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

Mean-field model for magnetic orders in NpTGa5 with T=Co, Ni or Rh

Characteristics of magnetic transitions in NpTGa$_5$ with T=Co, Ni, Rh are explained in a unified way with use of a crystalline electric field (CEF) model of localized 5$f^4$ electrons. The model takes a CEF doublet and a singlet as local states, and includes dipolar and quadrupolar intersite interactions in the mean-field theory. Diverse ordering phenomena are derived depending on the magnitude of interaction parameters, which qualitatively reproduce the experimentally observed magnetic behaviors in NpTGa$_5$. The quadrupole degrees of freedom are essential to the diverse magnetic orders. It is argued that NpRhGa$_5$ is close to a multicritical point where quadrupoles and dipoles with different directions are competing to order.Comment: 17 pages, 10 figure

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

SRBench: A streaming RDF/SPARQL benchmark

We introduce SRBench, a general-purpose benchmark primarily designed for streaming RDF/SPARQL engines, completely based on real-world data sets from the Linked Open Data cloud. With the increasing problem of too much streaming data but not enough tools to gain knowledge from them, researchers have set out for solutions in which Semantic Web technologies are adapted and extended for publishing, sharing, analysing and understanding streaming data. To help researchers and users comparing streaming RDF/SPARQL (strRS) engines in a standardised application scenario, we have designed SRBench, with which one can assess the abilities of a strRS engine to cope with a broad range of use cases typically encountered in real-world scenarios. The data sets used in the benchmark have been carefully chosen, such that they represent a realistic and relevant usage of streaming data. The benchmark defines a concise, yet omprehensive set of queries that cover the major aspects of strRS processing. Finally, our work is complemented with a functional evaluation on three representative strRS engines: SPARQLStream, C-SPARQL and CQELS. The presented results are meant to give a first baseline and illustrate the state-of-the-art

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

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

Glucocorticoids for acute urticaria: study protocol for a double-blind non-inferiority randomised controlled trial

INTRODUCTION: This study protocol describes a trial designed to investigate whether antihistamine alone in patients with acute urticaria does not increase the 7-day Urticaria Activity Score (UAS7) in comparison with an association of antihistamine and glucocorticoids and reduces short-term relapses and chronic-induced urticaria. METHODS AND ANALYSIS: This is a prospective, double-blind, parallel-group, multicentre non-inferiority randomised controlled trial. Two-hundred and forty patients with acute urticaria admitted to emergency department will be randomised in a 1:1 ratio to receive levocetirizine or an association of levocetirizine and prednisone. Randomisation will be stratified by centre. The primary outcome will be the UAS7 at day 7. The secondary outcomes will encompass recurrence of hives and/or itch at day 7; occurrence of spontaneous hives or itch for >6 weeks; patients with angioedema at day 7, and 2, 6, 12 and 24 weeks; new emergency visits for acute urticaria recurrences at days 7 and 14, and 3 months; Dermatology Life Quality Index at days 7 and 14, and 3 and 6 months; and Chronic Urticaria Quality of Life Questionnaire at 6 weeks. ETHICS AND DISSEMINATION: The protocol has been approved by the and will be carried out in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. A steering committee will oversee the progress of the study. Findings will be disseminated through national and international scientific conferences and publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03545464

Type I interferon negatively controls plasmacytoid dendritic cell numbers in vivo

Production of type I interferon in response to virus infection reduces plasmacytoid dendritic cell numbers, thus creating a negative feedback loop

Essential versus accessory aspects of cell death: recommendations of the NCCD 2015

Cells exposed to extreme physicochemical or mechanical stimuli die in an uncontrollable manner, as a result of their immediate structural breakdown. Such an unavoidable variant of cellular demise is generally referred to as ‘accidental cell death’ (ACD). In most settings, however, cell death is initiated by a genetically encoded apparatus, correlating with the fact that its course can be altered by pharmacologic or genetic interventions. ‘Regulated cell death’ (RCD) can occur as part of physiologic programs or can be activated once adaptive responses to perturbations of the extracellular or intracellular microenvironment fail. The biochemical phenomena that accompany RCD may be harnessed to classify it into a few subtypes, which often (but not always) exhibit stereotyped morphologic features. Nonetheless, efficiently inhibiting the processes that are commonly thought to cause RCD, such as the activation of executioner caspases in the course of apoptosis, does not exert true cytoprotective effects in the mammalian system, but simply alters the kinetics of cellular demise as it shifts its morphologic and biochemical correlates. Conversely, bona fide cytoprotection can be achieved by inhibiting the transduction of lethal signals in the early phases of the process, when adaptive responses are still operational. Thus, the mechanisms that truly execute RCD may be less understood, less inhibitable and perhaps more homogeneous than previously thought. Here, the Nomenclature Committee on Cell Death formulates a set of recommendations to help scientists and researchers to discriminate between essential and accessory aspects of cell death

Factor XII mutations, estrogen-dependent inherited angioedema, and related conditions

The clinical, biochemical and genetic features of the conditions known as estrogen-dependent inherited angioedema, estrogen-associated angioedema, hereditary angioedema with normal C-1 inhibitor, type III angioedema, or factor XII angioedema are reviewed. Discussion emphasizes pathogenesis, diagnosis, and management