Nd isotope variation between the Earth-Moon system and enstatite chondrites.

Reconstructing the building blocks that made Earth and the Moon is critical to constrain their formation and compositional evolution to the present. Neodymium (Nd) isotopes identify these building blocks by fingerprinting nucleosynthetic components. In addition, the 146Sm-142Nd and 147Sm-143Nd decay systems, with half-lives of 103 million years and 108 billion years, respectively, track potential differences in their samarium (Sm)/Nd ratios. The difference in Earth's present-day 142Nd/144Nd ratio compared with chondrites1,2, and in particular enstatite chondrites, is interpreted as nucleosynthetic isotope variation in the protoplanetary disk. This necessitates that chondrite parent bodies have the same Sm/Nd ratio as Earth's precursor materials2. Here we show that Earth and the Moon instead had a Sm/Nd ratio approximately 2.4 ± 0.5 per cent higher than the average for chondrites and that the initial 142Nd/144Nd ratio of Earth's precursor materials is more similar to that of enstatite chondrites than previously proposed1,2. The difference in the Sm/Nd ratio between Earth and chondrites probably reflects the mineralogical distribution owing to mixing processes within the inner protoplanetary disk. This observation simplifies lunar differentiation to a single stage from formation to solidification of a lunar magma ocean3. This also indicates that no Sm/Nd fractionation occurred between the materials that made Earth and the Moon in the Moon-forming giant impact.

Monitoring uranium mine pollution on Native American lands: Insights from tree bark particulate matter on the Spokane Reservation, Washington, USA.

The uranium boom in the United States from the 1940's to the 1980's was a period of extensive uranium mining on Native American lands. However, detailed environmental investigations of the resulting uranium pollution are sparse and typically ignore contributions from airborne particulate matter. The Midnite Mine is a 350-acre inactive open pit uranium mine located on the Spokane Indian Reservation in eastern Washington that operated from 1954 to 1981. Approximately 2.4 million tons of ore and 33 million tons of waste rock were left behind in stockpiles and have also been utilized as gravel on access and haul roads. Although the Midnite Mine is now a Superfund Site, and governmental investigations of water and soil contamination have been done, no investigations of airborne particulate matter pollution have been conducted. This study applies tree bark from 31 Pinus ponderosa trees as a biomonitor of this airborne particulate matter. Bulk trace elemental analyses via inductively coupled plasma - mass spectrometry (ICP-MS) of tree bark show that U is the most abundant trace element of interest present up to 232 ppb. Other metals that are of potential human health concern include Th, Pb, and As which are present at 20 ppb, 104 ppb, and 20 ppb respectively. Calculated geoaccumulation indices determine these metals to be at high (U), moderate (Th), and low (Pb and As) levels of contamination. Detailed scanning electron microscopy (SEM) investigations of particulate matter from the surface of tree bark confirm that U and Th-bearing particulate matter exist in the

In vivo detection of cerebral tau pathology in long-term survivors of traumatic brain injury.

Traumatic brain injury (TBI) can trigger progressive neurodegeneration, with tau pathology seen years after a single moderate-severe TBI. Identifying this type of posttraumatic pathology in vivo might help to understand the role of tau pathology in TBI pathophysiology. We used flortaucipir positron emission tomography (PET) to investigate whether tau pathology is present many years after a single TBI in humans. We examined PET data in relation to markers of neurodegeneration in the cerebrospinal fluid (CSF), structural magnetic resonance imaging measures, and cognitive performance. Cerebral flortaucipir binding was variable, with many participants with TBI showing increases in cortical and white matter regions. At the group level, flortaucipir binding was increased in the right occipital cortex in TBI when compared to healthy controls. Flortaucipir binding was associated with increased total tau, phosphorylated tau, and ubiquitin carboxyl-terminal hydrolase L1 CSF concentrations, as well as with reduced fractional anisotropy and white matter tissue density in TBI. Apolipoprotein E (APOE) ε4 genotype affected the relationship between flortaucipir binding and time since injury, CSF ß amyloid 1-42 (Aß42) concentration, white matter tissue density, and longitudinal Mini-Mental State Examination scores in TBI. The results demonstrate that tau PET is a promising approach to investigating progressive neurodegeneration associated with tauopathy after TBI.

ACVR1R206H FOP mutation alters mechanosensing and tissue stiffness during heterotopic ossification.

