Heterogenous bone response to biologic DMARD therapies in rheumatoid arthritis patients and their relationship to functional indices.

Objectives: Previous studies of high-resolution peripheral quantitative computed tomography (HR-pQCT) imaging of hand joints in patients with rheumatoid arthritis (RA) have suggested that erosion healing may occur. Our objective was to examine changes in erosion volume, joint space width (JSW), bone mineral density (BMD), and bone remodelling, and their association with clinical outcomes and measures of patient hand function.Method: We examined 48 patients who achieved a good response to a newly initiated biologic therapy. HR-pQCT images of the dominant hands' second and third metacarpophalangeal joints were obtained 3 and 12 months after therapy initiation. Bone erosion volume, JSW, BMD, and bone remodelling were quantified from HR-pQCT images, with improvement, no change (unchanged), or progression in these measures determined by least significant change. Disease activity and hand function measures were collected.Results: There were no significant group changes in HR-pQCT outcomes over the 9 month period. Twenty-two patients had total erosion volumes that remained unchanged, nine showed improvement, and two progressed. The majority of JSW and BMD measures remained unchanged. There was a significant association between the baseline Health Assessment Questionnaire score and the change in minimum JSW, but no other significant associations between HR-pQCT outcomes and function were observed.Conclusions: The vast majority of patients maintained unchanged JSW and BMD over the course of follow-up. Significant improvements in total erosion volume occurred in 27% of patients, suggesting that biologic therapies may lead to erosion healing in some patients, although this did not have an impact on self-reported and demonstrated hand function.

Shielding commissioning factors in nuclear medicine facilities.

This article reviews the essential considerations in planning and designing nuclear medicine departments. There are four proposed categories to consider as 'shielding commissioning factors' (SCF). The first SCF: 'Patient flow optimisation and workload' emphasises the importance of carefully considering patient flow in the departmental design, which would impact the cost of the shielding and the management of radioactive patients. The second SCF: 'Equipment and space allocation' discusses the principles of space allocations in the department for cost-effective designs. The third SCF: 'Shielding calculation methods' reviews the methodologies of shielding calculations in nuclear medicine to offer a standardised approach. The fourth SCF: 'Shielding integrity' reviews the plan to inspect, eyewitness and verify shielding integrity. All discussions were supplemented by practical examples. Overall, this article aims to be a practical manual which health or medical physicists can use when providing counsels to the design committee.

A genomic screen for angiosuppressor genes in the tumor endothelium identifies a multifaceted angiostatic role for bromodomain containing 7 (BRD7).

Tumor angiogenesis is characterized by deregulated gene expression in endothelial cells (EC). While studies until now have mainly focused on overexpressed genes in tumor endothelium, we here describe the identification of transcripts that are repressed in tumor endothelium and thus have potential suppressive effects on angiogenesis. We identified nineteen putative angiosuppressor genes, one of them being bromodomain containing 7 (BRD7), a gene that has been assigned tumor suppressor properties. BRD7 was studied in more detail, and we demonstrate that BRD7 expression is inversely related to EC activation. Ectopic expression of BRD7 resulted in a dramatic reduction of EC proliferation and viability. Furthermore, overexpression of BRD7 resulted in a bromodomain-dependent induction of NFκB-activity and NFκB-dependent gene expression, including ICAM1, enabling leukocyte-endothelial interactions. In silico functional annotation analysis of genome-wide expression data on BRD7 knockdown and overexpression revealed that the transcriptional signature of low BRD7 expressing cells is associated with increased angiogenesis (a.o. upregulation of angiopoietin-2, VEGF receptor-1 and neuropilin-1), cytokine activity (a.o. upregulation of CXCL1 and CXCL6), and a reduction of immune surveillance (TNF-α, NFκB, ICAM1). Thus, combining in silico and in vitro data reveals multiple pathways of angiosuppressor and anti-tumor activities of BRD7.

A key role for galectin-1 in sprouting angiogenesis revealed by novel rationally designed antibodies.

Galectins are carbohydrate binding proteins that function in many key cellular processes. We have previously demonstrated that galectins are essential for tumor angiogenesis and their expression is associated with disease progression. Targeting galectins is therefore a potential anti-angiogenic and anti-cancer strategy. Here, we used a rational approach to generate antibodies against a specific member of this conserved protein family, i.e. galectin-1. We characterized two novel mouse monoclonal antibodies that specifically react with galectin-1 in human, mouse and chicken. We demonstrate that these antibodies are excellent tools to study galectin-1 expression and function in a broad array of biological systems. In a potential diagnostic application, radiolabeled antibodies showed specific targeting of galectin-1 positive tumors. In a therapeutic setting, the antibodies inhibited sprouting angiogenesis in vitro and in vivo, underscoring the key function of galectin-1 in this process.

