Evaluation of circulating tumor cells (CTCs) has demonstrated clinical validity as a prognostic tool based on enumeration, but since the introduction of this tool to the clinic in 2004, further ...clinical utility and widespread adoption have been limited. However, immense efforts have been undertaken to further the understanding of the mechanisms behind the biology and kinetics of these rare cells, and progress continues toward better applicability in the clinic. This review describes recent advances within the field, with a particular focus on understanding the biological significance of CTCs, and summarizes emerging methods for identifying, isolating, and interrogating the cells that may provide technical advantages allowing for the discovery of more specific clinical applications. Included is an atlas of high-definition images of CTCs from various cancer types, including uncommon CTCs captured only by broadly inclusive nonenrichment techniques.
Methods standardisation in microplastics research is needed. Apart from reagent-dependent effects on microplastics, varying target particle sizes can hinder result comparison between studies. Human ...health concerns warrant recovery of small microplastics. We compared existing techniques using hydrogen peroxide, Proteinase-K, Trypsin and potassium hydroxide to digest bivalve tissue. Filterability, digestion efficacy, recoverability of microplastics and subsequent polymer identification using Raman spectroscopy and a matching software were assessed. Only KOH allowed filtration at ≤25 μm. When adding a neutralisation step prior to filtration, KOH digestates were filterable using 1.2-μm filters. Digestion efficacies were >95.0% for oysters, but lower for clams. KOH destroyed rayon at 60 °C but not at 40 °C. Acrylic fibre identification was affected due to changes in Raman spectra peaks. Despite those effects, we recommend KOH as the most viable extraction method for exposure risk studies, due to microplastics recovery from bivalve tissues of single-digit micrometre size.
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•Neutralising KOH prior to filtration allows for recovery of particles to 1.2 μm.•Polymer damage can be prevented by incubating samples at 40 °C instead of 60 °C.•Validation with an extended range of microplastics, including fibres and film.•Ultrapure water can effect Raman spectra.•Evaluation of Raman spectra of KOH-exposed microplastics with a matching software.
Microplastics are contaminants of emerging concern; they are ingested by marine biota. About a quarter of global marine fish landings is used to produce fishmeal for animal and aquaculture feed. To ...provide a knowledge foundation for this matrix we reviewed the existing literature for studies of microplastics in fishmeal-relevant species. 55% of studies were deemed unsuitable due to focus on large microplastics (> 1 mm), lack of, or limited contamination control and polymer testing techniques. Overall, fishmeal-relevant species exhibit 0.72 microplastics/individual, with studies generally only assessing digestive organs. We validated a density separation method for effectiveness of microplastic extraction from this medium and assessed two commercial products for microplastics. Recovery rates of a range of dosed microplastics from whitefish fishmeal samples were 71.3 ± 1.2%. Commercial samples contained 123.9 ± 16.5 microplastics per kg of fishmeal-mainly polyethylene-including 52.0 ± 14.0 microfibres-mainly rayon. Concentrations in processed fishmeal seem higher than in captured fish, suggesting potential augmentation during the production process. Based on conservative estimates, over 300 million microplastic particles (mostly < 1 mm) could be released annually to the oceans through marine aquaculture alone. Fishmeal is both a source of microplastics to the environment, and directly exposes organisms for human consumption to these particles.
Copper (Cu) is a redox-active metal ion essential for most aerobic organisms. Cu serves as a catalytic and structural cofactor for enzymes that function in energy generation, iron acquisition, oxygen ...transport, cellular metabolism, peptide hormone maturation, blood clotting, signal transduction and a host of other processes. The inability to control Cu balance is associated with genetic diseases of overload and deficiency and has recently been tied to neurodegenerative disorders and fungal virulence. The essential nature of Cu, the existence of human genetic disorders of Cu metabolism and the potential impact of Cu deposition in the environment have been driving forces for detailed investigations in microbial and eukaryotic model systems. Here we review recent advances in the identification and function of cellular and systemic molecules that drive Cu accumulation, distribution and sensing.
