Inhibition of KDM4 with QC6352 to Target High-Risk Neuroblastoma

Neuroblastoma (NB) is a malignancy of improperly maturated nerve tissues of the sympathetic nervous system. It is the most diagnosed extracranial solid tumor of childhood, and it accounts for roughly up to 10% of all childhood malignancies and 15% of all childhood malignancy-related deaths. MYCN amplification, occurring in 20-25% of all NB patients and 50% of all high-risk NB patients, is the well-characterized genetic abnormality and is associated with ill-fated outcomes. Regrettably, in spite of the contemporary therapeutic advances and aggressive combinatorial treatments, the overall 5-year event-free survival rate is roughly 51% with a 5-year overall survival rate of nearly 63%. Unfortunately, close to 50% of high-risk NB patients develop disease relapses, which are largely incurable with no salvageable therapies so far. Recent evidence highlights that NB exhibits two cellular heterogeneities, namely adrenergic (ADRN) and mesenchymal (MES), which are tightly controlled by core regulatory circuitry-transcription factors (CRC-TFs). Driven by super-enhancers, these CRC-TFs, produce interrelated, feed-forward transcriptional loops that ultimately reinforce a specific gene expression program that defines the cellular state and identity of the cell. We showed that histone lysine demethylase subfamily 4 (KDM4) protein expression was higher in MYCN-amplified (MNA) NB cell lines and patient-derived xenografts (PDXs) compared with non-MNA counterparts. Additionally, genetic depletion of KDM4 correlated with reduced proliferation in vitro and in vivo. Interestingly, forced MYCN overexpression in MES-dominant NB cells facilitated MES to ADRN cellular state shift that was accompanied by induction of KDM4 proteins. Through various functional and genetic assays, we further validated the importance of the MYCN/KDM4/ADRN CRC-TF axis in maintaining the ADRN cellular state of NB. In view of these thrilling results, we opted to expand the clinical utility and examine the prospect of pharmacologic inhibition of KDM4 with QC6352, a selective and potent KDM4 inhibitor. Our data depicted that monotherapy QC6352 was selectively sensitive against MNA NB cells in vitro. Additionally, monotherapy QC6352 depicted satisfactory antitumor activities in high-risk cell line-based xenografts (NB1691), PDXs, and TH-MYCN/ALKF1178L transgenic mouse model in vivo. Molecularly, QC6352 reduced the mRNA and protein levels of oncogenic drivers and various ADRN CRC-TFs. Interestingly, QC6352 also decreased KDM4 expression at the translational protein level. Additionally, QC6352 culminated in favorable anticancer effects in vitro and in vivo, reflected by differentiation induction, apoptosis instigation, DNA damage, cell cycle cessation, and interestingly type-I interferon reactivation. Epigenomic-based investigations utilizing assay for transposase-accessible chromatin with sequencing (ATAC-seq) showed QC6352 reduced chromatin accessibility of MYCN and ADRN CRC-TFs, whereas chromatin immunoprecipitation with sequencing (ChIP-seq) and cleavage under targets and tagmentation (CUT&TAG) analyses showed KDM4 proteins were bound to genomic loci of MYCN and ADRN CRC-TFs, and QC6352 treatment promoted induction of the transcriptional repressive H3K9me3 mark. Lastly, combination therapy comprising QC6352 and standard-of-care chemotherapeutics (vincristine and irinotecan) led to 100% complete response in MNA NB xenografts without overt toxicity and accompanied by prolongation of survival. All in all, this research offers a solid proof-of-concept that pharmacologic inhibition of KDM4 with QC6352 may be translated from bench to bedside as a novel therapeutic tactic for high-risk MNA NB patients. Moreover, two orthogonal drug screens comprising CRISPR-Cas9 knockout (metabolism and kinase libraries), and high-throughput PRISM analysis highlighted enhanced anticancer effects between QC6352 and mammalian target of rapamycin (mTOR) inhibition. We demonstrated that combination of QC6352 and some mTOR inhibitors resulted in enhanced anticancer effects in vitro in several MNA and non-MNA NB cells. Functional genetic assays to validate the enhanced anticancer effects between dual KDM4 and mTOR inhibition failed. Lastly, combination of QC6352+rapamycin did not result in enhanced anticancer effects in SKNAS xenografts in vivo. Unless more in vivo work is performed, the present findings do not provide a compelling motivation to combine QC6352 with mTOR inhibition in the treatment of NB tumors

