug, cisplatin, revealed antagonism of chemotherapy efficacy in vivo. Emergence of chemotherapy resistance was confirmed in the genetic PHGDH knockout model in vitro. Altogether, PHGDH knockout or inhibition by small molecules consistently slows proliferation, but stops short of killing the cells, which then establish resistance to classical chemotherapy. Although PHGDH inhibition with small molecules has produced encouraging results in other preclinical cancer models, this approach has limited attractiveness for patients with neuroblastoma.


Assuntos
Amplificação de Genes , Proteína Proto-Oncogênica N-Myc/genética , Neuroblastoma/tratamento farmacológico , Fosfoglicerato Desidrogenase/antagonistas & inibidores , Animais , Linhagem Celular Tumoral , Feminino , Glicina/metabolismo , Humanos , Camundongos , Neuroblastoma/genética , Serina/metabolismo
4.
J Enzyme Inhib Med Chem ; 36(1): 1282-1289, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34192988

RESUMO

The small-molecule inhibitor of phosphoglycerate dehydrogenase, NCT-503, reduces incorporation of glucose-derived carbons into serine in vitro. Here we describe an off-target effect of NCT-503 in neuroblastoma cell lines expressing divergent phosphoglycerate dehydrogenase (PHGDH) levels and single-cell clones with CRISPR-Cas9-directed PHGDH knockout or their respective wildtype controls. NCT-503 treatment strongly reduced synthesis of glucose-derived citrate in all cell models investigated compared to the inactive drug control and independent of PHGDH expression level. Incorporation of glucose-derived carbons entering the TCA cycle via pyruvate carboxylase was enhanced by NCT-503 treatment. The activity of citrate synthase was not altered by NCT-503 treatment. We also detected no change in the thermal stabilisation of citrate synthase in cellular thermal shift assays from NCT-503-treated cells. Thus, the direct cause of the observed off-target effect remains enigmatic. Our findings highlight off-target potential within a metabolic assessment of carbon usage in cells treated with the small-molecule inhibitor, NCT-503.


Assuntos
Inibidores Enzimáticos/farmacologia , Fosfoglicerato Desidrogenase/antagonistas & inibidores , Piperazinas/farmacologia , Piridinas/farmacologia , Tioamidas/farmacologia , Sistemas CRISPR-Cas , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ciclo do Ácido Cítrico/efeitos dos fármacos , Cromatografia Gasosa-Espectrometria de Massas/métodos , Glucose/metabolismo , Humanos , Metabolômica , Fosfoglicerato Desidrogenase/genética
5.
Int J Mol Sci ; 23(1)2021 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-35008547

RESUMO

Development of new anticancer drugs with currently available animal models is hampered by the fact that human cancer cells are embedded in an animal-derived environment. Neuroblastoma is the most common extracranial solid malignancy of childhood. Major obstacles include managing chemotherapy-resistant relapses and resistance to induction therapy, leading to early death in very-high-risk patients. Here, we present a three-dimensional (3D) model for neuroblastoma composed of IMR-32 cells with amplified genes of the myelocytomatosis viral related oncogene MYCN and the anaplastic lymphoma kinase (ALK) in a renal environment of exclusively human origin, made of human embryonic kidney 293 cells and primary human kidney fibroblasts. The model was produced with two pneumatic extrusion printheads using a commercially available bioprinter. Two drugs were exemplarily tested in this model: While the histone deacetylase inhibitor panobinostat selectively killed the cancer cells by apoptosis induction but did not affect renal cells in the therapeutically effective concentration range, the peptidyl nucleoside antibiotic blasticidin induced cell death in both cell types. Importantly, differences in sensitivity between two-dimensional (2D) and 3D cultures were cell-type specific, making the therapeutic window broader in the bioprinted model and demonstrating the value of studying anticancer drugs in human 3D models. Altogether, this cancer model allows testing cytotoxicity and tumor selectivity of new anticancer drugs, and the open scaffold design enables the free exchange of tumor and microenvironment by any cell type.


