BMP axis in cancer cachexia

BACKGROUND Cancer cachexia is a devastating metabolic syndrome characterized by systemic inflammation and massive muscle and adipose tissue wasting. Although cancer cachexia is responsible for about 25% of cancer deaths, no effective therapies are available, and the underlying mechanisms have not been fully elucidated. Its occurrence complicates patients’ management, reduces tolerance to treatments and negatively affects patient quality of life. Muscle wasting, mainly due to increased protein breakdown rates, is one of the most prominent features of cachexia. Blocking muscle loss in cachexia mouse models dramatically prolongs survival even of animals in which tumor growth is not inhibited. Recent observations showed that bone morphogenetic protein (BMP) signaling, acting through Smad1, Smad5 and Smad8 (Smad1/5/8), is a master regulator of muscle homeostasis. BMP-Smad1/5/8 axis negatively regulates a novel ubiquitin ligase (MUSA1) required for muscle loss induced by denervation. MATERIALS AND METHODS First aim of the present work was to test if alterations of the BMP signaling pathway occur in cancer-induced muscle wasting in patients. For this purpose we checked the state of activation of the BMP pathway in muscle of cachectic vs non–cachectic patients affected by colon, pancreatic and esophagus cancer and in control subjects. We checked by Western Blot the phosphorylation levels of Smad1/5/8 and of Smad3 and by quantitative Real-Time PCR (qRT-PCR) the expression levels of different atrophy-related genes The second aim was to evaluate the degree of muscle atrophy and distribution of muscle fibers in patients and control subjects using morphometric and immunohistochemical analyses. We also performed analysis on distribution of NCAM positive muscle fibers to assess the effect of denervation on muscle tropism. RESULTS From December 2014 we collected 95 rectus abdominis muscle biopsies of cancer patients and 11 from control subjects. In line with the results we obtained in C26 mice model (a well-established cancer cachexia experimental model) Smad1/5/8 phosphorylation, readout of the state of activation of the BMP pathway, was nearly completely abrogated in the muscles of cancer cachectic patients compared to cancer non-cachectic ones. Interestingly, the level of phosphorylation of Smad3 was not significantly affected suggesting specific effects of cancer growth on BMP pathway. The expression levels of different atrophy-related genes including MUSA1 were induced in the cachectic muscles. Interestingly, several BMP related genes are also changing the expression during cancer growth. We also found a correlation between suppression of BMP pathway, expression of atrophy related genes and Noggin, known to block BMP pathway. Morphometric analysis shown that patients with cancer cachexia have smaller myofiber diameter (in particular fast type fibers) in comparison to age-matched controls. In skeletal muscle from cancer patients (either cachectic or non-cachectic) we detected a prevalence of flat shaped, angulated and severely atrophic myofibers (i.e. morphological features of denervated myofibers), big fiber-type grouping (i.e. typical hallmark of denervation/reinnervation events) and numerous NCAM positive myofibers (i.e. specific marker of denervation). CONCLUSIONS These findings are consistent with the hypothesis that BMP inhibition is permissive to cachexia onset. Since the reactivation of the BMP-dependent signaling and MUSA1 suppression was sufficient to prevent tumor-induced muscle atrophy in our C26 mouse model (data not shown), the present data suggest that the BMP axis can be an effective target for therapeutic approaches to counteract cachexia also in cancer patients. The results of morphometric and immunohistochemical studies collected till now may suggest that denervation contributes to myofiber atrophy in cancer cachexia

Parameterized hysteresis model for high-temperature superconductors

High-temperature superconductors (HTS) exhibit hysteresis, which is the main cause for losses in the subcritical domain. This behavior is well predicted by Bean's critical-state model, which is a subset of the classical Preisach model. We present a parameterized Preisach model that describes the hysteresis of HTS specimens in self-field, where the parameters are identified from electrical lock-in (loss) measurements. That means the model can be used independent of geometry, number of filaments, and other physical measures as long as Bean's model applies. An advantage of the model is that it can predict outputs (flux, voltage) and losses for arbitrary input currents once the HTS has been characterized from measurements. We have further derived exact models for the hysteretic losses in strip and elliptic geometry strips, where the energy losses were calculated by Norris

