Interaction of inflammatory cytokines and erythropoeitin in iron metabolism and erythropoiesis in anaemia of chronic disease

In chronic inflammatory conditions increased endogenous release of specific cytokines (TNFα, IL-1, IL-6, IFNγ and others) is presumed. It has been shown that those of monocyte lineage play a key role in cytokine expression and synthesis. This may be associated with changes in iron metabolism and impaired erythropoiesis and may lead to development of anaemia in patients with rheumatoid arthritis. Firstly, increased synthesis of acute phase proteins, like ferritin, during chronic inflammation is proposed as the way by which the toxic effect of iron and thereby the synthesis of free oxy-radicals causing the damage on the affected joints, may be reduced. This is associated with a shift of iron towards the mononuclear phagocyte system which may participate in the development of anaemia of chronic disease. Secondly, an inhibitory action of inflammatory cytokines (TNFα, IL-1), on proliferation and differentiation of erythroid progenitors as well as on synthesis of erythropoietin has been shown, thereby also contributing to anaemia. Finally, chronic inflammation causes multiple, complex disturbances in the delicate physiologic equilibrium of interaction between cytokines and cells (erythroid progenitors, cells of mononuclear phagocyte system and erythropoietin producing cells) leading to development of anaemia of chronic disease (Fig. 1)

A multiscale model to design therapeutic strategies that overcome drug resistance to tyrosine kinase inhibitors in multiple myeloma

Drug resistance (DR) is a phenomenon characterized by the tolerance of a disease to pharmaceutical treatment. In cancer patients, DR is one of the main challenges that limit the therapeutic potential of the existing treatments. Therefore, overcoming DR by restoring the sensitivity of cancer cells would be greatly beneficial. In this context, mathematical modeling can be used to provide novel therapeutic strategies that maximize the efficiency of anti-cancer agents and potentially overcome DR. In this paper, we present a new multiscale model devoted to the interaction of potential treatments with multiple myeloma (MM) development. In this model, MM cells are represented as individual objects that move, divide, and die by apoptosis. The fate of each cell depends on intracellular and extracellular regulation, as well as the administered treatment. The model is used to explore the combined effects of a tyrosine-kinase inhibitor (TKI) with a pentose phosphate pathway (PPP) inhibitor. We use numerical simulations to tailor effective and safe treatment regimens that may eradicate the MM tumors. The model suggests that an interval for the daily dose of the PPP inhibitor can maximize the responsiveness of MM cells to the treatment with TKIs. Then, it demonstrates that the combination of high-dose pulsatile TKI treatment with high-dose daily PPP inhibitor therapy can potentially eradicate the tumor.The predictions of numerical simulations using such a model can be considered as testable hypotheses in future pre-clinical experiments and clinical studies. © 2019 Elsevier Inc

Transition to 37°C reveals importance of NADPH in mitigating oxidative stress in stored RBCs.

The RBC storage lesion is a multiparametric response that occurs during storage at 4°C, but its impact on transfused patients remains unclear. In studies of the RBC storage lesion, the temperature transition from cold storage to normal body temperature that occurs during transfusion has received limited attention. We hypothesized that multiple deleterious events might occur in this period of increasing temperature. We show dramatic alterations in several properties of therapeutic blood units stored at 4°C after warming them to normal body temperature (37°C), as well as febrile temperature (40°C). In particular, the intracellular content and redox state of NADP(H) were directly affected by post-storage incubation at 37°C, as well as by pro-oxidant storage conditions. Modulation of the NADPH-producing pentose phosphate pathway, but not the prevention of hemoglobin autoxidation by conversion of oxyhemoglobin to carboxyhemoglobin, provided protection against storage-induced alterations in RBCs, demonstrating the central role of NADPH in mitigating increased susceptibility of stored RBCs to oxidative stress. We propose that assessing RBC oxidative status after restoration of body temperature constitutes a sensitive method for detecting storage-related alterations that has the potential to improve the quality of stored RBCs for transfusion

Estimativas de componentes de (co)variância para peso e escores visuais de conformação frigorífica em bovinos Nelore

Estimaram-se os componentes de (co)variância e herdabilidade da conformação frigorífica à desmama (CFD), conformação frigorífica ao sobreano (CFS), peso à desmama (PD) e peso ao sobreano (PS) de animais Nelore, e as correlações genéticas entre essas características. Um modelo animal multicaracterística foi proposto para analisar 6.397 informações de peso e escores visuais de conformação frigorífica, obtidas à desmama e ao sobreano. Esse modelo incluiu os efeitos aleatórios genético aditivo direto, genético aditivo materno, ambiente permanente materno e residual, além dos efeitos fixos de grupo contemporâneo e das covariáveis idade da mãe ao parto - para peso e conformação frigorífica à desmama e ao sobreano - e idade do animal à data da avaliação - para conformação frigorífica, à desmama e ao sobreano. As herdabilidades estimadas para CFD, CFS, PD e PS foram, respectivamente, 0,13, 0,25, 0,22 e 0,29. Correlações genéticas positivas e de alta magnitude entre as características de peso e as características de avaliação visual sugerem que a seleção para uma delas pode resultar em resposta indireta na outra. A característica de conformação frigorífica pode ser selecionada em idade mais precoce em razão da correlação genética alta e positiva entre mensurações feitas nas duas idades estudadas