Rapid optimization of drug combinations for the optimal angiostatic treatment of cancer.

Drug combinations can improve angiostatic cancer treatment efficacy and enable the reduction of side effects and drug resistance. Combining drugs is non-trivial due to the high number of possibilities. We applied a feedback system control (FSC) technique with a population-based stochastic search algorithm to navigate through the large parametric space of nine angiostatic drugs at four concentrations to identify optimal low-dose drug combinations. This implied an iterative approach of in vitro testing of endothelial cell viability and algorithm-based analysis. The optimal synergistic drug combination, containing erlotinib, BEZ-235 and RAPTA-C, was reached in a small number of iterations. Final drug combinations showed enhanced endothelial cell specificity and synergistically inhibited proliferation (p < 0.001), but not migration of endothelial cells, and forced enhanced numbers of endothelial cells to undergo apoptosis (p < 0.01). Successful translation of this drug combination was achieved in two preclinical in vivo tumor models. Tumor growth was inhibited synergistically and significantly (p < 0.05 and p < 0.01, respectively) using reduced drug doses as compared to optimal single-drug concentrations. At the applied conditions, single-drug monotherapies had no or negligible activity in these models. We suggest that FSC can be used for rapid identification of effective, reduced dose, multi-drug combinations for the treatment of cancer and other diseases.

Rituximab: an emerging treatment for recurrent diffuse alveolar hemorrhage in systemic lupus erythematosus.

Diffuse alveolar hemorrhage (DAH) is a rare manifestation of systemic lupus erythematosus (SLE) and is associated with high mortality rates. Treatment typically consists of aggressive immunosuppression with pulse-dose steroids, cyclophosphamide, and plasma exchange therapy. Mortality rates remain high despite use of multiple medical therapies. We present a case of recurrent DAH in a 52-year-old female with SLE after a deceased donor renal transplant who was successfully treated with rituximab. Our report highlights the pathophysiologic importance of B-cell-mediated immunosuppression in SLE-associated DAH and suggests that rituximab may represent a viable alternative to cyclophosphamide in the treatment of this disease. We also review eight other reported cases of rituximab use in SLE-associated DAH.

Mechanisms for pressure-induced crystal-crystal transition, amorphization, and devitrification of SnI4.

The pressure-induced amorphization and subsequent recrystallization of SnI4 have been investigated using first principles molecular dynamics calculations together with high-pressure (119)Sn nuclear resonant inelastic x-ray scattering measurements. Above ∼8 GPa, we observe a transformation from an ambient crystalline phase to an intermediate crystal structure and a subsequent recrystallization into a cubic phase at ∼64 GPa. The crystalline-to-amorphous transition was identified on the basis of elastic compatibility criteria. The measured tin vibrational density of states shows large amplitude librations of SnI4 under ambient conditions. Although high pressure structures of SnI4 were thought to be determined by random packing of equal-sized spheres, we detected electron charge transfer in each phase. This charge transfer results in a crystal structure packing determined by larger than expected iodine atoms.

Novel characterization of bEnd.3 cells that express lymphatic vessel endothelial hyaluronan receptor-1.

Murine bEnd.3 endothelioma cell line has been widely used in vascular research and here we report the novel finding that bEnd.3 cells express lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) and vascular endothelial growth factor receptor-3 (VEGFR-3). Moreover, these cells express progenitor cell markers of Sca-1 and CD133. Upon stimulation with tumor necrosis factor-alpha (TNF-alpha), the bEnd.3 cells demonstrate enhanced formation of capillary-type tubes, which express LYVE-1. As the bEnd.3 cell line is derived from murine endothelioma, we further examined human tissues of endothelioma and identified lymphatic vessels in the tumor samples which express both LYVE-1 and podoplanin. Moreover, a significantly higher number of lymphatic vessels were detected in the endothelioma samples compared with normal control. Taken together, this study not only redefines bEnd.3 cells for vascular research, but also indicates a broader category of human diseases that are associated with lymphatics, such as endothelioma.

Mechanistic Insights into Bioengineered Antibiofilm Enamel Pellicles.

