Potential Involvement of Micro vesicle Particles in the Synergistic Effects of Ultraviolet-B Radiation and Platelet -Activating Factor Receptor Agonists on Cytokine Production

Cytokines play a pivotal role in regulating inflammation, which is a condition that makes the tissue vulnerable to different pathological and physiological conditions. Thus, how cytokines are regulated is an important area of study. Skin that receives ultraviolet B radiation (UVB), a major pro-oxidative stressor, results in the release of multiple cytokines and chemokines like tumor necrosis factor (TNF)-alpha and interleukin (IL)-8. Previous studies from our group and others have demonstrated synergistic release of TNF-alpha when UVB is combined with IL-1 or the lipid mediator Platelet-activating factor (PAF). Of interest, subcellular microvesicle particles (MVP) have been proposed to play an important role in intercellular communication. Moreover, UVB and PAF agonists cause MVP release in keratinocytes. Therefore, we believe that understanding the role of MVP in these inflammatory responses could be insightful for photosensitivity mechanisms and to suppress inflammation. The current study focuses on the combination of low concentrations of PAF agonist and UVB in-vitro and ex-vivo to observe potential synergism in the release of cytokines and MVP. We also studied the effects of acid sphingomyelinase (aSMase) inhibitor imipramine, for its ability to modulate both MVP and cytokine release. The application of aSMase inhibitor inhibited the synergistic response of MVP and cytokines allows us to conclude the potential involvement of MVP in the exaggerated response of cytokines from combining UVB and PAF. These studies have potential relevance in understanding abnormal skin reactions such as photosensitivity

Factors Influencing the Efficacy of Agile Usage

Agile techniques that utilize iterative development are broadly used in various industry projects as a lightweight development technique which can satisfy the continuous changes of requirements. Short repetitions are used that are required for efficient product delivery. Traditional and old software development methods are not much efficient and effective to control the rapid change in requirements. Despite the benefits of Agile, criticism on agile methodology states that it couldn’t succeed to pay attention to architectural and design issues and therefore is bound to produce small design-decisions. The past decade has observed numerous changes in systems development with many organizations accepting agile techniques as a viable methodology for developing systems. An increase in the number of research studies reveals the growing demand and acceptance of agile methodologies. While most research has focused on acceptance rate and adaptation of agile practices, there is very limited knowledge of their post-adoption usage and incorporation within organizations. Several factors explain the effective usage of agile methodologies. A combination of previous research in Agile Methodologies, Diffusion of Innovations, Information Systems implementation, and Systems Development has been carried out to develop a research model that identifies the main factors relevant to the propagation and effective usage of agile methodologies in organizations

Implementation of a Si/SiC Hybrid Optically Controlled High-Power Switching Device

The ever-increasing performance and economy of operation requirements placed on commercial and military transport aircraft are resulting in very complex systems. As a result, the use of fiber optic component technology has lead to high data throughput, immunity to EMI, reduced certification and maintenance costs and reduced weight features. In particular, in avionic systems, data integrity and high data rates are necessary for stable flight control. Fly-by-Light systems that use optical signals to actuate the flight control surfaces of an aircraft have been suggested as a solution to the EMI problem in avionic systems. Current fly-by-light systems are limited by the lack of optically activated high-power switching devices. The challenge has been the development of an optoelectronic switching technology that can withstand the high power and harsh environmental conditions common in a flight surface actuation system. Wide bandgap semiconductors such as Silicon Carbide offer the potential to overcome both the temperature and voltage blocking limitations that inhibit the use of Silicon. Unfortunately, SiC is not optically active at the near IR wavelengths where communications grade light sources are readily available. Thus, we have proposed a hybrid device that combines a silicon based photoreceiver model with a SiC power transistor. When illuminated with the 5mW optical control signal the silicon chip produces a 15mA drive current for a SiC Darlington pair. The SiC Darlington pair then produces a 150 A current that is suitable for driving an electric motor with sufficient horsepower to actuate the control surfaces on an aircraft. Further, when the optical signal is turned off, the SiC is capable of holding off a 270 V potential to insure that the motor drive current is completely off. We present in this paper the design and initial tests from a prototype device that has recently been fabricated

