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Sufficient information is the foundation for efficient and high-quality health care services. In the field of extramural health care, this challenge is particularly evident: missing or insufficient information can lead to underuse, overuse, or misuse of health care, e.g. due to the necessity of multiple assessments or lack of relevant information. The noticeable shortage of health care professionals further underscores the urgent need for efficient and quality-assured health care services. The aim of the project LICA - linked care - is to provide a platform for better coordination and information exchange between health professionals involved in home care, with a focus on ICT in nursing in Austria. The project is funded by the Austrian Research Promotion agency (FFG) as part of the “benefit - demografischer Wandel als Chance” program (April 2020-March 2025). The requirement analysis was conducted from April to December 2021. In light of the user-centered approach a mix of methods was chosen, consisting of: literature analysis, 5 guideline-based focus group interviews, guideline-based expert interviews n = 44 (people in need of care n = 23, health professionals n = 21), documentation-analysis (4 care documentation systems - from participating project partners) and working diaries: n = 5 on 5 consecutive working days (=25 diaries). Therefore, three main target groups were identified: i) people in need of care, ii) healthcare professionals and iii) healthcare providers. The data were analyzed using a qualitative content analysis based on Kuckartz. The main results regarding the status quo are: i) different documentation systems are utilized, ii) lack of digitized documents, iii) currently no standardized documentation system is in use. Thus, following requirements could be identified: i) interoperability with existing systems, ii) setting comprehensive function, iii) usability, iv) interdisciplinary readability, v) error-management, and vi) proper data protection measures. Key messages • Healthcare systems are under great pressure worldwide. Innovative solutions can help maintain and improve the quality and efficacy of healthcare services. • Gapless and efficient information provision is a key essential to high quality healthcare. The project offers a user-centric approach to develop a platform for connectivity of existing systems.

Orthogonal Frequency-Division Multiplexing with Random multiple access (OFDRMA) is discussed for uplink communications, whereby several active users send information towards a single base-station (BS), while all other users are dormant. Originally, uplink communication methods included sharing the frequency resources among the active users in an orthogonal fashion, i.e., a central unit is required to dynamically allocate the resources. More recently, non-orthogonal methods have arisen, meaning that several active users share the same frequency bins, but they still do require a central unit to dynamically allocate the resources in a uniform (as possible) manner over the available bandwidth. The task and overhead required for managing the frequency allocations among the users can be quite cumbersome. In OFDRMA, the frequency allocations for any user are independent of the frequency allocations for the other users, and independent of which of the other users are currently active. Rather, OFDRMA relies on random, yet predetermined, allocation of frequency bins for each user, known only to that user and the BS. A multi-user detection approach is presented based on a graphical representation of the system. It is shown to provide robustness against the forced randomness of the scheme. Capacity of OFDRMA and its optimization are analyzed and provided in detail. Simulation results are provided for demonstrating the performance attainable with OFDRMA and the proposed detection scheme. Both the capacity and the simulations are compared with modern multi-user multiple-input multiple-output (MU-MIMO) schemes.

Nevus comedonicus (NC) is a rare type of organoid epidermal nevus with comedones and inflammatory cysts 1 . It may be associated with extracutaneous manifestations (cataract, neurological and skeletal anomalies), defining NC syndrome 2 . Acne nevus, a clinically similar mosaic skin condition, is related to FGFR2, whereas postzygotic NEK9 mutations have been identified in four NC patients so far, including only one with NC syndrome 3 4 . Here we report on novel clinical findings, fibrous dysplasia and premature puberty in a case of NC syndrome associated with a NEK9 mutation.

Oxidation of docosahexaenoate (DHA)-containing phospholipids in the cell plasma membrane leads to release of the α,β-unsaturated aldehyde 4-hydroxy-7-oxo-5-heptenoic acid (HOHA) lactone which is capable of inducing retinal pigmented epithelial (RPE) cell dysfunction. Previously, HOHA lactone was shown to induce apoptosis and angiogenesis, and to activate the alternative complement pathway. RPE cells metabolize HOHA lactone through enzymatic conjugation with glutathione (GSH). Competing with this process is the adduction of HOHA lactone to protein lysyl residues generating 2-(ω-carboxyethyl)pyrrole (CEP) derivatives that have pathological relevance to age-related macular degeneration (AMD). We now find that HOHA lactone induces mitochondrial dysfunction. It decreases ATP levels, mitochondrial membrane potentials, enzymatic activities of mitochondrial complexes, depletes GSH and induces oxidative stress in RPE cells. The present study confirmed that pyridoxamine and other primary amines, which have been shown to scavenge γ-ketoaldehydes formed by carbohydrate or lipid peroxidation, are ineffective for scavenging the α,β-unsaturated aldehydes. Histidyl hydrazide (HH), that has both hydrazide and imidazole nucleophile functionalities, is an effective scavenger of HOHA lactone and it protects ARPE-19 cells against HOHA lactone-induced cytotoxicity. The HH α-amino group is not essential for this electrophile trapping activity. The Nα-acyl L-histidyl hydrazide derivatives with 2- to 7-carbon acyl groups with increasing lipophilicities are capable of maintaining the effectiveness of HH in protecting ARPE-19 cells against HOHA lactone toxicity, which potentially has therapeutic utility for treatment of age related eye diseases.

