Concept: Lactate dehydrogenase
Metabolic modifications of tumor cells are hallmarks of cancer. They exhibit an altered metabolism that allows them to sustain higher proliferation rates in hostile environment outside the cell. In thyroid tumors, the expression of the estrogen-related receptor α (ERRα), a major factor of metabolic adaptation, is closely related to the oxidative metabolism and the proliferative status of the cells. To elucidate the role played by ERRα in the glycolytic adaptation of tumor cells, we focused on the regulation of lactate dehydrogenases A and B (LDHA, LDHB) and the LDHA/LDHB ratio. Our study included tissue samples from 10 classical and 10 oncocytic variants of follicular thyroid tumors and 10 normal thyroid tissues, as well as samples from three human thyroid tumor cell lines: FTC-133, XTC.UC1 and RO82W-1. We identified multiple cis-acting promoter elements for ERRα, in both the LDHA and LDHB genes. The interaction between ERRα and LDH promoters was confirmed by chromatin immunoprecipitation assays and in vitro analysis for LDHB. Using knock-in and knock-out cellular models, we found an inverse correlation between ERRα expression and LDH activity. This suggests that thyroid tumor cells may reprogram their metabolic pathways through the up-regulation of ERRα by a process distinct from that proposed by the recently revisited Warburg hypothesis.
Central nervous system involvement in mantle cell lymphoma: clinical features, prognostic factors and outcomes from the European Mantle Cell Lymphoma Network
- Annals of oncology : official journal of the European Society for Medical Oncology / ESMO
- Published almost 6 years ago
BackgroundCentral nervous system (CNS) involvement in mantle cell lymphoma (MCL) is uncommon, and the manifestations and natural history are not well described.Patients and methodsWe present the data on 57 patients with MCL who developed CNS involvement, from a database of 1396 consecutively treated patients at 14 institutions.ResultsThe crude incidence of CNS involvement was 4.1%, with 0.9% having CNS involvement at diagnosis. Blastoid histology, B-symptoms, elevated lactate dehydrogenase, Eastern Cooperative Group performance status ≥2 and a high Mantle Cell Lymphoma International Prognostic Index score were enriched in the cohort with CNS involvement, and the presence of ≥1 of these features defined a high-risk subset (an actuarial risk of CNS involvement 15% at 5 years) in a single-institution subset. The median time to CNS relapse was 15.2 months, and the median survival from time of CNS diagnosis was 3.7 months. The white blood cell count at diagnosis <10.9 × 10(9)/l, treatment of CNS involvement with high-dose anti-metabolites, consolidation with stem cell transplant and achievement of complete response were all associated with improved survival.ConclusionsIn MCL, CNS involvement is uncommon, although some features may predict risk. Once manifest outlook is poor; however, some patients who receive intensive therapy survive longer than 12 months.
Background We observed an apparent increase in the rate of device thrombosis among patients who received the HeartMate II left ventricular assist device, as compared with preapproval clinical-trial results and initial experience. We investigated the occurrence of pump thrombosis and elevated lactate dehydrogenase (LDH) levels, LDH levels presaging thrombosis (and associated hemolysis), and outcomes of different management strategies in a multi-institutional study. Methods We obtained data from 837 patients at three institutions, where 895 devices were implanted from 2004 through mid-2013; the mean (±SD) age of the patients was 55±14 years. The primary end point was confirmed pump thrombosis. Secondary end points were confirmed and suspected thrombosis, longitudinal LDH levels, and outcomes after pump thrombosis. Results A total of 72 pump thromboses were confirmed in 66 patients; an additional 36 thromboses in unique devices were suspected. Starting in approximately March 2011, the occurrence of confirmed pump thrombosis at 3 months after implantation increased from 2.2% (95% confidence interval [CI], 1.5 to 3.4) to 8.4% (95% CI, 5.0 to 13.9) by January 1, 2013. Before March 1, 2011, the median time from implantation to thrombosis was 18.6 months (95% CI, 0.5 to 52.7), and from March 2011 onward, it was 2.7 months (95% CI, 0.0 to 18.6). The occurrence of elevated LDH levels within 3 months after implantation mirrored that of thrombosis. Thrombosis was presaged by LDH levels that more than doubled, from 540 IU per liter to 1490 IU per liter, within the weeks before diagnosis. Thrombosis was managed by heart transplantation in 11 patients (1 patient died 31 days after transplantation) and by pump replacement in 21, with mortality equivalent to that among patients without thrombosis; among 40 thromboses in 40 patients who did not undergo transplantation or pump replacement, actuarial mortality was 48.2% (95% CI, 31.6 to 65.2) in the ensuing 6 months after pump thrombosis. Conclusions The rate of pump thrombosis related to the use of the HeartMate II has been increasing at our centers and is associated with substantial morbidity and mortality.
