Protein networks linking Warburg and reverse Warburg effects to cancer cell metabolism.

It was 80 years after the Otto Warburg discovery of aerobic glycolysis, a major hallmark in the understanding of cancer. The Warburg effect is the preference of cancer cell for glycolysis that produces lactate even when sufficient oxygen is provided. "reverse Warburg effect" refers to the interstitial tissue communications with adjacent epithelium, that in the process of carcinogenesis, is needed to be explored. Among these cell-cell communications, the contact between epithelial cells; between epithelial cells and matrix; and between fibroblasts and inflammatory cells in the underlying matrix. Cancer involves dysregulation of Warburg and reverse Warburg cellular metabolic pathways. How these gene and protein-based regulatory mechanisms have functioned has been the basis for this review. The importance of the Warburg in oxidative phosphorylation suppression, with increased glycolysis in cancer growth and proliferation is emphasized. Studies that are directed at pathways that would be expected to shift cell metabolism to an increased oxidation and to a decrease in glycolysis are emphasized. Key enzymes required for oxidative phosphorylation, and affect the inhibition of fatty acid metabolism and glutamine dependence are conferred. The findings are of special interest to cancer pharmacotherapy. Studies described in this review are concerned with the effects of therapeutic modalities that are intimately related to the Warburg effect. These interactions described may be helpful as adjuvant therapy in controlling the process of proliferation and metastasis.

Biomarkers of stress-mediated metabolic deregulation in diabetes mellitus.

This review illustrates the relationship of oxidative and nitrative stress to diabetes mellitus and its complications. This is of considerable interest because diabetes mellitus is a lifetime systemic metabolic disease that may have childhood or adult onset and affects not only a triad of pancreatic islet cell insulin, pituitary insulin-like growth hormone, and liver steatosis, it has a long-term association with adiposity, atherosclerosis, coronary vascular disease, kidney disease of the nature afferent arteriolar sclerosis and nodular glomerulosclerosis, cerebrovascular disease, and amyloid deposition in the pancreas and kidney. Only at the end of the 20th century do we gain insight into oxidative and nitrative stress and their consequences. Of special interest here is the fact that reactive oxygen and nitrogen radicals are with us generated throughout the life cycle, and the roles for glutathione and Fe3+ are key elements in the metabolic picture, which brings into the picture dietary factors. More research is required to demonstrate the clinical relivance of naturally-occuring whole-food antioxidants in ameliorating human diabetic complications in vivo.

Plasma Transthyretin as a Biomarker of Lean Body Mass and Catabolic States.

Plasma transthyretin (TTR) is a plasma protein secreted by the liver that circulates bound to retinol-binding protein 4 (RBP4) and its retinol ligand. TTR is the sole plasma protein that reveals from birth to old age evolutionary patterns that are closely superimposable to those of lean body mass (LBM) and thus works as the best surrogate analyte of LBM. Any alteration in energy-to-protein balance impairs the accretion of LBM reserves and causes early depression of TTR production. In acute inflammatory states, cytokines induce urinary leakage of nitrogenous catabolites, deplete LBM stores, and cause an abrupt decrease in TTR and RBP4 concentrations. As a result, thyroxine and retinol ligands are released in free form, creating a second frontline that strengthens that primarily initiated by cytokines. Malnutrition and inflammation thus keep in check TTR and RBP4 secretion by using distinct and unrelated physiologic pathways, but they operate in concert to downregulate LBM stores. The biomarker complex integrates these opposite mechanisms at any time and thereby constitutes an ideally suited tool to determine residual LBM resources still available for metabolic responses, hence predicting outcomes of the most interwoven disease conditions.

Downsizing of lean body mass is a key determinant of Alzheimer's disease.