Integration of artificial intelligence into nursing practice

BACKGROUND: Artificial Intelligence (AI) is developing at a rapid pace and finding new applications across the health service team. Some professionals have voiced concerns over the implementation of AI, whilst others predict greater job opportunities in the future. Nursing practice will be directly affected and further information is required on the knowledge and perceptions of nurses regarding the integration of AI in practice. The study aims to assess the knowledge, attitude, willingness, and organizational readiness in integrating AI into nursing practice. METHODS: An exploratory cross-sectional survey of nurses working in health organisations. A survey link was emailed to participants. Nurses working in the United Arab Emirates (UAE) health organisations were invited to participate. Eligibility criteria included registered nurses in government or private hospitals. The survey captured the nurses demographic, knoweldage, preceptions, orgianizational readinesss and challenges regarding implementation of AI into nursing practice. RESULTS: 553 responses were returned from 650 invitation giving a response rate of 85%. 51% of respondents stated their knowledge on AI was obtained through self-taught measures for most of the participants, while 20% of them gained it through various courses. Only 8% stated they learned through postgraduate courses, while 9% stated they lack knowledge of AI. 75% of all respondents agreed that the nursing curriculum should include some basic knowledge of AI. CONCLUSIONS: There is a lack of understanding of the principles of AI across the nursing profession. Further education and training is required to enable a seamless and safe integration of AI into nursing practice

Radiation dose associated with multi-detector 64-slice computed tomography brain examinations in Khartoum State, Sudan

Background: Radiation exposure due to computed tomography (CT) has become an important issue, as the number of CT examinations has been increasing worldwide. Radiation doses associated with CT are higher in comparison to other imaging procedures. CT-related radiation doses should be monitored and controlled in order to ensure reduction of radiation exposure and optimization of image quality. The aim of this study was to evaluate radiation doses in adult patient who underwent routine CT brain examinations, and to assess how CT scanning protocols affect patient doses in practice. Material/Methods: A total of 118 patients underwent brain CT at two radiology departments equipped with 64-slice CT scanners, Khartoum, Sudan. Patient doses regarding weighted CT dose index (CTDIw) and dose length product (DLP) values were recorded. Quality control tests were performed for both scanners. Results: The mean CTDIw values ranged from 62.9 to 65.8 mGy, DLP values ranged from 1003.7 to 1192.5 mGy, and the effective dose varied from 2.4 to 3.7 mSv. Conclusions: Patient doses in this study was higher compared to previous research, suggesting that patients exposed to unnecessary radiation. Therefore, optimization of radiation doses with the use of specified imaging protocols, well-documented indications for CT, training of technicians, and quality control programs will reduce the necessary radiation doses. Establishment of the diagnostic reference level is recommended for further dose reduction

Land degradation vulnerability mapping in a newly-reclaimed desert oasis in a hyper-arid agro-ecosystem using ahp and geospatial techniques

Modelling land degradation vulnerability (LDV) in the newly-reclaimed desert oases is a key factor for sustainable agricultural production. In the present work, a trial for using remote sensing data, GIS tools, and Analytic Hierarchy Process (AHP) was conducted for modeling and evaluating LDV. The model was then applied within 144,566 ha in Farafra, an inland hyper-arid Western Desert Oases in Egypt. Data collected from climate conditions, geological maps, remote sensing imageries, field observations, and laboratory analyses were conducted and subjected to AHP to develop six indices. They included geology index (GI), topographic quality index (TQI), physical soil quality index (PSQI), chemical soil quality index (CSQI), wind erosion quality index (WEQI), and vegetation quality index (VQI). Weights derived from the AHP showed that the effective drivers of LDV in the studied area were as follows: CSQI (0.30) > PSQI (0.29) > VQI (0.17) > TQI (0.12) > GI (0.07) > WEQI (0.05). The LDV map indicated that nearly 85% of the total area was prone to moderate degradation risks, 11% was prone to high risks, while less than 1% was prone to low risks. The consistency ratio (CR) for all studied parameters and indices were less than 0.1, demonstrating the high accuracy of the AHP. The results of the cross-validation demonstrated that the performance of ordinary kriging models (spherical, exponential, and Gaussian) was suitable and reliable for predicting and mapping soil properties. Integrated use of remote sensing data, GIS, and AHP would provide an effective methodology for predicting LDV in desert oases, by which proper management strategies could be adopted to achieve sustainable food security

