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PubMed2003

Human kallikrein 8, a novel biomarker for ovarian carcinoma.

Human kallikrein 8 (hK8; neuropsin) is a serine protease and new member of the hK family. The aim of this study was to examine if hK8 may serve as a novel cancer biomarker. An hk8-ELISA, developed in-house, was used to study the distribution of hK8 in various biological fluids and tissue extracts from healthy individuals and ovarian cancer patients of different stages of the disease (International Federation of Obstetrics and Gynecology II-IV). For ovarian cancer patients, very high levels in ascites fluid were observed (<or=1000 microg/liter; n = 85 samples). Elevated serum levels were seen in 24 of 40 (62%) of ovarian cancer patients. Higher ascites fluid hK8 concentration was associated with better ovarian cancer progression-free survival (P = 0.02). In both serum and ascites fluid, there is a significant correlation between hK8 and CA125 concentration (r = 0.51 and 0.58, respectively). The serum concentration of hK8 was an indicator of progression on regression on longitudinal monitoring of an ovarian cancer patient. These data suggest that hK8 protein is detectable in ovarian cancer tissue extracts, serum, and ascites fluid, indicating that it may serve as a new ovarian cancer marker.

Ascitic Fluid↗
PubMed1992

Effect of the chemopreventive agents piroxicam and D,L-alpha-difluoromethylornithine on intermediate biomarkers of colon carcinogenesis.

Our previous studies have shown that dietary piroxicam, a non-steroidal anti-inflammatory drug (NSAID), and D,L-alpha-difluoromethylornithine (DFMO), an ornithine decarboxylase (ODC) inhibitor, act as potential chemopreventive agents in inhibiting azoxymethane (AOM)-induced colon carcinogenesis in male F344 rats. The present study was designed to determine the effect of these chemopreventive agents on intermediate biomarkers, namely colonic epithelial cell proliferation and levels of prostaglandins, which can be used as effective predictors of colon cancer. Starting at 6 weeks of age, groups of animals were fed the control diet and experimental diets containing piroxicam or DFMO. At 7 weeks of age, all animals, except the vehicle controls, were injected s.c. with AOM at a dose level of 15 mg/kg body wt/week for 4 weeks. Vehicle controls received an equal volume of normal saline. Groups of animals were then killed at the end of last AOM or saline injection (baseline) and at week 4, 16, 24 and 32 following the last AOM or saline treatment. Animals intended for cell proliferation study were injected with bromodeoxyuridine (BrdU) at a dose level of 20 mg/kg body wt 1 h prior to being killed. The rate of colonic cell proliferation at all time points was assessed immunohistochemically using anti-BrdU. The levels of colonic mucosal prostaglandins were estimated by radioimmunoassay. The results indicate that carcinogen treatment increased the colonic cell proliferation measured as the crypt labeling index in proximal and distal colons and the concentrations of colonic prostaglandin E2 (PGE2) and 6-keto PGF1 alpha. The data demonstrate that DFMO significantly inhibited the AOM-induced labeling index in the distal and proximal colon at all time points, whereas piroxicam slightly decreased the labeling index. On the other hand, piroxicam exerted a pronounced inhibitory effect on the levels of both PGE2 and 6-keto PGF1 alpha. DFMO suppressed the colonic PGE2 levels to a lesser degree than piroxicam. The results demonstrate that DFMO, an inhibitor of ODC, suppresses cell proliferation, whereas piroxicam, a NSAID, inhibits prostaglandins, and emphasize the need to develop agent-dependent intermediate biomarker(s) to validate the efficacy of chemopreventive agent(s) in colon carcinogenesis.

6-Ketoprostaglandin F1 alpha↗
PubMed2026

Lipid metabolic reprogramming of tumor-associated macrophages drives resistance to immune checkpoint blockade in lung cancer: a narrative review of mechanisms and therapeutic strategies.

