A meta-analysis of previous falls and subsequent fracture risk in cohort studies.

The relationship between self-reported falls and fracture risk was estimated in an international meta-analysis of individual-level data from 46 prospective cohorts. Previous falls were associated with an increased fracture risk in women and men and should be considered as an additional risk factor in the FRAX® algorithm. INTRODUCTION: Previous falls are a well-documented risk factor for subsequent fracture but have not yet been incorporated into the FRAX algorithm. The aim of this study was to evaluate, in an international meta-analysis, the association between previous falls and subsequent fracture risk and its relation to sex, age, duration of follow-up, and bone mineral density (BMD). METHODS: The resource comprised 906,359 women and men (66.9% female) from 46 prospective cohorts. Previous falls were uniformly defined as any fall occurring during the previous year in 43 cohorts; the remaining three cohorts had a different question construct. The association between previous falls and fracture risk (any clinical fracture, osteoporotic fracture, major osteoporotic fracture, and hip fracture) was examined using an extension of the Poisson regression model in each cohort and each sex, followed by random-effects meta-analyses of the weighted beta coefficients. RESULTS: Falls in the past year were reported in 21.4% of individuals. During a follow-up of 9,102,207 person-years, 87,352 fractures occurred of which 19,509 were hip fractures. A previous fall was associated with a significantly increased risk of any clinical fracture both in women (hazard ratio (HR) 1.42, 95% confidence interval (CI) 1.33-1.51) and men (HR 1.53, 95% CI 1.41-1.67). The HRs were of similar magnitude for osteoporotic, major osteoporotic fracture, and hip fracture. Sex significantly modified the association between previous fall and fracture risk, with predictive values being higher in men than in women (e.g., for major osteoporotic fracture, HR 1.53 (95% CI 1.27-1.84) in men vs. HR 1.32 (95% CI 1.20-1.45) in women, P for interaction = 0.013). The HRs associated with previous falls decreased with age in women and with duration of follow-up in men and women for most fracture outcomes. There was no evidence of an interaction between falls and BMD for fracture risk. Subsequent risk for a major osteoporotic fracture increased with each additional previous fall in women and men. CONCLUSIONS: A previous self-reported fall confers an increased risk of fracture that is largely independent of BMD. Previous falls should be considered as an additional risk factor in future iterations of FRAX to improve fracture risk prediction.

Exploring the Usability of α-MSH-SM-Liposome as an Imaging Agent to Study Biodegradable Bone Implants In Vivo.

Novel biodegradable metal alloys are increasingly used as implant materials. The implantation can be accompanied by an inflammatory response to a foreign object. For studying inflammation in the implantation area, non-invasive imaging methods are needed. In vivo imaging for the implanted area and its surroundings will provide beneficiary information to understand implant-related inflammation and help to monitor it. Therefore, inflammation-sensitive fluorescent liposomes in rats were tested in the presence of an implant to evaluate their usability in studying inflammation. The sphingomyelin-containing liposomes carrying alpha-melanocyte-stimulating hormone (α-MSH)-peptide were tested in a rat bone implant model. The liposome interaction with implant material (Mg-10Gd) was analyzed with Mg-based implant material (Mg-10Gd) in vitro. The liposome uptake process was studied in the bone-marrow-derived macrophages in vitro. Finally, this liposomal tracer was tested in vivo. It was found that α-MSH coupled sphingomyelin-containing liposomes and the Mg-10Gd implant did not have any disturbing influence on each other. The clearance of liposomes was observed in the presence of an inert and biodegradable implant. The degradable Mg-10Gd was used as an alloy example; however, the presented imaging system offers a new possible use of α-MSH-SM-liposomes as tools for investigating implant responses.

Tumor cell lysis and synergistically enhanced antibody-dependent cell-mediated cytotoxicity by NKG2D engagement with a bispecific immunoligand targeting the HER2 antigen.

