Serum Biomarkers Associated with Clinical Outcomes Fail to Predict Brain Metastases in Patients with Stage IV Non-Small Cell Lung Cancers

BackgroundLung cancers account for the majority of brain metastases which pose major therapeutic challenges. Biomarkers prognosticating for the development of brain metastases in patients with non-small cell lung cancers (NSCLC) may improve personalized care. Six serum proteomic biomarkers were previously investigated at Memorial Sloan Kettering but their associations with brain metastases were unknown.MethodsSerum NSE, CYFRA 21–1, ProGRP, SCC-Ag, TIMP1, and HE4 by ELISA-based proteomic assays were prospectively collected from consecutive patients with stage IV NSCLC. Pre-treatment serum biomarker levels as well as age, histology, and epidermal growth factor receptor (EGFR) mutation status were evaluated for association with the baseline presence of brain metastases using logistic regression and multivariable analysis. For patients without brain metastases at baseline, the cumulative incidence of subsequent brain metastases were compared according to baseline biomarkers and clinical factors using Gray’s test.ResultsA total of 118 patients were enrolled, 31 (26%; 95% CI 0.19–0.35) had brain metastases at baseline and a further 26 (22%; 95% CI 0.15–0.30) developed brain metastases subsequently. Pre-treatment serum biomarker levels were available in 104 patients. There was no significant association between the six serum biomarkers and the baseline presence or subsequent development of brain metastases. Age younger than 65 years was the only clinical factor significantly associated with brain metastasis at baseline (OR 3.00; 95% CI 1.22–7.34, P = 0.02) by multivariable analysis. A trend toward increased cumulative incidence of subsequent brain metastases was observed in patients with EGFR mutation (p = 0.2), but this was not statistically significant possibly due to small sample size.ConclusionsSerum NSE, CYFRA 21–1, Pro-GRP, SCC-Ag, TIMP1, and HE4 are not significantly associated with brain metastases. Our methods taking into account follow-up time may be applied to independent datasets to identify a patient cohort with a higher biologic propensity for developing brain metastases. Such information may be useful for the study of agents targeting the development of brain metastases.     

An in vitro screening system to assess aluminum toxicity in sugarcane (Saccharum spp.) cultivars

In Vitro Cellular & Developmental Biology - Plant - Mutagenic breeding is an approach being developed especially for those characteristics that are not inherited through conventional genetic...     

The Safety and Pharmacokinetics of Carprofen,Flunixin and Phenylbutazone in the Cape Vulture (Gyps coprotheres) following Oral Exposure

The following study evaluates the overt toxic potential of carprofen (CRP), flunixin (FXN) and phenylbutazone (PBZ) in Old world vultures in relation to historic toxicity data for diclofenac and ketoprofen, with the Cape vulture (Gyps coprotheres) being the indicator species. The toxic potential of a single oral dose of CRP (11.5 mg/kg), FXN (1 mg/kg),PBZ (1.7 mg/kg) or water was evaluated by means of a four-way parallel study (n = 2), as means of ascertaining if these drugs were as toxic as diclofenac in the vulture. No unscheduled deaths or pathological lesions were noted following exposure. Clinical signs of lethargy and depression were, however, noted in one CRP, two FXN and one PBZ treated birds. Mild reversible inhibition of UA excretion was evident in all three groups, although UA remained within the population reference interval in contrast to the effects previously described for diclofenac and ketoprofen. All treatment groups had a drug concentration responsive increase in alanine transferase activity. CRP, FXN and PBZ were characterised by a maximum plasma concentration (Cmax) of 1051.8 ± 620.7 ng/ml, 335.9 ± 36.3 ng/ml and 11150 ± 2474.9 ng/ml at 4 ± 4.3, 0.45 ± 0.02 and 5.3 ± 5.2 hours (Tmax) respectively and a half-life of elimination of 13.3 ±5, 1.8±1 and 18.7 ±11.4 hours respectively. While we could not demonstrate a lethal effect of the tested substances, the presence of toxic clinical signs, clinical pathological changes and/or long half-lives of elimination suggests that all three drugs have a potential for toxicity in a larger population or on repeat administration. In conclusion while the studied substances were not as overtly toxic as diclofenac, they are of safety concern.     