BACKGROUND AND OBJECTIVE: Immune checkpoint inhibitors (ICIs), represented by programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1), have shown remarkable efficacy in non-small cell lung cancer (NSCLC); however, many patients still develop resistance to immunotherapy. Although small cell lung cancer (SCLC) is also an important histological type of lung cancer, NSCLC accounts for the majority of lung cancer cases. Current research on ICI development, first-line treatment efficacy, and the mechanisms of lipid metabolism in tumor-associated macrophages (TAMs) is predominantly focused on NSCLC. In patients with advanced NSCLC, objective response rates (ORRs) with PD-1/PD-L1 inhibitor monotherapy remain limited. Only in patients with high PD-L1 expression [tumor proportion score (TPS) &#x2265;50%] and without sensitizing epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements does the ORR increase to approximately 40-45%. TAMs are a key component of the immunosuppressive tumor microenvironment (TME). Lipid metabolic reprogramming profoundly influences the functional and transcriptional features of TAMs. This review aims to integrate relevant evidence, elucidate how TAM lipid metabolism promotes immunosuppression and resistance to ICIs, and outline potential therapeutic strategies. METHODS: We searched PubMed/MEDLINE, Web of Science, and Scopus for publications up to June 2026 using terms combining lung cancer, TAMs, lipid metabolism, and immune checkpoint blockade/resistance. Mechanistic, translational, and clinically relevant studies were selected by author consensus. KEY CONTENT AND FINDINGS: Lipid uptake, de novo lipogenesis, fatty acid oxidation (FAO), cholesterol remodeling, and eicosanoid metabolism are not independent processes in TAMs. Lipid metabolic reprogramming in TAMs ultimately suppresses type I interferon (IFN-I) signaling, upregulates PD-L1 expression, and impairs the function of CD8+ T cells with stem-like features, thereby establishing an immunosuppressive TME and leading to resistance to ICIs. In lung cancer, hypoxia, high lactate levels, and tobacco exposure further shape the lipid phenotype of TAMs, such as lipid raft enrichment and lipid-laden macrophage subsets like SPP1+ macrophages. Different driver genomic backgrounds differentially impact tumor cell-intrinsic metabolism and the lipid metabolic programs of myeloid cells. In preclinical models, interventions targeting these metabolic axes, including TAM-directed delivery systems, have demonstrated potential therapeutic benefit when combined with anti-PD-1/PD-L1 therapy. CONCLUSIONS: Targeting TAM lipid metabolism to convert immunologically cold tumors into more inflamed, ICI-responsive tumors is a promising strategy to overcome resistance in NSCLC. Identification of predictive biomarkers of therapeutic response and development of cell-selective drug delivery systems come to be major challenges.

Non-small cell lung cancer (NSCLC)↗
PubMed2000

Functional foods: the US perspective.

Widespread interest in the possibility that selected foods might promote health has resulted in the coining of the term functional food, although agreement about what is and what is not a functional food is lacking. Public interest in functional foods is increasing because of higher health care costs; the passage of federal legislation affecting many food categories, including the expanded category of dietary supplements; and recent scientific discoveries linking dietary habits with the development of many diseases, including coronary heart disease and some cancers. A variety of foods have been proposed as providing health benefits by altering one or more physiologic processes. Biomarkers are needed to assess the ability of functional foods or their bioactive components to modify disease and to evaluate the ability of these foods to promote health, growth, and well-being. Evidence suggests that several biomarkers may be useful for distinguishing between diseased and nondiseased states and even for predicting future susceptibility to disease. A variety of biomarkers will probably be needed to develop a profile for an individual that reflects the impact of diet on performance and health. Another area of interest is the interaction of nutrients and their association with genetics. These interactions may account for the inconsistent interrelations observed between specific dietary constituents and the incidence of disease. Greater understanding of how diet influences a person's genetic potential, overall performance, and susceptibility to disease can have enormous implications for society. As new discoveries are made in this area, consumers will need access to this information so that they can make informed decisions.

Biological Availability↗
PubMed2006

Huntington disease patients and transgenic mice have similar pro-catabolic serum metabolite profiles.