Assuntos
Antineoplásicos/farmacologia , Rim/efeitos dos fármacos , Neuroblastoma/tratamento farmacológico , Microambiente Tumoral/efeitos dos fármacos , Quinase do Linfoma Anaplásico/metabolismo , Apoptose/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Células HEK293 , Humanos , Rim/metabolismo , Proteína Proto-Oncogênica N-Myc/metabolismo , Neuroblastoma/metabolismo , Panobinostat/farmacologia
6.
Sci Rep ; 14(1): 12795, 2024 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-38834580

RESUMO

Cytokine-mediated systemic inflammation after open thoracoabdominal aortic aneurysm (TAAA) repairs plays a pivotal role in disrupting circulatory homeostasis, potentially leading to organ dysfunction. The bioactive form of adrenomedullin (bio-ADM) is a peptide hormone with immunomodulatory and vasomotor effects, making it a potential diagnostic agent in these cases. This retrospective, bicentric study, conducted between January 2019 and December 2022, recruited 36 elective open TAAA repair patients in two German centres. Serum and plasma samples were collected at multiple time points to measure bio-ADM levels. The primary objective was to evaluate the association of bio-ADM levels with the onset of acute respiratory distress syndrome (ARDS), with secondary endpoints focusing on mortality and SIRS-related morbidity. Results showed a significant association between postoperative bio-ADM levels (12-48 h after surgery) and the onset of ARDS (p < .001), prolonged ventilation (p = .015 at 12h after surgery), atrial fibrillation (p < .001), and mortality (p = .05 at 24h). The biomarker was also strongly associated with sepsis (p = .01 at 12 h) and multi-organ dysfunction syndrome (MODS) (p = .02 at 24 h after surgery). The study underscores the potential utility of bio-ADM as a diagnostic tool for identifying patients at risk of postoperative complications following open TAAA repairs.


Assuntos
Adrenomedulina , Aneurisma da Aorta Torácica , Biomarcadores , Complicações Pós-Operatórias , Síndrome do Desconforto Respiratório , Humanos , Adrenomedulina/sangue , Masculino , Feminino , Síndrome do Desconforto Respiratório/etiologia , Síndrome do Desconforto Respiratório/sangue , Pessoa de Meia-Idade , Idoso , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/sangue , Estudos Retrospectivos , Aneurisma da Aorta Torácica/cirurgia , Aneurisma da Aorta Torácica/sangue , Biomarcadores/sangue , Sepse/sangue , Sepse/etiologia , Insuficiência de Múltiplos Órgãos/etiologia , Insuficiência de Múltiplos Órgãos/sangue , Insuficiência de Múltiplos Órgãos/mortalidade , Insuficiência de Múltiplos Órgãos/diagnóstico , Período Pós-Operatório
7.
Cancers (Basel) ; 16(9)2024 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-38730615

RESUMO

Glyceraldehyde (GA) is a three-carbon monosaccharide that can be present in cells as a by-product of fructose metabolism. Bruno Mendel and Otto Warburg showed that the application of GA to cancer cells inhibits glycolysis and their growth. However, the molecular mechanism by which this occurred was not clarified. We describe a novel multi-modal mechanism by which the L-isomer of GA (L-GA) inhibits neuroblastoma cell growth. L-GA induces significant changes in the metabolic profile, promotes oxidative stress and hinders nucleotide biosynthesis. GC-MS and 13C-labeling was employed to measure the flow of carbon through glycolytic intermediates under L-GA treatment. It was found that L-GA is a potent inhibitor of glycolysis due to its proposed targeting of NAD(H)-dependent reactions. This results in growth inhibition, apoptosis and a redox crisis in neuroblastoma cells. It was confirmed that the redox mechanisms were modulated via L-GA by proteomic analysis. Analysis of nucleotide pools in L-GA-treated cells depicted a previously unreported observation, in which nucleotide biosynthesis is significantly inhibited. The inhibitory action of L-GA was partially relieved with the co-application of the antioxidant N-acetyl-cysteine. We present novel evidence for a simple sugar that inhibits cancer cell proliferation via dysregulating its fragile homeostatic environment.

