Metabolic profiling of cell growth and death in cancer: applications in drug discovery.

Metabolic profiling using stable-isotope tracer technology enables the measurement of substrate redistribution within major metabolic pathways in living cells. This technique has demonstrated that transformed human cells exhibit profound metabolic shifts and that some anti-cancer drugs produce their effects by forcing the reversion of these metabolic changes. By revealing tumor-specific metabolic shifts in tumor cells, metabolic profiling enables drug developers to identify the metabolic steps that control cell proliferation, thus aiding the identification of new anti-cancer targets and screening of lead compounds for anti-proliferative metabolic effects.

A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease.

Currently available inhaled bronchodilators used as therapy for chronic obstructive pulmonary disease (COPD) necessitate multiple daily dosing. The present study evaluates the long-term safety and efficacy of tiotropium, a new once-daily anticholinergic in COPD. Patients with stable COPD (age 65.

Effect of hyperoxia on gas exchange and lactate kinetics following exercise onset in nonhypoxemic COPD patients.

Study Objectives: The slow oxygen uptake (VO(2)) kinetics observed in COPD patients is a manifestation of skeletal muscle dysfunction of multifactorial origin. We determined whether oxygen supplementation during exercise makes the dynamic VO(2) response faster and reduces transient lactate increase.

Design: Ten patients with severe COPD (ie, mean [+/- SD] FEV(1), 31 +/- 10% predicted) and 7 healthy subjects of similar age performed four repetitions of the transition between rest and 10 min of moderate-intensity, constant-work rate exercise while breathing air or 40% oxygen in random order.

Breast cancer risk reduction: strategies for women at increased risk.

Breast cancer risk reduction now represents an achievable medical objective. Current interventions include selective estrogen receptor modulators (SERMs), prophylactic surgery, and lifestyle change. For SERMs, current evidence supports tamoxifen use for breast cancer risk reduction whereas raloxifene requires further study.

Inhibition of intracellular macromolecular synthesis in Staphylococcus aureus by thrombin-induced platelet microbicidal proteins.

Thrombin-induced platelet microbicidal proteins (tPMP-1 and tPMP-2) are believed to initiate their staphylocidal effects via cytoplasmic membrane perturbation. The aim of the present study was to investigate the role of subsequent inhibition of macromolecular synthesis in the staphylocidal mechanisms of tPMP-1 and tPMP-2 in an isogenic tPMP-susceptible and -resistant strain pair (ISP479C and ISP479R, respectively). In ISP479C, tPMP-1 and tPMP-2 (2 microg/mL) exerted significant bactericidal effects and significantly reduced DNA and RNA synthesis (P <.

Clinical and demographic predictors of exercise capacity in end-stage renal disease.

Patients on maintenance hemodialysis therapy for end-stage renal disease have reduced exercise tolerance. Multiple processes related to uremia and hemodialysis have been implicated in the pathophysiology of this impairment. However, limited data are available to identify the separate and combined effects of clinical factors on the degree of impairment for individuals within this population.

Glomerular mRNAs in human type 1 diabetes: biochemical evidence for microalbuminuria as a manifestation of diabetic nephropathy.

Background: In patients with type 1 diabetes, some consider microalbuminuria to be a predictor of diabetic nephropathy while others believe it is an early feature of diabetic nephropathy.

Methods: Levels of mRNAs that are of pathogenetic relevance in diabetic nephropathy were compared in glomeruli isolated from microalbuminuric and overtly proteinuric subjects and in control normoalbuminuric diabetic subjects and living renal transplant donors.

Results: In subjects with microalbuminuria and overt proteinuria, glomerular mRNAs were virtually identical and approximately twofold higher for connective tissue growth factor (CTGF; P < 0.

Optimal ECG trigger point in electron-beam CT studies: three methods for minimizing motion artifacts.

Rationale And Objectives: The authors hypothesized that electrocardiographic triggering near end systole could minimize motion artifacts in electron-beam computed tomography (CT) of the coronary artery.

Materials And Methods: The study included 2,660 patients who underwent coronary artery calcium scanning with electron-beam CT. Trigger times were as follows: end of T wave, 120 to 25 msec before end of T wave, 25-50 msec after end of T wave, 40%, 45%, 50%, 55%, 60%, 70%, 75%, 80%, 90%, and 100% of R-R interval.