Comparative metabolism as a key driver of wildlife species sensitivity to human and veterinary pharmaceuticals

Human and veterinary drug development addresses absorption, distribution, metabolism, elimination and toxicology (ADMET) of the Active Pharmaceutical Ingredient (API) in the target species. Metabolism is an important factor in controlling circulating plasma and target tissue API concentrations and in generating metabolites which are more easily eliminated in bile, faeces and urine. The essential purpose of xenobiotic metabolism is to convert lipid-soluble, non-polar and non-excretable chemicals into water soluble, polar molecules that are readily excreted. Xenobiotic metabolism is classified into Phase I enzymatic reactions (which add or expose reactive functional groups on xenobiotic molecules), Phase II reactions (resulting in xenobiotic conjugation with large water-soluble, polar molecules) and Phase III cellular efflux transport processes. The human–fish plasma model provides a useful approach to understanding the pharmacokinetics of APIs (e.g. diclofenac, ibuprofen and propranolol) in freshwater fish, where gill and liver metabolism of APIs have been shown to be of importance. By contrast, wildlife species with low metabolic competency may exhibit zero-order metabolic (pharmacokinetic) profiles and thus high API toxicity, as in the case of diclofenac and the dramatic decline of vulture populations across the Indian subcontinent. A similar threat looms for African Cape Griffon vultures exposed to ketoprofen and meloxicam, recent studies indicating toxicity relates to zero-order metabolism (suggesting P450 Phase I enzyme system or Phase II glucuronidation deficiencies). While all aspects of ADMET are important in toxicity evaluations, these observations demonstrate the importance of methods for predicting API comparative metabolism as a central part of environmental risk assessment.     

Ultrastructural responses of the desiccation tolerant plants Xerophyta viscosa and X. retinervis to dehydration and rehydration

This paper compares the changes in water content, chlorophyll a fluorescence and leaf ultrastructure during dehydration and rehydration in two desiccation tolerant plants Xerophyta viscosa and X. retinervis. Both species showed decreasing quantum efficiency of photosystem 2 (F_v/F_m) with decreasing water content. Extreme water loss observed after 25 d of dehydration resulted in considerable damage of leaf tissue ultrastructure. After rehydration, both species need several days to reconstitute their photosynthetic machinery.     

Haemozoin (beta-haematin) biomineralization occurs by self-assembly near the lipid/water interface

Several blood-feeding organisms, including the malaria parasite detoxify haem released from host haemoglobin by conversion to the insoluble crystalline ferriprotoporphyrin IX dimer known as haemozoin. To date the mechanism of haemozoin formation has remained unknown, although lipids or proteins have been suggested to catalyse its formation. We have found that beta-haematin (synthetic haemozoin) forms rapidly under physiologically realistic conditions near octanol/water, pentanol/water and lipid/water interfaces. Molecular dynamics simulations show that a precursor of the haemozoin dimer forms spontaneously in the absence of the competing hydrogen bonds of water, demonstrating that this substance probably self-assembles near a lipid/water interface in vivo.     

Responses of the saltmarsh rush Juncus kraussii to salinity and waterlogging

Juncus kraussii Hochst., an important saltmarsh macrophyte, is intensively harvested for many commercially orientated products and current populations are under threat of overexploitation. In saline, intertidal mud banks, this species occurs on higher ground, suggesting that it is adapted to lower salinities and less frequent inundation. The objectives of this study were to determine biomass accumulation, as well as morphological and physiological adaptations of J. kraussii to salinity and waterlogging stresses. Plants collected from the field were subjected to 0.2, 10, 30, 50 and 70% seawater under drained or flooded conditions for three months. Measurements were made of biomass accumulation, CO₂ exchange, chlorophyll fluorescence, ion and water relations. Furthermore, seed germination responses to a range of salinities were investigated. Total dry biomass accumulation, as well as the number and height of culms, decreased with increase in salinity under both flooded and drained conditions. Generally, CO₂ exchange, stomatal conductance, Photosystem II (PSII) quantum yield and electron transport rate (ETR) through PSII declined with increase in salinity in both the flooded and drained treatments. Predawn and midday ψ in culms decreased with increase in salinity, being lower under drained than flooded conditions. Inorganic solute concentrations in culms increased with increase in salinity, with Na⁺ and Cl⁻ being the predominant ions. Na⁺/K⁺ ratios in culms increased significantly with increase in salinity. Proline concentrations in roots and culms, which increased with salinity, were considerably higher under drained than flooded conditions. Germination was best at salinities less than 20% seawater and decreased significantly with further increase in salinity to 110% seawater. Transfer of ungerminated salt-treated seeds to distilled water stimulated germination. This study has demonstrated that J. kraussii is a highly salt and flood tolerant species, being able to grow and survive in salinities up to 70% seawater, under both drained and flooded conditions. Maximal growth occurred at low salinities (<10% seawater) under flooded condition.