| 1. |
- Qayoom, Irfan, et al.
(författare)
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A biphasic nanohydroxyapatite/calcium sulphate carrier containing Rifampicin and Isoniazid for local delivery gives sustained and effective antibiotic release and prevents biofilm formation
- 2020
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Long term multiple systemic antibiotics form the cornerstone in the treatment of bone and joint tuberculosis, often combined with local surgical eradication. Implanted carriers for local drug delivery have recently been introduced to overcome some of the limitations associated with conventional treatment strategies. In this study, we used a calcium sulphate hemihydrate (CSH)/nanohydroxyapatite (nHAP) based nanocement (NC) biomaterial as a void filler as well as a local delivery carrier of two standard of care tuberculosis drugs, Rifampicin (RFP) and Isoniazid (INH). We observed that the antibiotics showed different release patterns where INH showed a burst release of 67% and 100% release alone and in combination within one week, respectively whereas RFP showed sustained release of 42% and 49% release alone and in combination over a period of 12 weeks, respectively indicating different possible interactions of antibiotics with nHAP. The interactions were studied using computational methodology, which showed that the binding energy of nHAP with RFP was 148 kcal/mol and INH was 11 kcal/mol, thus varying substantially resulting in RFP being retained in the nHAP matrix. Our findings suggest that a biphasic ceramic based drug delivery system could be a promising treatment alternative to bone and joint TB.
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| 2. |
- Raina, Deepak Bushan, et al.
(författare)
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Long-term response to a bioactive biphasic biomaterial in the femoral neck of osteoporotic rats
- 2020
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Ingår i: Tissue Engineering - Part A. - : Mary Ann Liebert Inc. - 1937-3341 .- 1937-335X. ; 26:19-20, s. 1042-1051
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Tidskriftsartikel (refereegranskat)abstract
- Osteoporosis often leads to fragility fractures of the hip, resulting in impaired quality of life and increased mortality. Augmenting the proximal femur could be an attractive option for prevention of fracture or fixation device failure. We describe a tissue engineering based strategy to enhance long-term bone formation in the femoral neck of osteoporotic rats by locally delivering bioactive molecules; recombinant human bone morphogenic protein-2 (rhBMP-2), and zoledronic acid (ZA) by using a calcium sulfate/ hydroxyapatite (CaS/HA) biomaterial. A defect was created by reaming the femoral neck canal of osteoporotic (OVX) rats and they were treated as follows: G1. Empty, G2. CaS/HA, G3. CaS/HA+Systemic ZA, G4. CaS/HA+Local ZA, and G5. CaS/HA+Local ZA+rhBMP-2. Bone formation was evaluated 6 months after treatment. Further, radioactively labeled 14C-ZA was used to study the bioavailability of ZA at the defect location, which was determined by using scintillation counting. Micro-CT indicated significantly higher bone volume in groups G4 and G5 compared with the other treatment groups. This was confirmed qualitatively by histological assessment. Addition of rhBMP-2 gave no additional benefit in this model. Local delivery of ZA performed better than systemic administration of ZA. Mechanical testing showed no differences between the groups, likely reflecting that the addition of bioactive molecules had limited effect on cortical bone or the choice of mechanical testing setup was not optimal. Scintillation counting revealed higher amounts of 14C-ZA present in the treated leg of G4 compared with its contralateral control and compared with G3, indicating that local ZA delivery can be used to achieve high local concentrations without causing a systemic effect. This long-term study shows that local delivery of ZA using a CaS/HA carrier can regenerate cancellous bone in the femoral neck canal and has clear implications for enhancing implant integration and fixation in fragile bone.
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| 3. |
- Alay, Özgü, et al.
(författare)
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Monitoring and Analytics (Release B)
- 2021
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Rapport (refereegranskat)abstract
- This document describes the design and implementation of the 5GENESIS Monitoring & Analytics (M&A) framework in its Release B, developed within Task T3.3 of the project work plan. M&A Release B leverages and extends M&A Release A, which has been documented in the previous Deliverable D3.5 [1]. In particular, we present new features and enhancements introduced in this new Release compared to the Release A. We also report some examples of usage of the M&A framework, in order to showcase its integrated in the 5GENESIS Reference Architecture.
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| 4. |
- Kumar, Arun, 1991
(författare)
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Subjective perception and prediction model of vehicle stability under aerodynamic excitations
- 2021
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The current automotive era is moving towards electrified vehicle propulsion. As a result, an energy efficient vehicle design becomes one of the top priorities. From an aerodynamics point of view, the vehicle should be more streamlined for minimal aerodynamic drag. Such designs have the potential to enhance vehicle sensitivity when exposed to external disturbances such as unsteady aerodynamic forces and moments created by the flow of air around the vehicle. Before signing off for production, several on-road test scenarios are conducted by professional drivers to evaluate the new vehicle’s performance. Finding vehicle instabilities and proposing solutions to problem’s during such late phases of development is challenging in many aspects. The objective of this paper is to correlate and predict the driver’s subjective perception on high-speed straight-line driving stability with measurable quantities in the early phase of development. In this work, different aerodynamic devices were used for generating higher lift and asymmetric aerodynamic forces resulting in substandard straight-line drivability on-road. An inverted wing, an inverted wing with an asymmetric flat plate, and an asymmetric air curtain attached under the bumper were the selected aerodynamic devices paired with and without bumper side-kicks. The side-kicks help define the flow separation, thus improving the drivability of the tested vehicle. Plots of mean and standard deviation and ride diagrams of lateral acceleration, yaw velocity, steering angle, and steering torque are used to understand vehicle behaviour for the paired configurations and relate to the difference of subjective judgment of drivability within each pair. The ride diagram was used to separate the presence of transient behaviour and study its impact on subjective judgement. The qualitative assessment of the resulting trends agrees well with the subjective judgement of the driver. Clinical tests were conducted using driving simulators, in order to have an in-depth understanding of the subjective perception and responses of drivers towards external disturbances. Both common and experienced test drivers were involved in this test. The results provided an insight towards the disturbance frequencies and amplitudes of interest. From the test data, a model is generated that can predict the drivers’ subjective perception after experiencing induced external disturbances. The outcome also shows the impact of drivers’ steering action on their subjective perceptions towards these disturbances.
