Gemcitabine has limited clinical benefits in pancreatic ductal adenocarcinoma. The solvent-based traditional taxanes docetaxel and paclitaxel have not shown clinical results superior to gemcitabine. ...Nab-paclitaxel, a water-soluble albumin-bound paclitaxel, may carry superior distribution properties into the tumor microenvironment and has shown efficacy in multiple tumor types. We evaluated nab-paclitaxel effects compared with gemcitabine or docetaxel. For pancreatic ductal adenocarcinoma cells AsPC-1, BxPC-3, MIA PaCa-2 and Panc-1, gemcitabine IC50 ranged from 494nM to 23.9 μM; docetaxel IC50 range was from 5 to 34nM; nab-paclitaxel IC50 range was from 243nM to 4.9 μM. Addition of IC25 dose of docetaxel or nab-paclitaxel decreased gemcitabine IC50. Net tumor growth inhibition after gemcitabine, docetaxel or nab-paclitaxel was 67, 31 and 72%, which corresponded with intratumoral proliferative and apoptotic indices. Tumor stromal density was decreased by nab-paclitaxel and to a lesser extent by docetaxel as measured through reduction in α-smooth muscle actin, S100A4 and collagen 1 expression. Animal survival was prolonged after nab-paclitaxel treatment (41 days, P < 0.002) compared with gemcitabine (32 days, P = 0.005), docetaxel (32 days, P = 0.005) and controls (20 days). Survival in nab-paclitaxel/gemcitabine and docetaxel/gemcitabine sequential treatment groups was not superior to nab-paclitaxel alone. Low-dose combination of gemcitabine with nab-paclitaxel or docetaxel was more effective compared with controls or gemcitabine alone but not superior to regular dose nab-paclitaxel alone. Combination treatment of gemcitabine+nab-paclitaxel or gemcitabine+docetaxel increased gemcitabine concentration in plasma and tumor. The superior antitumor activity of nab-paclitaxel provides a strong rationale for considering nab-paclitaxel as first-line monotherapy in pancreatic ductal adenocarcinoma.
Summary
Calories from any food have the potential to increase risk for obesity and cardiometabolic disease because all calories can directly contribute to positive energy balance and fat gain. ...However, various dietary components or patterns may promote obesity and cardiometabolic disease by additional mechanisms that are not mediated solely by caloric content. Researchers explored this topic at the 2017 CrossFit Foundation Academic Conference ‘Diet and Cardiometabolic Health – Beyond Calories’, and this paper summarizes the presentations and follow‐up discussions. Regarding the health effects of dietary fat, sugar and non‐nutritive sweeteners, it is concluded that food‐specific saturated fatty acids and sugar‐sweetened beverages promote cardiometabolic diseases by mechanisms that are additional to their contribution of calories to positive energy balance and that aspartame does not promote weight gain. The challenges involved in conducting and interpreting clinical nutritional research, which preclude more extensive conclusions, are detailed. Emerging research is presented exploring the possibility that responses to certain dietary components/patterns are influenced by the metabolic status, developmental period or genotype of the individual; by the responsiveness of brain regions associated with reward to food cues; or by the microbiome. More research regarding these potential ‘beyond calories’ mechanisms may lead to new strategies for attenuating the obesity crisis.
Beside the well-known deficiency in serotonergic neurotransmission as pathophysiological correlate of major depression (MD), recent evidence points to a pivotal role of increased glutamate receptor ...activation as well. However, cause and interaction of these neurotransmitter alterations are not understood. In this review, we present a hypothesis integrating current concepts of neurotransmission and hypothalamus-pituitary-adrenal (HPA) axis dysregulation with findings on immunological alterations and alterations in brain morphology in MD. An immune activation including increased production of proinflammatory cytokines has repeatedly been described in MD. Proinflammatory cytokines such as interleukin-2, interferon-gamma, or tumor necrosis factor-alpha activate the tryptophan- and serotonin-degrading enzyme indoleamine 2,3-dioxygenase (IDO). Depressive states during inflammatory somatic disorders are also associated with increased proinflammatory cytokines and increased consumption of tryptophan via activation of IDO. An enhanced consumption of serotonin and its precursor tryptophan through IDO activation could well explain the reduced availability of serotonergic neurotransmission in MD. An increased activation of IDO and its subsequent enzyme kynurenine monooxygenase by proinflammatory cytokines, moreover, leads to an enhanced production of quinolinic acid, a strong agonist of the glutamatergic N-methyl-D-aspartate receptor. In inflammatory states of the central nervous system, IDO is mainly activated in microglial cells, which preferentially metabolize tryptophan to the NMDA receptor agonist quinolinic acid, whereas astrocytes - counteracting this metabolism due to the lack of an enzyme of this metabolism - have been observed to be reduced in MD. Therefore the type 1/type 2 immune response imbalance, associated with an astrocyte/microglia imbalance, leads to serotonergic deficiency and glutamatergic overproduction. Astrocytes are further strongly involved in re-uptake and metabolic conversion of glutamate. The reduced number of astrocytes could contribute to both, a diminished counterregulation of IDO activity in microglia and an altered glutamatergic neurotransmission. Further search for antidepressant agents should take into account anti-inflammatory drugs, for example, cyclooxygenase-2 inhibitors, might exert antidepressant effects by acting on serotonergic deficiency, glutamatergic hyperfunction and antagonizing neurotoxic effects of quinolinic acid.
