A Practical Approach to Fatigue Management in Colorectal Cancer.

Cancer-related fatigue is serious and complex, as well as one of the most common symptoms experienced by patients with colorectal cancer, with the potential to compromise quality of life, activities of daily living, and ultimately survival. There is a lack of consensus about the definition of cancer-related fatigue; however, definitions have been put forward by the European Association for Palliative Care (EAPC) and the National Comprehensive Cancer Network (NCCN). Numerous cancer- and treatment-related factors can contribute to fatigue, including disease progression, comorbidities, medical complications such as anemia, side effects of other medications, and a number of physical and psychologic factors. This underlines the importance of tackling factors that may contribute to fatigue before reducing the dose of treatment. NCCN guidelines and the EAPC have proposed approaches to managing fatigue in cancer patients; however, relatively few therapeutic agents have been demonstrated to reduce fatigue in randomized controlled trials. It is recognized that physical activity produces many beneficial physiologic modifications to markers of physical performance that can help to counteract various causes of fatigue. In appropriately managed and monitored patients with colorectal cancer, emerging evidence indicates that exercise programs may have a favorable influence on cancer-related fatigue, quality of life, and clinical outcomes, and therefore may help patients tolerate chemotherapy. This review assesses fatigue in patients with colorectal cancer and proposes updates to a treatment algorithm that may help clinicians manage this common problem

Loss of Bim Increases T Cell Production and Function in Interleukin 7 Receptor–deficient Mice

Interleukin (IL)-7 receptor (R) signaling is essential for T and B lymphopoiesis by promoting proliferation, differentiation, and survival of cells. Mice lacking either IL-7 or the IL-7Rα chain have abnormally low numbers of immature as well as mature T and B lymphocytes. Transgenic expression of the apoptosis inhibitor Bcl-2 rescues T cell development and function in IL-7Rα–deficient mice, indicating that activation of a proapoptotic Bcl-2 family member causes death of immature and mature T cells. BH3-only proteins such as Bim, which are distant proapoptotic members of the Bcl-2 family, are essential initiators of programmed cell death and stress-induced apoptosis. We generated Bim/IL-7Rα double deficient mice and found that loss of Bim significantly increased thymocyte numbers, restored near normal numbers of mature T cells in the blood and spleen, and enhanced cytotoxic T cell responses to virus infection in IL-7Rα−/− mice. These results indicate that Bim cooperates with other proapoptotic proteins in the death of IL-7–deprived T cell progenitors in vivo, but is the major inducer of this pathway to apoptosis in mature T cells. This indicates that pharmacological inhibition of Bim function might be useful for boosting immune responses in immunodeficient patients

Cytokine-dependent and cytokine-independent roles for Mcl-1: genetic evidence for multiple mechanisms by which Mcl-1 promotes survival in primary T lymphocytes

Myeloid cell leukemia sequence-1 (Mcl-1) is a critical anti-apoptotic factor in T lymphocytes. However, in spite of the many pro-apoptotic proteins with proposed binding to Mcl-1, the specific interactions by which Mcl-1 regulates primary T-cell survival under different conditions have not been fully explored. Further, how different trophic cytokines modulate the specific role(s) of Mcl-1 is unknown. Here, we use genetic mouse models to dissect the roles of Mcl-1 in primary T lymphocytes. Using the inducible Mcl-1-floxed estrogen receptor-Cre fusion protein (Mcl-1f/fERCre) deletion system in combination with genetic modification of other B-cell lymphoma 2 (Bcl-2) family members, we show that loss of pro-apoptotic Bcl-2 homologous antagonist/killer (Bak) rescues the survival of Mcl-1-deficient T cells in the presence of IL-7. Without IL-7, the survival of Mcl-1-deficient cells cannot be rescued by loss of Bak, but is partially rescued by overexpression of Bcl-2 or loss of Bcl-2-interacting mediator of cell death (Bim). Thus, Mcl-1 and Bcl-2 have a shared role, the inhibition of Bim, in promoting T-cell survival during cytokine withdrawal. Finally, we show that other common gamma-chain (γc) cytokines differentially modulate the roles of Mcl-1. IL-15 has effects similar to those of IL-7 in memory T cells and naïve CD8+ cells, but not naïve CD4+ cells. However, IL-4 maintains Mcl-1 and Bcl-2 but also upregulates Bim and Bcl-2-associated X protein (Bax), thus altering the cell's dependence on Mcl-1

VE-cadherin in arachnoid and pia mater cells serves as a suitable landmark for in vivo imaging of CNS immune surveillance and inflammation.