An activating bone morphogenetic proteins (BMP) type I receptor ACVR1 (ACVR1R206H) mutation enhances BMP pathway signaling and causes the rare genetic disorder of heterotopic (extraskeletal) bone formation fibrodysplasia ossificans progressiva. Heterotopic ossification frequently occurs following injury as cells aberrantly differentiate during tissue repair. Biomechanical signals from the tissue microenvironment and cellular responses to these physical cues, such as stiffness and rigidity, are important determinants of cell differentiation and are modulated by BMP signaling. We used an Acvr1R206H/+ mouse model of injury-induced heterotopic ossification to examine the fibroproliferative tissue preceding heterotopic bone and identified pathologic stiffening at this stage of repair. In response to microenvironment stiffness, in vitro assays showed that Acvr1R206H/+ cells inappropriately sense their environment, responding to soft substrates with a spread morphology similar to wild-type cells on stiff substrates and to cells undergoing osteoblastogenesis. Increased activation of RhoA and its downstream effectors demonstrated increased mechanosignaling. Nuclear localization of the pro-osteoblastic factor RUNX2 on soft and stiff substrates suggests a predisposition to this cell fate. Our data support that increased BMP signaling in Acvr1R206H/+ cells alters the tissue microenvironment and results in misinterpretation of the tissue microenvironment through altered sensitivity to mechanical stimuli that lowers the threshold for commitment to chondro/osteogenic lineages.

High fidelity visualization of cell-to-cell variation and temporal dynamics in nascent extracellular matrix formation.

Extracellular matrix dynamics are key to tissue morphogenesis, homeostasis, injury, and repair. The spatiotemporal organization of this matrix has profound biological implications, but is challenging to monitor using standard techniques. Here, we address these challenges by using noncanonical amino acid tagging to fluorescently label extracellular matrix synthesized in the presence of bio-orthogonal methionine analogs. This strategy labels matrix proteins with high resolution, without compromising their distribution or mechanical function. We demonstrate that the organization and temporal dynamics of the proteinaceous matrix depend on the biophysical features of the microenvironment, including the biomaterial scaffold and the niche constructed by cells themselves. Pulse labeling experiments reveal that, in immature constructs, nascent matrix is highly fibrous and interdigitates with pre-existing matrix, while in more developed constructs, nascent matrix lacks fibrous organization and is retained in the immediate pericellular space. Inhibition of collagen crosslinking increases matrix synthesis, but compromises matrix organization. Finally, these data demonstrate marked cell-to-cell heterogeneity amongst both chondrocytes and mesenchymal stem cells undergoing chondrogenesis. Collectively, these results introduce fluorescent noncanonical amino acid tagging as a strategy to investigate spatiotemporal matrix organization, and demonstrate its ability to identify differences in phenotype, microenvironment, and matrix assembly at the single cell level.

Single-cell differences in matrix gene expression do not predict matrix deposition.

Mesenchymal stem cells (MSCs) display substantial cell-to-cell heterogeneity, complicating their use in regenerative medicine. However, conventional bulk assays mask this variability. Here we show that both chondrocytes and chondrogenically induced MSCs exhibit substantial mRNA expression heterogeneity. Single-molecule RNA FISH to measure mRNA expression of differentiation markers in single cells reveals that sister cell pairs have high levels of mRNA variability, suggesting that marker expression is not heritable. Surprisingly, this variability does not correlate with cell-to-cell differences in cartilage-like matrix production. Transcriptome-wide analysis suggests that no combination of markers can predict functional potential. De-differentiating chondrocytes also show a disconnect between mRNA expression of the cartilage marker aggrecan and cartilage-like matrix accumulation. Altogether, these quantitative analyses suggest that sorting subpopulations based on these markers would only marginally enrich the progenitor population for 'superior' MSCs. Our results suggest that instantaneous mRNA abundance of canonical markers is tenuously linked to the chondrogenic phenotype at the single-cell level.

Microstructural heterogeneity directs micromechanics and mechanobiology in native and engineered fibrocartilage.

Treatment strategies to address pathologies of fibrocartilaginous tissue are in part limited by an incomplete understanding of structure-function relationships in these load-bearing tissues. There is therefore a pressing need to develop micro-engineered tissue platforms that can recreate the highly inhomogeneous tissue microstructures that are known to influence mechanotransductive processes in normal and diseased tissue. Here, we report the quantification of proteoglycan-rich microdomains in developing, ageing and diseased fibrocartilaginous tissues, and the impact of these microdomains on endogenous cell responses to physiologic deformation within a native-tissue context. We also developed a method to generate heterogeneous tissue-engineered constructs (hetTECs) with non-fibrous proteoglycan-rich microdomains engineered into the fibrous structure, and show that these hetTECs match the microstructural, micromechanical and mechanobiological benchmarks of native tissue. Our tissue-engineered platform should facilitate the study of the mechanobiology of developing, homeostatic, degenerating and regenerating fibrous tissues.

