Gasdermin D Hypermethylation Inhibits Pyroptosis And LPS-Induced IL-1β Release From NK92 Cells

INTRODUCTION: Although natural killer (NK) are major cells used to treat cancer patients, recent clinical trials showed that NK92 cells can be also used for the same purpose due to their high anti-tumor activity. Here, we examined whether these cells might be inflammatory due to the release of interleukin-1β (IL-1β), and whether the anti-inflammatory molecules dimethyl fumarate (DMF), or monomethyl fumarate (MMF) impair this activity. METHODS: NK92 cells were examined for the synthesis and release of IL-1β utilizing RT-PCR and ELISA assay, respectively. The expression of hydroxy-carboxylic acid receptors (HCA)1, HCA2 and HCA3 was detected by immunoblotting, flow cytometry, immunofluorescence and RT-PCR assays. The activation of caspase-1 and Gasdermin D (GSDMD) was evaluated by immunoblot assay. Pyroptosis was demonstrated by immunofluorescence imaging. Expression of DNA methyltransferases (DNMTs) mRNA was determined by whole transcriptome and immunoblot analyses. RESULTS: LPS-induced the release of IL-1β from NK92 cells, whereas DMF or MMF inhibited this induction. The effect of these drugs was due to inhibiting the conversion of procaspase-1 into active caspase-1. NK92 cells highly expressed GSDMD, a pyroptotic-mediated molecule. However, LPS induced the distribution of GSDMD into the cell membranes, corroborated with the presence of pyroptotic bodies, an activity that was inhibited by DMF or MMF. These molecule also inhibited the generation of GSDMD through DNMT-mediated hypermethylation of the promoter region of GSDMD gene. These results were supported by increased expression of DNMTs mRNA as determined by whole transcriptome analysis. DISCUSSION: Our results are the first to show that NK92 cells utilize GSDMD pathway to release IL-1β. Further, DMF and MMF which were previously shown to enhance NK cell cytotoxicity, also inhibit the inflammatory effects of these cells, making them most suitable for treating cancer patients

On correlation functions of Wilson loops, local and non-local operators

We discuss and extend recent conjectures relating partial null limits of correlation functions of local gauge invariant operators and the expectation value of null polygonal Wilson loops and local gauge invariant operators. We point out that a particular partial null limit provides a strategy for the calculation of the anomalous dimension of short twist-two operators at weak and strong coupling.Comment: 29 pages, 8 figure

Non-conformal Hydrodynamics in Einstein-dilaton Theory

In the Einestein-dilaton theory with a Liouville potential parameterized by $\eta$, we find a Schwarzschild-type black hole solution. This black hole solution, whose asymptotic geometry is described by the warped metric, is thermodynamically stable only for $0 \le \eta < 2$. Applying the gauge/gravity duality, we find that the dual gauge theory represents a non-conformal thermal system with the equation of state depending on $\eta$. After turning on the bulk vector fluctuations with and without a dilaton coupling, we calculate the charge diffusion constant, which indicates that the life time of the quasi normal mode decreases with $\eta$. Interestingly, the vector fluctuation with the dilaton coupling shows that the DC conductivity increases with temperature, a feature commonly found in electrolytes.Comment: 27 pages and 2 figures, published in JHE

Ultra-fast Microwave Synthesis of ZnO Nanowires and their Dynamic Response Toward Hydrogen Gas

Ultra-fast and large-quantity (grams) synthesis of one-dimensional ZnO nanowires has been carried out by a novel microwave-assisted method. High purity Zinc (Zn) metal was used as source material and placed on microwave absorber. The evaporation/oxidation process occurs under exposure to microwave in less than 100 s. Field effect scanning electron microscopy analysis reveals the formation of high aspect-ratio and high density ZnO nanowires with diameter ranging from 70 to 80 nm. Comprehensive structural analysis showed that these ZnO nanowires are single crystal in nature with excellent crystal quality. The gas sensor made of these ZnO nanowires exhibited excellent sensitivity, fast response, and good reproducibility. Furthermore, the method can be extended for the synthesis of other oxide nanowires that will be the building block of future nanoscale devices

Theoretical analysis of the dose dependence of the oxygen enhancement ratio and its relevance for clinical applications