There has been considerable progress recently towards developing therapeutic strategies for Huntington's disease (HD), with several compounds showing beneficial effects in transgenic mouse models. However, human trials in HD are difficult, costly and time-consuming due to the slow disease course, insidious onset and patient-to-patient variability. Identification of molecular biomarkers associated with disease progression will aid the development of effective therapies by allowing further validation of animal models and by providing hopefully more sensitive measures of disease progression. Here, we apply metabolic profiling by gas chromatography-time-of-flight-mass spectrometry to serum samples from human HD patients and a transgenic mouse model in a hypothesis-generating search for disease biomarkers. We observed clear differences in metabolic profiles between transgenic mice and wild-type littermates, with a trend for similar differences in human patients and control subjects. Thus, the metabolites responsible for distinguishing transgenic mice also comprised a metabolic signature tentatively associated with the human disease. The candidate biomarkers composing this HD-associated metabolic signature in mouse and humans are indicative of a change to a pro-catabolic phenotype in early HD preceding symptom onset, with changes in various markers of fatty acid breakdown (including glycerol and malonate) and also in certain aliphatic amino acids. Our data raise the prospect of a robust molecular definition of progression of HD prior to symptom onset, and if validated in a genuinely prospective fashion these biomarker trajectories could facilitate the development of useful therapies for this disease.

Adult↗
PubMed2001

Liquid chromatography electrospray-mass spectrometry of urinary aflatoxin biomarkers: characterization and application to dosimetry and chemoprevention in rats.

A liquid chromatography electrospray tandem mass spectrometry (LC-ESI-MS/MS) method for the measurement of aflatoxin biomarkers in urine has been developed and validated. The two major aflatoxin-DNA adducts formed in rat tissues, aflatoxin N(7)-guanine and its imidazole ring opened derivative, 8,9-dihydro-8-(2,6-diamino-4-oxo-3,4-dihydropyrimid-5-yl formamido)-9-hydroxy-aflatoxin B(1), were detected and quantified in urine by the LC-ESI-MS/MS technique. Other metabolites derived from the conjugation and/or oxidation of aflatoxin B(1) measured in the urine of dosed rats included aflatoxin P(1), aflatoxin P(1)-glucuronide, aflatoxin Q(1), aflatoxin M(1), 8,9-dihydro-8,9-dihydroxy aflatoxin B(1), aflatoxin B(1)-mercapturic acid, the aflatoxin-cysteine glycine adduct derived from the aflatoxin-glutathione conjugate, aflatoxin M(1)P(1) and the aflatoxin B(1)-dialcohol. For in vivo studies to determine the dosimetry of certain aflatoxin metabolites, aflatoxin B(2) was used as an internal standard for recovery since this compound is not naturally produced in rats. In the final method using the internal standard, the coefficient of variation of six replicate analyses of in vivo rat urine samples for aflatoxin N(7)-guanine, aflatoxin B(1)-mercapturic acid, and aflatoxin M(1) was 12.5, 12.8, and 5.8%, respectively. Further, the LC-ESI-MS/MS method to detect aflatoxin N(7)-guanine in in vivo rat urine samples was at least 20-fold more sensitive than prior techniques. Using the LC-ESI-MS/MS technique, the dosimetry, on a weekly basis, of major urinary aflatoxin metabolites was assessed in animals chronically dosed over a 5-week period. Of particular importance was the application of this method to determine the modulation of levels of urinary aflatoxin metabolites by treatment with oltipraz, a chemopreventive agent that can completely ablate aflatoxin hepatocarcinogenesis in the rat. After 1 week, oltipraz administration diminished urinary aflatoxin N(7)-guanine, aflatoxin B(1)-mercapturic acid and aflatoxin M(1) levels by 83, 92, and 82%, respectively. The magnitude of this reduction was persistent at the day 14, 21, 28, and 35-day time points with the average decrease of aflatoxin N(7)-guanine, aflatoxin B(1)-mercapturic acid and aflatoxin M(1) being 73, 92, and 90%, respectively. Importantly, even under circumstances where the oltipraz intervention was most efficient in reducing aflatoxin metabolite levels, the LC-ESI-MS/MS method was still sensitive enough to detect the reduced biomarker content. This outcome has important translational implications for the application and analysis of the efficacy of primary and secondary prevention interventions in human populations where ambient exposure levels are low, but the toxicologic hazards of these exposures remain high.