Evaluating the use of plerixafor in stem cell mobilisation - an economic analysis of the PHANTASTIC trial.

Plerixafor is an effective haematopoietic stem cell mobilising agent in candidates for autologous transplantation, including patients with myeloma and lymphoma. Here we compare 98 plerixafor recipients in the PHANTASTIC trial with 151 historic controls mobilised by conventional chemotherapy (each with granulocyte colony-stimulating factor, G-CSF). Seventy (71.4%) plerixafor-mobilised patients achieved the composite primary endpoint of ≥4 × 10(6) CD34+ cells kg(-1) in ≤2 aphereses and no clinically significant neutropenia, compared to 48 (31.8%) historic controls (P < 0.001), and this significant advantage was maintained in scenario analyses testing components of this composite endpoint. A patient-level cost analysis was undertaken for 249 patients, which included the cost of remobilising patients where initial mobilisation had failed. Combined mean treatment cost for plerixafor mobilised patients was £12,679 compared with £11,694 for historical controls. However, plerixafor produces an average saving of £3,828 per lymphoma patient but average cost increase by £5,245 per myeloma patient. The present data demonstrate cost-effectiveness for plerixafor as a first line mobilisation agent, certainly for lymphoma patients, where substantial resource savings and achievement of the primary endpoint are likely. J. Clin. Apheresis 31:434-442, 2016. © 2015 Wiley Periodicals, Inc.

Through a glass darkly: economics and personalised medicine.

Personalised medicine and pharmacogenetic-test-guided treatment strategies will be of increasing importance in the future, both in terms of healthcare provision and evaluation. It is well recognised that significant variability exists in the response of patients to drugs resulting from genetic or biological variations; however, we are only now gradually becoming aware of the complexities involved. Enormous variability occurs in the risk-benefit ratio that will be experienced by each individual patient as a consequence of their overall genetic make-up. Although not a panacea, enhanced scientific knowledge of the genetic basis for such variability offers the potential for a more 'tailored' approach to prescribing in the future, making it more closely attuned to the needs of the individual patient. Such 'personalised' medicine has the potential to revolutionise care provision in a manner that provides a range of challenges to current structures and processes of 'conventional' healthcare delivery. The aim of this paper is to outline such challenges and analyse potential ways in which they may be addressed in the future. It provides non-expert readers with a non-technical case study of the complexities inherent in the evaluation of a pharmacogenetic-test-guided treatment strategy from a health economic perspective. Wherever possible, technical issues have been minimised; however, references are provided for readers who wish to enhance their knowledge of the pharmacological basis of the case study of cytochrome P450 test-guided treatment. The case study aims simply to illustrate the approach and difficulties encountered in the health economic evaluation of complex pharmacogenetic technologies. Such technologies present a range of new and complex issues which have crucial implications for health economists attempting to obtain an accurate assessment of the 'value' of the technology in clinical practice in an array of patient subgroups. Personalised medicine is the future and this paper highlights how pharmaceutical manufacturers, clinicians, regulators and other stakeholders must all play their part in the inevitable and accelerating move into this complex and uncertain future.

Variations in primary care prescribing: lessons to be learnt for GP commissioners.

The quality and quantity of primary care prescribing represents a fundamental determinant of the clinical and cost-effectiveness of the UK NHS. The aim of this study was to determine the 'supply' factors that affect primary care prescribing, controlling for 'demand' factors and consider the implications for clinical commissioning groups (CCGs). A detailed regression analysis was undertaken of prescribing in six therapeutic areas to determine differences in prescribing across primary care trusts (PCTs) in England. Results indicate that there are large unexplained variations in primary care prescribing. With the disbanding of the PCTs, and budgets moving to general practitioners (GPs), the role of efficiently and effectively managing prescribing will fall to GP commissioners. Therefore, mechanisms need to be put in place now to ensure that GPs are able to monitor their prescribing and reduce unnecessary drug usage, and further research into the reasons for variations in prescribing needs to be conducted at the CCG level.

Microscopic matrix remodeling precedes endothelial morphological changes during capillary morphogenesis.