Orthogonal Frequency-Division Multiplexing with Random multiple access (OFDRMA) is discussed for uplink communications, whereby several active users send information towards a single base-station (BS), while all other users are dormant. Originally, uplink communication methods included sharing the frequency resources among the active users in an orthogonal fashion, i.e., a central unit is required to dynamically allocate the resources. More recently, non-orthogonal methods have arisen, meaning that several active users share the same frequency bins, but they still do require a central unit to dynamically allocate the resources in a uniform (as possible) manner over the available bandwidth. The task and overhead required for managing the frequency allocations among the users can be quite cumbersome. In OFDRMA, the frequency allocations for any user are independent of the frequency allocations for the other users, and independent of which of the other users are currently active. Rather, OFDRMA relies on random, yet predetermined, allocation of frequency bins for each user, known only to that user and the BS. A multi-user detection approach is presented based on a graphical representation of the system. It is shown to provide robustness against the forced randomness of the scheme. Capacity of OFDRMA and its optimization are analyzed and provided in detail. Simulation results are provided for demonstrating the performance attainable with OFDRMA and the proposed detection scheme. Both the capacity and the simulations are compared with modern multi-user multiple-input multiple-output (MU-MIMO) schemes.

SUMMARY Retinal degeneration is a form of neurodegenerative disease and is the leading cause of vision loss globally. The Toll-like receptors (TLRs) are primary components of the innate immune system involved in signal transduction. Here we show that TLR2 induces complement factors C3 and CFB, the common and rate-limiting factors of the alternative pathway in both retinal pigment epithelial (RPE) cells and mononuclear phagocytes. Neutralization of TLR2 reduces opsonizing fragments of C3 in the outer retina and protects photoreceptor neurons from oxidative stress-induced degeneration. TLR2 deficiency also preserves tight junction expression and promotes RPE resistance to fragmentation. Finally, oxidative stress-induced formation of the terminal complement membrane attack complex and Iba1+ cell infiltration are strikingly inhibited in the TLR2-deficient retina. Our data directly implicate TLR2 as a mediator of retinal degeneration in response to oxidative stress and present TLR2 as a bridge between oxidative damage and complement-mediated retinal pathology., Graphical Abstract, In Brief Oxidative stress and complement deposition are common to many retinal degenerative diseases. Mulfaul et al. demonstrate that TLR2 blockade protects against photoreceptor neuronal cell death and RPE fragmentation in experimental models of oxidative stress-induced retinal degeneration and present TLR2 as a bridge between oxidative damage and complement-mediated retinal pathology.

Previously, we discovered that free radical-induced oxidative fragmentation of the docosahexaenoate ester of 2-lysophosphatidylcholine produces 4-hydroxy-7-oxo-5-heptenoic acid (HOHA) lactone that, in turn, promotes the migration and invasion of endothelial cells. This suggested that HOHA lactone might similarly promote migration and invasion of glioblastoma multiformae (GBM) brain cancer stem cells (CSCs). A bioinformatics analysis of clinical cancer genomic data revealed that matrix metalloproteinase (MMP)1 and three markers of oxidative stress - superoxide dismutase 2, NADPH oxidase 4, and carbonic anhydrase 9 - are upregulated in human mesenchymal GBM cancer tissue, and that MMP1 is positively correlated to all three of these oxidative stress markers. In addition, elevated levels of MMP1 are indicative of GBM invasion, while low levels of MMP1 indicate survival. We also explored the hypothesis that the transition from the proneural to the more aggressive mesenchymal phenotype, e.g., after treatment with an anti-angiogenic therapy, is promoted by the effects of lipid oxidation products on GBM CSCs. We found that low micromolar concentrations of HOHA lactone increase the cell migration velocity of cultured GBM CSCs, and induce the expression of MMP1 and two protein biomarkers of the proneural to mesenchymal transition (PMT): p65 NF-κβ and vimentin. Exposure of cultured GBM CSCs to HOHA lactone causes an increase in phosphorylation of mitogen-activated protein kinases and Akt kinases that are dependent on both protease-activated receptor 1 (PAR1) and MMP1 activity. We conclude that HOHA lactone promotes the PMT in GBM through the activation of PAR1 and MMP1. This contributes to a fatal flaw in antiangiogenic, chemo, and radiation therapies: they promote oxidative stress and the generation of HOHA lactone in the tumor that fosters a change from the proliferative proneural to the migratory mesenchymal GBM CSC phenotype that seeds new tumor growth. Inhibition of PAR1 and HOHA lactone are potential new therapeutic targets for impeding GBM tumor recurrence.