Meninges cover the surface of the brain and spinal cord and contribute to protection and immune surveillance of the central nervous system (CNS). How the meningeal layers establish CNS compartments with different accessibility to immune cells and immune mediators is, however, not well understood. Here, using 2-photon imaging in female transgenic reporter mice, we describe VE-cadherin at intercellular junctions of arachnoid and pia mater cells that form the leptomeninges and border the subarachnoid space (SAS) filled with cerebrospinal fluid (CSF). VE-cadherin expression also marked a layer of Prox1+ cells located within the arachnoid beneath and separate from E-cadherin+ arachnoid barrier cells. In vivo imaging of the spinal cord and brain in female VE-cadherin-GFP reporter mice allowed for direct observation of accessibility of CSF derived tracers and T cells into the SAS bordered by the arachnoid and pia mater during health and neuroinflammation, and detection of volume changes of the SAS during CNS pathology. Together, the findings identified VE-cadherin as an informative landmark for in vivo imaging of the leptomeninges that can be used to visualize the borders of the SAS and thus potential barrier properties of the leptomeninges in controlling access of immune mediators and immune cells into the CNS during health and neuroinflammation

Glucose Induces Pancreatic Islet Cell Apoptosis That Requires the BH3-Only Proteins Bim and Puma and Multi-BH Domain Protein Bax

OBJECTIVE: High concentrations of circulating glucose are believed to contribute to defective insulin secretion and beta-cell function in diabetes and at least some of this effect appears to be caused by glucose-induced beta-cell apoptosis. In mammalian cells, apoptotic cell death is controlled by the interplay of proapoptotic and antiapoptotic members of the Bcl-2 family. We investigated the apoptotic pathway induced in mouse pancreatic islet cells after exposure to high concentrations of the reducing sugars ribose and glucose as a model of beta-cell death due to long-term metabolic stress. RESEARCH DESIGN AND METHODS: Islets isolated from mice lacking molecules implicated in cell death pathways were exposed to high concentrations of glucose or ribose. Apoptosis was measured by analysis of DNA fragmentation and release of mitochondrial cytochrome c. RESULTS: Deficiency of interleukin-1 receptors or Fas did not diminish apoptosis, making involvement of inflammatory cytokine receptor or death receptor signaling in glucose-induced apoptosis unlikely. In contrast, overexpression of the prosurvival protein Bcl-2 or deficiency of the apoptosis initiating BH3-only proteins Bim or Puma, or the downstream apoptosis effector Bax, markedly reduced glucose- or ribose-induced killing of islets. Loss of other BH3-only proteins Bid or Noxa, or the Bax-related effector Bak, had no impact on glucose-induced apoptosis. CONCLUSIONS: These results implicate the Bcl-2 regulated apoptotic pathway in glucose-induced islet cell killing and indicate points in the pathway at which interventional strategies can be designed

CHOP Potentially Co-Operates with FOXO3a in Neuronal Cells to Regulate PUMA and BIM Expression in Response to ER Stress

Endoplasmic reticulum (ER) stress-induced apoptosis has been implicated in various neurodegenerative diseases including Parkinson Disease, Alzheimer Disease and Huntington Disease. PUMA (p53 upregulated modulator of apoptosis) and BIM (BCL2 interacting mediator of cell death), pro-apoptotic BH3 domain-only, BCL2 family members, have previously been shown to regulate ER stress-induced cell death, but the upstream signaling pathways that regulate this response in neuronal cells are incompletely defined. Consistent with previous studies, we show that both PUMA and BIM are induced in response to ER stress in neuronal cells and that transcriptional induction of PUMA regulates ER stress-induced cell death, independent of p53. CHOP (C/EBP homologous protein also known as GADD153; gene name Ddit3), a critical initiator of ER stress-induced apoptosis, was found to regulate both PUMA and BIM expression in response to ER stress. We further show that CHOP knockdown prevents perturbations in the AKT (protein kinase B)/FOXO3a (forkhead box, class O, 3a) pathway in response to ER stress. CHOP co-immunoprecipitated with FOXO3a in tunicamycin treated cells, suggesting that CHOP may also regulate other pro-apoptotic signaling cascades culminating in PUMA and BIM activation and cell death. In summary, CHOP regulates the expression of multiple pro-apoptotic BH3-only molecules through multiple mechanisms, making CHOP an important therapeutic target relevant to a number of neurodegenerative conditions

Plantations d'eucalyptus et sidérurgie en Amazonie: apports du modèle 3-PG.

