Understanding cachexia as a cancer metabolism syndrome

Metabolic reprogramming occurs in tumors to foster cancer cell proliferation, survival and metastasis, but as well at a systemic level affecting the whole organism, eventually leading to cancer cachexia. Indeed, as cancer cells rely on external sources of nitrogen and carbon skeleton to grow, systemic metabolic deregulation promoting tissue wasting and metabolites mobilization ultimately supports tumor growth. Cachectic patients experience a wide range of symptoms affecting several organ functions such as muscle, liver, brain, immune system and heart, collectively decreasing patients’ quality of life and worsening their prognosis. Moreover, cachexia is estimated to be the direct cause of at least 20% of cancer deaths. The main aspect of cachexia syndrome is the unstoppable skeletal muscle and fat storage wasting, even with an adequate caloric intake, resulting in nutrient mobilization – both directly as lipid and amino acids and indirectly as glucose derived from the exploitation of liver gluconeogenesis – that reaches the tumor through the bloodstream. From a metabolic standpoint, cachectic host develops a wide range of dysfunctions, from increased insulin and IGF-1 resistance to induction of mitochondrial uncoupling proteins and fat tissue browning resulting in an increased energy expenditure and heat generation, even at rest. For a long time, cachexia has been merely considered an epiphenomenon of end-stage tumors. However, in specific tumor types, such as pancreatic cancers, it is now clear that patients present markers of tissue wasting at a stage in which tumor is not yet clinically detectable, and that host amino acid supply is required for tumor growth. Indeed, tumor cells actively promote tissue wasting by secreting specific factors such as parathyroid hormone-related protein and micro RNAs. Understanding the molecular and metabolic mediators of cachexia will not only advance therapeutic approaches against cancer, but also improve patients’ quality of life

Hierarchy of models for meandering rivers and related morphodynamic processes

We review the importance of the physical mechanisms involved in river meandering by comparing some existing linear models and extensions thereof. Such models are hierarchically derived from a common and general mathematical framework and then analyzed with a detailed discussion of the physical processes and relevant hypotheses that are involved. Experiments and field data are also used to discuss the related morphodynamic processes. The analysis of the models shows the importance of the closure of secondary currents especially in the modeling of eddy viscosity. This aspect confirms the usefulness of using simplified models for some practical applications, provided the secondary currents are modeled in detail. On the other hand, the free response of the sediments, the phase lag of secondary currents, and the momentum redistribution due to the coupling between the main and the transverse flow are shown to be less relevant. Hence the second-order models, which neglect the effect of superelevation induced by the topography-driven lateral flow on the longitudinal flow, can reasonably be considered a good approximation for both predictive analysis and the computation of the resonant conditions. Finally, the analysis of higher harmonics suggests that the multilobed pattern can intrinsically be present in both second- and fourth-order models

Soil nutrient cycles as a nonlinear dynamical system

International audienceAn analytical model for the soil carbon and nitrogen cycles is studied from the dynamical system point of view. Its main nonlinearities and feedbacks are analyzed by considering the steady state solution under deterministic hydro-climatic conditions. It is shown that, changing hydro-climatic conditions, the system undergoes dynamical bifurcations, shifting from a stable focus to a stable node and back to a stable focus when going from dry, to well-watered, and then to saturated conditions, respectively. An alternative degenerate solution is also found in cases when the system can not sustain decomposition under steady external conditions. Different basins of attraction for "normal" and "degenerate" solutions are investigated as a function of the system initial conditions. Although preliminary and limited to the specific form of the model, the present analysis points out the importance of nonlinear dynamics in the soil nutrient cycles and their possible complex response to hydro-climatic forcing

Rainfall intensification increases the contribution of rewetting pulses to soil heterotrophic respiration

