Does Immune Signaling Contribute to PARP inhibitor induced Synthetic Lethality?

https://openworks.mdanderson.org/sumexp21/1192/thumbnail.jp

Az intellektuális tőke mérésének és értékelésének különválasztása értékelő függvények alkalmazásával

A tanulmány alapgondolata az intellektuális tőke mérésének és értékelésének különválasztása értékelő és abból származtatott hasznosság függvények alkalmazásával az intellektuális tőkeelemek mutatószámrendszer alapú méréseiből kiindulva. A szerzők megközelítése lehetővé teszi, hogy a mérőrendszer által szolgáltatott mértékeket felülértékeljék a vállalat értékrendjét megtestesítő értékelő függvények segítségével. Ez utóbbi paramétereinek megfelelő kalibrálásával a vállalat intellektuális tőkeelemekre vonatkozó preferenciái jutnak kifejezésre, ezért a felülértékelés eredményeként az intellektuális tőkeelemek vállalati értékének egy jobb közelítését eredményezik

Vacuum-ultraviolet photolysis of non-steroidal anti-inflammatory drugs

Non-steroidal anti-inflammatory drugs (NSAIDs) ibuprofen, ketoprofen, diclofenac and naproxen are detected even in natural waters. Their degradation was achieved through the generation of reactive oxygen containing species (ROS, such as *OH, 1102* and •O2’) by using a xenon excimer lamp (Xmax. = 172 ± 14 nm). The effect of the initial drug concentration, dissolved molecular oxygen, methanol as *OH scavenger and the effect of these pharmaceuticals on each other were investigated. According to the results, not only the reactions based on *OH, but the reactions with other ROS and excited water molecules should also be taken under consideration for the interpretation of the transformation of the four investigated NSAIDs

The effect of the simultaneous presence of four non-steroidal anti-inflammatory drugs during the vacuum ultraviolet photolysis

Non-steroidal anti-inflammatory drugs (NSAIDs) are somewhat recently recognized pollutants, which are widely used by the society. Their sources in natural waters are the domestic and industrial effluents. Moreover, their possible interference with the water cycle and concurrent effects on the human health system has been implicated. Advanced oxidation processes (AOPs) could help to solve this problem as alternative methods, which are based on the generation of reactive radicals to induce the transformation of organic contaminants beside biological methods, which are often ineffective for this purpose. Vacuum ultraviolet (VUV) photolysis is a suitable method among AOPs to study the effects of different parameters on the radical set and on the degradation of organic contaminants, since the generated radical set is well-known. In this study, we aimed to investigate the simultaneous determination of pharmaceuticals (four non-steroidal anti-inflammatory drugs), namely ibuprofen, ketoprofen, naproxen and diclofenac. In this work we examined the degradation of compounds simultaneously, as wastewaters generally are multi-component solutions, where the components can effect the rate of decomposition of each other due to the competition for the reactive radicals. The pairing of the binary compounds in solution were ibuprofen+naproxen and ketoprofen+diclofenac, in order to be able to separate them by liquid chromatography. The results show that under the applied conditions (photon flux an initial concentration) the rates of the simultaneous degradation were slightly lower than in cases of one-component solutions because of the competition of the pharmaceuticals for the reactive species as we expected, however the influence of the competition was minor

Toxicology Aspects of the Decomposition of Diuron by Advanced Oxidation Processes

Diuron is a phenylurea-based residual herbicide with toxic and endocrine disrupting effects. The aims of the present work were the comparison of the efficiency of various advanced oxidation processes, such as direct ultraviolet photolysis, ozonation, their combination, and heterogeneous photocatalysis from the point of view of the transformation rate of diuron, rate of mineralisation and dehalogenation, formation of aromatic intermediates, and ecotoxicological effects of the formed multicomponent solutions during the treatments. The initial rates of transformation of diuron are in the order of ozonation < heterogeneous photocatalysis < UV photolysis < combination of UV photolysis and ozonation. Each method provided similar tendencies in the decrease of the concentration of organically bound chlorines (AOX) since, until the diuron was completely degraded, the concentration of AOX decreased almost to zero in each case. However, only heterogeneous photocatalysis was found to be effective in terms of mineralisation. Ecotoxicological results showed that in each case, except for ozonation, the toxicity of the treated solutions changed through a maximum during the transformation of diuron. The maximum value was found to be lower in the case of heterogeneous photocatalysis. Thus, the formation and decomposition of by-products of relatively higher toxicity than diuron can be supposed. Our results confirmed that the amount of the formed (aromatic) intermediates, their quality and specific toxicity strongly depend on the applied processes

The anti-inflammatory effect of dimethyl trisulfide in experimental acute pancreatitis