The formation of microvascular networks (MVNs) is influenced by many aspects of the microenvironment, including soluble and insoluble biochemical factors and the biophysical properties of the surrounding matrix. It has also become clear that a dynamic and reciprocal interaction between the matrix and cells influences cell behavior. In particular, local matrix remodeling may play a role in driving cellular behaviors, such as MVN formation. In order to explore the role of matrix remodeling, an in vitro model of MVN formation involving suspending human umbilical vein endothelial cells within collagen hydrogels was used. The resulting cell and matrix morphology were microscopically observed and quantitative metrics of MVN formation and collagen gathering were applied to the resulting images. The macroscopic compaction of collagen gels correlates with the extent of MVN formation in gels of different stiffness values, with compaction preceding elongation leading to MVN formation. Furthermore, the microscopic analysis of collagen between cells at early timepoints demonstrates the alignment and gathering of collagen between individual adjacent cells. The results presented are consistent with the hypothesis that endothelial cells need to gather and align collagen between them as an early step in MVN formation.

Pericellular conditions regulate extent of cell-mediated compaction of collagen gels.

Cell-mediated compaction of the extracellular matrix (ECM) plays a critical role in tissue engineering, wound healing, embryonic development, and many disease states. The ECM is compacted as a result of cellular traction forces. We hypothesize that a cell mechanically remodels the nearby ECM until some target conditions are obtained, and then the cell stops compacting. A key feature of this hypothesis is that ECM compaction primarily occurs in the pericellular region and the properties of the ECM in the pericellular region govern cellular force generation. We developed a mathematical model to describe the amount of macroscopic compaction of cell-populated collagen gels in terms of the initial cell and collagen densities, as well as the final conditions of the pericellular environment (defined as the pericellular volume where the collagen is compacted (V(*)) and the mass of collagen within this volume (m(*))). This model qualitatively predicts the effects of varying initial cell and collagen concentrations on the extent of gel compaction, and by fitting V(*) and m(*), provides reasonable quantitative agreement with the extent of gel compaction observed in experiments with endothelial cells and fibroblasts. Microscopic analysis of compacted gels supports the assumption that collagen compaction occurs primarily in the pericellular environment.

Cetuximab for recurrent and/or metastatic squamous cell carcinoma of the head and neck: a NICE single technology appraisal.

The National Institute for Health and Clinical Excellence (NICE) invited the manufacturer of cetuximab (Merck Serono) to submit evidence for the clinical and cost effectiveness of cetuximab in combination with platinum-based chemotherapy (CTX) for the treatment of patients with recurrent and/or metastatic squamous cell cancer of the head and neck (SCCHN) according to the Institute's Single Technology Appraisal (STA) process. The Liverpool Reviews and Implementation Group at the University of Liverpool was commissioned to act as the Evidence Review Group (ERG). This article summarizes the ERG's review of the evidence submitted by the manufacturer. A summary of the Appraisal Committee (AC) decision is provided. The ERG reviewed the clinical evidence in accordance with the decision problem defined by NICE. The analysis of the submitted model assessed the appropriateness of the manufacturer's approach to modelling the decision problem, the reliability of model implementation and the extent of conformity to published standards and prevailing norms of practice within the health economics modelling community. Particular attention was paid to issues likely to impact substantially on the base-case cost-effectiveness results. Clinical-effectiveness evidence was derived from a single randomized controlled trial (RCT). Results presented for clinical outcomes were strongly supportive of benefits resulting from the use of cetuximab. Cetuximab + platinum-based CTX with 5 fluorouracil (5-FU) extended median overall survival (OS) from 7.4 months in the CTX group to 10.1 months in the cetuximab + CTX group. Median progression-free survival rose from 3.3 months to 5.6 months, best overall response to therapy increased from 19.5% to 35.6%, disease control rate rose from 60% to 81.1% and median time to treatment failure was 4.8 months compared with 3.0 months. Exploratory subgroup analyses indicated significant OS benefits in 11 of 16 pre-planned analyses. The ERG identified a number of issues relating to the clinical-effectiveness results: consideration was limited to first-line use of cetuximab; patients in the trial were younger and fitter than those presenting in UK clinical practice; there was no evidence of survival advantage for patients with metastatic disease; there was no evidence of effectiveness in patients not cetuximab-naive; and the quality-of-life data were poor. The submitted incremental cost-effectiveness ratio was considerably above the NICE threshold. The ERG questioned the submitted economic model on a number of grounds: the rationale for creating an economic model rather than direct analysis of trial data; the use of Weibull functions for survival models; inaccurate CTX costs; selection of health state utilities; inaccurate unit costs; and lack of mid-cycle correction. After amending the model, the ERG considered the use of cetuximab to be not cost effective for NICE at any price. The AC concluded that cetuximab in combination with platinum-based CTX should not be recommended for the treatment of patients with recurrent and/or metastatic SCCHN. Patients already receiving this treatment for this indication should have the option to continue treatment until they and their clinician consider it appropriate to stop. This was the first appraisal to consider the end-of-life medicines criteria introduced by NICE in January 2009.