Aflatoxins↗
PubMed2003

A new in vitro blood load test using a magnesium stable isotope for assessment of magnesium status.

Magnesium (Mg) status is currently assessed by various biochemical biomarkers, most of which, however, have some limitations. We developed an in vitro blood load test as a new Mg biomarker using a Mg stable isotope. This test is based on the hypothesis that cellular Mg uptake is increased in Mg deficiency. For this purpose, Wister male rats were fed either Mg-deficient or Mg-adequate diets for 1 mo and blood was sampled and incubated with the (25)Mg isotope (10 mg/L) for 2 h at 37 degrees C. Erythrocytes, lymphocytes and platelets were isolated and (25)Mg concentrations were determined by inductively coupled plasma/mass spectrometry. The feasibility of this approach was then tested on human blood. (25)Mg enrichments in erythrocytes, lymphocytes and platelets from Mg-deficient rats were greater than those from controls. (25)Mg enrichment was low in human erythrocytes (3%) compared with rat erythrocytes (38%), whereas high (25)Mg enrichments were obtained in human lymphocytes and platelets, suggesting that lymphocytes and platelets may be more appropriate cells than erythrocytes for examining Mg status in humans with this approach. More studies are required to validate the utilization of this test as a Mg status biomarker in humans.

Animals↗
PubMed2006

Nutrition and food science go genomic.

The wealth of genomic information and high-throughput profiling technologies are now being exploited by scientists in the disciplines of nutrition and food science. Diet and food components are prime environmental factors that affect the genome, transcriptome, proteome and metabolome, and this life-long interaction defines the health or disease state of an individual. For the first time the interaction of foods, and individual food constituents, with the biological systems can be defined on a molecular basis. Profiling technologies are used in basic-science applications for identifying the mode of action of foods or particular ingredients, and are similarly taken into the science-driven development of foods with a defined biofunctionality. Biomarker profiles and patterns derived from genomics applications in humans should guide nutrition and food science in developing evidence-based dietary recommendations and health-promoting foods.

Food↗
PubMed2006

Quantitative and qualitative differences in protein expression between papillary thyroid carcinoma and normal thyroid tissue.

In order to better understand basic mechanisms of tumor development and identify potential new biomarkers, we have performed difference gel electrophoresis (DIGE) and peptide mass fingerprinting on pooled protein extracts from patients with papillary thyroid carcinoma (PTC) compared with matched normal thyroid tissue. Image analysis of DIGE gels comparing PTC and matched normal thyroid tissue protein indicated that 25% of the protein spots were differentially expressed at a 2.5-fold cutoff and 35% at two-fold. Comparison between two different pools of protein from normal thyroid tissues revealed differential protein expression of only 4% at 2.5-fold and 6% at two-fold cutoff. One hundred ninety-two protein spots were identified by MALDI-TOFMS, representing 90 distinct proteins. Excluding albumin, globins and thyroglobulin, imaging software determined 31 proteins to be differentially expressed at the two-fold (or greater) level. Individual gel comparisons (PTC vs. matched normal) from five patients established that 15/31 (48%) of these proteins exhibited statistically significant differential expression. Previously identified molecular markers in this group of proteins include cathepsin B, cytokeratin 19, and galectin-3. Novel differentially expressed proteins include S100A6, moesin, HSP70 (BiP), peroxiredoxin 2, protein phosphatase 2, selenium binding protein 1, vitamin D binding protein, and proteins involved in mitochondrial function. The use of two-dimensional gel electrophoresis (2DGE) revealed a significantly altered protein mass and/or pI in 10%-15% of proteins, suggesting alternatively spliced forms and other posttranslational modification of proteins revealed by this approach. We confirmed S100A6 as a potentially useful biomarker using immunohistochemical analysis (85% sensitivity and 69% specificity for distinguishing benign from malignant thyroid neoplasms). In summary, proteomic analysis of PTC using DIGE and mass spectrometry has confirmed several known biomarkers, uncovered novel potential biomarkers, and provided insights into global pathophysiologic changes in PTC. Many of the differences observed would not have been detected by genomic or other proteomic approaches.