Im Rahmen der Primardiagnostik des Prostatakarzinoms (PCA) vollzieht sich derzeit ein Paradigmenwechsel von der systematischen Stanzbiopsie mit der Magnetresonanztomographie (MRT) als Problemloser hin zum flachendeckenden Einsatz der MRT vor Biopsie mit dem Einsatz von Fusionsverfahren zur gezielten Biopsie von Prostatalasionen. Damit verliert das PCA die letzte Bastion eines soliden Tumors, der durch ungezielte Biopsien primar diagnostiziert wird und reiht sich in die anderen soliden Tumoren ein, welche ebenfalls durch gezielte bildgebende Verfahren vor bioptischer Sicherung lokalisiert werden. Die Komplexitat des Hintergrundsignals der Prostata macht jedoch die Lokalisation zu einem nicht trivialen Unterfangen, daher soll in diesem Artikel ein Uberblick uber die multiparametrische MRT und ihre strukturierte Befundung anhand des PI-RADSv2-Systems („prostate imaging reporting and data system version 2“) sowie neue Ultraschallverfahren zur Primardiagnostik gegeben werden.

Retinal pigment epithelial (RPE) cell dysfunction and death play vital roles in age-related macular degeneration (AMD) pathogenesis. Previously we showed that oxidative cleavage of docosahexenoate (DHA) phospholipids generates an α,β-unsaturated aldehyde, 4-hydroxy-7-oxohept-4-enoic acid (HOHA) lactone, that forms ω-carboxyethylpyrrole (CEP) derivatives through adduction to proteins and ethanolamine phospholipids. CEP derivatives and autoantibodies accumulate in the retinas and blood plasma of individuals with AMD and are a biomarker of AMD. They promote the choroidal neovascularization of “wet AMD”. Immunization of mice with CEP-modified mouse serum albumin induces “dry AMD”-like lesions in their retinas as well as interferon-gamma and interleukin-17 production by CEP-specific T cells that promote inflammatory M1 polarization of macrophages. The present study confirms that oxidative stress or inflammatory stimulus produces CEP in both the primary human ARPE-19 cell line and hRPE cells. Exposure of these cells to HOHA lactone fosters production of reactive oxygen species. Thus, HOHA lactone participates in a vicious cycle, promoting intracellular oxidative stress leading to oxidative cleavage of DHA to produce more HOHA lactone. We now show that HOHA lactone is cytotoxic, inducing apoptotic cell death through activation of the intrinsic pathway. This suggests that therapeutic interventions targeting HOHA lactone-induced apoptosis may prevent the loss of RPE cells during the early phase of AMD. We also discovered that ARPE-19 cells are more susceptible than hRPE cells to HOHA lactone cytotoxicity. This is consistent with the view that, compared to normal RPE cells, ARPE-19 cells exhibit a diseased RPE phenotype that also includes elevated expression of the mesenchymal indicator vimentin, elevated integrin a5 promotor strength and deficient secretion of the anti-VEGF molecule pigment-epithelium-derived factor fostering weaker tight junctions.

Early stages of inflammation are characterized by extensive oxidative insult by recruited and activated neutrophils. Secretion of peroxidases, including the main enzyme, myeloperoxidase, leads to the generation of reactive oxygen species. We show that this oxidative insult leads to polyunsaturated fatty acid (eg, docosahexaenoate), oxidation, and accumulation of its product 2-(ω-carboxyethyl)pyrrole (CEP), which, in turn, is capable of protein modifications. In vivo CEP is generated predominantly at the inflammatory sites in macrophage-rich areas. During thioglycollate-induced inflammation, neutralization of CEP adducts dramatically reduced macrophage accumulation in the inflamed peritoneal cavity while exhibiting no effect on the early recruitment of neutrophils, suggesting a role in the second wave of inflammation. CEP modifications were abundantly deposited along the path of neutrophils migrating through the 3-dimensional fibrin matrix in vitro. Neutrophil-mediated CEP formation was markedly inhibited by the myeloperoxidase inhibitor, 4-ABH, and significantly reduced in myeloperoxidase-deficient mice. On macrophages, CEP adducts were recognized by cell adhesion receptors, integrin αMβ2 and αDβ2 Macrophage migration through CEP-fibrin gel was dramatically augmented when compared with fibrin alone, and was reduced by β2-integrin deficiency. Thus, neutrophil-mediated oxidation of abundant polyunsaturated fatty acids leads to the transformation of existing proteins into stronger adhesive ligands for αMβ2- and αDβ2-dependent macrophage migration. The presence of a carboxyl group rather than a pyrrole moiety on these adducts, resembling characteristics of bacterial and/or immobilized ligands, is critical for recognition by macrophages. Therefore, specific oxidation-dependent modification of extracellular matrix, aided by neutrophils, promotes subsequent αMβ2- and αDβ2-mediated migration/retention of macrophages during inflammation.