<p>Abstract</p> <p>Background</p> <p>The increased resistance of hypoxic cells to ionizing radiation is usually believed to be the primary reason for treatment failure in tumors with oxygen-deficient areas. This oxygen effect can be expressed quantitatively by the oxygen enhancement ratio (OER). Here we investigate theoretically the dependence of the OER on the applied local dose for different types of ionizing irradiation and discuss its importance for clinical applications in radiotherapy for two scenarios: small dose variations during hypoxia-based dose painting and larger dose changes introduced by altered fractionation schemes.</p> <p>Methods</p> <p>Using the widespread Alper-Howard-Flanders and standard linear-quadratic (LQ) models, OER calculations are performed for T1 human kidney and V79 Chinese hamster cells for various dose levels and various hypoxic oxygen partial pressures (pO2) between 0.01 and 20 mmHg as present in clinical situations <it>in vivo</it>. Our work comprises the analysis for both low linear energy transfer (LET) treatment with photons or protons and high-LET treatment with heavy ions. A detailed analysis of experimental data from the literature with respect to the dose dependence of the oxygen effect is performed, revealing controversial opinions whether the OER increases, decreases or stays constant with dose.</p> <p>Results</p> <p>The behavior of the OER with dose per fraction depends primarily on the ratios of the LQ parameters alpha and beta under hypoxic and aerobic conditions, which themselves depend on LET, pO2 and the cell or tissue type. According to our calculations, the OER variations with dose <it>in vivo </it>for low-LET treatments are moderate, with changes in the OER up to 11% for dose painting (1 or 3 Gy per fraction compared to 2 Gy) and up to 22% in hyper-/hypofractionation (0.5 or 20 Gy per fraction compared to 2 Gy) for oxygen tensions between 0.2 and 20 mmHg typically measured clinically in hypoxic tumors. For extremely hypoxic cells (0.01 mmHg), the dose dependence of the OER becomes more pronounced (up to 36%). For high LET, OER variations up to 4% for the whole range of oxygen tensions between 0.01 and 20 mmHg were found, which were much smaller than for low LET.</p> <p>Conclusions</p> <p>The formalism presented in this paper can be used for various tissue and radiation types to estimate OER variations with dose and help to decide in clinical practice whether some dose changes in dose painting or in fractionation can bring more benefit in terms of the OER in the treatment of a specific hypoxic tumor.</p

A new implicit review instrument for measuring quality of care delivered to pediatric patients in the emergency department

BackgroundThere are few outcomes experienced by children receiving care in the Emergency Department (ED) that are amenable to measuring for the purposes of assessing of quality of care. The purpose of this study was to develop, test, and validate a new implicit review instrument that measures quality of care delivered to children in EDs.MethodsWe developed a 7-point structured implicit review instrument that encompasses four aspects of care, including the physician's initial data gathering, integration of information and development of appropriate diagnoses; initial treatment plan and orders; and plan for disposition and follow-up. Two pediatric emergency medicine physicians applied the 5-item instrument to children presenting in the highest triage category to four rural EDs, and we assessed the reliability of the average summary scores (possible range of 5-35) across the two reviewers using standard measures. We also validated the instrument by comparing this mean summary score between those with and without medication errors (ascertained independently by two pharmacists) using a two-sample t-test.ResultsWe reviewed the medical records of 178 pediatric patients for the study. The mean and median summary score for this cohort of patients were 27.4 and 28.5, respectively. Internal consistency was high (Cronbach's alpha of 0.92 and 0.89). All items showed a significant (p &lt; 0.005) positive correlation between reviewers using the Spearman rank correlation (range 0.24 to 0.39). Exact agreement on individual items between reviewers ranged from 70.2% to 85.4%. The Intra-class Correlation Coefficient for the mean of the total summary score across the two reviewers was 0.65. The validity of the instrument was supported by the finding of a higher score for children without medication errors compared to those with medication errors which trended toward significance (mean score = 28.5 vs. 26.0, p = 0.076).ConclusionThe instrument we developed to measure quality of care provided to children in the ED has high internal consistency, fair to good inter-rater reliability and inter-rater correlation, and high content validity. The validity of the instrument is supported by the fact that the instrument's average summary score was lower in the presence of medication errors, which trended towards statistical significance

Single feature polymorphisms (SFPs) for drought tolerance in pigeonpea (Cajanus spp.)