Natural killer group 2 member D (NKG2D) plays an important role in the regulation of natural killer (NK) cell cytotoxicity in cancer immune surveillance. With the aim of redirecting NK cell cytotoxicity against tumors, the NKG2D ligand UL-16 binding protein 2 (ULBP2) was fused to a single-chain fragment variable (scFv) targeting the human epidermal growth factor receptor 2 (HER2). The resulting bispecific immunoligand ULBP2:HER2-scFv triggered NK cell-mediated killing of HER2-positive breast cancer cells in an antigen-dependent manner and required concomitant interaction with NKG2D and HER2 as revealed in antigen blocking experiments. The immunoligand induced tumor cell lysis dose-dependently and was effective at nanomolar concentrations. Of note, ULBP2:HER2-scFv sensitized tumor cells for antibody-dependent cell-mediated cytotoxicity (ADCC). In particular, the immunoligand enhanced ADCC by cetuximab, a therapeutic antibody targeting the epidermal growth factor receptor (EGFR) synergistically. No significant improvements were obtained by combining cetuximab and anti-HER2 antibody trastuzumab. In conclusion, dual-dual targeting by combining IgG1 antibodies with antibody constructs targeting another tumor associated antigen and engaging NKG2D as a second NK cell trigger molecule may be promising. Thus, the immunoligand ULBP2:HER2-scFv may represent an attractive biological molecule to promote NK cell cytotoxicity against tumors and to boost ADCC.

Dasatinib prevents skeletal metastasis of osteotropic MDA-MB-231 cells in a xenograft mouse model.

PURPOSE: Bone metastasis in breast cancer has been linked to activity of c-Src kinase, one of the extensively explored tyrosine kinases in cell biology. The impact of TNF-related apoptosis inducing ligand (TRAIL) and TRAIL receptors has just recently been integrated into this conception. METHODS: An osteotropic clone of MDA-MB-231 cells simulated a model for bone metastasis of triple-negative breast cancer (TNBC). The effects of Dasatinib, a clinically established inhibitor of Src kinases family and Abl were evaluated in vitro and in vivo. In vivo effects of Dasatinib treatment on the occurrence of skeletal metastases were tested in a xenograft mouse model after intra-cardiac injection of osteotropic MDA-MB-231-cells. Ex vivo analyses of the bone sections confirmed intraosseous growth of metastases and allowed determination of osteoclastic activity. RESULTS: Treatment of osteotropic MDA-MB-231 cells with Dasatinib inhibited proliferation rates in vitro. A shift in TRAIL-receptor expression towards an induction of oncogenic TRAIL-R2 was observed. In vivo, 15 of 30 mice received an intra-peritoneal treatment with Dasatinib. These mice showed significantly less skeletal metastases in bioluminescence scans. Moreover, a pronounced increase in bone volume was observed in the treatment group, as detected by µ-Computed Tomography. Dasatinib treatment also led to a greater increase in bone density in tibiae without metastatic affection, which was accompanied by reduced recruitment of osteoclasts. CONCLUSION: Our observations support the concept of utilizing Dasatinib in targeting early-stage bone metastatic TNBC and sustaining bone health.

Estimation of Skeletal Muscle Mass and Visceral Adipose Tissue Volume by a Single Magnetic Resonance Imaging Slice in Healthy Elderly Adults.

BACKGROUND: Assessing skeletal muscle (SM) and visceral adipose tissue (VAT) by a single MRI slice at lumbar vertebra (L) 3 can replace whole-body MRI in young and middle-aged adults. However, this technique has not been proven in older adults. OBJECTIVE: The aim of this analysis was to reinvestigate the best estimate for SM and VAT in an independent population of healthy elderly people. METHODS: SM and VAT were assessed by whole-body MRI in 84 subjects ≥60 y [45 men; mean ± SD age: 68.4 ± 5.4 y, mean ± SD body mass index (in kg/m2): 25.5 ± 3.5]. SM and VAT areas of 9 slices at the lumbar spine were analyzed. The best estimate was investigated by Pearson correlations. Total volumes (in liters) were predicted by the area at lumbar vertebra 3 (AL3). Besides Bland-Altman analysis, linear regressions were performed to explain the variance of the bias by age, height, and percentage of fat mass (%FM). In a mixed population (healthy elderly plus reference population), linear regression with total SM and VAT volume as dependent variables and AL3, age, and height as independent variables was applied. RESULTS: When comparing the correlation coefficients between the tissue areas and total volumes, L3 was identified as the best estimate (r range: 0.71-0.94; all P < 0.05). However, Bland-Altman analysis showed a positive SM bias in men (mean ± SD: -1.0% ± 9.0%; P < 0.05) and a negative SM bias in women (mean ± SD: 3.7% ± 9.6%; P < 0.05). Contrary to SM, no significant bias was observed for VAT. In the elderly, stepwise linear regression showed height as a predictor for SM bias (R2 = 0.21, SEE = 2.07 L; P < 0.05) and %FM and age as predictors of the nonsignificant VAT bias (R2 = 0.26, SEE = 0.22L, P < 0.05), in men only. In the mixed population, AL3 and height were predictors for total SM, and AL3 for total VAT, independent of sex. CONCLUSIONS: AL3 was confirmed as the best estimate for SM and VAT volumes in healthy elderly adults. Contrary to VAT, there is a bias for SM, and height has to be added to the algorithm.