We previously discovered that oxidative cleavage of docosahexaenoate (DHA), which is especially abundant in the retinal photoreceptor rod outer segments and retinal pigmented endothelial (RPE) cells, generates 4-hydroxy-7-oxo-5-heptenoate (HOHA) lactone, and that HOHA lactone can enter RPE cells that metabolize it through conjugation with glutathione (GSH). The consequent depletion of GSH results in oxidative stress. We now find that HOHA-lactone induces upregulation of the antioxidant transcription factor Nrf2 in ARPE-19 cells. This leads to expression of GCLM, HO1, and NQO1, three known Nrf2-responsive antioxidant genes. Besides this protective response, HOHA lactone also triggers a countervailing inflammatory activation of innate immunity. Evidence for a contribution of the complement pathway to age-related macular degeneration (AMD) pathology includes the presence of complement proteins in drusen and Bruch’s membrane from AMD donor eyes, and the identification of genetic susceptibility loci for AMD in the complement pathway. In eye tissues from a mouse model of AMD, accumulation of complement protein in Bruch’s membrane below the RPE suggested that the complement pathway targets this interface where lesions occur in the RPE and photoreceptor rod outer segments. In animal models of AMD, intravenous injection of NaIO(3) to induce oxidative injury selectively destroys the RPE, and causes secretion of factor C3 from the RPE into areas directly adjacent to sites of RPE damage. However, a molecular level link between oxidative injury and complement activation remained elusive. We now find that submicromolar concentrations of HOHA lactone foster expression of C3, CFB and C5 in ARPE-19 cells, and induce a countervailing upregulation of CD55, an inhibitor of C3 convertase production and complement cascade amplification. Ultimately, HOHA lactone causes membrane attack complex formation on the plasma membrane. Thus, HOHA lactone provides a molecular level connection between free radical-induced oxidative cleavage of DHA and activation of the complement pathway in AMD pathology.

Xeroderma pigmentosum (XP) is an orphan disease of poor prognosis. We report one case of parallel efficacy with anti-programmed cell death-1 (PD-1) antibody on both melanoma and skin carcinoma in a patient with XP. A 17-year-old patient presented with metastatic melanoma and multiple nonmelanoma skin cancers. He was treated with pembrolizumab, a monoclonal anti-PD-1 antibody, at a dose of 2 mg kg-1 , every 3 weeks. Parallel therapeutic efficacy of anti-PD-1 was observed in metastatic melanoma and skin carcinomas, and maintained at week 24. This observation suggests anti-PD-1 may be considered in patients with XP and metastatic melanoma in addition to advanced nonmelanoma skin cancer.

CAG/CTG trinucleotide repeat expansions cause several degenerative neurological and muscular diseases. Koch et al. show that the chromatin remodeling..., CAG/CTG trinucleotide repeats are unstable sequences that are difficult to replicate, repair, and transcribe due to their structure-forming nature. CAG repeats strongly position nucleosomes; however, little is known about the chromatin remodeling needed to prevent repeat instability. In a Saccharomyces cerevisiae model system with CAG repeats carried on a YAC, we discovered that the chromatin remodeler Isw1 is required to prevent CAG repeat expansions during transcription. CAG repeat expansions in the absence of Isw1 were dependent on both transcription-coupled repair (TCR) and base-excision repair (BER). Furthermore, isw1∆ mutants are sensitive to methyl methanesulfonate (MMS) and exhibit synergistic MMS sensitivity when combined with BER or TCR pathway mutants. We conclude that CAG expansions in the isw1∆ mutant occur during a transcription-coupled excision repair process that involves both TCR and BER pathways. We observed increased RNA polymerase II (RNAPII) occupancy at the CAG repeat when transcription of the repeat was induced, but RNAPII binding did not change in isw1∆ mutants, ruling out a role for Isw1 remodeling in RNAPII progression. However, nucleosome occupancy over a transcribed CAG tract was altered in isw1∆ mutants. Based on the known role of Isw1 in the reestablishment of nucleosomal spacing after transcription, we suggest that a defect in this function allows DNA structures to form within repetitive DNA tracts, resulting in inappropriate excision repair and repeat-length changes. These results establish a new function for Isw1 in directly maintaining the chromatin structure at the CAG repeat, thereby limiting expansions that can occur during transcription-coupled excision repair.