Single feature polymorphisms (SFPs) are microarray-based molecular markers that are detected by hybridization of DNA or cRNA to oligonucleotide probes. With an objective to identify the potential polymorphic markers for drought tolerance in pigeonpea [Cajanus cajan (L.) Millspaugh], an important legume crop for the semi-arid tropics but deficient in genomic resources, Affymetrix Genome Arrays of soybean (Glycine max), a closely related species of pigeonpea were used on cRNA of six parental genotypes of three mapping populations of pigeonpea segregating for agronomic traits like drought tolerance and pod borer (Helicoverpa armigiera) resistance. By using robustified projection pursuit method on 15 pair-wise comparisons for the six parental genotypes, 5,692 SFPs were identified. Number of SFPs varied from 780 (ICPL 8755 × ICPL 227) to 854 (ICPL 151 × ICPL 87) per parental combination of the mapping populations. Randomly selected 179 SFPs were used for validation by Sanger sequencing and good quality sequence data were obtained for 99 genes of which 75 genes showed sequence polymorphisms. While associating the sequence polymorphisms with SFPs detected, true positives were observed for 52.6% SFPs detected. In terms of parental combinations of the mapping populations, occurrence of true positives was 34.48% for ICPL 151 × ICPL 87, 41.86% for ICPL 8755 × ICPL 227, and 81.58% for ICP 28 × ICPW 94. In addition, a set of 139 candidate genes that may be associated with drought tolerance has been identified based on gene ontology analysis of the homologous pigeonpea genes to the soybean genes that detected SFPs between the parents of the mapping populations segregating for drought tolerance

Specialist antenatal clinics for women at high risk of preterm birth: a systematic review of qualitative and quantitative research

Background Preterm birth (PTB) is the leading cause of perinatal morbidity and mortality. Women with previous prenatal loss are at higher risk of preterm birth. A specialist antenatal clinic is considered as one approach to improve maternity and pregnancy outcomes. Methods A systematic review of quantitative, qualitative and mixed method studies conducted on women at high risk of preterm birth (PTB). The review primary outcomes were to report on the specialist antenatal clinics effect in preventing or reducing preterm birth, perinatal mortality and morbidity and women’s perceptions and experiences of a specialist clinic whether compared or not compared with standard antenatal care. Other secondary maternal, infant and economic outcomes were also determined. A comprehensive search strategy was carried out in English within electronic databases as far back as 1980. The reviewers selected studies, assessed the quality, and extracted data independently. Results were summarized and tabulated. Results Eleven studies fully met the review inclusion criteria, ten were quantitative design studies and only one was a qualitative design study. No mixed method design study was included in the review. All were published after 1989, seven were conducted in the USA and four in the UK. Results from five good to low quality randomised controlled trials (RCTs), all conducted before 1990, did not illustrate the efficacy of the clinic in reducing preterm birth. Whereas results from more recent low quality cohort studies showed some positive neonatal outcomes. Themes from one good quality qualitative study reflected on the emotional and psychological need to reduce anxiety and stress of women referred to such a clinic. Women expressed their negative emotional responses at being labelled as high risk and positive responses to being assessed and treated in the clinic. Women also reported that their partners were struggling to cope emotionally. Conclusions Findings from this review were mixed. Evidence from cohort studies indicated a specialist clinic may be a means of predicting or preventing preterm birth. Testing this in a randomised controlled trial is desirable, though may be hard to achieve due to the growing focus of such clinics on managing women at high risk of preterm birth. Ongoing research has to recognize women’s experiences and perceptions of such a clinic. Further clarification of the optimal referral route and a clear and standardized management and cost economic evaluation plan are also required. Fathers support and experience of PTB clinics should also be included in further research

The state of the art: immune-mediated mechanisms of monoclonal antibodies in cancer therapy

A number of antibody products have now become accepted as effective anti-cancer therapies. Despite being mainly designed to act by inhibiting functional tumour antigens, there is increasing evidence that Fc-mediated engagement of the immune system is an important contributor to the efficacy of several of these therapies. The optimisation of this engagement offers the potential not only to augment efficacy against existing targets, but also to exploit non-functional tumour antigens. Antibodies that achieve efficacy wholly or predominantly through Fc-mediated mechanisms, represent rich opportunities for future therapeutics in oncology. This mini review summarises some of the key challenges, which need to be addressed to select the most effective molecules. These include the identification of optimal antibody characteristics and improvement of the drug discovery process, in particular, the relevance and predictive power of existing in vitro and in vivo screening methods. Advances in our understanding of tumour immunobiology and successful application of technologies designed to enhance immune system engagement will further aid this process