Lean body mass (LBM) encompasses all metabolically active organs distributed into visceral and structural tissue compartments and collecting the bulk of N and K stores of the human body. Transthyretin (TTR) is a plasma protein mainly secreted by the liver within a trimolecular TTR-RBP-retinol complex revealing from birth to old age strikingly similar evolutionary patterns with LBM in health and disease. TTR is also synthesized by the choroid plexus along distinct regulatory pathways. Chronic dietary methionine (Met) deprivation or cytokine-induced inflammatory disorders generates LBM downsizing following differentiated physiopathological processes. Met-restricted regimens downregulate the transsulfuration cascade causing upstream elevation of homocysteine (Hcy) safeguarding Met homeostasis and downstream drop of hydrogen sulfide (H2S) impairing anti-oxidative capacities. Elderly persons constitute a vulnerable population group exposed to increasing Hcy burden and declining H2S protection, notably in plant-eating communities or in the course of inflammatory illnesses. Appropriate correction of defective protein status and eradication of inflammatory processes may restore an appropriate LBM size allowing the hepatic production of the retinol circulating complex to resume, in contrast with the refractory choroidal TTR secretory process. As a result of improved health status, augmented concentrations of plasma-derived TTR and retinol may reach the cerebrospinal fluid and dismantle senile amyloid plaques, contributing to the prevention or the delay of the onset of neurodegenerative events in elderly subjects at risk of Alzheimer's disease.

The increasing role for the laboratory in nutritional assessment.

The laboratory role in nutritional management of the patient has seen remarkable growth while there have been dramatic changes in technology over the last 25 years, and it is bound to be transformative in the near term. This editorial is an overview of the importance of the laboratory as an active participant in nutritional care.

Measurement of granulocyte maturation may improve the early diagnosis of the septic state.

BACKGROUND: Sepsis is a costly diagnosis in hospitalized patients. Failure to diagnose sepsis in a timely manner creates a potential financial and safety hazard. The use of transthyretin, C-reactive protein and procalcitonin measurement as early markers of systemic inflammatory response syndrome (SIRS) and sepsis in association with admission of emergency department patients to the intensive care unit (ICU) has been studied. In these studies the SIRS criteria as well as the use of an elevated neutrophil count with granulocyte precursors (left shift) have proved to be problematic. Despite the validity of procalcitonin measurement (PCT, Brahms) in the early diagnosis of SIRS the cost and time for testing are limiting considerations. Immature granulocyte (IG) measurement has been proposed as a more readily available indicator of the presence of granulocyte precursors (left shift). METHODS: This study calibrates and validates the measurement of granulocyte maturation [Immature granulocytes (IG)] to the identification of sepsis, a study carried out on a Sysmex Analyzer, model XE 2100 (Kobe, Japan). The Sysmex IG parameter is a crucial measure of immature granulocyte counts and includes metamyelocytes and myelocytes, but not band neutrophils. RESULTS AND CONCLUSIONS: We found agreement with previous work that designated an IG measurement cut-off of 3.2 as optimal. The analysis was then carried a step further with a multivariable discriminator.

Effect of renal function loss on NT-proBNP level variations.

OBJECTIVE: NT-proBNP level is used for the detection of acute CHF and as a predictor of survival. However, a number of factors, including renal function, may affect the NT-proBNP levels. This study aims to provide a more precise way of interpreting NT-proBNP levels based on GFR, independent of age. METHODS: This study includes 247 pts in whom CHF and known confounders of elevated NT-proBNP were excluded, to show the relationship of GFR in association with age. The effect of eGFR on NT-proBNP level was adjusted by dividing 1000 x log(NT-proBNP) by eGFR then further adjusting for age in order to determine a normalized NT-proBNP value. RESULTS: The normalized NT-proBNP levels were affected by eGFR independent of the age of the patient. CONCLUSION: A normalizing function based on eGFR eliminates the need for an age-based reference ranges for NT-proBNP.

Transthyretin as a marker to predict outcome in critically ill patients.