Relationship between submaximal oxygen uptake, detailed body composition, and resting energy expenditure in overweight subjects.

OBJECTIVE: We investigated the impact of detailed body composition on aerobic fitness to determine whether regional components of fat mass have independent effects on VO2submax , and whether VO2submax and detailed body composition independently explain variation in REE. METHODS: 71 healthy adults (80% female, 20% male, BMI 28.2-43.8 kg/m(2) ) were investigated. Body composition was measured by the four-compartment model together with whole body magnetic resonance imaging (MRI) to assess high and low metabolic rate organs and regional fat depots. VO2submax was estimated at 75% of predicted maximum heart rate. RESULTS: There was a strong association between VO2submax and FFM and all organ masses except for heart. Skeletal muscle mass accounted for 34.8% of the variance in VO2submax . In addition, subcutaneous adipose tissue (SAT) of extremities explained additional 14.4%. FFM and FM explained 71.3% of the variance in REE. Including the components of FFM and FM, the explained variance in REE increased by about 5.8%; skeletal muscle mass explained 70.0% of the variance in REE and kidney and liver masses explained additional 7.1%. VO2submax correlated with REE. Taking into account body composition, VO2submax did not add to the variance in REE. CONCLUSION: FFM is a determinant of both VO2submax and REE. Modeling either REE or VO2submax from individual components of FFM, about 77.1% of variance in REE (by muscle, liver and kidneys mass) and 34.8% of variance in VO2submax (by skeletal muscle mass) could be explained. FM explained additional variance in REE, whereas SAT of extremities added to the variance in VO2submax only.

AI-based automated detection and stability analysis of traumatic vertebral body fractures on computed tomography.

PURPOSE: We developed and tested a neural network for automated detection and stability analysis of vertebral body fractures on computed tomography (CT). MATERIALS AND METHODS: 257 patients who underwent CT were included in this Institutional Review Board (IRB) approved study. 463 fractured and 1883 non-fractured vertebral bodies were included, with 190 fractures unstable. Two readers identified vertebral body fractures and assessed their stability. A combination of a Hierarchical Convolutional Neural Network (hNet) and a fracture Classification Network (fNet) was used to build a neural network for the automated detection and stability analysis of vertebral body fractures on CT. Two final test settings were chosen: one with vertebral body levels C1/2 included and one where they were excluded. RESULTS: The mean age of the patients was 68 ± 14 years. 140 patients were female. The network showed a slightly higher diagnostic performance when excluding C1/2. Accordingly, the network was able to distinguish fractured and non-fractured vertebral bodies with a sensitivity of 75.8 % and a specificity of 80.3 %. Additionally, the network determined the stability of the vertebral bodies with a sensitivity of 88.4 % and a specificity of 80.3 %. The AUC was 87 % and 91 % for fracture detection and stability analysis, respectively. The sensitivity of our network in indicating the presence of at least one fracture / one unstable fracture within the whole spine achieved values of 78.7 % and 97.2 %, respectively, when excluding C1/2. CONCLUSION: The developed neural network can automatically detect vertebral body fractures and evaluate their stability concurrently with a high diagnostic performance.

Inflammatory response toward a Mg-based metallic biomaterial implanted in a rat femur fracture model.

The immune system plays an important role in fracture healing, by modulating the pro-inflammatory and anti-inflammatory responses occurring instantly upon injury. An imbalance in these responses can lead to adverse outcomes, such as non-union of fractures. Implants are used to support and stabilize complex fractures. Biodegradable metallic implants offer the potential to avoid a second surgery for implant removal, unlike non-degradable implants. However, considering our dynamic immune system it is important to conduct in-depth studies on the immune response to these implants in living systems. In this study, we investigated the immune response to Mg and Mg-10Gd in vivo in a rat femur fracture model with external fixation. In vivo imaging using liposomal formulations was used to monitor the fluorescence-related inflammation over time. We combine ex vivo methods with our in vivo study to evaluate and understand the systemic and local effects of the implants on the immune response. We observed no significant local or systemic effects in the Mg-10Gd implanted group compared to the SHAM and Mg implanted groups over time. Our findings suggest that Mg-10Gd is a more compatible implant material than Mg, with no adverse effects observed in the early phase of fracture healing during our 4-week study. STATEMENT OF SIGNIFICANCE: Degradable metallic implants in form of Mg and Mg-10Gd intramedullary pins were assessed in a rat femur fracture model, alongside a non-implanted SHAM group with special respect to the potential to induce an inflammatory response. This pre-clinical study combines innovative non-invasive in vivo imaging techniques associated with multimodal, ex vivo cellular and molecular analytics. The study contributes to the development and evaluation of degradable biometals and their clinical application potential. The study results indicate that Mg-10Gd did not exhibit any significant harmful effects compared to the SHAM and Mg groups.

