Amicrobial pustulosis of the folds związany z przeciwciałami przeciwko peroksydazie tarczycowej

Amicrobial pustulosis of the folds (APF) is a rare neutrophilic dermatosis, co-existing with autoimmune disorders, especially systemic lupus erythematosus. The disease is characterized by the presence of sterile pustules localized in the skin folds, intraepidermal pustules with mainly neutrophilic infiltrate on histology, negative microbial cultures from an unopened pustule and the presence of circulating autoantibodies or autoinflammatory diseases. Due to its rare incidence, data on effective therapeutic options are limited to individual clinical cases. We present a 69-year-old man with disseminated pustular lesions in the main skin folds, focusing on the clinical, histopathological and immunological characteristics of the disease. Based on the clinical presentation and laboratory investigation, amicrobial pustulosis of the folds was diagnosed with an accompanying increased concentration of anti-thyreoperoxidase antibodies with compensated thyroid hormones. After 2 weeks of treatment with local glucocorticosteroids, skin lesions disappeared, leaving post-inflammatory discoloration. The patient remains without recurrence of any skin lesions during the five-month observation. In conclusion, in the diagnosis of this rare disease, the clinicopathological correlation plays a crucial role as well as the investigation for co-existing autoimmune disorders.Amicrobial pustulosis of the folds (APF) jest rzadką dermatozą neutrofilową, wspołistniejącą z zaburzeniami autoimmunologicznymi, zwłaszcza toczniem rumieniowatym układowym. Choroba charakteryzuje się obecnością: 1. jałowych środnaskorkowych krost zlokalizowanych w fałdach skornych, 2. odczynow zapalnych neutrofilowych w skorze właściwej, przy negatywnych posiewach mikrobiologicznych oraz 3. obecnością krążących autoprzeciwciał lub wspołistnieniem chorob autozapalnych. W związku z rzadkim występowaniem, dane dotyczące skutecznych opcji terapeutycznych ograniczają się do opisow pojedynczych przypadkow klinicznych. Prezentujemy przypadek 69-letniego mężczyzny z rozsianymi zmianami krostkowymi w fałdach i ich otoczeniu, skupiając się na obrazie klinicznym, histopatologicznym oraz immunologicznym choroby. Na podstawie wykonanych badań, w oparciu o obraz kliniczny, u pacjenta rozpoznano amicrobial pustulosis of the folds z towarzyszącym wzrostem stężenia przeciwciał przeciwko tyreoperoksydazie, przy wyrownanych hormonach tarczycy. Po dwutygodniowej terapii miejscowymi glikokortykosteroidami uzyskano ustąpienie zmian skornych, z pozostawieniem przebarwień pozapalnych. Pacjent pozostaje w remisji w trakcie 5-miesięcznego okresu obserwacji. W podsumowaniu, w rozpoznaniu tej rzadkiej jednostki chorobowej dużą rolę odgrywa korelacja kliniczno-patologiczna i poszukiwanie wspołistniejących zaburzeń autoimmunologicznych

FLIP: A Targetable Mediator of Resistance to Radiation in Non-Small Cell Lung Cancer

Resistance to radiotherapy due to insufficient cancer cell death is a significant cause of treatment failure in non-small cell lung cancer (NSCLC). The endogenous caspase-8 inhibitor, FLIP, is a critical regulator of cell death that is frequently overexpressed in NSCLC and is an established inhibitor of apoptotic cell death induced via the extrinsic death receptor pathway. Apoptosis induced by ionizing radiation (IR) has been considered to be mediated predominantly via the intrinsic apoptotic pathway; however, we found that IR-induced apoptosis was significantly attenuated in NSCLC cells when caspase-8 was depleted using RNA interference (RNAi), suggesting involvement of the extrinsic apoptosis pathway. Moreover, overexpression of wild-type FLIP, but not a mutant form that cannot bind the critical death receptor adaptor protein FADD, also attenuated IR-induced apoptosis, confirming the importance of the extrinsic apoptotic pathway as a determinant of response to IR in NSCLC. Importantly, when FLIP protein levels were down-regulated by RNAi, IRinduced cell death was significantly enhanced. The clinically relevant histone deacetylase (HDAC) inhibitors vorinostat and entinostat were subsequently found to sensitize a subset of NSCLC cell lines to IR in a manner that was dependent on their ability to suppress FLIP expression and promote activation of caspase-8. Entinostat also enhanced the anti-tumor activity of IR in vivo. Therefore, FLIP down-regulation induced by HDAC inhibitors is a potential clinical strategy to radio-sensitize NSCLC and thereby improve response to radiotherapy. Overall, this study provides the first evidence that pharmacological inhibition of FLIP may improve response of NCSLC to IR