Amino Acid Sequence↗
PubMed2004

Comparison of analyses of urinary 8-hydroxy-2'-deoxyguanosine by isotope-dilution liquid chromatography with electrospray tandem mass spectrometry and by enzyme-linked immunosorbent assay.

A highly sensitive and selective method, using isotope-dilution liquid chromatography with tandem mass spectrometry (LC/MS/MS), for quantification of urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG), an important biomarker of oxidative stress, was developed and compared with a method using an enzyme-linked immunosorbent assay (ELISA). The synthesis of (15)N(5)-8-OHdG is described. In this study, 140 urine samples were collected from workers in a coke oven plant, including samples from 49 control workers and 91 workers who had been occupationally exposed to polyaromatic hydrocarbons (PAHs). The major urinary metabolite of PAHs, 1-hydroxypyrene (1-OHP), was measured for the exposed workers. Results from the present study showed a significant correlation between these two measurements for determination of 8-OHdG (p < 0.05, r(2) = 0.70). However, only the LC/MS/MS measurements of urinary levels of 8-OHdG showed a significant difference between the exposed and the control subjects (p < 0.05). The ELISA method failed to demonstrate this difference. Furthermore, only by using the LC/MS/MS method was a significant correlation observed between the urinary levels of 1-OHP and 8-OHdG. These findings suggest that a highly specific and sensitive analytical method such as isotope-dilution LC/MS/MS is extremely important and necessary for accurate measurement and a comprehensive study of oxidative stress in human subjects.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1999

Dose-dependent metabolism of fluoromethyl-2,2-difluoro-1-(trifluoromethyl)vinyl ether (compound A), an anesthetic degradation product, to mercapturic acids and 3,3,3-trifluoro-2-(fluoromethoxy)propanoic acid in rats.

The volatile anesthetic sevoflurane is degraded in anesthesia machines to fluoromethyl-2,2-difluoro-1-(trifluoromethyl)vinyl ether (FDVE), to which humans are exposed. FDVE is metabolized in rats and humans to two alkane and two alkene glutathione S-conjugates that are hydrolyzed to the corresponding cysteine S-conjugates. The latter are N-acetylated to mercapturic acids, or bioactivated by renal cysteine conjugate beta-lyase to metabolites which may react with cellular macromolecules or hydrolyze to 3,3,3-trifluoro-2-(fluoromethoxy)propanoic acid. FDVE causes nephrotoxicity in rats, which evidence suggests is mediated by renal uptake of FDVE S-conjugates and metabolism by beta-lyase. Although pathways of FDVE metabolism have been described qualitatively, the purpose of this investigation was to quantify FDVE metabolism via mercapturic acid and beta-lyase pathways. Fischer 344 rats underwent 3-h nose-only exposure to FDVE (0 +/- 0, 46 +/- 19, 98 +/- 7, 150 +/- 29, and 220 +/- 40 ppm), and urine was collected for 24 h. Urine concentrations of the mercapturates, N-acetyl-S-(1,1,3,3, 3-pentafluoro-2-fluoromethoxypropyl)-L-cysteine and N-acetyl-S-(1-fluoro-2-fluoromethoxy-2-(trifluoromethyl)vinyl)-L- cysteine, the beta-lyase-dependent metabolite 3,3, 3-trifluoro-2-(fluoromethoxy)propanoic acid, and its degradation product trifluorolactic acid, were determined by GC/MS. There was dose-dependent urinary excretion of the alkane mercapturate N-acetyl-S-(1,1,3,3,3-pentafluoro-2-fluoromethoxypropyl)-L- cysteine and 3,3,3-trifluoro-2-(fluoromethoxy)propanoic acid, while excretion of the alkene mercapturate N-acetyl-S-(1-fluoro-2-fluoromethoxy-2-(trifluoromethyl)vinyl)-L- cysteine plateaued at higher FDVE exposures. The alkane:alkene mercapturic acid excretion ratio was between 2:1 and 4:1. Trifluorolactic acid was only rarely observed. Urine excretion of the beta-lyase-dependent metabolite 3,3, 3-trifluoro-2-(fluoromethoxy)propanoic acid was 10-fold greater than that of the combined mercapturates. Results show that FDVE cysteine S-conjugates undergo facile metabolism via renal beta-lyase, particularly in comparison with detoxication by mercapturic acid formation. The quantitative assay developed herein may provide a biomarker for FDVE exposure and relative metabolism via toxification and detoxifying pathways, applicable to animal and human investigations.