•A strategy to evaluate chemical category membership is presented.•Templates to assess similarity and characterise uncertainty are developed.•A strategy to apply new toxicological data to strengthen ...read-across predictions.•A workflow for reporting a read-across prediction is described.•Read-across prediction to aid in regulatory decisions.
Category formation, grouping and read across methods are broadly applicable in toxicological assessments and may be used to fill data gaps for chemical safety assessment and regulatory decisions. In order to facilitate a transparent and systematic approach to aid regulatory acceptance, a strategy to evaluate chemical category membership, to support the use of read-across predictions that may be used to fill data gaps for regulatory decisions is proposed. There are two major aspects of any read-across exercise, namely assessing similarity and uncertainty. While there can be an over-arching rationale for grouping organic substances based on molecular structure and chemical properties, these similarities alone are generally not sufficient to justify a read-across prediction. Further scientific justification is normally required to justify the chemical grouping, typically including considerations of bioavailability, metabolism and biological/mechanistic plausibility. Sources of uncertainty include a variety of elements which are typically divided into two main issues: the uncertainty associated firstly with the similarity justification and secondly the completeness of the read-across argument. This article focuses on chronic toxicity, whilst acknowledging the approaches are applicable to all endpoints. Templates, developed from work to prepare for the application of new toxicological data to read-across assessment, are presented. These templates act as proposals to assist in assessing similarity in the context of chemistry, toxicokinetics and toxicodynamics as well as to guide the systematic characterisation of uncertainty both in the context of the similarity rationale, the read across data and overall approach and conclusion. Lastly, a workflow for reporting a read-across prediction is suggested.
In circuit quantum electrodynamics (QED), where superconducting artificial atoms are coupled to on-chip cavities, the exploration of fundamental quantum physics in the strong-coupling regime has ...greatly evolved. In this regime, an atom and a cavity can exchange a photon frequently before coherence is lost. Nevertheless, all experiments so far are well described by the renowned Jaynes-Cummings model. Here, we report on the first experimental realization of a circuit QED system operating in the ultrastrong-coupling limit, where the atom-cavity coupling rate g reaches a considerable fraction of the cavity transition frequency ωr. Furthermore, we present direct evidence for the breakdown of the Jaynes-Cummings model. We reach remarkable normalized coupling rates g/ωr of up to 12% by enhancing the inductive coupling of a flux qubit to a transmission line resonator. Our circuit extends the toolbox of quantum optics on a chip towards exciting explorations of ultrastrong light-matter interaction.
J. Neurochem. (2012) 120, 948–963.
Microglia are the resident immune cells within the brain and their production of immune molecules such as cytokines and chemokines is critical for the processes of ...normal brain development including neurogenesis, axonal migration, synapse formation, and programmed cell death. Notably, sex differences exist in many of these processes throughout brain development; however, it is unknown whether a sex difference concurrently exists in the colonization, number, or morphology of microglia within the developing brain. We demonstrate for the first time that the number and morphology of microglia throughout development is dependent upon the sex and age of the individual, as well as the brain region of interest. Males have overall more microglia early in postnatal development postnatal day (P) 4, whereas females have more microglia with an activated/amoeboid morphology later in development, as juveniles and adults (P30–60). Finally, gene expression of a large number of cytokines, chemokines and their receptors shifts dramatically over development, and is highly dependent upon sex. Taken together, these data warrant further research into the role that sex‐dependent mechanisms may play in microglial colonization, number, and function, and their potential contribution to neural development, function, or potential dysfunction.
Colonization of Microglia in Cognitive Brain Regions: Sex Differences Neonatal male rats have significantly more amoeboid microglia than females within the hippocampus, cortex and amygdala. Before adolescence and into adulthood, females have significantly more microglia with long, branched processes than males in these same brain regions. These data may lend valuable insight into distinct windows of vulnerability between the sexes following an immune challenge.
