Cancer therapy-induced PAFR ligand expression: any role for caspase activity?

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Caspase-generated fragment of the Met receptor favors apoptosis via the intrinsic pathway independently of its tyrosine kinase activity

The receptor tyrosine kinase Met and its ligand, the hepatocyte growth factor, are essential to embryonic development, whereas the deregulation of Met signaling is associated with tumorigenesis. While ligand-activated Met promotes survival, caspase-dependent generation of the p40 Met fragment leads to apoptosis induction – hallmark of the dependence receptor. Although the survival signaling pathways induced by Met are well described, the pro-apoptotic signaling pathways are unknown. We show that, although p40 Met contains the entire kinase domain, it accelerates apoptosis independently of kinase activity. In cell cultures undergoing apoptosis, the fragment shows a mitochondrial localization, required for p40 Met-induced cell death. Fulminant hepatic failure induced in mice leads to the generation of p40 Met localized also in the mitochondria, demonstrating caspase cleavage of Met in vivo. According to its localization, the fragment induces mitochondrial permeabilization, which is inhibited by Bak silencing and Bcl-xL overexpression. Moreover, Met silencing delays mitochondrial permeabilization induced by an apoptotic treatment. Thus, the Met-dependence receptor in addition to its well-known role in survival signaling mediated by its kinase activity, also participates in the intrinsic apoptosis pathway through the generation of p40 Met – a caspase-dependent fragment of Met implicated in the mitochondrial permeabilization process

Notes on the Economics of Residential Hybrid Energy System

Despite advances in small-scale hybrid renewable energy technologies, there are limited economic frameworks that model the different decisions made by a residential hybrid system owner. We present a comprehensive review of studies that examine the techno-economic feasibility of small-scale hybrid energy systems, and we find that the most common approach is to compare the annualized life-time costs to the expected energy output and choose the system with the lowest cost per output. While practical, this type of benefit—cost analysis misses out on other production and consumption decisions that are simultaneously made when adopting a hybrid energy system. In this paper, we propose a broader and more robust theoretical framework–based on production and utility theory–to illustrate how the production of renewable energy from multiple sources affects energy efficiency, energy services, and energy consumption choices in the residential sector. Finally, we discuss how the model can be applied to guide a hybrid-prosumer\u27s decision-making in the US residential sector. Examining hybrid renewable energy systems within a solid economic framework makes the study of hybrid energy more accessible to economists, facilitating interdisciplinary collaborations

Widespread mitochondrial depletion via mitophagy does not compromise necroptosis

Programmed necrosis (or necroptosis) is a form of cell death triggered by the activation of receptor interacting protein kinase-3 (RIPK3). Several reports have implicated mitochondria and mitochondrial reactive oxygen species (ROS) generation as effectors of RIPK3-dependent cell death. Here, we directly test this idea by employing a method for the specific removal of mitochondria via mitophagy. Mitochondria-deficient cells were resistant to the mitochondrial pathway of apoptosis, but efficiently died via tumor necrosis factor (TNF)-induced, RIPK3-dependent programmed necrosis or as a result of direct oligomerization of RIPK3. Although the ROS scavenger butylated hydroxyanisole (BHA) delayed TNF-induced necroptosis, it had no effect on necroptosis induced by RIPK3 oligomerization. Furthermore, although TNF-induced ROS production was dependent on mitochondria, the inhibition of TNF-induced necroptosis by BHA was observed in mitochondria-depleted cells. Our data indicate that mitochondrial ROS production accompanies, but does not cause, RIPK3-dependent necroptotic cell death

Limited mitochondrial permeabilisation causes DNA-damage and genomic instability in the absence of cell death

During apoptosis, the mitochondrial outer membrane is permeabilized, leading to the release of cytochrome c that activates downstream caspases. Mitochondrial outer membrane permeabilization (MOMP) has historically been thought to occur synchronously and completely throughout a cell, leading to rapid caspase activation and apoptosis. Using a new imaging approach, we demonstrate that MOMP is not an all-or-nothing event. Rather, we find that a minority of mitochondria can undergo MOMP in a stress-regulated manner, a phenomenon we term "minority MOMP." Crucially, minority MOMP leads to limited caspase activation, which is insufficient to trigger cell death. Instead, this caspase activity leads to DNA damage that, in turn, promotes genomic instability, cellular transformation, and tumorigenesis. Our data demonstrate that, in contrast to its well-established tumor suppressor function, apoptosis also has oncogenic potential that is regulated by the extent of MOMP. These findings have important implications for oncogenesis following either physiological or therapeutic engagement of apoptosis

Liver retransplantation as a therapeutic method in graft dysfunctions in the immediate postoperative period