BACKGROUND: A determination of serum Transthyretin (TTR, Prealbumin) level is an objective method of assessing protein catabolic loss of severely ill patients and numerous studies have shown that TTR levels correlate with patient outcomes of non-critically ill patients. We evaluated whether TTR level correlates with the prevalence of PEM in the ICU and evaluated serum TTR level as an indicator of the effectiveness of nutrition support and the prognosis in critically ill patients. METHODS: We studied PEM prevalence in 118 patients admitted to a community hospital's medical intensive care unit and the association between TTR, low albumin (ALB) concentration and high-risk disease (HRD), i.e., sepsis, inability to take in oral nutrients, etc. Serum TTR was measured on the day of admission, day 3 and day 7 of their ICU stay. APACHE II and SOFA score was assessed on the day of admission and the nutritional status and nutritional requirement was assessed for their entire ICU stay. Patients were divided into three groups based on initial TTR level and the outcome analysis was performed for APACHE II score, SOFA score, ICU length of stay, hospital length of stay, and mortality. RESULTS: TTR showed excellent concordance with patients classified with PEM or at high malnutrition risk, and followed for 7 days, it is a measure of the metabolic burden. TTR levels decline from day 1 to day 7 in spite of providing nutritional support. Patients were classified in 3 categories with respect to the level of TTR: more than 170 mg/L, twenty-five patients (group 3); 100-170 mg/L, forty-eight patients (group 2); less than 100 mg/L, forty-five patients (group 1). TTR level correlated with ICU length of stay, hospital length of stay, and APACHE II score, and predicts mortality. CONCLUSIONS: TTR identified patients at highest risk for metabolic losses associated with stress hypermetabolism as serum TTR levels did not respond early to nutrition support because of the delayed return to anabolic status. It is particularly helpful in removing interpretation bias, and it is an excellent measure of the systemic inflammatory response concurrent with a preexisting state of chronic inanition.

A model for automated screening of thalassemia in hematology (math study).

BACKGROUND: beta-thalassemia screening is primarily limited to pregnant women. The ratio of the mean corpuscular volume (MCV) and red blood cell count (RBC) can be automatically calculated with any of the newer hematology analyzers. METHODS: The results of 398 patient screens were collected. Data from the set were divided into training and validation subsets. The Mentzer ratio was determined through a receiver operating characteristic (ROC) curve on the first subset, and screened for thalassemia using the second subset. HgbA2 levels were used to confirm beta-thalassemia. RESULTS: We determined the correct decision point of the Mentzer index to be a ratio of 20. Physicians can screen patients using this index before further evaluation for beta-thalassemia (P < .05). CONCLUSION: The proposed method can be implemented by hospitals and laboratories to flag positive matches for further definitive evaluation, and will enable beta-thalassemia screening of a much larger population at little to no additional cost.

Minor elevations in troponin T values enhance risk assessment in emergency department patients with suspected myocardial ischemia: analysis of novel troponin T cut-off values.

BACKGROUND: A consensus document developed by a joint committee of the European Society of Cardiology and the American College of Cardiology redefines myocardial infarction (MI) using an increase of troponin I or T as compared to a reference control population (i.e., troponin T (TnT) of 0.01 microg/l). A clinical problem arises when an arbitrary cut-off point is selected for determination of MI (i.e., TnT> or =0.1 microg/l), as minor elevations of troponin are associated with increased cardiovascular risk in selected patients with acute coronary syndromes. METHODS: We prospectively studied 420 unselected patients being evaluated for suspected myocardial ischemia in the emergency department (ED). We compared a 99th percentile MI cut-off limit for TnT, determined by constructing a standard receiver operator curve from our ED population in whom an acute coronary syndrome was excluded, to a standard MI cut-off limit of 0.1 microg/l in assessing cardiovascular risk. We also assessed the prognostic value of detectable TnT concentrations below this 99th percentile MI cut-off, but above the upper reference limit of healthy controls. RESULTS: The diagnosis of acute coronary syndromes (ACS) was more frequent in groups with higher TnT concentrations: 16.8% with a normal TnT (<0.03 microg/l), 29.5% with detectable TnT below the 99th percentile MI limit (0.03-0.066 microg/l), 64.3% with detectable TnT between the 99th percentile and standard MI cut-offs (0.067-0.099 microg/l), and 85.4% with TnT> or =0.1 microg/l (p<0.001 for the trend). Thirty-day cardiovascular event rates increased for any detectable concentration of troponin: 1.3% with normal TnT, 4.8% with detectable TnT below the 99th percentile MI limit, 15.4% with TnT between the 99th percentile and standard MI cut-off limits, and 12.5% with TnT> or =0.1 microg/l (p<0.01 for the trend). CONCLUSION: Using an MI cut-off concentration for TnT from a "non-ACS reference" improves risk stratification, but fails to detect a positive TnT in 11.7% of subjects with an acute coronary syndrome.