Deformation Rate and Temperature Sensitivity in TWIP/TRIP VCrFeCoNi Multi-Principal Element Alloy

High-entropy alloys (HEAs) and medium-entropy alloys (MEAs), also sometimes referred to as multi-principal element alloys (MPEAs), present opportunities to develop new materials with outstanding mechanical properties. Through the careful selection of constituent elements along with optimized thermal processing for proper control of structure, grain size, and deformation mechanisms, many of the newly developed HEA systems exhibit superior strength and ductility levels across a wide range of temperatures, particularly at cryogenic deformation temperatures. Such a remarkable response has been attributed to the hardening capacity of many MPEAs that is achieved through the activation of deformation twinning. More recent compositions have considered phase transforming systems, which have the potential for enhanced strengthening and therefore high strength and ductility levels. However, the strain rate sensitivity of such transforming MPEAs is not well understood and requires further investigation. In this study, the tensile properties of the non-equiatomic V10Cr10Fe45Co30Ni5 MPEA were investigated at different deformation rates and temperatures ranging from 77 K (-196 degrees C) to 573 K (300 degrees C). Depending on the deformation temperature, the considered MPEA exhibits plasticity through either crystallographic slip, deformation twinning, or solid-state phase transformation. At 300 degrees C, only slip-mediated plasticity was observed for all the considered deformation rates. Deformation twinning was detected in samples deformed at room temperature, while face-centered cubic to body-centered cubic phase transformation became more favorable at cryogenic deformation temperatures. The trends are nonlinear with twinning-induced plasticity (TWIP) favored at the intermediate deformation rate, while transformation-induced plasticity (TRIP) was observed, although limited, only at the slowest deformation rate. For all the considered deformation rates at cryogenic deformation temperature, a significant TRIP activity was always detected. The extent of TRIP, however, was dependent on the deformation rate. Increasing the deformation rate is not conducive to TRIP and thus hinders the hardening capacity

Solar Central Receiver with an Irising Aperture

Variable sun elevation, azimuthal and declination angles with the time of day, and seasons of the year respectively, give variable projected image size defects produced by field site concave mirrors on the central cavity receiver's aperture entrance. If the aperture is small, it will be inefficient for periods when the solar isolation is inclined due to spillage. However, if the aperture is large, it will be inefficient for periods when the solar isolation is normal, due to excess heat radiation and convection losses. Thus, the fixed aperture area size is a compromise between ideal sizes for different conditions. The end result is a loss of efficiency as a function of time of day and seasons of the year. This research presents an approach to maximize the interception factor on the receiver entrance, with reducing the heat losses by radiation and convection through its aperture area. A central receiver system, having a down-looking cavity with an irises aperture is being proposed for application in rich environmental solar conditions, utilized solar flux insolation throughout the day on the city of Kuwait. Solar tower focusing collector with a cavity type receiver having a fixed area aperture at the entrance is presented for comparison with the proposed technique. This collector is proved to be less efficient than the suggested design. The isiring cavity receiver with a variable area aperture provides an approximately constant efficiency regardless of the time of day or season of the year. The end result is the proposed system shows improved performance and capability. However, over the life-time of installation these advantages of the proposed system should overweigh its disadvantages of additional cost due to extra automation

Safety and Efficacy of miltefosine alone and in combination with sodium stibogluconate and liposomal amphotericin B for the treatment of primary visceral leishmaniasis in East Africa: study protocol for a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Treatment options for Visceral Leishmaniasis (VL) in East Africa are far from satisfactory due to cost, toxicity, prolonged treatment duration or emergence of parasite resistance. Hence there is a need to explore alternative treatment protocols such as miltefosine alone or in combinations including miltefosine, sodium stibogluconate (SSG) or liposomal amphotericin B. The aim of this trial is to identify regimen(s) which are sufficiently promising for future trials in East Africa.</p> <p>Methods/Design</p> <p>A phase II randomized, parallel arm, open-labelled trial is being conducted to assess the efficacy of each of the three regimens: liposomal amphotericin B with SSG, Liposomal amphotericin B with miltefosine and miltefosine alone. The primary endpoint is cure at day 28 with secondary endpoint at day 210 (6 months). Initial cure is a single composite measure based on parasitologic evaluation (bone marrow, spleen or lymph node aspirate) and clinical assessment. Repeated interim analyses have been planned after recruitment of 15 patients in each arm with a maximum sample size of 63 for each. These will follow group-sequential methods (the triangular test) to identify when a regimen is inadequate (<75% efficacy) or adequate (>90% efficacy). We describe a method to ensure consistency of the sequential analysis of day 28 cure with the non-sequential analysis of day 210 cure.</p> <p>Discussion</p> <p>A regimen with adequate efficacy would be a candidate for treatment of VL with reasonable costs. The design allows repeated testing throughout the trial recruitment period while maintaining good statistical properties (Type I & II error rates) and reducing the expected sample sizes.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT01067443">NCT01067443</a></p