Expression of aquaporin-8 in human placenta and chorioamniotic membranes: evidence of molecular mechanism for intramembranous amniotic fluid resorption.

Objective: The intramembranous pathway of amniotic fluid absorption has recently been recognized as a critical regulatory path for amniotic fluid resorption, which contributes importantly to amniotic fluid volume homeostasis. Yet, the underlying molecular and cellular mechanisms for water absorption across the amniotic membranes remain unknown. We hypothesize that amniotic fluid water is absorbed across aquaporin water channels in the chorioamniotic membranes.

Loss of tubular bone morphogenetic protein-7 in diabetic nephropathy.

Bone morphogenetic protein-7 (BMP7), a member of the transforming growth factor-beta (TGF-beta) superfamily of cytokines, is highly expressed in renal tubules and generally promotes maintenance of epithelial phenotype. It was examined whether, during the evolution of experimental diabetic nephropathy, the renal expression of BMP7 and BMP7 receptors declines, and the hypothesis that loss of BMP7 activity is profibrogenic in proximal tubular cells was tested. Moreover, in vitro studies in cultured proximal tubular cells were performed to examine putative mechanisms that cause these changes.

Function and inhibition sensitivity of the N-terminal segment of surfactant protein B (SP-B1-25) in preterm rabbits.

Background: Surfactant protein B (SP-B) is an essential component of pulmonary surfactant, but shorter SP-B sequences may exert equivalent surface activity.

Methods: We synthesised a peptide based on the amino-terminal domain of SP-B (SP-B1-25), a full length SP-B1-78, and a full length palmitoylated SP-C peptide (SP-C1-35) and compared the in vivo function and sensitivity to plasma inhibition of preparations consisting of mixtures of phospholipids with SP-B1-25 or SP-B1-78 and/or SP-C1-35 to Survanta. Preterm rabbits born at 27 days of gestation were treated at birth with surfactant and ventilated for 60 minutes.

Factors influencing the role of bisphosphonates in breast cancer management.

Bone metastases represent a significant tumor-related complication affecting many breast cancer patients. The resulting bone destruction or osteolysis that frequently accompanies metastatic bone disease results in considerable morbidity for patients including a high rate of skeletal complications, severe pain, and a reduced quality of life. Traditionally, the treatment of metastatic bone disease has relied heavily on the use of multidisciplinary therapies, such as radiotherapy in combination with systemic treatment, supported by analgesia.

Isofenphos induced metabolic changes in K562 myeloid blast cells.

The organophosphate pesticide, isofenphos, is associated with human myeloid leukemia. In this study we describe metabolic changes in K562 myeloid blast cells from exposure to varying concentrations of isofenphos using the stable [1,2-13C(2)]glucose isotope as the single tracer and biological mass spectrometry. Isofenphos (1, 10, 100 microg/ml/72 h) treated K562 cells showed increases of 10.

Effect of electrocardiogram triggering on reproducibility of coronary artery calcium scoring.

Purpose: To test the hypothesis that computed tomographic (CT) scanning during early rather than middle diastole can significantly reduce the interscan variability of coronary artery calcium (CAC) scores.

Materials And Methods: Five hundred thirty-eight patients were initially enrolled; 282 of them were found to have CAC at electron-beam CT and underwent repeat scanning to measure interscan variability with different electrocardiogram (ECG) triggers. Eight patients were excluded owing to respiratory motion; thus, 274 asymptomatic patients were examined.

Dose-response effect of oxygen on hyperinflation and exercise endurance in nonhypoxaemic COPD patients.

Dynamic hyperinflation contributes to exertional breathlessness and reduced exercise tolerance in chronic obstructive pulmonary disease (COPD) patients. This study examined whether oxygen supplementation results in a dose-dependent decrease in hyperinflation associated with functional and symptomatic improvement. Ten severe COPD patients without clinically significant oxygen (O2) desaturation during exercise, and seven healthy subjects, performed five exercise tests at 75% of maximally tolerated work rate.

Improved reproducibility of coronary artery calcium scoring by electron beam tomography with a new electrocardiographic trigger method.

Rationale And Objectives: To improve the interscan reproducibility with electron beam tomography (EBT) by choosing an optimal electrocardiographic (ECG) trigger time.