Dose-efficient assessment of trabecular microstructure using ultra-high-resolution photon-counting CT.

Photon-counting (PC) detectors for clinical computed tomography (CT) may offer improved imaging capabilities compared to conventional energy-integrating (EI) detectors, e.g. superior spatial resolution and detective efficiency. We here investigate if PCCT can reduce the administered dose in examinations aimed at quantifying trabecular bone microstructure. Five human vertebral bodies were scanned three times in an abdomen phantom (QRM, Germany) using an experimental dual-source CT (Somatom CounT, Siemens Healthineers, Germany) housing an EI detector (0.60 mm pixel size at the iso-center) and a PC detector (0.25 mm pixel size). A tube voltage of 120 kV was used. Tube current-time product for EICT was 355 mAs (23.8 mGy CTDI32 cm). Dose-matched UHR-PCCT (UHRdm, 23.8 mGy) and noise-matched acquisitions (UHRnm, 10.5 mGy) were performed and reconstructed to a voxel size of 0.156 mm using a sharp kernel. Measurements of bone mineral density (BMD) and trabecular separation (Tb.Sp) and Tb.Sp percentiles reflecting the different scales of the trabecular interspacing were performed and compared to a gold-standard measurement using a peripheral CT device (XtremeCT, SCANCO Medical, Switzerland) with an isotropic voxel size of 0.082 mm and 6.6 mGy CTDI10 cm. The image noise was quantified and the relative error with respect to the gold-standard along with the agreement between CT protocols using Lin's concordance correlation coefficient (rCCC) were calculated. The Mean ±â€¯StdDev of the measured image noise levels in EICT was 109.6 ±â€¯3.9 HU. UHRdm acquisitions (same dose as EICT) showed a significantly lower noise level of 78.6 ±â€¯4.6 HU (p = 0.0122). UHRnm (44% dose of EICT) showed a noise level of 115.8 ±â€¯3.7 HU, very similar to EICT at the same spatial resolution. For BMD the overall Mean ±â€¯StdDev for EI, UHRdm and UHRnm were 114.8 ±â€¯28.6 mgHA/cm3, 121.6 ±â€¯28.8 mgHA/cm3 and 121.5 ±â€¯28.6 mgHA/cm3, respectively, compared to 123.1 ±â€¯25.5 mgHA/cm3 for XtremeCT. For Tb.Sp these values were 1.86 ±â€¯0.54 mm, 1.80 ±â€¯0.56 mm and 1.84 ±â€¯0.52 mm, respectively, compared to 1.66 ±â€¯0.48 mm for XtremeCT. The ranking of the vertebrae with regard to Tb.Sp data was maintained throughout all Tb.Sp percentiles and among the CT protocols and the gold-standard. The agreement between protocols was very good for all comparisons: UHRnm vs. EICT (BMD rCCC = 0.97; Tb.Sp rCCC = 0.998), UHRnm vs. UHRdm (BMD rCCC = 0.998; Tb.Sp rCCC = 0.993) and UHRdm vs. EICT (BMD rCCC = 0.97; Tb.Sp rCCC = 0.991). Consequently, the relative RMS-errors from linear regressions against the gold-standard for EICT, UHRdm and UHRnm were very similar for BMD (7.1%, 5.2% and 5.4%) and for Tb.Sp (3.3%, 3.3% and 2.9%), with a much lower radiation dose for UHRnm. Short-term reproducibility for BMD measurements was similar and below 0.2% for all protocols, but for Tb.Sp showed better results for UHR (about 1/3 of the level for EICT). In conclusion, CT with UHR-PC detectors demonstrated lower image noise and better reproducibility for assessments of bone microstructure at similar dose levels. For UHRnm, radiation exposure levels could be reduced by 56% without deterioration of performance levels in the assessment of bone mineral density and bone microstructure.