Purpose The current study aimed to develop a three-dimensional (3D) dynamic oxygen-17 (17O) MR imaging method with high temporal and spatial resolution to delineate the kinetics of 17O water uptake and washout in the brains of mice with glioblastoma (GBM). Methods A 3D imaging method with a stack-of-stars golden-ratio–based radial sampling scheme was employed to acquire 17O signal in vivo. A k-space–weighted image reconstruction method was used to improve the temporal resolution while preserving spatial resolution. Simulation studies were performed to validate the method. Using this method, the kinetics of 17O water uptake and washout in the brains of mice with GBM were delineated after an intravenous bolus injection of 17O water. Results The proposed 17O imaging method achieved an effective temporal resolution of 7.56 s with a nominal voxel size of 5.625 μL in the mouse brain at 9.4 T. Reduced uptake and prolonged washout of 17O water were observed in tumor tissue, suggesting compromised cerebral perfusion. Conclusion This study demonstrated a promising dynamic 17O imaging approach that can delineate 17O water kinetics in vivo with high temporal and spatial resolution. It can also be used to image cerebral oxygen consumption rate in oxygen-17 inhalation studies. Magn Reson Med, 2017. © 2017 International Society for Magnetic Resonance in Medicine.

To investigate the predictors of recurrence and of de novo incontinence in patients treated by transurethral incision or resection for vesico-urethral anastomotic stenosis (VUAS) after radical prostatectomy.All patients undergoing endoscopic treatment for VUAS between March 2009 and October 2016 were identified in our multi-institutional database. Digital chart reviews were performed and patients contacted for follow-up. Recurrence was defined as any need for further instrumentation or surgery, and de-novo-incontinence as patient-reported outcome.Of 103 patients undergoing endoscopic VUAS treatment, 67 (65%) underwent transurethral resection (TR) and 36 (35%) transurethral incision (TI). TI was performed more frequently as primary treatment compared to TR (58% vs. 37%; p = 0.041). Primary and repeated treatment was performed in 46 (45%) and 57 patients (55%), respectively. Overall, 38 patients (37%) had a history of radiation therapy. There was no difference in time to recurrence for primary vs repeat VUAS treatment, previous vs no radiation, TR compared to TI (all p 0.08). Regarding treatment success, no difference was found for primary vs. repeat VUAS treatment (50% vs. 37%), previous radiation vs. no radiation (42% vs. 43%), and TR vs. TI (37% vs. 53%; all p ≥ 0.1). Postoperative de novo incontinence was more common after TI vs. TR (31% vs. 12%; p = 0.032), no difference was observed for previous radiation therapy vs. no radiation therapy (18% vs. 18%; p 0.9) or primary vs. repeat VUAS treatment (22% vs. 16%; p = 0.5).VUAS recurrence after endoscopic treatment is not predictable. Endoscopic treatment with TI showed a higher risk for de novo incontinence than TR, and previous irradiation and the number of treatments do not influence incontinence.

Following definitive treatment with curative intent a subset of patients with prostate cancer experience biochemical recurrence. In these patients clinical parameters are mostly used to decide if a local or systemic disease recurrence is present. While salvage radiation treatment is advocated for local recurrence after radical prostatectomy, no standard recommendations exist in cases of local recurrence after primary radiation therapy although salvage prostatectomy may be considered. Imaging procedures have traditionally not routinely been recommended for the onset of prostate-specific antigen (PSA) relapse; however, prostate-specific membrane antigen (PSMA) positron emission tomography (PET) computed tomography (CT) exhibits high detection rates even at low PSA values. Thus, the current German guidelines state that PSMA PET/CT can be considered if this could result in a decisive change in further treatment management. Currently, a positive influence on oncological long-term outcome, however, has not yet been proven.

The initial diagnosis of prostate cancer has been traditionally performed using systematic core biopsies with the use of magnetic resonance imaging (MRI) reserved to problem-solving scenarios. There is currently an ongoing paradigm shift towards the use of MRI prior to targeted biopsy as the standard approach. Prostate cancer therefore does not remain the last solid tumor entity diagnosed by non-targeted techniques but joins other solid tumor entities for which targeted diagnostic approaches have existed for a while. However, the complexity of the background tissue signal in the prostate makes lesion detection challenging. This article will provide an overview of the components of multiparametric prostate MRI and their interpretation using structured interpretation according to the current PI-RADSv2 (Prostate Imaging Reporting and Data System version 2) guidelines and of novel ultrasound techniques for primary diagnosis.

Levuglandins (LG)D2 and LGE2 are γ-ketoaldehyde levulinaldehyde derivatives with prostanoid side chains produced by spontaneous rearrangement of the endoperoxide intermediate PGH2 in the biosynthesis of prostaglandins. Covalent adduction of LGs with the amyloid peptide Aβ1–42 promotes formation of the type of oligomers that have been associated with neurotoxicity and are a pathologic hallmark of Alzheimer’s disease. Within 1 min of their generation during the production of PGH2 by cyclooxygenation of arachidonic acid, LGs are sequestered by covalent adduction to proteins. In view of this high proclivity for covalent adduction, it is understandable that free LGs have never been detected in vivo. Recently a catabolite, believed to be an oxidized derivative of LGD2 (ox-LGD2), a levulinic acid hydroxylactone with prostanoid side chains, was isolated from the red alga Gracilaria edulis and detected in mouse tissues and in the lysate of phorbol-12-myristate-13-acetate-treated THP-1 cells incubated with arachido...