Dental caries remains the most widespread chronic disease worldwide. Basically, caries originates within biofilms accumulated on dental enamel. Despite the nonrenewable nature of the enamel tissue, targeted preventive strategies are still very limited. We previously introduced customized multifunctional proteinaceous pellicles (coatings) for controlling bacterial attachment and subsequent biofilm succession. Stemmed from our whole proteome/peptidome analysis of the in vivo acquired enamel pellicle, we designed these pellicles using hybrid mixtures of the most abundant and complementary-acting antimicrobial and antifouling proteins/peptides for synergetic suppression of early biofilms. In conjugating these domains synthetically, their bioinhibitory efficacy was remarkably boosted. Herein, we sought to explore the key structure-function relationship of these potent de novo hybridized conjugates in comparison with their individual domains, solely or in physical mixtures. Specifically, we interrelated the following facets: physicochemical and 3-dimensional folding characteristics via molecular dynamics simulations, adopted secondary structure by circular dichroism, immobilization capacity on enamel through high-spatial resolution multiphoton microscopy, and biofilm suppression potency. Our data showed consistent associations among the increased preference for protein folding structures, α-helix content, and enamel-immobilization capacity; all were inversely correlated with the attached bioburden. The expressed phenotypes could be explained by the adopted strongly amphipathic helical conformation upon conjugation, mediated by the highly anionic and acidic N-terminal pentapeptide shared region/motif for enhanced immobilization on enamel. In conclusion, conjugating bioactive proteins/peptides is a novel translational approach to engineer robust antibiofilm pellicles for caries prevention. The adopted α-helical conformation is key to enhance the antibiofilm efficacy and immobilization capacity on enamel that are promoted by certain physicochemical properties of the constituent domains. These data are valuable for bioengineering versatile therapeutics to prevent/arrest dental caries, a condition that otherwise requires invasive treatments with substantial health care expenditures.

Sensitivity of the Kß″ X-ray Emission Line to Coordination Changes in GeO2 and TiO2.

The hard X-ray Kß″ emission line shows sensitivity with respect to a wide range of cation-ligand coordination, which we investigate in the cases of GeO2 and TiO2 on the basis of ab initio spectral calculations on amorphous and crystalline structures. In compressed amorphous GeO2, the sampling of a large number of instantaneous coordination polyhedra from an ab initio molecular dynamics trajectory reveals that the functional relation between the Kß″ shift and coordination is close to linear between 4-fold and 7-fold coordination. A similar sensitivity of the Kß″ emission line exists in the coordination range between six and nine of crystalline high-pressure TiO2 polymorphs. Our results demonstrate the potential of the Kß″ emission line in research on the structure of amorphous oxide material.

Angiostatic kinase inhibitors to sustain photodynamic angio-occlusion.

Targeted angiostatic therapy receives major attention for the treatment of cancer and exudative age-related macular degeneration (AMD). Photodynamic therapy (PDT) has been used as an effective clinical approach for these diseases. As PDT can cause an angiogenic response in the treated tissue, combination of PDT with anti-angiogenic compounds should lead to improved therapy. This study was undertaken to test the clinically used small molecule kinase inhibitors Nexavar® (sorafenib), Tarceva® (erlotinib) and Sutent® (sunitinib) for this purpose, and to compare the results to the combination of Visudyne®-PDT with Avastin® (bevacizumab) treatment. When topically applied to the chicken chorioallantoic membrane at embryo development day (EDD) 7, a clear inhibition of blood vessel development was observed, with sorafenib being most efficient. To investigate the combination with phototherapy, Visudyne®-PDT was first applied on EDD11 to close all <100 µm vessels. Application of angiostatics after PDT resulted in a significant decrease in vessel regrowth in terms of reduced vessel density and number of branching points/mm(2) . As the 50% effective dose (ED50) for all compounds was approximately 10-fold lower, Sorafenib outperformed the other compounds. In vitro, all kinase inhibitors decreased the viability of human umbilical vein endothelial cells. Sunitinib convincingly inhibited the in vitro migration of endothelial cells. These results suggest the therapeutic potential of these compounds for application in combination with PDT in anti-cancer approaches, and possibly also in the treatment of other diseases where angiogenesis plays an important role.

Using ecological niche modelling to predict spatial and temporal distribution patterns in Chinese gibbons: lessons from the present and the past.

Ecological niche modelling (ENM) is used to predict species' tolerance to changing environmental conditions. Understanding changes in the spatial distribution of species across time is essential in order to develop effective conservation strategies. Here we map the past and present distribution of gibbons across China, a country experiencing extensive anthropogenic habitat destruction and ongoing biodiversity loss. The distribution of gibbons across three time intervals is described based on fossil, historical and modern-day data, and ENM, implemented using DIVA-GIS, is used to predict how modern-day gibbon distributions might respond to future climate change. Predictions based on modern-day data alone fail to reveal patterns of environmental tolerance and geographical distribution shown by gibbons in the relatively recent historical period, emphasizing the need to incorporate past as well as present data in conservation analyses.

Extracellular vimentin mimics VEGF and is a target for anti-angiogenic immunotherapy.