Creatinine phosphokinase (CPK) and lactate dehydrogenase (LDH) are important biological markers of various myocardial disorders and exercise-induced muscle damage. Lycopene, on the other side, is a natural anti-oxidant with protective action against cardiovascular risk. Fifteen anaerobically trained athletes with elevated LDH and CPK baseline levels were enrolled in this study after undergoing thorough biochemical and cardiovascular evaluation with echocardiocraphy. In nine athletes tomato juice, a lycopene plain juice, was administered during and after exercise, replacing the carbohydrate supplementation beverages commonly used during training for over a two-month period. Tomato juice administration significantly reduced LDH and CPK levels, which returned back to almost normal levels. At the same time homocysteine and C-reactive protein were also attenuated. No changes were observed in the control group, where the usual carbohydrate supplementation had been followed.
Outside of the biological arena the term ‘repression’ often has a negative connotation. However, in the pancreatic β-cell a small group of genes, which are abundantly expressed in most if not all other mammalian tissues, are highly selectively repressed, with likely functional consequences. The two ‘founder’ members of this group, lactate dehydrogenase A (Ldha) and monocarboxylate transporter-1 (MCT-1/Slc16a1), are inactivated by multiple mechanisms including histone modifications and microRNA-mediated silencing. Their inactivation ensures that pyruvate and lactate, derived from muscle during exercise, do not stimulate insulin release inappropriately. Correspondingly, activating mutations in the MCT-1 promoter underlie ‘exercise-induced hyperinsulinism’ (EIHI) in man, a condition mimicked by forced over-expression of MCT-1 in the β-cell in mice. Furthermore, LDHA expression in the β-cell is upregulated in both human type 2 diabetes and in rodent models of the disease. Recent work by us and by others has identified a further ∼60 genes which are selectively inactivated in the β-cell, a list which we refine here up to seven by detailed comparison of the two studies. These genes include key regulators of cell proliferation and stimulus-secretion coupling. The present, and our earlier results, thus highlight the probable importance of shutting down a subset of ‘disallowed’ genes for the differentiated function of β-cells, and implicate previously unsuspected signalling pathways in the control of β-cell expansion and insulin secretion. Targeting of deregulated ‘disallowed’ genes in these cells may thus, in the future, provide new therapeutic avenues for type 2 diabetes.
Gallic acid, a polyphenyl class natural product from gallnut and green tea, is known to be antioxidant, anti-inflammatory and radical scavenger. In this study, we aimed to investigate the possible protective effects of gallic acid on paraoxonase and arylesterase activities in liver exposed to acute alcohol intoxication. Paraoxonase and arylesterase activities in liver tissue and serum aspartate aminotransferase, alanine aminotransferase and lactate dehydrogenase levels were measured. Histological investigations were also made. In our study, we observed a significant increase of serum alanine aminotransferase, aspartate aminotransferase and lactate dehydrogenase activities, which are indicators of liver damage after acute ethanol consumption. Gallic acid therapy has significantly reduced the increase in these biomarkers, indicating a possible hepatoprotective effect of gallic acid. Ethanol consumption caused a significant decrease in liver paraoxonase activity (P < 0.001). Gallic acid treatment partly restored this decreased paraoxonase activity, which resulted from ethanol administration. A gallic acid dose of 100 mg/kg was observed as highest restoring effect for paraoxonase activity (P < 0.05). The activity of arylesterase was decreased in the ethanol group as compared with the control group, but this was not significant. However, 50 mg/kg of gallic acid treatment restored the loss of this activity due to ethanol exposure (P < 0.001). We observed that gallic acid ameliorates the liver damage caused by excessive alcohol consumption in a dose-dependent way. Our results in this study showed that gallic acid might have a protective effect against alcoholic liver disease. Copyright © 2012 John Wiley & Sons, Ltd.