Acetylcysteine↗
PubMed2005

Spectrin and calpain: a 'target' and a 'sniper' in the pathology of neuronal cells.

It is well documented that activation of calpain, a calcium-sensitive cysteine protease, marks the pathology of naturally and experimentally occurring neurodegenerative conditions. Calpain-mediated proteolysis of major membrane-skeletal protein, alphaII-spectrin, results in the appearance of two unique and highly stable breakdown products, which is an early event in neural cell pathology. This review focuses on spectrin degradation by calpain within neurons induced by diverse conditions, emphasizing a current picture of multi-pattern neuronal death and a recent success in the development of spectrin-based biomarkers. The issue is presented in the context of the major structural and functional properties of the two proteins.

Aging↗
PubMed1992

Adduction of hemoglobin and albumin in vivo by metabolites of trichloroethylene, trichloroacetate, and dichloroacetate in rats and mice.

Adducts to macromolecules from trichloroethylene formed by in vivo and in vitro metabolism have been reported by many investigators. We examined the in vivo adduction of the blood proteins hemoglobin (Hb) and albumin in rats and mice dosed orally with [14C]trichloroethylene ([14C]TRI) to explore the development of a protein adduct biomarker of TRI exposure. We also examined the adduction of these two proteins from doses of [14C]trichloroacetate (TCA) and [14C]dichloroacetate (DCA), two metabolites of TRI. Association of label with albumin peaked at 4-8 hr in the rat (2480 nmol eq TRI/mg protein) and 2-4 hr in the mouse (1580 nmol eq TRI/mg protein). The decay was exponential with a half-life consistent with that of rat or mouse albumin (approx 24 hr). The time course of label with Hb was characterized by an early plateau at 8 hr in rat (28 nmol eq TRI/mg protein), 4 hr in mouse (7 nmol eq TRI/mg protein), and followed by a slow steady increase, peaking at 120 hr (54 nmol eq TRI/mg protein, rat; 38 nmol eq TRI/mg protein, mouse). This apparent binding was linear with dose in the rat, but was convex in the mouse albumin (mouse Hb label was below detection at low dose). We also found that a portion of the irreversibly associated label, referred to by previous investigators as "binding," could be accounted for as metabolic incorporation of label into glycine and serine.(ABSTRACT TRUNCATED AT 250 WORDS)

Albumins↗
PubMed2006

Selected Proceedings of the NICHD/FDA newborn drug development initiative: Part II.

