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

Patient-reported outcome measures for cancer caregivers: a systematic review

Purpose Informal caregivers provide invaluable help and support to people with cancer. As treatments extend survival and the potential burdens on carers increase, there is a need to assess the impact of the role. This systematic review identified instruments that measure the impact of caregiving, evaluated their psychometric performance specifically in cancer and appraised the content. Methods A 2-stage search strategy was employed to: 1. identify instruments that measure the impact of caregiving, 2. run individual searches on each measure to identify publications evaluating psychometric performance in the target population. Searches were conducted in Medline, Embase, CINAHL and Psychinfo and restricted to English for instrument used and article language. Psychometric performance was evaluated for content and construct validity, internal consistency, test-retest reliability, precision, responsiveness and acceptability. Individual scale items were extracted and systematically categorised into conceptual domains. Results 10 papers were included reporting on the psychometric properties of 8 measures. Although construct validity and internal consistency were most frequently evaluated, no study comprehensively evaluated all relevant properties. Few studies met our inclusion criteria so it was not possible to consider the psychometric performance of the measures across a group of studies. Content analysis resulted in 16 domains with 5 overarching themes: lifestyle disruption; wellbeing; health of the caregiver; managing the situation and relationships. Conclusions Few measures of caregiver impact have been subject to psychometric evaluation in cancer caregivers. Those that have do not capture well changes in roles and responsibilities within the family and career, indicating the need for a new instrument

Pancreatic β-Cell Death in Response to Pro-Inflammatory Cytokines Is Distinct from Genuine Apoptosis

A reduction in functional β-cell mass leads to both major forms of diabetes; pro-inflammatory cytokines, such as interleukin-1beta (IL-1β) and gamma-interferon (γ-IFN), activate signaling pathways that direct pancreatic β-cell death and dysfunction. However, the molecular mechanism of β-cell death in this context is not well understood. In this report, we tested the hypothesis that individual cellular death pathways display characteristic phenotypes that allow them to be distinguished by the precise biochemical and metabolic responses that occur during stimulus-specific initiation. Using 832/13 and INS-1E rat insulinoma cells and isolated rat islets, we provide evidence that apoptosis is unlikely to be the primary pathway underlying β-cell death in response to IL-1β+γ-IFN. This conclusion was reached via the experimental results of several different interdisciplinary strategies, which included: 1) tandem mass spectrometry to delineate the metabolic differences between IL-1β+γ-IFN exposure versus apoptotic induction by camptothecin and 2) pharmacological and molecular interference with either NF-κB activity or apoptosome formation. These approaches provided clear distinctions in cell death pathways initiated by pro-inflammatory cytokines and bona fide inducers of apoptosis. Collectively, the results reported herein demonstrate that pancreatic β-cells undergo apoptosis in response to camptothecin or staurosporine, but not pro-inflammatory cytokines

TAT-RasGAP317-326-mediated tumor cell death sensitization can occur independently of Bax and Bak.

The increase of cancer specificity and efficacy of anti-tumoral agents are prime strategies to overcome the deleterious side effects associated with anti-cancer treatments. We described earlier a cell-permeable protease-resistant peptide derived from the p120 RasGAP protein, called TAT-RasGAP317-326, as being an efficient tumor-specific sensitizer to apoptosis induced by genotoxins in vitro and in vivo. Bcl-2 family members regulate the intrinsic apoptotic response and as such could be targeted by TAT-RasGAP317-326. Our results indicate that the RasGAP-derived peptide increases cisplatin-induced Bax activation. We found no evidence, using in particular knock-out cells, of an involvement of other Bcl-2 family proteins in the tumor-specific sensitization activity of TAT-RasGAP317-326. The absence of Bax and Bak in mouse embryonic fibroblasts rendered them resistant to cisplatin-induced apoptosis and consequently to the sensitizing action of the RasGAP-derived peptide. Surprisingly, in the HCT116 colon carcinoma cell line, the absence of Bax and Bak did not prevent cisplatin-induced apoptosis and the ability of TAT-RasGAP317-326 to augment this response. Our study also revealed that p53, while required for an efficient genotoxin-induced apoptotic response, is dispensable for the ability of the RasGAP-derived peptide to improve the capacity of genotoxins to decrease long-term survival of cancer cells. Hence, even though genotoxin-induced Bax activity can be increased by TAT-RasGAP317-326, the sensitizing activity of the RasGAP-derived peptide can operate in the absence of a functional mitochondrial intrinsic death pathway

Elimination, fundamental principle and duality for analytic linear systems of partial differential-difference equations with constant coefficients

International audienceIn this paper we investigate the solvability of inhomogeneous linear systems of partial differential-difference equations with constant coefficients and also the corresponding duality problem in how far the solutions of the corresponding homogeneous systems determine the equations. For ordinary delay-differential (DD) equations these behavioral problems were investigated in a seminal paper by Glüsing-Lürssen (1997) and in later papers by Habets, Glüsing-Lürssen, Vettori and Zampieri. In these papers the delay-differential operators are considered as distributions with compact support which act on smooth functions or on arbitrary distributions via convolution. The entire analytic Laplace transforms of the distributions with compact support play an important part in the quoted papers. In our approach the partial differential-difference operators belong to various topological operator rings A of holomorphic functions on subsets of C n and are thus studied in the frequency domain , the arguments of these (operator) functions being interpreted as generalized frequencies. We show that the topological duals A of these operator rings with the canonical action of A on A have strong elimination and duality properties for AA-behaviors and admit concrete representations as spaces of analytic functions of systems theoretic interest. In particular, we study systems with generalized frequencies in the vicinity of suitable compact sets. An application to elimination for systems of periodic signals is given. We also solve an open problem of the quoted authors for DD-equations with incommensurate delays and analytic signals. Module theoretic methods in context with DD-equations have also been used by other authors, for instance by Fliess, Mounier, Rocha and Willems

Farside explorer: Unique science from a mission to the farside of the moon

Farside Explorer is a proposed Cosmic Vision medium-size mission to the farside of theMoon consisting of two landers and an instrumented relay satellite. The farside of the Moon is a unique scientific platform in that it is shielded from terrestrial radio-frequency interference, it recorded the primary differentiation and evolution of the Moon, it can be continuously monitored from the Earth–Moon L2 Lagrange point, and there is a complete lack of reflected solar illumination from the Earth. Farside Explorer will exploit these properties and make the first radio-astronomy measurements from the most radio-quiet region of near-Earth space, determine the internal structure and thermal evolution of the Moon, from crust to core, and quantify impact hazards in near-Earth space by the measurement of flashes generated by impact events. The Farside Explorer flight system includes two identical solarpowered landers and a science/telecommunications relay satellite to be placed in a halo orbit about the Earth–Moon L2 Lagrange point. One lander would explore the largest and oldest recognized impact basin in the Solar System—the South Pole–Aitken basin—and the other would investigate the primordial highlands crust. Radio astronomy, geophysical, and geochemical instruments would be deployed on the surface, and the relay satellite would continuously monitor the surface for impact events.Space EngineeringAerospace Engineerin