Dynamic in vivo monitoring of fracture healing process in response to magnesium implant with multimodal imaging: pilot longitudinal study in a rat external fixation model.

Rodent models are commonly used in pre-clinical research of magnesium (Mg)-based and other types of biomaterials for fracture treatment. Most studies selected unstable fixation methods, and there is a lack of multimodal longitudinal in vivo monitoring of bone healing. The purpose of this study is to develop a rat femoral fracture model stabilized by external fixation with intra-medullary Mg implant, and to investigate the dynamic bone union process with several imaging techniques offering complementing insights into the process. Pure Mg pins were prepared, followed by an in vitro degradation test. Male Sprague-Dawley rats in the experimental group underwent femoral osteotomy stabilized by external fixators with intra-medullary implantation of Mg pins, and the control group underwent external fixation without intra-medullary implants. Post-operative radiograph, micro-CT and B-mode ultrasonography were acquired directly after surgery, and re-examined at week 4, 8 and 12. Bone tissue volume, in vivo implant degradation, histological staining and MRI images were analyzed using ex vivo samples. Both groups achieved fracture union at week 12, and the dynamic healing process was illustrated by in vivo radiograph, micro-CT and ultrasonography. Bilateral whole femur ex vivo analysis further demonstrated increased ratio of bone tissue volume in the surgical femur with Mg implants, and in vivo degradation of Mg pins was slower than in vitro results. Titanium screws rather than intra-medullary Mg pins were the source of artifact in MRI. This pilot study showed the rat fracture model with external fixation and intra-medullary Mg implantation to be an effective method for dynamic in vivo monitoring of the bone healing process. Future application of the animal model may facilitate pre-clinical translational research of biodegradable orthopaedic implant materials for fracture treatment.

Tissue responses after implantation of biodegradable Mg alloys evaluated by multimodality 3D micro-bioimaging in vivo.

The local response of tissue triggered by implantation of degradable magnesium-based implant materials was investigated in vivo in a murine model. Pins (5.0 mm length by 0.5 mm diameter) made of Mg, Mg-10Gd, and Ti were implanted in the leg muscle tissue of C57Bl/6N mice (n = 6). Implantation was generally well tolerated as documented by only a mild short term increase in a multidimensional scoring index. Lack of difference between the groups indicated that the response was systemic and surgery related rather than material dependent. Longitudinal in vivo monitoring utilizing micro-computed tomography over 42 days demonstrated the highest and most heterogeneous degradation for Mg-10Gd. Elemental imaging of the explants by micro X-ray fluorescence spectrometry showed a dense calcium-phosphate-containing degradation layer. In order to monitor resulting surgery induced and/or implant material associated local cell stress, sphingomyelin based liposomes containing indocyanine green were administered. An initial increase in fluorescent signals (3-7 days after implantation) indicating cell stress at the site of the implantation was measured by in vivo fluorescent molecular tomography. The signal decreased until the 42nd day for all materials. These findings demonstrate that Mg based implants are well tolerated causing only mild and short term adverse reactions.

Measurement site for waist circumference affects its accuracy as an index of visceral and abdominal subcutaneous fat in a Caucasian population.

Following experts' consensus, waist circumference (WC) is the best anthropometric obesity index. However, different anatomic sites are used, and currently there is no universally accepted protocol for measurement of WC. In this study, we compare the associations between WC measured at different sites with total visceral adipose tissue (VAT) volume and cardiometabolic risk. Cross-sectional data were obtained from 294 adults and 234 children and adolescents. In addition, longitudinal data were provided in 75 overweight adults before and after dietary-induced weight loss. WC was measured below the lowest rib (WC(rib)), above the iliac crest (WC(iliac crest)), and midway between both sites (WC(middle)). Volumes of VAT and abdominal subcutaneous adipose tissue (SAT) were obtained using MRI. Cardiometabolic risk included blood pressure, plasma lipids, glucose, and homeostasis model (HOMA index). WC differed according to measurement site as WC(rib) < WC(middle) < WC(iliac crest) (P < 0.001) in children and women, and WC(rib) < WC(middle), WC(iliac crest) (P < 0.001) in men. Elevated WC differed by 10-20% in females and 6-10% in males, dependent on measurement site. In men and children, all WC had similar relations with VAT, SAT, and cardiometabolic risk factors. In women, WC(rib) correlated with weight loss-induced decreases in VAT (r = 0.35; P < 0.05). By contrast, WC(iliac crest) had the lowest associations with VAT and cardiometabolic risk factors in women. Each WC had a stronger correlation with SAT than with VAT, suggesting that WC is predominantly an index of abdominal subcutaneous fat. There is need for a unified measurement protocol.