Résumé: Le secteur sidérurgique de Carajás, en Amazonie Brésilienne, fait l'objet de contestations environnementales du fait de sa forte consommation en charbon de bois. Ce charbon est essentiellement produit à partir de biomasse de forêts naturelles, avec des impacts directs et indirects sur la déforestation et la dégradation de ces écosystèmes. Les plantations d'eucalyptus à vocation énergétique installées sur des pâturages dégradés constituent une alternative intéressante. Peu de ces plantations ont été mises en place jusqu'à présent et faute d'évaluations valables de leur potentiel de production, une étude a été menée pour présenter une estimation consolidée de la croissance et de la productivité des plantations d'eucalyptus du pôle de Carajás. Celles-ci ont été obtenues à partir du modèle 3-PG (Physiological Principles in Predicting Growth). Son paramétrage a été réalisé à partir de données de croissance du massif d'eucalyptus d'une entreprise de la municipalité de Breu Branco dans l'État du Pará au Brésil. La calibration locale du modèle s'est avérée beaucoup plus performante que l'utilisation de paramètres établis pour des plantations d'eucalyptus dans d'autres régions du Brésil, d'Afrique du sud ou d'Australie. Les simulations réalisées indiquent que l'accroissement moyen annuel actuel de l'ordre de 20 m³ à l'hectare, obtenu pour une période de six ans, pourrait augmenter jusqu'à 30 m³ avec des fertilisations adaptées et un contrôle efficace du sous bois. Elles suggèrent aussi que des productions supérieures seraient obtenues sans déficit hydrique. Cela montre la nécessité de sélectionner les zones de plantation où la saison sèche est la moins marquée autour du pôle de Carajás. La calibration du modèle 3-PG a permis d'améliorer cet outil de gestion des plantations industrielles dans les conditions amazoniennes. (Résumé d'auteur) | Abstract: The Carajás steel industry sector in the Brazilian Amazon has aroused protest on environmental grounds because of its heavy reliance on charcoal. The charcoal is mainly produced from natural forest biomass, with direct and indirect impacts on deforestation and forest ecosystem degradation. Establishing eucalyptus plantations for fuel on degraded pastures could be a workable alternative. Few such plantations exist as yet, and because there are no validated assessments of their production potential, a study was conducted to provide consolidated estimations of the growth and productivity of the Carajás eucalyptus plantations. The estimations were obtained with the 3-PG model (Physiological Principles in Predicting Growth). The model parameters are based on growth data for the eucalyptus plantations established by a company in Breu Branco municipality in Brazil’s Pará State. Calibrating the model with local data proved to be far more effective than using the parameters set for eucalyptus plantations in other areas in Brazil, South Africa or Australia. The simulations made show that the current annual average growth rate, over a six-year period, of about 20 m³ per hectare could increase to 30 m³ with appropriate fertilisation and effective underbrush control. They also suggest that production could be higher without water deficit. Plantation zones shall be selected as a priority in areas where the dry season is the least severe around Carajás. These 3-PG model settings have made it a more effective management tool for industrial plantations in Amazonian conditions

Overexpression of Mcl-1 exacerbates lymphocyte accumulation and autoimmune kidney disease in lpr mice

Cell death by apoptosis has a critical role during embryonic development and in maintaining tissue homeostasis. In mammals, there are two converging apoptosis pathways: the ‘extrinsic’ pathway, which is triggered by engagement of cell surface ‘death receptors’ such as Fas/APO-1; and the ‘intrinsic’ pathway, which is triggered by diverse cellular stresses, and is regulated by prosurvival and pro-apoptotic members of the Bcl-2 family of proteins. Pro-survival Mcl-1, which can block activation of the proapoptotic proteins, Bax and Bak, appears critical for the survival and maintenance of multiple haemopoietic cell types. To investigate the impact on haemopoiesis of simultaneously inhibiting both apoptosis pathways, we introduced the vavP-Mcl-1 transgene, which causes overexpression of Mcl-1 protein in all haemopoietic lineages, into Faslpr/lpr mice, which lack functional Fas and are prone to autoimmunity. The combined mutations had a modest impact on myelopoiesis, primarily an increase in the macrophage/monocyte population in Mcl-1tg/lpr mice compared with lpr or Mcl-1tg mice. The impact on lymphopoiesis was striking, with a marked elevation in all major lymphoid subsets, including the non-conventional double-negative (DN) T cells (TCRβ+ CD4– CD8– B220+ ) characteristic of Faslpr/lpr mice. Of note, the onset of autoimmunity was markedly accelerated in Mcl-1tg/lpr mice compared with lpr mice, and this was preceded by an increase in immunoglobulin (Ig)-producing cells and circulating autoantibodies. This degree of impact was surprising, given the relatively mild phenotype conferred by the vavP-Mcl-1 transgene by itself: a two- to threefold elevation of peripheral B and T cells, no significant increase in the non-conventional DN T-cell population and no autoimmune disease. Comparison of the phenotype with that of other susceptible mice suggests that the development of autoimmune disease in Mcl-1tg/lpr mice may be influenced not only by Ig-producing cells but also other haemopoietic cell types