Methods: Two hundred fourteen asymptomatic subjects found to have coronary artery calcium (CAC) on EBT were rescanned immediately to measure the interscan variability. Subjects were randomized to one of two different ECG trigger interval groups: the new trigger method (group 1) and the 80% R-R interval trigger method (group 2).

Wheat germ extract decreases glucose uptake and RNA ribose formation but increases fatty acid synthesis in MIA pancreatic adenocarcinoma cells.

The fermented wheat germ extract with standardized benzoquinone composition has potent tumor propagation inhibitory properties. The authors show that this extract induces profound metabolic changes in cultured MIA pancreatic adenocarcinoma cells when the [1,2-13C2]glucose isotope is used as the single tracer with biologic gas chromatography-mass spectrometry. MIA cells treated with 0.

p38 MAPK and MAPK kinase 3/6 mRNA and activities are increased in early diabetic glomeruli.

Background: The p38 mitogen-activated protein kinase (MAPK) pathway is activated by several stress factors, potentially leading to cellular apoptosis and growth. Little is known about the pattern of glomerular p38 MAPK pathway activation during the course of diabetic nephropathy (DN). We examined the activity and expression of the p38 MAPK pathway members, p38 MAPK, MKK3/6, cAMP-responsive element binding protein (CREB), and MAPK phosphatase-1 (MKP-1), in experimental DN in rats over the course of four months.

Skeletal muscle dysfunction in chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a major health care problem. Formerly mainly a disease of men, women are increasingly frequently afflicted. In many of these patients, exercise intolerance is the chief complaint.

Cardiovascular limitations in chronic pulmonary disease.

Chronic lung disease has significant impact on cardiovascular function. Much of this effect is because of increased right ventricular afterload caused by increased pulmonary vascular resistance resulting from structural changes in the pulmonary circulation, and because of hypoxic pulmonary vasoconstriction. In the case of chronic obstructive diseases, there may be additional increases in afterload resulting from dynamic hyperinflation.

Biological differences in depression and anxiety across races and ethnic groups.

A growing number of studies clearly indicate the importance of race and ethnicity in the psychopharmacologic management of depression and anxiety disorders. The data highlight important pharmacokinetic, pharmacodynamic, and pharmacogenetic ethnic differences that may have profound implications for the efficacy and safety of psychotropic therapies. General treatment considerations based on these differences include greater attention to adverse event profiles, the possibility of improved clinical response at any given dose, and the potential need for lower starting doses and slower increases in dosage.

Connective tissue growth factor in tubulointerstitial injury of diabetic nephropathy.

Background: Chronic interstitial fibrosis, which follows the onset of glomerular proteinuria, importantly contributes to progressive renal failure in diabetic nephropathy. The present studies examine the potential role of tubular connective tissue growth factor (CTGF).

Methods: The expression of CTGF was examined in rats with diabetic nephropathy.

12-lipoxygenase is increased in glucose-stimulated mesangial cells and in experimental diabetic nephropathy.

Background: Arachidonic acid-derived 12-lipoxygenase (12-LO) products have potent growth and chemotactic properties. The present studies examined whether 12-LO and fibronectin are induced in cultured rat mesangial cells (MCs) exposed to high glucose and whether they are expressed in experimental diabetic nephropathy.

Methods: To determine the effect of high glucose on MC 12-LO mRNA and protein expression, rat MCs were incubated with RPMI medium containing 100 (NG) or 450 mg/dL glucose (HG).

Automatic scan prescription for brain MRI.

Diagnostic brain MRI scans are usually performed by trained medical technologists who manually prescribe the position and orientation of a scanning volume. In this study, a fully automatic computer algorithm is described which compensates for variable patient positioning and acquires brain MRI scans in a predefined reference orientation. The method involves acquiring a rapid water-only pilot scan, segmenting the brain surface, and matching it to a reference surface.

Genistein inhibits nonoxidative ribose synthesis in MIA pancreatic adenocarcinoma cells: a new mechanism of controlling tumor growth.

Genistein is a plant isoflavonoid bearing potent tumor growth-regulating characteristics. This effect of genistein has been attributed partially to its tyrosine kinase-regulating properties, resulting in cell-cycle arrest and limited angiogenesis. Genistein has been used in chemotherapy-resistant cases of advanced leukemia with promising results.