8.
Sci Rep ; 13(1): 4873, 2023 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-36964268

RESUMO

An early and reliable prediction of outcomes after stroke is important for early effective stroke management and the adequate optimal planning of post-stroke rehabilitation and long-term care. Bioactive adrenomedullin (bio-ADM) is a 52-amino acid peptide that is an important peptide hormone in nervous system diseases. The aim of this study was to investigate the prognostic value of bio-ADM on outcomes after rehabilitation in patients with stroke. A total of 557 consecutive patients with a primary diagnosis of ischemic or hemorrhagic stroke (age 69.6-12.9 years, male 51.3%, ischemic stroke 72.5%), who were admitted to an in-patient early rehabilitation center directly after discharge from acute stroke hospital care, were enrolled in this prospective observational study. Plasma concentrations of bio-ADM were determined by using a chemiluminescence immunoassay (functional assay sensitivity 8 pg/ml). The early rehabilitation barthel index (ERBI) was used for the neurological assessment of the patients. The plasma bio-ADM level was analyzed in association with 6-month all-cause mortality as well as a composite outcome of all-cause mortality, unscheduled re-hospitalization, or transfer to a long-term care facility in a vegetative or minimally conscious state. Bio-ADM levels significantly increased in patients with ischemic stroke who died compared to surviving patients (40.4 pg/ml vs. 23.8 pg/ml, p < 0.001) or in those with composite outcomes compared to those with no events (36.9 pg/ml vs. 23.5 pg/ml, p < 0.001). Six-month all-cause mortality was higher in all patients with bio-ADM levels > 70 pg/ml (HR 4.83 [CI 2.28-10.2]). Patients with bio-ADM levels > 70 pg/ml also had higher rates of 6-month composite outcomes (HR 3.82 [CI 2.08-7.01]). Bio-ADM was an independent predictor of all-cause mortality and 6-month composite outcomes after adjusting for age, gender, and ERBI (adjusted OR 1.5; 95% CI 1.0-2.1; p = 0.047 and adjusted OR 1.48; 95% CI 1.1-2.0; p = 0.01, respectively). Bio-ADM may be a suitable novel biomarker to assess the outcomes of patients in rehabilitation after acute stroke. Elevated bio-ADM concentrations may have prognostic value for fatal and nonfatal events in patients with ischemic stroke during early rehabilitation.


Assuntos
AVC Isquêmico , Reabilitação do Acidente Vascular Cerebral , Acidente Vascular Cerebral , Humanos , Masculino , Adrenomedulina , Prognóstico , Biomarcadores
9.
Kidney Int Rep ; 8(11): 2345-2355, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-38025210

RESUMO

Introduction: In clinical practice, kidney (dys)function is monitored through creatinine-based estimations of glomerular filtration rate (eGFR: Modification of Diet in Renal Disease [MDRD], Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI]). Creatinine is recognized as a late and insensitive biomarker of glomerular filtration rate (GFR). The novel biomarker proenkephalin (PENK) may overcome these limitations, but no PENK-based equation for eGFR is currently available. Therefore, we developed and validated a PENK-based equation to assess GFR. Methods: In this international multicenter study in 1354 stable and critically ill patients, GFR was measured (mGFR) through iohexol or iothalamate clearance. A generalized linear model with sigmoidal nonlinear transfer function was used for equation development in the block-randomized development set. Covariates were selected in a data-driven fashion. The novel equation was assessed for bias, precision (mean ± SD), and accuracy (eGFR percentage within ±30% of mGFR, P30) in the validation set and compared with MDRD and CKD-EPI. Results: Median mGFR was 61 [44-81] ml/min per 1.73 m2. In order of importance, PENK, creatinine, and age were included, and sex or race did not improve performance. The PENK-based equation mean ± SD bias of the mGFR was 0.5 ± 15 ml/min per 1.73 m2, significantly less compared with MDRD (8 ± 17, P < 0.001) and 2009 CKD-EPI (5 ± 17, P < 0.001), not reaching statistical significance compared with 2021 CKD-EPI (1.3 ± 16, P = 0.06). The P30 accuracy of the PENK-based equation was 83%, significantly higher compared with MDRD (68%, P < 0.001) and 2009 CKD-EPI (76%, P < 0.001), similar to 2021 CKD-EPI (80%, P = 0.13). Conclusion: Overall, the PENK-based equation to assess eGFR performed better than most creatinine-based equations without using sex or race.

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