Accumulation of potentially toxic metals in egyptian alluvial soils, berseem clover (Trifolium alexandrinum l.), and groundwater after long-term wastewater irrigation

The reduced availability of water resources in Egypt has imposed the need to intensify the use of wastewater for crop irrigation in the alluvial soils of anthropogenic origin. Relevant effects can derive from contents of potentially toxic metals (PTMs) in supply resources soils, crops, and groundwater in these areas. For this reason the PTM content has to be monitored to evaluate and minimize health hazards. Therefore, in this context, two areas of the SE Nile Delta subjected to 25 year of wastewater irrigation, using agricultural drainage water (ADW) and mixed wastewater (MWW) were chosen and compared with a nearby site irrigated with Nile freshwater (NFW). At each of the three sites, ten samples of irrigation water, topsoil, berseem clover (Trifolium alexandrinum L.) plants, and seven groundwater samples were collected and analyzed for Cr, Co, Cu, Pb, Ni, and Zn. Results indicate that the total contents of Co, Cu, Ni, and Zn in soils collected from the three sampling sites and Pb in the MWW-irrigated soils were higher than their average natural contents in the earth’s crust, indicating potential risks. The DTPA-extractable contents of Cu in the three sites, in addition to Pb and Zn in the MWW-irrigated soils, exceeded the safe limits. The MWW-irrigated soils showed a considerable degree of metal contamination, while the NFW-and ADW-irrigated soils showed moderate and low levels of contamination, respectively. The contents of the six PTMs in the three sites showed low individual ecological risks, except for Pb in the MWW-irrigated soils that showed a moderate risk; however, the overall ecological risk remained low in all samples. The values of Co, Cu, and Ni in berseem shoot in addition to Pb from the MWW-irrigated soils were over the maximum permissible levels for animal feeding. Values of root-to-shoot translocation factor were lower than 1.0 for Cr, Co and Ni but higher than 1.0 for Cu, Pb, and Zn. Berssem plant is a good candidate for phytofiltration of Cr, Co and Ni, while for extracting Cu, Pb and Zn from polluted soils. The groundwater samples collected from the three sampling sites showed lower metal concentrations than the safe limits for drinking standards. Further remediation studies should be taken into account to alleviate potential environmental and health-related risks when using supply resources different from freshwater