Prediction of respiratory distress syndrome using the Abbott FLM-II amniotic fluid assay.

BACKGROUND: Most laboratories using the Abbott FLM-II assay for assessing fetal lung maturity follow the manufacturer's recommendations for interpreting the surfactant to albumin ratio (S/A). Thus, values >55 mg/g are considered mature and values <40 mg/g, immature-leaving a wide range of indeterminate values. Little data is available to assist the clinician in interpreting values between 40 and 55 mg/g. The goal of this study was to determine decision levels that would more clearly identify risk for RDS based on S/A results. METHODS: Respiratory distress syndrome was identified based on medical record review in 46 infants (born at six hospitals), who had S/A measurements on amniotic fluid within 72 h of delivery. An additional 257 women, who had had the S/A test requested but had non-RDS infants, were also identified for this study. The probability of RDS was calculated based on S/A values and on gestational age. Odds ratios were computed for different S/A ratios and different gestational ages. RESULTS: Probability of RDS increased with decreasing S/A and decreasing gestational age. At gestational age >36 weeks, the probability of developing RDS ranged from 1% at S/A>44 mg/g to 39% at S/A44 mg/g to 92% at S/A

Value of a single troponin T at the time of presentation as compared to serial CK-MB determinations in patients with suspected myocardial ischemia.

BACKGROUND: Prior studies with cardiac markers have focused predominantly on subjects presenting to the emergency department with chest pain or unstable angina, and have relied on serial markers for the diagnosis of acute myocardial infarction. We evaluated the diagnostic utility of a single cardiac troponin T (cTnT) determination at the time of presentation as compared to serial creatine kinase (CK) MB determinations in a broad spectrum of patients with suspected myocardial ischemia. METHODS: A total of 267 consecutive patients presenting to the emergency department with suspected myocardial ischemia had a single, blinded cTnT determination drawn at the time of presentation to the emergency department in addition to routine serial electrocardiographic and CK-MB determinations. RESULTS: The specificity (93.7% vs. 87.1%; p<0.05) and positive predictive value (80.0% vs. 69.4%; p<0.05) of a single cTnT determination were superior to that of serial CK-MB determinations without compromising sensitivity. Forty-six percent of patients with confirmed myocardial infarction and an abnormal cTnT at presentation had a normal initial CK-MB determination. Conversely, 20% of patients without acute coronary syndromes had an abnormal CK-MB determination in the setting of a normal cTnT. The initial cTnT was abnormal in all patients with confirmed myocardial infarction and a symptom duration of at least 3.5 h. CONCLUSIONS: In a heterogeneous population of patients with suspected myocardial ischemia, the initial cTnT determination drawn at the time of presentation is a powerful diagnostic tool that, when used in context with symptom duration, allows for more rapid and accurate triage of patients than serial CK-MB determinations.

Transthyretin: its response to malnutrition and stress injury. clinical usefulness and economic implications.

Serum transthyretin is an ideal marker for monitoring patients who are malnourished or have metabolic consequences of acute stress injury because it has a short half-life, it measures the level of metabolic deficit, the response to nutritional metabolic support, and because it is a prognostic indicator. Mounting clinical evidence indicates that the use of transthyretin to assess and monitor a patient's nutritional status results in improved treatment outcomes and lower overall healthcare costs.