Biological properties of iron oxide nanoparticles for cellular and molecular magnetic resonance imaging.

Superparamagnetic iron-oxide particles (SPIO) are used in different ways as contrast agents for magnetic resonance imaging (MRI): Particles with high nonspecific uptake are required for unspecific labeling of phagocytic cells whereas those that target specific molecules need to have very low unspecific cellular uptake. We compared iron-oxide particles with different core materials (magnetite, maghemite), different coatings (none, dextran, carboxydextran, polystyrene) and different hydrodynamic diameters (20-850 nm) for internalization kinetics, release of internalized particles, toxicity, localization of particles and ability to generate contrast in MRI. Particle uptake was investigated with U118 glioma cells und human umbilical vein endothelial cells (HUVEC), which exhibit different phagocytic properties. In both cell types, the contrast agents Resovist, B102, non-coated Fe(3)O(4) particles and microspheres were better internalized than dextran-coated Nanomag particles. SPIO uptake into the cells increased with particle/iron concentrations. Maximum intracellular accumulation of iron particles was observed between 24 h to 36 h of exposure. Most particles were retained in the cells for at least two weeks, were deeply internalized, and only few remained adsorbed at the cell surface. Internalized particles clustered in the cytosol of the cells. Furthermore, all particles showed a low toxicity. By MRI, monolayers consisting of 5000 Resovist-labeled cells could easily be visualized. Thus, for unspecific cell labeling, Resovist and microspheres show the highest potential, whereas Nanomag particles are promising contrast agents for target-specific labeling.

Comparison of photoacoustic and fluorescence tomography for the in vivo imaging of ICG-labelled liposomes in the medullary cavity in mice.

Few reports quantitatively compare the performance of photoacoustic tomography (PAT) versus fluorescence molecular tomography (FMT) in vivo. We compared both modalities for the detection of signals from injected ICG liposomes in the tibial medullary space of 10 BALB/c mice in vivo and ex vivo. Signals significantly correlated between modalities (R²â€¯= 0.69) and within each modality in vivo versus ex vivo (PAT: R²â€¯= 0.70, FMT: R²â€¯= 0.76). Phantom studies showed that signals at 4 mm depth are detected down to 3.3 ng ICG by PAT and 33 ng by FMT, with a nominal spatial resolution below 0.5 mm in PAT and limited to 1 mm in FMT. Our study demonstrates comparable in vivo sensitivity, but superior ex vivo sensitivity and in vivo resolution for our ICG liposomes of the VevoLAZR versus the FMT2500. PAT provides a useful new tool for the high-resolution imaging of bone marrow signals, for example for monitoring drug delivery.

A variant in IL6ST with a selective IL-11 signaling defect in human and mouse.

The GP130 cytokine receptor subunit encoded by IL6ST is the shared receptor for ten cytokines of the IL-6 family. We describe a homozygous non-synonymous variant in IL6ST (p.R281Q) in a patient with craniosynostosis and retained deciduous teeth. We characterize the impact of the variant on cytokine signaling in vitro using transfected cell lines as well as primary patient-derived cells and support these findings using a mouse model with the corresponding genome-edited variant Il6st p.R279Q. We show that human GP130 p.R281Q is associated with selective loss of IL-11 signaling without affecting IL-6, IL-27, OSM, LIF, CT1, CLC, and CNTF signaling. In mice Il6st p.R279Q lowers litter size and causes facial synostosis and teeth abnormalities. The effect on IL-11 signaling caused by the GP130 variant shows incomplete penetrance but phenocopies aspects of IL11RA deficiency in humans and mice. Our data show that a genetic variant in a pleiotropic cytokine receptor can have remarkably selective defects.

Improved accuracy in the assessment of vertebral cortical thickness by quantitative computed tomography using the Iterative Convolution OptimizatioN (ICON) method.

