Dasatinib is a small molecule kinase inhibitor that has recently been shown to inhibit Src family kinases (SFK) and also has activity against CaP. Of importance to metastatic CaP, which frequently ...metastasises to bone, SFK are also vital to the regulation of bone remodelling. We sought to determine the ability of dasatinib to inhibit growth of CaP in bone.
C4-2B CaP cells were injected into tibiae of SCID mice and treated with dasatinib, alone or in combination with docetaxel. Serum prostate-specific antigen levels, bone mineral density, radiographs and histology were analysed.
Treatment with dasatinib alone significantly lowered sacrifice serum prostate-specific antigen levels compared to control, 2.3+/-0.4 vs 9.2+/-2.1 (P=0.004). Combination therapy improved efficacy over dasatinib alone (P=0.010). Dasatinib increased bone mineral density in tumoured tibiae by 25% over control tumoured tibiae (P<0.001).
Dasatinib inhibits growth of C4-2B cells in bone with improved efficacy when combined with docetaxel. Additionally, dasatinib inhibits osteolysis associated with CaP. These data support further study of dasatinib in clinical trials for men with CaP bone metastases.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
We present new constraints on the dark matter-induced annual modulation signal using 1.7 years of COSINE-100 data with a total exposure of 97.7 kg yr. The COSINE-100 experiment, consisting of 106 kg ...of NaI(Tl) target material, is designed to carry out a model-independent test of DAMA/LIBRA's claim of WIMP discovery by searching for the same annual modulation signal using the same NaI(Tl) target. The crystal data show a 2.7 cpd/kg/keV background rate on average in the 2-6 keV energy region of interest. Using a χ-squared minimization method we observe best fit values for modulation amplitude and phase of 0.0092±0.0067 cpd/kg/keV and 127.2±45.9 d, respectively.
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CMK, CTK, FMFMET, IJS, NUK, PNG, UL, UM
Sarcopenia and frailty are highly prevalent conditions in older hospitalized patients, which are associated with a myriad of adverse clinical outcomes. This paper, prepared by a multidisciplinary ...expert working group from the Australian and New Zealand Society for Sarcopenia and Frailty Research (ANZSSFR), provides an up-to-date overview of current evidence and recommendations based on a narrative review of the literature for the screening, diagnosis, and management of sarcopenia and frailty in older patients within the hospital setting. It also includes suggestions on potential pathways to implement change to encourage widespread adoption of these evidence-informed recommendations within hospital settings. The expert working group concluded there was insufficient evidence to support any specific screening tool for sarcopenia and recommends an assessment of probable sarcopenia/sarcopenia using established criteria for all older (≥65 years) hospitalized patients or in younger patients with conditions (e.g., comorbidities) that may increase their risk of sarcopenia. Diagnosis of probable sarcopenia should be based on an assessment of low muscle strength (grip strength or five times sit-to-stand) with sarcopenia diagnosis including low muscle mass quantified from dual energy X-ray absorptiometry, bioelectrical impedance analysis or in the absence of diagnostic devices, calf circumference as a proxy measure. Severe sarcopenia is represented by the addition of impaired physical performance (slow gait speed). All patients with probable sarcopenia or sarcopenia should be investigated for causes (e.g., chronic/acute disease or malnutrition), and treated accordingly. For frailty, it is recommended that all hospitalized patients aged 70 years and older be screened using a validated tool Clinical Frailty Scale (CFS), Hospital Frailty Risk Score, the FRAIL scale or the Frailty Index. Patients screened as positive for frailty should undergo further clinical assessment using the Frailty Phenotype, Frailty Index or information collected from a Comprehensive Geriatric Assessment (CGA). All patients identified as frail should receive follow up by a health practitioner(s) for an individualized care plan. To treat older hospitalized patients with probable sarcopenia, sarcopenia, or frailty, it is recommended that a structured and supervised multi-component exercise program incorporating elements of resistance (muscle strengthening), challenging balance, and functional mobility training be prescribed as early as possible combined with nutritional support to optimize energy and protein intake and correct any deficiencies. There is insufficient evidence to recommend pharmacological agents for the treatment of sarcopenia or frailty. Finally, to facilitate integration of these recommendations into hospital settings organization-wide approaches are needed, with the Spread and Sustain framework recommended to facilitate organizational culture change, with the help of ‘champions’ to drive these changes. A multidisciplinary team approach incorporating awareness and education initiatives for healthcare professionals is recommended to ensure that screening, diagnosis and management approaches for sarcopenia and frailty are embedded and sustained within hospital settings. Finally, patients and caregivers’ education should be integrated into the care pathway to facilitate adherence to prescribed management approaches for sarcopenia and frailty.