BACKGROUND: In February 2003, the National Institute of Child Health and Human Development (NICHD) and the US Food and Drug Administration (FDA) created the Newborn Drug Development Initiative (NDDI), an ongoing program to determine gaps in knowledge in neonatal therapeutics and to explore clinical study designs for use in the newborn population. Working groups were established in 3 therapeutic areas: the central nervous, pulmonary, and cardiovascular systems. Three additional groups discussed pain control, drug prioritization, and ethics in neonatal clinical trials. OBJECTIVE: The purpose of this article was to provide an overview of the 5 articles written by members of the Neurology, Cardiology, Drug Prioritization, and Ethics Groups. METHODS: Information for the current article, as well as the 5 articles presented in this supplemental section, was gathered from the proceedings of a workshop cosponsored by the NICHD and the FDA. This workshop took place March 29 and 30, 2004, in Baltimore, Maryland. RESULTS: The Neurology Group addressed the treatment of 2 common and interrelated conditions in the newborn population: neonatal seizures and hypoxic-ischemic encephalopathy. The unsubstantiated clinical preference for using phenobarbital to treat neonatal seizures, coupled with the development of several newer antiepileptic drugs with application in children, dictates the need for rigorous clinical trials of these drugs in the neonatal population. A number of pharmacologic agents currently undergoing extensive investigations in experimental animals and adult humans may have application in the newborn population. The Cardiology Group reviewed controversial approaches to the diagnosis and treatment of cardiovascular instability of preterm infants and identified gaps in knowledge. The group discussed issues of study design and developed 2 study proposals: (1) a placebo-controlled trial with a rescue arm for symptomatic infants; and (2) a targeted blood pressure (BP) trial. The Drug Prioritization Group focused on the fact that the uniqueness of the newborn population is due to distinctive and changing physiologic characteristics, conditions, and diseases that are different from those affecting older children, as well as the large differences in developmental patterns between 23 weeks of gestation and term. All of these factors help explain the lack of adequate trials and the sparseness of evidence regarding efficacy and toxicity risks of most drugs used in the newborn population. Unfortunately, the frequency of drug use and polypharmacy is highest in very-low-birth-weight infants. The large number of drugs requiring study and the uniqueness of the indications for those drugs preclude the use of the prioritization process used in older children. The focus of the Drug Prioritization Group was the determination of factors that identify which drugs are most important for study. The Ethics Group was unique in that its members were integrated into the therapeutic groups. This approach allowed for the identification of similarities and dissimilarities in the proposed clinical trial design framework. The summary report included here identifies common themes voiced in the various NDDI reports and deliberations. CONCLUSIONS: The 5 articles included in this issue address different issues but share common themes: the need to develop innovative trial designs and biomarkers of efficacy, consideration of ethical concerns, and selection of appropriate drugs for study.

Drug Approval↗
PubMed2006

Resveratrol prolongs lifespan and retards the onset of age-related markers in a short-lived vertebrate.

Resveratrol, a natural phytoalexin found in grapes and red wine, increases longevity in the short-lived invertebrates Caenorhabditis elegans and Drosophila and exerts a variety of biological effects in vertebrates, including protection from ischemia and neurotoxicity. Its effects on vertebrate lifespan were not yet known. The relatively long lifespan of mice, which live at least 2.5 years, is a hurdle for life-long pharmacological trials. Here, the authors used the short-lived seasonal fish Nothobranchius furzeri with a maximum recorded lifespan of 13 weeks in captivity. Short lifespan in this species is not the result of spontaneous or targeted genetic mutations, but a natural trait correlated with the necessity to breed in an ephemeral habitat and tied with accelerated development and expression of ageing biomarkers at a cellular level. Resveratrol was added to the food starting in early adulthood and caused a dose-dependent increase of median and maximum lifespan. In addition, resveratrol delays the age-dependent decay of locomotor activity and cognitive performances and reduces the expression of neurofibrillary degeneration in the brain. These results demonstrate that food supplementation with resveratrol prolongs lifespan and retards the expression of age-dependent traits in a short-lived vertebrate.

Aging↗
PubMed2005

Reduced risks of death and CHF are associated with statin therapy administered acutely within the first 24 h of AMI.

BACKGROUND: Reports have demonstrated an association between statin therapy during the first day of hospitalization for acute myocardial infarction (AMI) and reduced mortality. There are little data about whether early statin therapy reduces risk of CHF and alters timing of death. METHODS: We identified 3226 consecutive patients with AMI from 1993 through 2000 and divided them into early statin therapy (statins were administered within the initial 24 h of hospitalization, n=220) and non-statin therapy groups (n=3006). We compared mortality risks, rates of CHF development and measures of peak CK and CK-MB values between the groups. RESULTS: In-hospital mortality was lower in the early statin therapy group (2.7%) compared to the non-statin therapy group (9.2%), p=0.001. We observed no differences in the median time to death (statin group 132 h vs. non-statin group 72 h), p=0.3. Patients with very early statin treatment had lower peak CK (624 ng/ml) and CK-MB (46 ng/ml) values compared to non-statin patients (848 ng/ml and 84 ng/ml), p<0.01. Patients in the early statin group had lower risks of developing CHF during hospitalization (10.2 %) compared to the non-statin group (25.7%), p<0.001. CONCLUSION: Very early administration of statin therapy during the first day of hospitalization for AMI was associated with lower in-hospital mortality, lower rates of developing CHF and reduced peak biomarker release. These data support a benefit from early statin therapy in AMI and support the need for prospective studies which test whether very early statin therapy might also reduce infarct size.