Vertebral whole bone strength is substantially affected by cortical bone properties. Disease and therapy may affect cancellous and cortical bone differently. Unlike Dual X-ray Absorptiometry (DXA), Quantitative Computed Tomography (QCT) permits selective assessment of cortical and cancellous bone, but image quality limits the accuracy. We present an image processing method specifically adopted to thin cortices that substantially improves accuracy. Ten human vertebrae embedded in epoxy resin were imaged using clinical QCT and High-Resolution QCT (HR-QCT) protocols, both acquired on a clinical whole body CT scanner, whereas high resolution peripheral QCT (HR-pQCT) was used as gold standard. Microstructural variables and BMD were calculated using in-house software StructuralInsight for QCT and HR-QCT and the manufacturer's µCT evaluation software for HR-pQCT. An adjusted measure, a deconvolved cortical thickness (dcCt.Th), corrected for partial volume effects, was derived applying the new Iterative Convolution OptimizatioN (ICON) method. Direct measurements of cortical thickness (Ct.Th) showed substantial overestimation with mean ±â€¯standard deviation of 1.8 ±â€¯0.5 mm for QCT and 1.5 ±â€¯0.3 mm for HR-QCT compared to 0.37 ±â€¯0.07 mm using HR-pQCT. Correlations of both QCT (r2 = 0.05, p > 0.5.) and HR-QCT (r2 = 0.38, p = 0.060) with the gold standard HR-pQCT were not significant. Also QCT-based BMD and BMC as well as HR-QCT-based BMD did not show a significant correlation with the gold standard approach. Only HR-QCT-based BMC showed a modest correlation (r2 = 0.59, p = 0.01) After applying ICON corrections, dcCt.Th resulted in 0.52 ±â€¯0.09 mm for QCT and 0.43 ±â€¯0.07 mm for HR-QCT, both significantly correlated to HR-pQCT (r2 = 0.75, p = 0.0012 and r2 = 0.93, p < 0.0001, respectively). The average overestimation bias of Ct.Th was reduced from (402 ±â€¯157)% to (45 ±â€¯17)% for QCT and from (330 ±â€¯69)% to (19 ±â€¯8)% for HR-QCT. Due to inaccurate segmentation uncorrected QCT-based Ct.Th measures as well as BMD and BMC showed no correlation to HR-pQCT and thus such bias cortical data can be misleading. The application of ICON reduced random overestimation bias to about 50 µm and 20 µm for QCT and HR-QCT, respectively, leading to a recovery of a significant correlation with the reference data of HR-pQCT. This reveals the potential for fairly accurate assessment of cortical thickness, allowing to better characterize cortical mechanical competence. These results warrant testing of the performance in vivo.

The novel TRAIL-receptor agonist APG350 exerts superior therapeutic activity in pancreatic cancer cells.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has raised attention as a novel anticancer therapeutic as it induces apoptosis preferentially in tumor cells. However, first-generation TRAIL-receptor agonists (TRAs), comprising recombinant TRAIL and agonistic receptor-specific antibodies, have not demonstrated anticancer activity in clinical studies. In fact, cancer cells are often resistant to conventional TRAs. Therefore, in addition to TRAIL-sensitizing strategies, next-generation TRAs with superior apoptotic activity are warranted. APG350 is a novel, highly potent TRAIL-receptor agonist with a hexavalent binding mode allowing the clustering of six TRAIL-receptors per drug molecule. Here we report on preclinical in vitro and in vivo studies testing the activity of APG350 on pancreatic ductal adenocarcinoma (PDAC) cells. We found that APG350 potently induced apoptosis of Colo357, PancTuI and Panc89 cells in vitro. In addition, APG350 treatment activated non-canonical TRAIL signaling pathways (MAPK, p38, JNK, ERK1/ERK2 and NF-κB) and induced the secretion of IL-8. Stable overexpression of Bcl-xL inhibited APG350-induced cell death and augmented activation of non-canonical pathways. Intriguingly, pre-treatment of Bcl-xL-overexpressing cells with the BH3-mimic Navitoclax restored their sensitivity to APG350. To study the effects of APG350 on PDAC cells in vivo, we applied two different orthotopic xenotransplantation mouse models, with and without primary tumor resection, representing adjuvant and palliative treatment regimes, respectively. APG350 treatment of established tumors (palliative treatment) significantly reduced tumor burden. These effects, however, were not seen in tumors with enforced overexpression of Bcl-xL. Upon primary tumor resection and subsequent APG350 treatment (adjuvant therapy), APG350 limited recurrent tumor growth and metastases. Importantly, therapeutic efficacy of APG350 treatment was more effective compared with treatment with soluble TRAIL in both models. In conclusion, APG350 represents a promising next-generation TRA for the treatment of PDAC. Moreover, our results suggest that combining APG350 with Navitoclax might be a succesfull strategy for cancers harboring mitochondrial apoptosis resistance.