Aims/hypothesis
Bilirubin has antioxidant and anti-inflammatory activities. Previous studies demonstrated that higher bilirubin levels were associated with reduced prevalence of peripheral arterial ...disease (PAD). However, the relationship between bilirubin and lower-limb amputation, a consequence of PAD, is currently unknown. We hypothesised that, in patients with type 2 diabetes, bilirubin concentrations may inversely associate with lower-limb amputation.
Methods
The relationship between baseline plasma total bilirubin levels and amputation events was analysed in 9,795 type 2 diabetic patients from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. The analysis plan was pre-specified. Lower-limb amputation was adjudicated blinded to treatment allocation. Relevant clinical and biochemical data were available for analyses. Amputation was a pre-specified tertiary endpoint.
Results
Bilirubin concentrations were significantly inversely associated with lower-limb amputation, with a greater than threefold risk gradient across levels. Individuals with lower bilirubin concentrations had a higher risk for first amputation (HR 1.38 per 5 μmol/l decrease in bilirubin concentration, 95% CI 1.07, 1.79,
p
= 0.013). The same association persisted after adjustment for baseline variables, including age, height, smoking status, γ-glutamyltransferase level, HbA
1c
, trial treatment allocation (placebo vs fenofibrate), as well as previous PAD, non-PAD cardiovascular disease, amputation or diabetic skin ulcer, neuropathy, nephropathy and diabetic retinopathy (HR 1.38 per 5 μmol/l decrease in bilirubin concentration, 95% CI 1.05, 1.81,
p
= 0.019).
Conclusions/interpretation
Our results identify a significant inverse relationship between bilirubin levels and total lower-limb amputation, driven by major amputation. Our data raise the hypothesis that bilirubin may protect against amputation in type 2 diabetes.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
•Combining MFM (Membrane Factor Method) and SA (Saturation Analysis) to analyze the dynamic deformation of square plates considering transient phase and exact yield condition.•The complete solutions ...of the dynamic response of square plates subjected to rectangular pressure pulse and linear decay pressure pulse are obtained.•The results obtained from MFM+SA, mode approximation method and FEM are compared, so that the effects of transient phase, yield condition and elastic effect on the theoretical predictions on the dynamic behavior of plates are identified.•Two sets of simple calculation formulae based on MFM+SA are proposed for fully clamped square plates under rectangular pressure pulse and linear decay pressure pulse respectively, showing good agreement with FEM results in large deflection range.
Thin plates will experience large deformation under intense pulse loading, which may result in serious consequences. Numerous research work has been conducted since 1950s and some theoretical methods have been developed to predict the large deformation of plates based on Rigid-Plastic Idealization of material behavior. However, even with this idealization, it is often difficult to obtain complete solutions. Membrane Factor Method (MFM) has proved a powerful method to solve this problem, resulting in solutions taking into account of the effects of the transient phase and the interaction between membrane force and bending moment through a relatively simple procedure. On the other hand, Saturation Analysis (SA) based on the saturation phenomenon is more rational and accurate than the traditional analyses using total impulse of pulse loading. This paper combines these two approaches to study the dynamic plastic response of square plates under rectangular pressure pulse and linear decay pressure pulse loading, and then the results are compared with modal solutions and FE simulations. Meanwhile, the solutions of this combined method, which merely considers the modal phase are also provided to identify the effect of the transient phase. Finally, two sets of simple calculation formulae are proposed for the permanent deformation of plates so as to facilitate engineering applications.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
A randomised double-blind placebo-controlled phase II study was done to assess the efficacy of a prophylactic quadrivalent vaccine targeting the human papillomavirus (HPV) types associated with 70% ...of cervical cancers (types 16 and 18) and with 90% of genital warts (types 6 and 11).
277 young women (mean age 20·2 years SD 1·7) were randomly assigned to quadrivalent HPV (20 μg type 6, 40 μg type 11, 40 μg type 16, and 20 μg type 18) L1 virus-like-particle (VLP) vaccine and 275 (mean age 20·0 years 1·7) to one of two placebo preparations at day 1, month 2, and month 6. For 36 months, participants underwent regular gynaecological examinations, cervicovaginal sampling for HPV DNA, testing for serum antibodies to HPV, and Pap testing. The primary endpoint was the combined incidence of infection with HPV 6, 11, 16, or 18, or cervical or external genital disease (ie, persistent HPV infection, HPV detection at the last recorded visit, cervical intraepithelial neoplasia, cervical cancer, or external genital lesions caused by the HPV types in the vaccine). Main analyses were done per protocol.
Combined incidence of persistent infection or disease with HPV 6, 11, 16, or 18 fell by 90% (95% CI 71–97, p<0·0001) in those assigned vaccine compared with those assigned placebo.