Additive manufacturing, also known as 3D printing, has emerged over the past 3 decades as a disruptive technology for rapid prototyping and manufacturing. Vat polymerization, powder bed fusion, ...material extrusion, and binder jetting are distinct technologies of additive manufacturing, which have been used in a wide variety of fields, including biomedical research and tissue engineering. The ability to print biocompatible, patient-specific geometries with controlled macro- and micro-pores, and to incorporate cells, drugs and proteins has made 3D-printing ideal for orthopaedic applications, such as bone grafting. Herein, we performed a systematic review examining the fabrication of calcium phosphate (CaP) ceramics by 3D printing, their biocompatibility
in vitro
, and their bone regenerative potential
in vivo
, as well as their use in localized delivery of bioactive molecules or cells. Understanding the advantages and limitations of the different 3D printing approaches, CaP materials, and bioactive additives through critical evaluation of
in vitro
and
in vivo
evidence of efficacy is essential for developing new classes of bone graft substitutes that can perform as well as autografts and allografts or even surpass the performance of these clinical standards.
Abstract Orthopaedic devices are the most common surgical devices associated with implant-related infections and Staphylococcus aureus ( S. aureus ) is the most common causative pathogen in chronic ...bone infections (osteomyelitis). Treatment of these chronic bone infections often involves combinations of antibiotics given systemically and locally to the affected site via a biomaterial spacer. The gold standard biomaterial for local antibiotic delivery against osteomyelitis, poly(methyl methacrylate) (PMMA) bone cement, bears many limitations. Such shortcomings include limited antibiotic release, incompatibility with many antimicrobial agents, and the need for follow-up surgeries to remove the non-biodegradable cement before surgical reconstruction of the lost bone. Therefore, extensive research pursuits are targeting alternative, biodegradable materials to replace PMMA in osteomyelitis applications. Herein, we provide an overview of the primary clinical treatment strategies and emerging biodegradable materials that may be employed for management of implant-related osteomyelitis. We performed a systematic review of experimental biomaterials systems that have been evaluated for treating established S. aureus osteomyelitis in an animal model. Many experimental biomaterials were not decisively more efficacious for infection management than PMMA when delivering the same antibiotic. However, alternative biomaterials have reduced the number of follow-up surgeries, enhanced the antimicrobial efficacy by delivering agents that are incompatible with PMMA, and regenerated bone in an infected defect. Understanding the advantages, limitations, and potential for clinical translation of each biomaterial, along with the conditions under which it was evaluated (e.g. animal model), is critical for surgeons and researchers to navigate the plethora of options for local antibiotic delivery.
Abstract Low temperature 3D printing of calcium phosphate scaffolds holds great promise for fabricating synthetic bone graft substitutes with enhanced performance over traditional techniques. Many ...design parameters, such as the binder solution properties, have yet to be optimized to ensure maximal biocompatibility and osteoconductivity with sufficient mechanical properties. This study tailored the phosphoric acid-based binder solution concentration to 8.75 wt% to maximize cytocompatibility and mechanical strength, with a supplementation of Tween 80 to improve printing. To further enhance the formulation, collagen was dissolved into the binder solution to fabricate collagen-calcium phosphate composites. Reducing the viscosity and surface tension through a physiologic heat treatment and Tween 80, respectively, enabled reliable thermal inkjet printing of the collagen solutions. Supplementing the binder solution with 1–2 wt% collagen significantly improved maximum flexural strength and cell viability. To assess the bone healing performance, we implanted 3D printed scaffolds into a critically sized murine femoral defect for 9 weeks. The implants were confirmed to be osteoconductive, with new bone growth incorporating the degrading scaffold materials. In conclusion, this study demonstrates optimization of material parameters for 3D printed calcium phosphate scaffolds and enhancement of material properties by volumetric collagen incorporation via inkjet printing.
This paper explores the use of aligned chemical vapour deposition (CVD)-grown multi-wall carbon nanotubes as a conductive filler in an epoxy system based on a bisphenol-A resin and an amine hardener. ...During the production of composite samples containing 0.01 wt% nanotubes, stirring rates, resin temperatures, and curing temperatures were varied. Optical microscopy of bulk samples was used to classify the degree of nanotube agglomeration. In addition, the specific bulk conductivity of the materials was analysed by AC impedance spectroscopy. The resulting electrical properties of the composites ranged from purely dielectric behaviour to bulk conductivities of 10
−3 Sm
−1 and were found to depend strongly on three separate stages during processing. All samples contained individually dispersed carbon nanotubes after initial shear-intensive stirring. Negative surface charges on the nanotubes led to charge-stabilised dispersions. After the addition of the hardener, the nanotubes reaggregated upon application of elevated temperatures and/or modest shear forces. The formation of the final network depended on the curing temperature of the matrix. The experimental results are compared to previous studies on nanotube and carbon black epoxy composites and are discussed with respect to aspects of colloid theory.
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