A New Semantic Correlation Among Data Sets to Reduce Processing Latency

We propose close continuous and savvy semantic inquiries based methodology, called FAST. The thought behind FAST is to investigate and abuse the semantic connection inside and among datasets by means of relationship correlation-aware hashing and sensible level organized tending to altogether decrease the preparing idleness, while causing acceptably little loss of data look exactness. The near-real-time property of FAST enables quick distinguishing proof of related documents and the huge narrowing of the extent of data to be handled. FAST supports a few kinds of data investigation, which can be executed in existing accessible storage frameworks. We direct a true use case in which youngsters revealed missing in a to a great degree swarmed condition (e.g., an exceedingly famous grand spot on a pinnacle vacationer day) are recognized in an opportune design by investigating 60 million pictures using FAST

Stability of gene expression and epigenetic profiles highlights the utility of patient-derived paediatric acute lymphoblastic leukaemia xenografts for investigating molecular mechanisms of drug resistance

BACKGROUND: Patient-derived tumour xenografts are an attractive model for preclinical testing of anti-cancer drugs. Insights into tumour biology and biomarkers predictive of responses to chemotherapeutic drugs can also be gained from investigating xenograft models. As a first step towards examining the equivalence of epigenetic profiles between xenografts and primary tumours in paediatric leukaemia, we performed genome-scale DNA methylation and gene expression profiling on a panel of 10 paediatric B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) tumours that were stratified by prednisolone response. RESULTS: We found high correlations in DNA methylation and gene expression profiles between matching primary and xenograft tumour samples with Pearson\u27s correlation coefficients ranging between 0.85 and 0.98. In order to demonstrate the potential utility of epigenetic analyses in BCP-ALL xenografts, we identified DNA methylation biomarkers that correlated with prednisolone responsiveness of the original tumour samples. Differential methylation of CAPS2, ARHGAP21, ARX and HOXB6 were confirmed by locus specific analysis. We identified 20 genes showing an inverse relationship between DNA methylation and gene expression in association with prednisolone response. Pathway analysis of these genes implicated apoptosis, cell signalling and cell structure networks in prednisolone responsiveness. CONCLUSIONS: The findings of this study confirm the stability of epigenetic and gene expression profiles of paediatric BCP-ALL propagated in mouse xenograft models. Further, our preliminary investigation of prednisolone sensitivity highlights the utility of mouse xenograft models for preclinical development of novel drug regimens with parallel investigation of underlying gene expression and epigenetic responses associated with novel drug responses

Cediranib in patients with alveolar soft-part sarcoma (CASPS):a double-blind, placebo-controlled, randomised, phase 2 trial