4-Hydroxy-7-oxo-5-heptenic acid (HOHA)-lactone is a biologically active oxidative truncation product released (t1/2 = 30 min at 37 °C) by non-enzymatic transesterification/deacylation from docosahexaenoate lipids. We now report that HOHA-lactone readily diffuses into retinal pigmented epithelial (RPE) cells where it is metabolized. A reduced glutathione (GSH) Michael adduct of HOHA-lactone is the most prominent metabolite detected by LC-MS in both the extracellular medium and cell lysates. This molecule appeared inside of ARPE-19 cells within seconds after exposure to HOHA-lactone. The intracellular level reached a maximum concentration at 30 min and then decreased with concomitant increases in its level in the extracellular medium, thus revealing a unidirectional export of the reduced GSH-HOHA-lactone adduct from the cytosol to extracellular medium. This metabolism is likely to modulate the involvement of HOHA-lactone in the pathogenesis of human diseases. HOHA-lactone is biologically active, e.g., low concentrations (0.1-1 μM) induce secretion of vascular endothelial growth factor (VEGF) from ARPE-19 cells. HOHA-lactone is also a precursor of 2-(ω-carboxyethyl)pyrrole (CEP) derivatives of primary amino groups in proteins and ethanolamine phospholipids that have significant pathological and physiological relevance to age-related macular degeneration (AMD), cancer and wound healing. Both HOHA-lactone and the derived CEP can contribute to the angiogenesis that defines the neovascular “wet” form of AMD and that promotes the growth of tumors. While GSH depletion can increase the lethality of radiotherapy, because it will impair the metabolism of HOHA-lactone, the present study suggests that GSH depletion will also increase levels of HOHA-lactone and CEP that may promote recurrence of tumor growth.

γ-Hydroxy-α,β-unsaturated aldehydes, generated by oxidative damage of polyunsaturated phospholipids, form pyrrole derivatives that incorporate the ethanolamine phospholipid (EP) amino group such as 2-pentylpyrrole (PP)-EP and 2-(ω-carboxyalkyl)pyrrole (CAP)-EP derivatives: 2-(ω-carboxyethyl)-pyrrole (CEP)-EP, 2-(ω-carboxypropyl)pyrrole (CPP)-EP, and 2-(ω-carboxyheptyl)pyrrole (CHP)-EP. Because EPs occur in vivo in various forms, a complex mixture of pyrrole-modified EPs with different molecular weights is expected to be generated. To provide a sensitive index of oxidative stress, all of the differences in mass related to the glycerophospholipid moieties were removed by releasing a single CAP-ethanolamine (ETN) or PP-ETN from each mixture by treatment with phospholipase D. Accurate quantization was achieved using the corresponding ethanolamine-d4 pyrroles as internal standards. The product mixture obtained by phospholipolysis of total blood phospholipids from sickle cell disease (SCD) patients, was analyzed by LC-MS/MS. The method was applied to measure CAP-EP and PP-EP levels in blood plasma from clinical monitoring of SCD patients. We found uniformly elevated blood levels of CEP-EP (63.9 ± 9.7 nM) similar to mean levels in blood from age-related macular degeneration (AMD) patients (56.3 ± 37.1 nM), two fold lower levels (27.6 ± 3.6 nM, n = 5) were detected in plasma from SCD patients hospitalized to treat a sickle cell crisis, although mean levels remain higher than those (12.1 ± 10.5 nM) detected in blood from healthy controls. Plasma levels of CPP-EPs from SCD clinic patients were four-fold higher than those of SCD patients hospitalized to treat a sickle cell crisis (45.1 ± 10.9 nM, n = 5 versus 10.9 ± 3.4 nM, n = 6; p < 0.002). PP-EP concentration in plasma from SCD clinic patients is nearly 4.8-fold higher than its level in plasma samples from SCD patients hospitalized to treat a sickle cell crisis (7.06 ± 4.05 vs 1.48 ± 0.92 nM; p < 0.05). Because CAP-EPs promote angiogenesis and platelet activation, the elevated levels present in SCD blood can contribute to the hypercoaguability and vaso-occlusive events that are critical pathophysiologic features of SCD.