Longitudinal micro-computed tomography monitoring of progressive liver regeneration in a mouse model of partial hepatectomy.

The partial hepatectomy (PH) model is widely used to study liver regeneration. Currently, the extent of regeneration is analyzed by measuring the weight of the liver post-mortem or by magnetic resonance imaging. In this study we aimed to determine whether liver volume gain can be accurately measured using micro-computed tomography (microCT). Approximately 42% of the liver was removed by ligation in C57BL/6 N mice. Mice were divided into two study groups. In group 1 conventional characterization of liver hyperplasia was performed by weighing the liver post-mortem. In group 2, liver volume gain was determined by microCT volume estimation. MicroCT results showed equivalent regeneration rates compared with the conventional method without the need to mathematically determine initial liver weights before PH. This parameter is strongly influenced by the age, strain and sex of the mice. In addition non-invasive microCT determination of volume gain over multiple time-points using the same animal reduces the number of animals needing to be used (in line with the 3R principle of replacement, reduction and refinement).

An extract from the Atlantic brown algae Saccorhiza polyschides counteracts diet-induced obesity in mice via a gut related multi-factorial mechanisms.

In this study we addressed the questions whether an Atlantic brown algae extract (BAE) affects diet induced obesity in mice and which would be the primary targets and underlying key mechanisms. Male C57 BL/6 mice were fed a hypercaloric diet, referred to as high fat diet (HFD), supplemented with a freeze-dried aqueous BAE from Saccorhiza polyschides (5 %) for 8 months. Compared to the control group, dietary BAE supplementation significantly attenuated increase in body weight and fat mass. We observed apparent metabolic improvement including normalization of blood glucose, reduced plasma leptin, reduced fecal bile salt hydrolase activity with lower microbial production of toxic bile acid metabolites in the gut and increased systemic bile acid circulation in BAE-fed mice counteracting adverse effects of long term HFD feeding. Survival of mice receiving dietary BAE supplementation appeared slightly enhanced; however, median and maximal life spans as well as hepatic mTOR activation were not significantly different between BAE and control mice. We suggest that the beneficial metabolic effects of our BAE are at least partly mediated by alterations in gut microbiota associated with fermentation of indigestible polysaccharides that are major components of brown algae such as alginates and fucoidans. We moreover propose a multi-factorial mechanism that involves profound alterations in bile acid homeostasis, changes in intestinal and systemic glucose metabolism likely including increased intestinal gluconeogenesis, increased activity of the intestinally derived hormone GLP-1 contributing to promote systemic insulin sensitivity, and inhibition of α-amylase activity, which expectably limits dietary carbohydrate digestion and glucose release.

Gender-Specific Associations in Age-Related Changes in Resting Energy Expenditure (REE) and MRI Measured Body Composition in Healthy Caucasians.

BACKGROUND: The effect of gender as well as gender-specific changes of fat free mass (FFM) and its metabolic active components (muscle mass and organ masses [OMs]) and fat mass (FM) on age-related changes in resting energy expenditure (REE) are not well defined. We hypothesized that there are gender differences in (1) the age-specific onset of changes in detailed body composition (2); the onset of changes in body composition-REE associations with age. METHODS: Using a cross-sectional magnetic resonance imaging database of 448 Caucasian participants (females and males) with comprehensive data on skeletal muscle (SM) mass, adipose tissue (AT), OMs, and REE. RESULTS: We observed gender-specific differences in the onset of age-related changes in metabolic active components and REE. Declines in body composition and REE started earlier in females than in males for SM (29.4 vs 39.6 years), AT (38.2 vs 49.9 years), OM (34.7 vs 45.7 years), and REE (31.9 vs 36.8 years). The age-related decrease of AT was significantly higher in females than in males (-5.69kg/decade vs -0.59kg/decade). In females adjusted REEmFFM&FM (resting energy expenditure measured adjusted for FFM and FM) and REEmSM/OM/AT (resting energy expenditure measured adjusted for skeletal muscle and organ mass and adipose tissue) decreased by -145 kJ/d/decade and -604.8 kJ/d/ decade after the age of 35.2 respectively 34.3 years. SM was main determinant of REEm in females (R (2) = .67) and males (R (2) = .66) with remaining variance mainly explained by kidney mass (R (2) = .07) in females and liver mass (R (2) = .09) in males. CONCLUSION: We concluded that gender affects the age-related changes in body composition as well as changes in body composition-REE relationship. This trial was registered at linicaltrials.gov as NCT01737034.