Preisach-type hysteresis modelling in Bi-2223 tapes

. An identification method for Preisach-type models of hysteresis is presented. By using a phenomenological Preisach-type model for hysteresis we can obtain an exact model for the magnetisation hysteresis in the cases of tapes with strip and with elliptical cross section geometries. With a parametrisation by Maclaurin series, it is possible to identify such a model for any other geometry. An additional advantage of this method is that the parameters are identified from the measurements of energy losses per cycle. Finally the results of application of the modelling method to the case of a cuprate ceramic (Bi--2223) superconductor strip is presented. 1. Introduction In the recent years we have witnessed an increasing interest to apply ceramic superconductors in power transmission and distribution. However, there is a need for an accurate macroscopic model of electro-magnetic behaviour of these materials, without which a reliable design cannot be achieved. Due to the magnetic hysteresis ..

Parametrised Preisach Modelling of Hysteresis in High Temperature Superconductors

We present a parametrised Preisach-type model that describes the hysteresis exhibited by the high temperature superconductors (HTSC); hysteresis is the main cause for losses in the subcritical domain. The parametrised model, in combination with electrical measurements, is independent of geometry, number of filaments and other physical measures, and is identified by a novel method that uses electrical lock-in (loss) measurement technique, which greatly enhances the signal to noise ratio. Identification results from measurements on Bi-2223 multi-filamentary tapes are presented. We have further derived exact models for the hysteretic losses in strip and elliptic geometry strips, where the energy losses were calculated by Norris. The paper contains analysis of the Preisach model, of its losses and of the suggested parametrisation. I. Introduction HTSC is a new material with characteristics differing totally from conventional metallic conductors. The material is not fully free from losses,..

CONSUMER PRICE INDEX OF SERBIA FOR SELECTED PRODUCTS

Consumer Price Index (CPI) is one of the national most observed economical statistic items. Its purpose is to weight the current state of goods and services to produce the overall prices index shares in the total of the consumer expenditures. CPI is used to measure effect of inflation and deflation and to adjust real value of wages, salaries, pensions, to regulate prices and deflate monetary magnitudes, to show changes in real values. In this paper, we discuss CPI of Serbia for several years period using selected products and statistical data obtained from federal research

Adiponectin as a potential biomarker of low bone mineral density in postmenopausal women with metabolic syndrome

© 2018, Acta Endocrinologica Foundation. All rights reserved. Context. Adiponectin is an abundant adipokine, which has antiinflammatory, anti-atherosclerotic and vasoprotective actions, and potential antiresorptive effects on bone metabolism. It seems to be directly involved in the improvement and control of energy homeostasis, protecting bone health and predicting osteoporotic fracture risk. Objective. To examine the relationship between adiponectin level and bone mineral density (BMD) in postmenopausal women with metabolic syndrome (MetS) and low BMD, and to estimate the prognostic significance of adiponectin in osteoporosis. Design. Clinical-laboratory cross-sectional study including 120 middle-aged and elder women (average 69.18±7.56 years). Subjects and Methods. The anthropometric parameters were measured for all examinees. Lumbar spine and hip BMD, as well as body fat percentage, were measured using a Hologic DEXA scanner. In all subjects serum adiponectin concentration was measured by ELISA method. Results. The level of adiponectin was significantly positively correlated with BMD-total, BMD of the lumbar spine and BMD of the femoral neck (r=0.618, r=0.521, r=0.567; p<0.01). Levels of adiponectin and BMD are significantly lower in post-menopausal women with MetS and osteoporosis compared to patients with osteopenia (856.87±453.43 vs. 1287.32±405.21 pg/mL, p<0.01; BMD, p<0.05), and the highest values in healthy examinees. A cutoff value of adiponectin level for osteoporosis/osteopenia was 1076.22/1392.74 pg/mL. Conclusions. Post-menopausal women with MetS have significantly lower adiponectin level and low BMD compared to healthy examinees. Adiponectin may be an early, significant and independent predictor of developing osteoporosis in women with MetS, especially in postmenopausal period