Trends in the sources and sinks of carbon dioxide

Efforts to control climate change require the stabilization of atmospheric CO2 concentrations. This can only be achieved through a drastic reduction of global CO2 emissions. Yet fossil fuel emissions increased by 29% between 2000 and 2008, in conjunction with increased contributions from emerging economies, from the production and international trade of goods and services, and from the use of coal as a fuel source. In contrast, emissions from land-use changes were nearly constant. Between 1959 and 2008, 43% of each year's CO2 emissions remained in the atmosphere on average; the rest was absorbed by carbon sinks on land and in the oceans. In the past 50 years, the fraction of CO2 emissions that remains in the atmosphere each year has likely increased, from about 40% to 45%, and models suggest that this trend was caused by a decrease in the uptake of CO2 by the carbon sinks in response to climate change and variability. Changes in the CO2 sinks are highly uncertain, but they could have a significant influence on future atmospheric CO2 levels. It is therefore crucial to reduce the uncertainties

Modelling and targeting FLIP's interactions at the DISC

FLIP is a well-established regulator of the extrinsic apoptotic pathway which is mediated through death receptors. Following death receptor ligation a protein complex called the DISC is formed and this is where procaspase 8 is gets activated by homodimerisation and autoprocessing. By binding to the DISC and dimerizing with procaspase 8, FLIP can prevent caspase 8 processing and thus inhibit the extrinsic apoptotic signalling cascade. .. " FLIP overexpression is a mechanism by which cancer cells survive apoptotic pressure therefore FLIP is an attractive target for anti-cancer therapies. However, strategies for targeting FLIP are challenging due to its lack of enzymatic activity and a crystal structure. Based on the structure of viral FLIP, a homology model of FLIP was built. Using a combination of molecular modelling, mutagenesis and functional assays, we determined the preferential sites and mode of interaction for FLIP-FADD. Moreover an homology model of procaspase 8 was also developed, again based on the structure of MC159 vFLlP. Using similar molecular modelling, mutagenesis and functional assays, we determined the mode of interaction of all three key apoptotic players at the DISC and a novel model of DISC assembly was developed. In addition, small molecule inhibitors of FLIP were developed. Having identified the critical region of the FLIP-FADD interaction, virtual screening was performed to identify candidate small molecules. The panel of candidate compounds was tested in a high throughput assay and this led to identification and prioritisation of a leading hit series. The selected compounds were further tested in a panel both cell-free and cell-based assays for FLIP-FADD inhibition and apoptosis induction. In summary, these studies provide insight into the modes of interaction between FLIP, FADD and procaspase 8 at the DISC and identify small molecule starting points for the development of inhibitors for therapeutically targeting FLIP for the treatment of cancer.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Biofilm Formation Reducing Properties of Manuka Honey and Propolis in Proteus mirabilis Rods Isolated from Chronic Wounds

Chronic wound infections are difficult to manage because of the biofilm formation in the wound environment. New measures for eliminating infections are necessary to increase the chance of wound healing. Apitherapy may be the new solution. The aim of this study was to assess the prevalence of wound infection factors and to examine the impact of Manuka honey and ethanol extract of propolis on biofilm formation of Proteus mirabilis isolated from chronic wound infections. According to the findings, the most frequent factors of infection are Staphylococcus aureus (46.1%), Pseudomonas aeruginosa (35.0%), and Proteus mirabilis (10.6%). Minimal inhibitory concentration and minimal bactericidal concentration values were assigned using the microbroth dilution test according to the Clinical and Laboratory Standards Institute. Biofilm of Proteus mirabilis isolates was formed in 96-well polystyrene plates and treated with Manuka honey (concentrations from 1.88% to 30.0%) and ethanol extract of propolis (1.0% to 40.0%). After 24 h, the biofilm viability was expressed by formazan absorbance (λ = 470 nm). Manuka honey reduced the biofilm viability in all, and ethanol extract of propolis in most, of the concentrations tested. Ethanol extract of propolis at the concentrations of 20.0% and 40.0%, reduced biofilm viability stronger than ethanol itself. With these results comes the conclusion that these substances can reduce biofilm formation

Cytoplasmic FLIP(S) and nuclear FLIP(L) mediate resistance of castrate-resistant prostate cancer to apoptosis induced by IAP antagonists