Aged↗
PubMed2026

Quantitative N-glycoproteomic analysis reveals glycosylation signatures of plasma immunoglobulin G in sepsis.

INTRODUCTION: Sepsis is a life-threatening condition resulting from organ dysfunction due to a dysregulated immune response to infection. Immunoglobulin G (IgG) plays a role in modulating immune responses. However, the precise IgG subclass-specific N-glycosylation profiles in patients with sepsis remain poorly characterized. METHODS: This study aimed to define the site-specific N-glycosylation signatures of plasma IgG subclasses in sepsis patients with different prognoses using quantitative glycoproteomics. By employing our established GlycoQuant strategy, we quantified the intact N-glycopeptides (IGPs) of IgG subclasses in 40 healthy controls and 40 sepsis patients with a clear prognosis. RESULTS: We identified 12 IGPs with altered abundances between patients with sepsis and healthy controls. After Benjamini-Hochberg (BH) correction of the 31 outcome-stratified IGP comparisons, IGP24 and IGP25 remained significant and met the prespecified fold-change criterion. Global BH correction across 124 IGP-clinical parameter correlations retained positive associations of IGP19, IGP22, and IGP23 with procalcitonin (PCT). In exploratory outcome-stratified ROC analyses, candidates were selected using the original unadjusted P-value and fold-change screen; five IGPs were evaluated, with IGP25 and IGP24 yielding the highest individual AUCs. Collectively, our findings underscore the potential of IgG subclass-specific glycosylation profiling as a novel translational approach for clinical applications in sepsis management. SIGNIFICANCE: Sepsis remains a leading cause of global mortality, with patient outcomes heavily dependent on timely diagnosis and accurate prognosis. The dysregulated host immune response, particularly involving immunoglobulins, is central to its pathophysiology. This study provides a significant advance in the field of clinical glycoproteomics by applying a quantitative, site-specific strategy to delineate the plasma IgG subclass N-glycosylation landscape in sepsis. We report, for the first time, a panel of subclass-specific intact IgG N-glycopeptides (IGPs) that are significantly altered in sepsis patients compared to healthy controls. The identified IGPs not only demonstrate diagnostic and prognostic potential but also show a significant correlation with procalcitonin, a key clinical severity index. These findings bridge a critical knowledge gap by moving beyond bulk IgG glycosylation analysis to subclass-resolved profiling, offering novel molecular insights into sepsis immunopathology. The identified glycosylation signatures hold substantial translational promise as a foundation for developing innovative, glycan-based biomarker panels to improve the precision management of this heterogeneous and life-threatening syndrome.

Humans↗
PubMed2005

Biophotonic imaging in HO-1.luc transgenic mice: real-time demonstration of gender-specific chloroform induced renal toxicity.

The metabolism of luciferin in mice transgenic for luciferase (luc) produces light that may be detected trans vivo by an intensified CCD camera (biophotonics). Thus, the generation of transgenic promoter-luciferase animals for genes regulated by specific toxic processes, coupled with real-time evaluation of site-specific gene expression may provide novel, non-invasive biomarkers which are predictive of developing toxicity in vivo. As part of a programme to evaluate the potential of biophotonics for predictive toxicology we have conducted a series of studies in HO-1.luc transgenic mice. Male and female animals were treated with chloroform (200 mg/kg, p.o., daily for 5 days) and imaged 2 and 6 h after dosing. During a 2-day washout period, female animals were treated daily with testosterone prior to repeat administration of chloroform for a further 5 days. Comparison of the in vivo response of the luciferase reporter with markers of toxicity measured ex vivo (differential gene expression of adaptive antioxidant response genes, clinical chemistry and microscopic examination) confirms the gender-specific difference in chloroform renal toxicity in HO-1.luc transgenic mice and its reversal following androgenisation of females and correlates with the expression of the endogenous haem oxygenase-1 (HO-1) gene. These studies demonstrate the capacity of biophotonics for real-time site-specific gene expression, which may be predictive of developing toxicity.

Animals↗