Soil drying and wetting cycles promote carbon(C) release through large heterotrophic respiration pulses at rewetting, known as the “Birch” effect. Empirical evidence shows that drier conditions before rewetting and larger changes in soil moisture at rewetting cause larger respiration pulses. Because soil moisture varies in response to rainfall, these respiration pulses also depend on the random timing and intensity of precipitation. In addition to rewetting pulses, heterotrophic respiration continues during soil drying, eventually ceasing when soils are too dry to sustain microbial activity. The importance of respiration pulses in contributing to the overall soil heterotrophic respiration flux hasbeen demonstrated empirically, but no theoretical investigation has so far evaluated how the relative contribution ofthese pulses may change along climatic gradients or as precipitation regimes shift in a given location. To fill this gap,we start by assuming that heterotrophic respiration rates during soil drying and pulses at rewetting can be treated as random variables dependent on soil moisture fluctuations, and we develop a stochastic model for soil heterotrophic respi-ration rates that analytically links the statistical properties of respiration to those of precipitation. Model results show that both the mean rewetting pulse respiration and the mean respiration during drying increase with increasing mean pre-cipitation. However, the contribution of respiration pulses to the total heterotrophic respiration increases with decreasing precipitation frequency and to a lesser degree with decreas-ing precipitation depth, leading to an overall higher contribution of respiration pulses under future more intermittent and intense precipitation. Specifically, higher rainfall intermittency at constant total rainfall can increase the contribution of respiration pulses up to ∼10 % or 20 % of the total heterotrophic respiration in mineral and organic soils, respectively. Moreover, the variability of both components of soil heterotrophic respiration is also predicted to increase under these conditions. Therefore, with future more intermittent precipitation, respiration pulses and the associated nutrient release will intensify and become more variable, contributing more to soil biogeochemical cycling

Testing a model of pacific oysters’ (Crassostrea gigas) growth in the adriatic sea: Implications for aquaculture spatial planning

Assessing the potential biomass yield is a key step in aquaculture site selection. This is challenging, especially for shellfish, as the growth rate depends on both trophic status and water temperature. Individual ecophysiological models can be used for mapping potential shellfish growth in coastal areas, using as input spatial time series of remotely sensed SST and chlorophyll-a. This approach was taken here to estimate the potential for developing oyster (Crassostrea gigas) farming in the western Adriatic Sea. Industry relevant indicators (i.e., shell length, total individual weight) and days required to reach marketable size were mapped using a dynamic energy budget model, finetuned on the basis of site-specific morphometric data collected monthly for a year. Spatially scaled-up results showed that the faster and more uniform growth in the northern Adriatic coastal area, compared with the southern one, where chlorophyll-a levels are lower and summer temperatures exceed the critical temperature limit for longer periods. These results could be used in planning the identification of allocated zones for aquaculture, (AZA), taking into account also the potential for farming or co-farming C. gigas. In perspective, the methodology could be used for getting insights on changes to the potential productivity indicators due to climatic changes

Long-term antigen exposure irreversibly modifies metabolic requirements for T cell function

Energy metabolism is essential for T cell function. However, how persistent antigenic stimulation affects T cell metabolism is unknown. Here, we report that long-term in vivo antigenic exposure induced a specific deficit in numerous metabolic enzymes. Accordingly, T cells exhibited low basal glycolytic flux and limited respiratory capacity. Strikingly, blockade of inhibitory receptor PD-1 stimulated the production of IFNγ in chronic T cells, but failed to shift their metabolism towards aerobic glycolysis, as observed in effector T cells. Instead, chronic T cells appeared to rely on oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO) to produce ATP for IFNγ synthesis. Check-point blockade, however, increased mitochondrial production of superoxide and reduced viability and effector function. Thus, in the absence of a glycolytic switch, PD-1-mediated inhibition appears essential for limiting oxidative metabolism linked to effector function in chronic T cells, thereby promoting survival and functional fitness.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Annual Meeting of the International Society of Cancer Metabolism (ISCaM): Metabolic Adaptations and Targets in Cancer

The metabolism of cancer cells differs from that of their normal counterparts in a spectrum of attributes, including imbalances in diverse metabolic arms and pathways, metabolic plasticity and extent of adaptive responses, levels, and activities of metabolic enzymes and their upstream regulators and abnormal fluxes of metabolic intermediates and products. These attributes endow cancer cells with the ability to survive stressors of the tumor microenvironment and enable them to landscape and exploit the host terrain, thereby facilitating cancer progression and therapy resistance. Understanding the molecular and physiological principles of cancer metabolism is one of the key prerequisites for the development of better anticancer treatments. Therefore, various aspects of cancer metabolism were addressed at the 5th annual meeting of the International Society of Cancer Metabolism (ISCaM) in Bratislava, Slovakia, on October 17\u201320, 2018. The meeting presentations and discussions were traditionally focused on mechanistic, translational, and clinical characteristics of metabolism and pH control in cancer, at the level of molecular pathways, cells, tissues, and organisms. In order to reflect major healthcare challenges of the current era, ISCaM has extended its scope to metabolic disorders contributing to cancer, as well as to opportunities for their prevention, intervention, and therapeutic targeting