Departament Chirurgie Generală, I.C. Fundeni, București, România, Al XIII-lea Congres al Asociației Chirurgilor „Nicolae Anestiadi” și al III-lea Congres al Societății de Endoscopie, Chirurgie miniminvazivă și Ultrasonografie ”V.M.Guțu” din Republica MoldovaCu toate că în ultimii ani au apărut progrese importante în domeniul hepatic, problema prevenirii apariției disfuncției și eșecului post-transplant nu a prezentat progrese semnificative. Intrucât disfuncția hepatică primară influențează dramatic evoluția grefei și a pacientului transplantat hepatic, prevenirea acestui fenomen devine obligatoriu. Creșterea penuriei de organe și a numărului persoanelor aflate pe lista de așteptare a dus la folosirea unor grefe ce depășesc criteriile normale de selecție pentru recoltare precum și transplantarea unor donatori considerați marginali. Aceste circumstanțe au adus în prim plan importanța diagnosticării și tratamentului disfuncției hepatice primare. Conceptul de disfuncție hepatică primară nu este clar definit. Există un spectru de evenimente ce definesc disfuncția hepatică postoperatorie precoce: non funcția primară (PNF), nonfuncția întârziată, funcția slabă/săracă inițială (initial poor function – IPF), non funcția inițială, insuficiența hepatică primară și disfuncția primară. Distincția între aceste entități ia în considerare gradul disfuncției hepatice, necesitatea retransplantării urgente, precum și apariția și durata acestor evenimente după transplantul hepatic.Although important progress has been made over the last few years, the problem of preventing dysfunction and post-transplant liver failure has not shown significant progress. Since primary liver dysfunction dramatically influences the progress of the graft and the liver transplant patient, prevention of this phenomenon becomes obligatory. The increase in organ shortage and the number of people on the waiting list led to the use of grafts that exceeded the normal selection criteria for harvesting as well as the transplantation of marginal donors. These circumstances have highlighted the importance of diagnosis and treatment of primary hepatic dysfunction. The concept of primary liver dysfunction is not clearly defined. There is a spectrum of events that defines early postoperative liver dysfunction: primary non-function (PNF), delayed dysfunction, initial poor function (IPF), primary hepatic failure, and primary dysfunction. The distinction between these entities takes into account the degree of hepatic dysfunction, the need for urgent retransplantation, and the occurrence and duration of these events after liver transplantation

Mitochondrial permeabilization engages NF-kappa B-dependent anti-tumour activity under caspase deficiency

Apoptosis represents a key anti-cancer therapeutic effector mechanism. During apoptosis, mitochondrial outer membrane permeabilization (MOMP) typically kills cells even in the absence of caspase activity. Caspase activity can also have a variety of unwanted consequences that include DNA damage. We therefore investigated whether MOMP-induced caspase-independent cell death (CICD) might be a better way to kill cancer cells. We find that cells undergoing CICD display potent pro-inflammatory effects relative to apoptosis. Underlying this, MOMP was found to stimulate NF-κB activity through the downregulation of inhibitor of apoptosis proteins. Strikingly, engagement of CICD displays potent anti-tumorigenic effects, often promoting complete tumour regression in a manner dependent on intact immunity. Our data demonstrate that by activating NF-κB, MOMP can exert additional signalling functions besides triggering cell death. Moreover, they support a rationale for engaging caspase-independent cell death in cell-killing anti-cancer therapies

Nuclear receptor NR2F6 inhibition potentiates responses to PD-L1/PD-1 cancer immune checkpoint blockade

Immune checkpoints blockade (ICB) is a viable anti-cancer strategy. Here the authors show that nuclear receptor NR2F6 acts as an immune checkpoint in T cells and, using mouse models and human T cells, they show NR2F6 inhibition might improve current ICB therapy or work as an alternative therapeutic strategy

Let-7 MicroRNA Family Is Selectively Secreted into the Extracellular Environment via Exosomes in a Metastatic Gastric Cancer Cell Line

Background: Exosomes play a major role in cell-to-cell communication, targeting cells to transfer exosomal molecules including proteins, mRNAs, and microRNAs (miRNAs) by an endocytosis-like pathway. miRNAs are small noncoding RNA molecules on average 22 nucleotides in length that regulate numerous biological processes including cancer pathogenesis and mediate gene downregulation by targeting mRNAs to induce RNA degradation and/or interfering with translation. Recent reports imply that miRNAs can be stably detected in circulating plasma and serum since miRNAs are packaged by exosomes to be protected from RNA degradation. Thus, profiling exosomal miRNAs are in need to clarify intercellular signaling and discover a novel disease marker as well. Methodology/Principal Findings: Exosomes were isolated from cultured cancer cell lines and their quality was validated by analyses of transmission electron microscopy and western blotting. One of the cell lines tested, a metastatic gastric cancer cell line, AZ-P7a, showed the highest RNA yield in the released exosomes and distinctive shape in morphology. In addition, RNAs were isolated from cells and culture media, and profiles of these three miRNA fractions were obtained using microarray analysis. By comparing signal intensities of microarray data and the following validation using RT-PCR analysis, we found that let-7 miRNA family was abundant in both the intracellular and extracellular fractions from AZ-P7a cells, while low metastatic AZ-521, the parental cell line of AZ-P7a, as well as other cancer cell lines showed no such propensity. Conclusions/Significance: The enrichment of let-7 miRNA family in the extracellular fractions, particularly, in the exosome