Disease-specific mutations facilitate diagnostic precision and drug target discovery. In myeloproliferative neoplasms (MPN), this is best exemplified by the chronic myeloid leukemia-associated ...BCR-ABL1. No other mutation in MPN has thus far shown a similar degree of diagnostic accuracy or therapeutic relevance. However, JAK2 and KIT mutations are detected in more than 90% of patients with polycythemia vera and systemic mastocytosis, respectively, and are therefore used as highly sensitive clonal markers in these diseases. JAK2 and MPL mutations also occur in essential thrombocythemia (ET) and primary myelofibrosis (PMF), but their diagnostic value is limited by suboptimal sensitivity and specificity. The molecular diagnostic gap in JAK2/MPL-unmutated ET/PMF is now partially addressed by the recent discovery of calreticulin (CALR) mutations in the majority of such cases. However, bone marrow morphology remains the central diagnostic platform and is essential for distinguishing ET from prefibrotic PMF and diagnosing patients those do not express JAK2, MPL or CALR (triple-negative). The year 2013 was also marked by the description of CSF3R mutations in the majority of patients with chronic neutrophilic leukemia (CNL). Herein, we argue for the inclusion of CALR and CSF3R mutations in the World Health Organization classification system for ET/PMF and CNL, respectively.
Copper (Cu) is an essential trace element for growth and development and abnormal Cu levels are associated with anemia, metabolic disease and cancer. Evolutionarily conserved from fungi to humans, ...the high-affinity Cu
transporter Ctr1 is crucial for both dietary Cu uptake and peripheral distribution, yet the mechanisms for selective permeation of potentially toxic Cu
ions across cell membranes are unknown. Here we present X-ray crystal structures of Ctr1 from Salmo salar in both Cu
-free and Cu
-bound states, revealing a homo-trimeric Cu
-selective ion channel-like architecture. Two layers of methionine triads form a selectivity filter, coordinating two bound Cu
ions close to the extracellular entrance. These structures, together with Ctr1 functional characterization, provide a high resolution picture to understand Cu
import across cellular membranes and suggest therapeutic opportunities for intervention in diseases characterized by inappropriate Cu accumulation.
Iron (Fe) is an essential micronutrient for virtually all organisms and serves as a cofactor for a wide variety of vital cellular processes. Although Fe deficiency is the primary nutritional disorder ...in the world, cellular responses to Fe deprivation are poorly understood. We have discovered a posttranscriptional regulatory process controlled by Fe deficiency, which coordinately drives widespread metabolic reprogramming. We demonstrate that, in response to Fe deficiency, the
Saccharomyces cerevisiae Cth2 protein specifically downregulates mRNAs encoding proteins that participate in many Fe-dependent processes. mRNA turnover requires the binding of Cth2, an RNA binding protein conserved in plants and mammals, to specific AU-rich elements in the 3′ untranslated region of mRNAs targeted for degradation. These studies elucidate coordinated global metabolic reprogramming in response to Fe deficiency and identify a mechanism for achieving this by targeting specific mRNA molecules for degradation, thereby facilitating the utilization of limited cellular Fe levels.
Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and prion-based neurodegeneration are associated with the accumulation ...of misfolded proteins, resulting in neuronal dysfunction and cell death. However, current treatments for these diseases predominantly address disease symptoms, rather than the underlying protein misfolding and cell death, and are not able to halt or reverse the degenerative process. Studies in cell culture, fruitfly, worm and mouse models of protein misfolding-based neurodegenerative diseases indicate that enhancing the protein-folding capacity of cells, via elevated expression of chaperone proteins, has therapeutic potential. Here, we review advances in strategies to harness the power of the natural cellular protein-folding machinery through pharmacological activation of heat shock transcription factor 1--the master activator of chaperone protein gene expression--to treat neurodegenerative diseases.
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