ПИТАННЯ ЕКОНОМІЧНОЇ ДОСТУПНОСТІ ЛІКАРСЬКИХ ЗАСОБІВ НА АФРИКАНСЬКОМУ КОНТИНЕНТІ

ISSUES OF ECONOMIC AVAILABILITY OF MEDICAL DRUGS IN AFRICAO. Ievtushenko, Osama Abuzayid Mohamed Nur AhmedNational University of Pharmacy, Kharkiv city INTRODUCTIONCurrently Africa with its highest index of diseases in the world maintains a serious dependence of imported medical drugs. Imported production comprises from 80 to 100% in some African countries, despite the fact that the incomes of population and medical support system doesn’t correspond completely with the consumption of expensive medical drugs (further MD). There is an extremely severe problem of physical and economical availability of MD  in theEastern Mediterraneancountries. OBJECTIVE STATEMENT OF THE ARTICLEIn connection with the above mentioned, the purpose of the work is the analysis of economic availability of MD in theEastern Mediterraneancountries, and also  the comparison of the received indexes with the indexes of  European countries. In the researches it has been participated such countries as Sudan, Egypt, Lebanon, Uganda and Ethiopia. To compare the received indexes of availability and their level determination it has been made the comparison of indexes among themselves and also with the indexes of the developed country of the European continent. As a standard it has been taken Germany as a country with one of the most developed pharmaceutical markets in the world and the strongest health care system, which finances medical and pharmaceutical assurance among all the EU countries.RESEARCH METHODSIn this work it has been taken into account the pharma-economic  methods of analysis and methodology of the World Health Organization  (WHO) and Health Action International (HAI) «Prices determination of MD, their availability and price of components ", data obtained during this methodology examination [1, 4, 6-11]; information from regional and national sources [12]; and also the scientific publications on this topic [2,3,5]. Data concerning prices for medicines and the cost of treatment course were obtained in studying of retail prices in pharmacies of the above mentioned countries. In the total examination it has been studied the MD  which are used for the treatment of chronic diseases and which are included in the international list recommended for the continuous monitoring (study) by the World Health Organization . RESULTS AND IT DELIBERATION According to WHO recommendations, it has been selected the basic MD for the treatment of 14 the most common diseases, which will allow to make the international research. Also it is allowable to include in this list of MD the most important for the treatment of specific diseases in certain countries. Yes, for the African countries  such drugs are the remedies for the  malaria treatment.In the study it has been participated the generic MD sold at the lowest price. Further it has been determined the economic availability of studied MD, taking into account the ratio of the treatment cost by this drug (according to the  international treatment protocols) and the daily wage of unskilled low paid public officer in these countries.During the determination of economic accessibility of medicines it has been used the paying capacity adequacy ratio, which includes the lowest retail price of the drug (or the treatment course price), and the average salary for a certain period of time.The analysis shows that the availability of MD in some African countries is situated at the unsatisfactory level. Regarding the indicators of availability general perception, the lowest indicators hasSudan, the highest accessible indexes has Egypt. By comparison of the availability of MD in African countries and in Germany, for the diclofenac treatment course in Germany it is necessary to spend 0.24 of one day wages, and in Sudan - 5.3, which is higher in 22 times; for the paracetamol treatment the Sudan patients spend more in 10 times.Thus, the availability economic analysis of basic MD confirms  thatEgyptandLebanonassist a relatively low cost of basic MD, which is close to the level of the European countries. Especially in Egypt, the major part of economic availability indicators of medical drugs corresponds to parameters of the country with the developed pharmaceutical market and a strong health care system and this is Germany. Thus, the indicators ofEgyptare almost identical with those ofGermanyat the prices of Diclofenac, Atenolol, Captopril, Glibenclamide, Ceftriaxone, Diazepam, and even lower - with  Salbutamol, Amitriptyline, the antimalarial medical drugs.Thus, in Sudan is marked with the rather high prices and, consequently, low availability on a number of medical drugs such as Diclofenac, Paracetamol, Captopril, Simvastatin, Amitriptyline. Thus, patient inSudanneed  spend in 22 times more of money to the diclofenac treatment than patients inGermany. A treatment will paracetamol will be in10 times more expensive, treatment with captopril will be in 7 times more expensive. Comparison of availability indexes in theSudanwith the African region countries is also accompanied by a situation where the indicators availability of MD are in 3 - 10 times worse than in other countries with similar health care system. The necessity of  generic MD availability analyses, especially for the countries with the health care systems which are forming will help to make the fast and low priced  determination of the availability level of medicines for the population, the  timely reaction in case of indexes deterioration, the regulation of public policy of countries in the pricing field on MD as well as coordination of original and generic drugs use, which allow to reduce the budgetary costs of medical assistance without the quality loss.References1. Vyvchennya spozhyvannya likarsʹkykh zasobiv za anatomo-terapevtychno-khimichnoyu klasyfikatsiyeyu ta vstanovlenymy dobovymy dozamy (AT·S/DDD – metodolohiya): metod. rek. / A. M. Morozov, L. V. Yakovlyeva, A. V. Stepanenko ta in. – Kharkiv: Stylʹ-Yzdat. – 2013. – 34 s.2. Hromovyk B.P. Farmatsevtychnyy marketynh: teoretychni ta prykladni zasady / B.P. Hromovyk, H.D. Hasyuk, O.R. Levytsʹka. – Vinnytsya: Nova Knyha, 2004. – 464 s.3. Dovhun S. S. 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