Various organosulfur compounds, such as dimethyl trisulfide (DMTS), display anti-inflammatory properties. We aimed to examine the effects of DMTS on acute pancreatitis (AP) and its mechanism of action in both in vivo and in vitro studies. AP was induced in FVB/n mice or Wistar rats by caerulein, ethanol-palmitoleic acid, or L-ornithine-HCl. DMTS treatments were administered subcutaneously. AP severity was assessed by pancreatic histological scoring, pancreatic water content, and myeloperoxidase activity measurements. The behaviour of animals was followed. Pancreatic heat shock protein 72 (HSP72) expression, sulfide, and protein persulfidation were measured. In vitro acinar viability, intracellular Ca 2+ concentration, and reactive oxygen species production were determined. DMTS dose-dependently decreased the severity of AP. It declined the pancreatic infiltration of leukocytes and cellular damage in mice. DMTS upregulated the HSP72 expression during AP and elevated serum sulfide and low molecular weight persulfide levels. DMTS exhibited cytoprotection against hydrogen peroxide and AP-inducing agents. It has antioxidant properties and modulates physiological but not pathophysiological Ca 2+ signalling. Generally, DMTS ameliorated AP severity and protected pancreatic acinar cells. Our findings indicate that DMTS is a sulfur donor with anti-inflammatory and antioxidant effects, and organosulfur compounds require further investigation into this potentially lethal disease

The Mitochondrion-lysosome Axis in Adaptive and Innate Immunity: Effect of Lupus Regulator Peptide P140 on Mitochondria Autophagy and NETosis

Mitochondria deserve special attention as sensors of cellular energy homeostasis and metabolic state. Moreover, mitochondria integrate intra- and extra-cellular signals to determine appropriate cellular responses that range from proliferation to cell death. In autoimmunity, as in other inflammatory chronic disorders, the metabolism of immune cells may be extensively remodeled, perturbing sensitive tolerogenic mechanisms. Here, we examine the distribution and effects of the therapeutic 21-mer peptide called P140, which shows remarkable efficacy in modulating immune responses in inflammatory settings. We measured P140 and control peptide effects on isolated mitochondria, the distribution of peptides in live cells, and their influence on the levels of key autophagy regulators. Our data indicate that while P140 targets macro- and chaperone-mediated autophagy processes, it has little effect, if any, on mitochondrial autophagy. Remarkably, however, it suppresses NET release from neutrophils exposed to immobilized NET-anti-DNA IgG complexes. Together, our results suggest that in the mitochondrion-lysosome axis, a likely driver of NETosis and inflammation, the P140 peptide does not operate by affecting mitochondria directly

The m.13051G>A mitochondrial DNA mutation results in variable neurology and activated mitophagy.

Maternally inherited mitochondrial DNA (mtDNA) mutations cause symptoms of Leber hereditary optic neuropathy (LHON) in -1 in 30,000 individuals. Most of the affected individuals lack respiratory chain defects1 and there is no proven prophylactic treatment

Dysregulated mitophagy and mitochondrial organization in optic atrophy due to OPA1 mutations

Objective: To investigate mitophagy in 5 patients with severe dominantly inherited optic atrophy (DOA), caused by depletion of OPA1 (a protein that is essential for mitochondrial fusion), compared with healthy controls. Methods: Patients with severe DOA (DOA plus) had peripheral neuropathy, cognitive regression, and epilepsy in addition to loss of vision. We quantified mitophagy in dermal fibroblasts, using 2 high throughput imaging systems, by visualizing colocalization of mitochondrial fragments with engulfing autophagosomes. Results: Fibroblasts from 3 biallelic OPA1(2/2) patients with severe DOA had increased mitochondrial fragmentation and mitochondrial DNA (mtDNA)–depleted cells due to decreased levels of OPA1 protein. Similarly, in siRNA-treated control fibroblasts, profound OPA1 knockdown caused mitochondrial fragmentation, loss of mtDNA, impaired mitochondrial function, and mitochondrial mislocalization. Compared to controls, basal mitophagy (abundance of autophagosomes colocalizing with mitochondria) was increased in (1) biallelic patients, (2) monoallelic patients with DOA plus, and (3) OPA1 siRNA–treated control cultures. Mitophagic flux was also increased. Genetic knockdown of the mitophagy protein ATG7 confirmed this by eliminating differences between patient and control fibroblasts. Conclusions: We demonstrated increased mitophagy and excessive mitochondrial fragmentation in primary human cultures associated with DOA plus due to biallelic OPA1 mutations. We previously found that increased mitophagy (mitochondrial recycling) was associated with visual loss in another mitochondrial optic neuropathy, Leber hereditary optic neuropathy (LHON). Combined with our LHON findings, this implicates excessive mitochondrial fragmentation, dysregulated mitophagy, and impaired response to energetic stress in the pathogenesis of mitochondrial optic neuropathies, potentially linked with mitochondrial mislocalization and mtDNA depletion