Anti-angiogenic cancer therapies possess immune-stimulatory properties by counteracting pro-angiogenic molecular mechanisms. We report that tumor endothelial cells ubiquitously overexpress and secrete the intermediate filament protein vimentin through type III unconventional secretion mechanisms. Extracellular vimentin is pro-angiogenic and functionally mimics VEGF action, while concomitantly acting as inhibitor of leukocyte-endothelial interactions. Antibody targeting of extracellular vimentin shows inhibition of angiogenesis in vitro and in vivo. Effective and safe inhibition of angiogenesis and tumor growth in several preclinical and clinical studies is demonstrated using a vaccination strategy against extracellular vimentin. Targeting vimentin induces a pro-inflammatory condition in the tumor, exemplified by induction of the endothelial adhesion molecule ICAM1, suppression of PD-L1, and altered immune cell profiles. Our findings show that extracellular vimentin contributes to immune suppression and functions as a vascular immune checkpoint molecule. Targeting of extracellular vimentin presents therefore an anti-angiogenic immunotherapy strategy against cancer.

How accurate is the electronic health record? - a pilot study evaluating information accuracy in a primary care setting.

BACKGROUND: Electronic health records (EHR) are increasingly used for both administrative and clinical tasks with major implications for patient safety and quality of care. This study aims to determine a baseline EHR level of accuracy present on measurable information fields within an Australian general practice. METHODS: Quantitative and descriptive pilot study of patients attending a private general practice. Patients who consented to participate in the study had their patient records reviewed to determine how many items were correct, incorrect or not recorded in each EHR information field. Statistical analysis was performed on the data collected. RESULTS: A total of 33 patients gave consent to participate in this study. High levels of accuracy were found in the area of demographic details (94%). Moderately high levels of accuracy were reported for allergies (61%) but also a considerable percentage of non-recorded information was present (36%). Inaccuracies in medication lists were reported in 51% of records reviewed with 32.1% of all medications being inaccurately recorded. While over 91% of participants had a history summary with eight or less items present, omissions were reported for one in every five participants. There were no significant associations present between inaccurate data and frequency of practice visits or those with more than five past medical conditions listed in the EHR. CONCLUSION: The study has confirmed that errors and inaccuracies exist in EHR in our Australian pilot study. The pilot study has also allowed us to complete a trial ensuring that a study of this type can be done safely and with correct methodology. As health informatics plays an increasingly important role in health care, studies of this type will better inform practitioners/ researchers in designing systems to ensure quality electronic patient information.

Integrating Phenotypic Search and Phosphoproteomic Profiling of Active Kinases for Optimization of Drug Mixtures for RCC Treatment.

Combined application of multiple therapeutic agents presents the possibility of enhanced efficacy and reduced development of resistance. Definition of the most appropriate combination for any given disease phenotype is challenged by the vast number of theoretically possible combinations of drugs and doses, making extensive empirical testing a virtually impossible task. We have used the streamlined-feedback system control (s-FSC) technique, a phenotypic approach, which converges to optimized drug combinations (ODC) within a few experimental steps. Phosphoproteomics analysis coupled to kinase activity analysis using the novel INKA (integrative inferred kinase activity) pipeline was performed to evaluate ODC mechanisms in a panel of renal cell carcinoma (RCC) cell lines. We identified different ODC with up to 95% effectivity for each RCC cell line, with low doses (ED5-25) of individual drugs. Global phosphoproteomics analysis demonstrated inhibition of relevant kinases, and targeting remaining active kinases with additional compounds improved efficacy. In addition, we identified a common RCC ODC, based on kinase activity data, to be effective in all RCC cell lines under study. Combining s-FSC with a phosphoproteomic profiling approach provides valuable insight in targetable kinase activity and allows for the identification of superior drug combinations for the treatment of RCC.

Structural Memory in Pressure-Amorphized AlPO4.

Molecular dynamics simulations reveal the mechanism of the structural memory effect in alpha-berlinite (AlPO(4)), where a single crystal transforms to an amorphous solid by compression and then reverts to the original crystalline structure upon release of pressure. The enhanced oxygen coordination around the aluminum atoms in AlPO(4) at high pressure leads to a mechanical instability that causes the phase transformation. The difference in the structural memory behavior between AlPO(4) and isostructural alpha-quartz, for which the pressure-induced amorphized phase is recoverable, can be attributed to the presence of the PO(4) units, which remain essentially four-coordinated even when severely distorted.

Dynamics of Carbonium Ions Solvated by Molecular Hydrogen: CH5+(H2)n (n = 1, 2, 3).

The dynamics of the carbonium ion (CH(5)(+)), a highly reactive intermediate with no equilibrium structure, was studied by measuring the infrared spectra for internally cold CH(5)(+)(H(2))n(n = 1, 2, 3) stored in an ion trap. First-principle molecular dynamics methods were used to directly simulate the internal motion for these ionic complexes. The combined experimental and theoretical efforts substantiated the anticipated scrambling motion in the CH(5)(+) core and revealed the effect of the solvent molecular hydrogen in slowing down the scrambling. The results indicate the feasibility of using solvent molecules to stabilize the floppy CH(5)(+) ion in order to make it amenable to spectroscopic study.