Abstract Expression of tumor necrosis factor-α (TNFα) in the serum of prostate cancer patients is associated with poorer outcome and progression to castrate-resistant (CRPC) disease. TNFα promotes the activity of NFκB, which regulates a number of anti-apoptotic and proinflammatory genes, including those encoding the inhibitor of apoptosis proteins (IAPs); however, in the presence of IAP antagonists, TNFα can induce cell death. In the presence of recombinant or macrophage-derived TNFα, we found that IAP antagonists triggered degradation of cIAP1 and induced formation of Complex-IIb, consisting of caspase-8, FADD and RIPK1 in CRPC models; however, no, or modest levels of apoptosis were induced. This resistance was found to be mediated by both the long (L) and short (S) splice forms of the caspase-8 inhibitor, FLIP, another NFκB-regulated protein frequently overexpressed in CRPC. By decreasing FLIP expression at the post-transcriptional level in PC3 and DU145 cells (but not VCaP), the Class-I histone deacetylase (HDAC) inhibitor Entinostat promoted IAP antagonist-induced cell death in these models in a manner dependent on RIPK1, FADD and Caspase-8. Of note, Entinostat primarily targeted the nuclear rather than cytoplasmic pool of FLIP(L). While the cytoplasmic pool of FLIP(L) was highly stable, the nuclear pool was more labile and regulated by the Class-I HDAC target Ku70, which we have previously shown regulates FLIP stability. The efficacy of IAP antagonist (TL32711) and Entinostat combination and their effects on cIAP1 and FLIP respectively were confirmed in vivo, highlighting the therapeutic potential for targeting IAPs and FLIP in proinflammatory CRPC

Perceptions of Clinical Adverse Event Reporting by Nurses and Midwives

The level of safety in healthcare units is mainly characterized by the occurrence of medical adverse events. The aim of the study was to present the experiences of reporting clinical adverse events and the perceptions of nurses working in internal medicine wards, surgical wards and midwives on these issues. The cross-sectional survey was conducted from October 2022 to April 2023. The study used the Author’s Survey Questionnaire and sampling by assessment was applied. The study included nurses working in internal medicine wards and surgical wards as well as midwives at nine hospitals in a large provincial city in Poland, amounting to 745 participants. A one-way analysis of variance ANOVA and a post-hoc test (Fisher’s NIR) were used. The significance level (p) did not exceed 0.05. Nurses working in surgical wards, internal medicine wards and midwives thought that clinical adverse events should be reported, and perceived this as an important and useful activity in ensuring patient safety. The most common adverse events reported by respondents were falls F(2.742) = 52.07; p = 0.001, bedsores F(2.742) = 19.62; p = 0.001, patient disappearances F(2.742) = 3.98; p = 0.019, and hospital-acquired infections F(2.742) = 3.88; p = 0.021. The most frequently selected factors influencing the abandonment of adverse event reporting were excessively complex paperwork, no or little harm to the patient or a fear of the negative consequences. The study suggests that an important way to overcome the barriers to nurses and midwives reporting adverse events would be to create a supportive atmosphere in which they could report errors and the reasons for them honestly and without fear, and to improve the way adverse events are reported at the personal and institutional levels

The SCFSkp2 ubiquitin ligase complex modulates TRAIL-R2-induced apoptosis by regulating FLIP(L)

TRAIL-R2 (DR5) is a clinically-relevant therapeutic target and a key target for immune effector cells. Herein, we identify a novel interaction between TRAIL-R2 and the Skp1-Cullin-1-F-box (SCF) Cullin-Ring E3 Ubiquitin Ligase complex containing Skp2 (SCFSkp2). We find that SCFSkp2 can interact with both TRAIL-R2’s pre-ligand association complex (PLAC) and ligand-activated death-inducing signalling complex (DISC). Moreover, Cullin-1 interacts with TRAIL-R2 in its active NEDDylated form. Inhibiting Cullin-1’s DISC recruitment using the NEDDylation inhibitor MLN4924 (Pevonedistat) or siRNA increased apoptosis induction in response to TRAIL. This correlated with enhanced levels of the caspase-8 regulator FLIP at the TRAIL-R2 DISC, particularly the long splice form, FLIP(L). We subsequently found that FLIP(L) (but not FLIP(S), caspase-8, nor the other core DISC component FADD) interacts with Cullin-1 and Skp2. Importantly, this interaction is enhanced when FLIP(L) is in its DISC-associated, C-terminally truncated p43-form. Prevention of FLIP(L) processing to its p43-form stabilises the protein, suggesting that by enhancing its interaction with SCFSkp2, cleavage to the p43-form is a critical step in FLIP(L) turnover. In support of this, we found that silencing any of the components of the SCFSkp2 complex inhibits FLIP ubiquitination, while overexpressing Cullin-1/Skp2 enhances its ubiquitination in a NEDDylation-dependent manner. DISC recruitment of TRAF2, previously identified as an E3 ligase for caspase-8 at the DISC, was also enhanced when Cullin-1’s recruitment was inhibited, although its interaction with Cullin-1 was found to be mediated indirectly via FLIP(L). Notably, the interaction of p43-FLIP(L) with Cullin-1 disrupts its ability to interact with FADD, caspase-8 and TRAF2. Collectively, our results suggest that processing of FLIP(L) to p43-FLIP(L) at the TRAIL-R2 DISC enhances its interaction with co-localised SCFSkp2, leading to disruption of p43-FLIP(L)’s interactions with other DISC components and promoting its ubiquitination and degradation, thereby modulating TRAIL-R2-mediated apoptosis