Background Alveolar soft-part sarcoma (ASPS) is a rare soft-tissue sarcoma that is unresponsive to chemotherapy. Cediranib, a tyrosine-kinase inhibitor, has shown substantial activity in ASPS in non-randomised studies. The Cediranib in Alveolar Soft Part Sarcoma (CASPS) study was designed to discriminate the effect of cediranib from the intrinsically indolent nature of ASPS.Methods In this double-blind, placebo-controlled, randomised, phase 2 trial, we recruited participants from 12 hospitals in the UK (n=7), Spain (n=3), and Australia (n=2). Patients were eligible if they were aged 16 years or older; metastatic ASPS that had progressed in the previous 6 months; had an ECOG performance status of 0-1; life expectancy of more than 12 weeks; and adequate bone marrow, hepatic, and renal function. Participants had to have no anti-cancer treatment within 4 weeks before trial entry, with exception of palliative radiotherapy. Participants were randomly assigned (2:1), with allocation by use of computer-generated random permuted blocks of six, to either cediranib (30 mg orally, once daily) or matching placebo tablets for 24 weeks. Treatment was supplied in number-coded bottles, masking participants and clinicians to assignment. Participants were unblinded at week 24 or sooner if they had progression defined by Response Evaluation Criteria in Solid Tumors (version 1.1); those on placebo crossed over to cediranib and all participants continued on treatment until progression or death. The primary endpoint was percentage change in sum of target marker lesion diameters between baseline and week 24 or progression if sooner, assessed in the evaluable population (all randomly assigned participants who had a scan at week 24 [or sooner if they progressed] with target marker lesions measured). Safety was assessed in all participants who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01337401; the European Clinical Trials database, number EudraCT2010-021163-33; and the ISRCTN registry, number ISRCTN63733470 recruitment is complete and follow-up is ongoing.Findings Between July 15, 2011, and July 29, 2016, of 48 participants recruited, all were randomly assigned to cediranib (n=32) or placebo (n=16). 23 (48%) were female and the median age was 31 years (IQR 27-45). Median follow-up was 34·3 months (IQR 23·7-55·6) at the time of data cutoff for these analyses (April 11, 2018). Four participants in the cediranib group were not evaluable for the primary endpoint (one did not start treatment, and three did not have their scan at 24 weeks). Median percentage change in sum of target marker lesion diameters for the evaluable population was -8·3% (IQR -26·5 to 5·9) with cediranib versus 13·4% (IQR 1·1 to 21·3) with placebo (one-sided p=0·0010). The most common grade 3 adverse events on (blinded) cediranib were hypertension (six [19%] of 31) and diarrhoea (two [6%]). 15 serious adverse reactions in 12 patients were reported; 12 of these reactions occurred on open-label cediranib, and the most common symptoms were dehydration (n=2), vomiting (n=2), and proteinuria (n=2). One probable treatment-related death (intracranial haemorrhage) occurred 41 days after starting open-label cediranib in a patient who was assigned to placebo in the masked phase.Interpretation Given the high incidence of metastatic disease and poor long-term prognosis of ASPS, together with the lack of efficacy of conventional chemotherapy, our finding of significant clinical activity with cediranib in this disease is an important step towards the goal of long-term disease control for these young patients. Future clinical trials in ASPS are also likely to involve immune checkpoint inhibitors.Funding Cancer Research UK and AstraZeneca

Association between local treatment modalities and event-free survival, overall survival, and local recurrence in patients with localised Ewing Sarcoma: report from the Ewing 2008 trial

BackgroundLocal treatment is a crucial element in the standard of care for Ewing sarcoma (EWS). While systemic treatment is improved in randomised clinical trials, local treatment modalities are discussed controversially. We analysed the association between local therapy and event-free survival (EFS), overall survival (OS), and local recurrence (LR) in prospectively collected data of patients with localised EWS.Patients and methodsWe analysed data from the international Ewing 2008 study registered between 2009 and 2019 in 117 centres. After induction chemotherapy, patients received surgery, radiotherapy, or a combination thereof. We performed Cox regression, conducted propensity score-weighted sensitivity analysis, and performed subgroup analyses. Hazard ratios (HRs) and 95% confidence intervals are reported.ResultsWe included 863 patients with localised EWS (surgery alone: 331, combination therapy: 358, definitive radiotherapy: 174). In patients treated with combination therapy compared to surgery alone, EFS HR was 0.84 (0.57–1.24; p = 0.38), OS HR was 0.84 (0.57–1.23; p = 0.41), and LR HR was 0.58 (0.26–1.31; p = 0.19). Hazards of any event were increased in patients treated with definitive radiotherapy compared to surgery only, HR 1.53 (1.02–2.31; p = 0.04). Patients with poor responses to chemotherapy benefitted from combination therapy over definitive surgery with an EFS HR 0.49 (0.27–0.89; p = 0.02). Patients with pelvic tumours benefitted from combination therapy over surgery only regarding LR, HR 0.12 (0.02–0.72; p = 0.02).ConclusionPatients with poor responses to chemotherapy benefitted from radiotherapy added to surgery. In the whole group, radiotherapy alone as opposed to surgery alone increased the hazards of any event.Experimentele farmacotherapi