Introduction L’eosinophile est produit dans la moelle osseuse sous l’influence de cytokines, en particulier l’interleukine 5 (IL5). Le syndrome hypereosinophilique (SHE) est defini par une hypereosinophilie sanguine > 1,5 G/L persistante, sans cause sous-jacente. La plupart des cohortes decrites proviennent de patients venant d’hematologie. Nous decrivons ici l’atteinte cutanee du SHE et la prise en charge therapeutique des patients en dermatologie. Materiel et methodes Etude retrospective monocentrique sur la periode 2011–2018. Resultats Vingt patients (14 H, 6 F), dont l’âge median au diagnostic etait de 74 ans, ont ete inclus. Le delai diagnostique median etait de 8 mois. L’eosinophilie sanguine moyenne au diagnostic etait de 7,1 G/L. Soixante-quinze pour cent des patients avaient un SHE idiopathique. Dix-neuf patients presentaient un prurit, de severite 8/10. Les lesions cutanees etaient polymorphes (eczematiformes, lichenoides, maculopapuleuses, angiooedeme, urticaire superficielle, prurigo, bulles, keratodermie palmoplantaire, erythrodermie, xerose, Fig. 1 ), avec souvent plusieurs types d’atteintes associes, et une predominance de lesions eczematiformes (65 %, Fig. 2 ). Dix patients avaient une atteinte cutanee isolee. Il n’y avait pas d’atteinte d’organe mettant en jeu le pronostic vital. Sur 54 biopsies cutanees, on notait des eosinophiles dans 74 % des cas. Une corticotherapie orale a ete initiee en monotherapie chez 13 patients, dont 62 % ont signale une reponse partielle ou complete a 3 mois. Elle a ete arretee chez 9 patients pour efficacite incomplete ou effets indesirables. L’hydroxyuree et le methotrexate ont ete les plus utilises en deuxieme ligne, avec une efficacite respective de 71 % et 80 % sur l’atteinte dermatologique. Discussion Les manifestations cutanees du SHE sont polymorphes, avec une predominance d’atteinte eczematiforme. Le prurit est tres present, mal supporte et resistant aux therapeutiques employees. Nos patients ont peu de manifestations extracutanees et nous n’avons pas note de formes graves, ce qui est different des cohortes hematologiques. La majorite des patients ont un SHE idiopathique, sous-type peu decrit car les donnees publiees concernent plutot les SHE myeloides ou lymphoides. L’hydroxyuree, conseillee en deuxieme ligne dans la litterature pour son efficacite sur l’atteinte hematologique, est une alternative utile en dermatologie. Conclusion Les patients avec SHE vus en dermatologie ont une presentation clinique polymorphe et le plus souvent un sous-type idiopathique. La corticotherapie generale peut permettre un soulagement rapide du prurit, mais doit etre remplacee tot par un traitement de fond type hydroxyuree afin de limiter les effets indesirables. Le mepolizumab, anticorps anti-IL5 ayant montre son efficacite sur l’atteinte hematologique en termes d’epargne cortisonique dans les formes non myeloides, represente un espoir pour ces patients.

Rationale: Oxidative stress is an important contributing factor in several human pathologies ranging from atherosclerosis to cancer progression; however, the mechanisms underlying tissue protection from oxidation products are poorly understood. Oxidation of membrane phospholipids, containing the polyunsaturated fatty acid docosahexaenoic acid, results in the accumulation of an end product, 2-(ω-carboxyethyl)pyrrole (CEP), which was shown to have proangiogenic and proinflammatory functions. Although CEP is continuously accumulated during chronic processes, such as tumor progression and atherosclerosis, its level during wound healing return to normal when the wound is healed, suggesting the existence of a specific clearance mechanism. Objective: To identify the cellular and molecular mechanism for CEP clearance. Methods and Results: Here, we show that macrophages are able to bind, scavenge, and metabolize carboxyethylpyrrole derivatives of proteins but not structurally similar ethylpyrrole derivatives, demonstrating the high specificity of the process. F4/80 hi and M2-skewed macrophages are much more efficient at CEP binding and scavenging compared with F4/80 lo and M1-skewed macrophages. Depletion of macrophages leads to increased CEP accumulation in vivo. CEP binding and clearance are dependent on 2 receptors expressed by macrophages, CD36 and toll-like receptor 2. Although knockout of each individual receptor results in diminished CEP clearance, the lack of both receptors almost completely abrogates macrophages’ ability to scavenge CEP derivatives of proteins. Conclusions: Our study demonstrates the mechanisms of recognition, scavenging, and clearance of pathophysiologically active products of lipid oxidation in vivo, thereby contributing to tissue protection against products of oxidative stress.