A vaccine targeting HPV types 6, 11, 16, 18 could substantially reduce the acquisition of infection and clinical disease caused by common HPV types.
Published online April 7, 2005 DOI 10.1016/S1470-2045(05)70101-7
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Our knowledge of the strengths of small bodies in the Solar System is limited by our poor understanding of their internal structures, and this, in turn, clouds our understanding of the formation and ...evolution of these bodies. Observations of the rotational states of asteroids whose diameters are larger than a few hundreds of meters have revealed that they are dominated by gravity and that most are unlikely to be monoliths; however, there is a wide range of plausible internal structures. Numerical and analytical studies of shape and spin limits of gravitational aggregates and their collisional evolution show a strong dependence on shear strength. In order to study this effect, we carry out a systematic exploration of the dependence of collision outcomes on dissipation and friction parameters of the material components making up the bodies. We simulate the catastrophic disruption (leading to the largest remnant retaining 50% of the original mass) of km-size asteroids modeled as gravitational aggregates using pkdgrav, a cosmology N-body code adapted to collisional problems and recently enhanced with a new soft-sphere collision algorithm that includes more realistic contact forces. We find that for a range of three different materials, higher friction and dissipation values increase the catastrophic disruption threshold by about half a magnitude. Furthermore, we find that pre-impact rotation systematically increases mass loss on average, regardless of the target׳s internal configuration. Our results have important implications for the efficiency of planet formation via planetesimal growth, and also more generally to estimate the impact energy threshold for catastrophic disruption, as this generally has only been evaluated for non-spinning bodies without detailed consideration of material properties.
•We model the catastrophic disruption of km-size planetesimals.•We examine the dependence of mass loss on shear strength and pre-impact rotation.•We vary shear strength by using three experimentally determined material properties.•Increasing shear strength will increase the catastrophic disruption threshold (QRD⁎).•For different materials, rotation causes equivalent fractional changes in QRD⁎.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Humanitarian and development agencies face difficult decisions about where and how to prioritise climate risk reduction measures. These tasks are especially challenging in regions with few ...meteorological stations, complex topography and extreme weather events. In this study, we blend surface meteorological observations, remotely sensed (TRMM and NDVI) data, physiographic indices, and regression techniques to produce gridded maps of annual mean precipitation and temperature, as well as parameters for site-specific, daily weather generation in Yemen. Maps of annual means were cross-validated and tested against independent observations. These replicated known features such as peak rainfall totals in the highlands and western escarpment, as well as maximum temperatures along the coastal plains and interior. The weather generator reproduced daily and annual diagnostics when run with parameters from observed meteorological series for a test site at Taiz. However, when run with interpolated parameters, the frequency of wet days, mean wet-day amount, annual totals and variability were underestimated. Stratification of sites for model calibration improved representation of the growing season's rainfall totals. Future work should focus on a wider range of model inputs to better discriminate controls exerted by different landscape units.
Epidemiologic studies examining the relations between dairy product and calcium intakes and breast cancer have been inconclusive, especially for tumor subtypes.
To evaluate the associations between ...intakes of specific dairy products and calcium and risk of breast cancer overall and for subtypes defined by estrogen receptor (ER) status.
We pooled the individual-level data of over 1 million women who were followed for a maximum of 8–20 years across studies. Associations were evaluated for dairy product and calcium intakes and risk of incident invasive breast cancer overall (n = 37,861 cases) and by subtypes defined by ER status. Study-specific multivariable hazard ratios (HRs) were estimated and then combined using random-effects models.
Overall, no clear association was observed between the consumption of specific dairy foods, dietary (from foods only) calcium, and total (from foods and supplements) calcium, and risk of overall breast cancer. Although each dairy product showed a null or very weak inverse association with risk of overall breast cancer (P, test for trend >0.05 for all), differences by ER status were suggested for yogurt and cottage/ricotta cheese with associations observed for ER-negative tumors only (pooled HR = 0.90, 95% CI: 0.83, 0.98 comparing ≥60 g/d with <1 g/d of yogurt and 0.85, 95% CI: 0.76, 0.95 comparing ≥25 g/d with <1 g/d of cottage/ricotta cheese). Dietary calcium intake was only weakly associated with breast cancer risk (pooled HR = 0.98, 95% CI: 0.97, 0.99 per 350 mg/d).
Our study shows that adult dairy or calcium consumption is unlikely to associate with a higher risk of breast cancer and that higher yogurt and cottage/ricotta cheese intakes were inversely associated with the risk of ER-negative breast cancer, a less hormonally dependent subtype with poor prognosis. Future studies on fermented dairy products, earlier life exposures, ER-negative breast cancer, and different racial/ethnic populations may further elucidate the relation.
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CMK, GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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