The aim of this study is to assess biological prognostic factors at the onset of vaso-occlusive crisis (VOC) in adults with sickle cell disease (SCD).
BACKGROUND: Metabolites of ethylene glycol (EG) can cross-react in l-lactate assays, leading to falsely elevated serum lactate levels in case of EG intoxication. In this study, we evaluated the effects of EG and its metabolites on routinely used lactate measuring methods. METHODS: Serum aliquots were spiked with either l-lactate, EG or one of its metabolites (all 12.5 mmol/L): glyoxal, glycolate, glyoxylic acid or oxalate. An unspiked sample (l-lactate 2.6 mmol/L) served as a control. l-Lactate levels in these samples were measured in 31 national hospitals on 20 different analysers from nine manufacturers. RESULTS: The l-lactate concentrations in the control sample and in the samples spiked with l-lactate, EG, glyoxal and oxalate provided correct results by all routinely used methods. However, the glycolate and glyoxylic acid spiked samples resulted in falsely elevated l-lactate concentration with all blood gas methods and with the majority of general chemistry methods using l-lactate oxidase. CONCLUSION: The EG metabolites glycolate and glyoxylic acid were shown to falsely elevate l-lactate results with most of the currently used methods due to cross-reactivity with the oxidase enzyme. Falsely elevated l-lactate results can lead to misdiagnosis and inappropriate management of patients with EG intoxication.
Pulmonary mucormycosis (PM) is a life-threatening opportunistic mycosis with a variable clinical evolution and few prognostic markers for outcome assessment. Several clinical risk factors for poor outcome present at the diagnosis of PM were analyzed in 75 consecutive hematology patients from 2000-2012. Significant variables (P < 0.1) were entered into a multivariate Cox-proportional hazard regression model adjusting for baseline APACHE II to identify independent risk factors for mortality within 28 days. Twenty-eight of 75 patients died within 4-week follow up. A lymphocyte count < 100/mm(3) at the time of diagnosis (adjusted hazard ratio 4.0, 1.7-9.4, P = 0.01) and high level of lactate dehydrogenase (AHR 3.7, 1.3-10.2, P = 0.015) were independent predictors along with APACHE II score for 28-day mortality. A weighted risk score based on these 3 baseline variables accurately identified non-surviving patients at 28 days (area under the receiver-operator curve of 0.87, 0.77-0.93, P < 0.001). A risk score > 22 was associated with 8-fold high rates of mortality (P < 0.0001) within 28 days of diagnosis and median survival of 7 days versus ≥28 days in patients with risk scores ≤22. We found that APACHE II score, severe lymphocytopenia and high LDH levels at the time of PM diagnosis were independent markers for rapid disease progression and death.
PURPOSE OF REVIEW: Light’s criteria combine three dichotomous tests into a decision rule that is considered positive if any one of the tests is positive. This strategy clearly maximizes sensitivity, although at the expense of specificity. Although Light’s criteria identify 98% of pleural exudates, they misclassify about 25% of transudates as exudates. The way to overcome this limitation is discussed in this review. RECENT FINDINGS: Traditionally, measurement of the protein gradient between the serum and pleural fluid has been recommended to decrease the misclassification rate of Light’s criteria. A recent study demonstrated that a gradient between the albumin levels in the serum and the pleural fluid more than 1.2 g/dl performs significantly better than a protein gradient more than 3.1 g/dl to correctly categorize mislabeled cardiac effusions (83 vs. 55%). On the other hand, the accuracy of a pleural fluid to serum albumin ratio less than 0.6 excelled when compared with albumin and protein gradients in patients with miscategorized hepatic hydrothoraces (77 vs. 62 vs. 61%). SUMMARY: The simplest strategy to reveal the true transudative nature of heart failure-related effusions, labeled as exudates by Light’s criteria, is to calculate the serum to pleural fluid albumin gradient. Conversely, for misclassified hepatic hydrothoraces, measurement of the pleural to serum albumin ratio is recommended. The serum to pleural fluid protein gradient should no longer be considered the preferred test for this purpose.