Significance: A diverse family of lipid-derived levulinaldehydes, isolevuglandins (isoLGs), is produced by rearrangement of endoperoxide intermediates generated through both cyclooxygenase (COX) and free radical-induced cyclooxygenation of polyunsaturated fatty acids and their phospholipid esters. The formation and reactions of isoLGs with other biomolecules has been linked to alcoholic liver disease, Alzheimer's disease, age-related macular degeneration, atherosclerosis, cardiac arythmias, cancer, end-stage renal disease, glaucoma, inflammation of allergies and infection, mitochondrial dysfunction, multiple sclerosis, and thrombosis. This review chronicles progress in understanding the chemistry of isoLGs, detecting their production in vivo and understanding their biological consequences. Critical Issues: IsoLGs have never been isolated from biological sources, because they form adducts with primary amino groups of other biomolecules within seconds. Chemical synthesis enabled investigation of isoLG chemistry and detection of isoLG adducts present in vivo. Recent Advances: The first peptide mapping and sequencing of an isoLG-modified protein present in human retina identified the modification of a specific lysyl residue of the sterol C27-hydroxylase Cyp27A1. This residue is preferentially modified by iso[4]LGE2 in vitro, causing loss of function. Adduction of less than one equivalent of isoLG can induce COX-associated oligomerization of the amyloid peptide Aβ1-42. Adduction of isoLGE2 to phosphatidylethanolamines causes gain of function, converting them into proinflammatory isoLGE2-PE agonists that foster monocyte adhesion to endothelial cells. Future Directions: Among the remaining questions on the biochemistry of isoLGs are the dependence of biological activity on isoLG isomer structure, the structures and mechanism of isoLG-derived protein–protein and DNA–protein cross-link formation, and its biological consequences. Antioxid. Redox Signal. 22, 1703–1718.

Early stages of inflammation are characterized by extensive oxidative insult by recruited and activated neutrophils. Secretion of peroxidases, including the main enzyme, myeloperoxidase, leads to the generation of reactive oxygen species. We show that this oxidative insult leads to polyunsaturated fatty acid (eg, docosahexaenoate), oxidation, and accumulation of its product 2-(ω-carboxyethyl)pyrrole (CEP), which, in turn, is capable of protein modifications. In vivo CEP is generated predominantly at the inflammatory sites in macrophage-rich areas. During thioglycollate-induced inflammation, neutralization of CEP adducts dramatically reduced macrophage accumulation in the inflamed peritoneal cavity while exhibiting no effect on the early recruitment of neutrophils, suggesting a role in the second wave of inflammation. CEP modifications were abundantly deposited along the path of neutrophils migrating through the 3-dimensional fibrin matrix in vitro. Neutrophil-mediated CEP formation was markedly inhibited by the myeloperoxidase inhibitor, 4-ABH, and significantly reduced in myeloperoxidase-deficient mice. On macrophages, CEP adducts were recognized by cell adhesion receptors, integrin α

The target of focal therapy (FT) in prostate cancer (PC) is partial treatment of the prostate aiming at preserving surrounding anatomical structures. The intention is to minimize typical side effects of radical treatment options combined with local tumor control. Numerous established and new technologies are used. Results of published studies showed a good safety profile, few side effects and good preservation of functional results. Oncologic long-term data are lacking so far. Photodynamic therapy (PDT) is the only technology that has been studied in a published prospective randomized trial. The FT is challenged by the multifocality of PC; therefore, the quality of prostate biopsy, histopathological assessment as well as imaging are of paramount importance. Multiparametric magnetic resonance imaging (MRI) has gained increasing importance. The FT is experimental and should only be offered within clinical trials.

Background: Angiogenesis is a fundamental process in the progression, invasion, and metastasis of tumors. Therapeutic drugs such as bevacizumab and ranibuzumab have thus been developed to inhibit vascular endothelial growth factor (VEFG)-promoted angiogenesis. While these anti-angiogenic drugs have been commonly used in the treatment of cancer, patients often develop significant resistance that limits the efficacy of anti-VEGF therapies to a short period of time. This is in part due to the fact that an independent pathway of angiogenesis exists, which is mediated by 2-(ω-carboxyethyl)pyrrole (CEP) in a TLR2 receptor-dependent manner that can compensate for inhibition of the VEGF-mediated pathway. Aims: In this work, we evaluated a CEP antibody as a new tumor growth inhibitor that blocks CEP-induced angiogenesis. Method: We first evaluated the effectiveness of a CEP antibody as a monotherapy to impede tumor growth in two human tumor xenograft models. We then determined the synergistic effects of bevacizumab and CEP antibody in a combination therapy, which demonstrated that blocking of the CEP-mediated pathway significantly enhanced the anti-angiogenic efficacy of bevacizumab in tumor growth inhibition indicating that CEP antibody is a promising chemotherapeutic drug. To facilitate potential translational studies of CEP-antibody, we also conducted longitudinal imaging studies and identified that FMISO-PET is a non-invasive imaging tool that can be used to quantitatively monitor the anti-angiogenic effects of CEP-antibody in the clinical setting. Results: That treatment with CEP antibody induces hypoxia in tumor tissue WHICH was indicated by 43% higher uptake of [18F]FMISO in CEP antibody-treated tumor xenografs than in the control PBS-treated littermates.