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| 5. |
- Mahajan, Prashant, et al.
(författare)
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A global survey of emergency department responses to the COVID-19 pandemic
- 2021
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Ingår i: Western Journal of Emergency Medicine. - 1936-900X. ; 22:5, s. 1037-1044
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Emergency departments (ED) globally are addressing the coronavirus disease 2019 (COVID-19) pandemic with varying degrees of success. We leveraged the 17-country, Emergency Medicine Education & Research by Global Experts (EMERGE) network and non-EMERGE ED contacts to understand ED emergency preparedness and practices globally when combating the COVID-19 pandemic. Methods: We electronically surveyed EMERGE and non-EMERGE EDs from April 3-June 1, 2020 on ED capacity, pandemic preparedness plans, triage methods, staffing, supplies, and communication practices. The survey was available in English, Mandarin Chinese, and Spanish to optimize participation. We analyzed survey responses using descriptive statistics. Results: 74/129 (57%) EDs from 28 countries in all six World Health Organization global regions responded. Most EDs were in Asia (49%), followed by North America (28%), and Europe (14%). Nearly all EDs (97%) developed and implemented protocols for screening, testing, and treating patients with suspected COVID-19 infections. Sixty percent responded that provider staffing/back-up plans were ineffective. Many sites (47/74, 64%) reported staff missing work due to possible illness with the highest provider proportion of COVID-19 exposures and infections among nurses. Conclusion: Despite having disaster plans in place, ED pandemic preparedness and response continue to be a challenge. Global emergency research networks are vital for generating and disseminating large-scale event data, which is particularly important during a pandemic.
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| 6. |
- Selvam, Arun Kumar
(författare)
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Selenium compounds as a novel class of experimental cancer chemotherapeutics
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Selenium is an essential micronutrient for humans, it has a narrow margin between antioxidant and pro-oxidant effects. Redox-active selenium compounds have the potency to increase ROS levels in cancer cells, providing a plausible window for therapeutic intervention. Redox-active selenium compounds such as sodium selenite (Se), selenocystine (SeC), and Se-methylselenocysteine (MSC) have been shown to inhibit growth, angiogenesis, and induce apoptosis by altering the redox potential (oxidative stress) in various tumor cells in vitro. Different selenium compounds produce different metabolites that act on tumor cells through multiple pathways. Sodium selenite is readily reduced to hydrogen selenide (HSe-) by extracellular cysteine, whereas selenocysteine is reduced to HSe- by enzymatic conversion by selenocysteine lyase. Another important selenium compound, MSC, is a prodrug metabolized to methylselenol by kynurenine aminotransferase 1 (KYAT1 or CCBL1). Hydrogen selenide (HSe-) and methylselenol (MS) are two important intermediate metabolites that are highly redox-active by inducing the production of ROS and initiating cell death via redox-regulated signaling pathways. Hydrogen selenide is more readily taken up by the cell compared to selenite. These intermediate molecules can effectively redox cycle with oxygen in the presence of NADPH and thiols, thus enhancing oxidative stress in malignant cells. Nevertheless, the anti-cancer properties of selenium compounds have not been fully characterized. In this work, our objective was to describe the anti-cancer properties of various selenium compounds using different methods and experimental models that are easily translatable from in vitro to in vivo. Selenite at physiological concentrations in combination with ATRA completely abolished the expression of the PML/RARα oncoprotein and increased the expression of the transcription factors RAR, PU.1 and FOXO3A, providing a plausible basis for the increased differentiation in cells of acute promyelocytic leukemia (APL). The extracellular milieu is important for selenite cytotoxicity, i.e. selenite is readily reduced to hydrogen selenide (HSe-) by extracellular cysteine, the xCT (cystine/glutamate transporter) antiporter is very important for HSe- turnover. Diphenyl diselenide, a small- molecule compound, increases the expression of xCT and its key regulatory genes such as NRF2 and ATF4 in vitro. When diphenyl diselenide was co-incubated with selenite or selenocysteine, we observed multiple sensitizing effects in almost all cancer cell lines tested. This provides a strong correlation between extracellular thiols and the cytotoxicity of selenite and selenocysteine. Kynurenine aminotransferase 1 (KYAT1 or CCBL1) is a PLP-dependent enzyme and plays an important role in MSC metabolism. KYAT1 has dual enzyme activity, transamination and β-elimination towards the single substrate. MSC is considered a prodrug that is not toxic as long as it is not metabolized by KYAT1. MSC is reduced by transamination to β-methylselenopyruvate (MSP) and by β-elimination to monomethylselenol. Several assays exist to determine the transamination activity of KYAT1, but very few simple assays exist to determine the β-elimination activity of KYAT1, which is not reliable because it is not a direct measure of MS. We introduced a simple novel coupled assay to determine the β-elimination activity of KYAT1. This assay method combines two enzyme systems, i.e. thioredoxin reductase1 (TrxR1) and KYAT1. MS is an excellent substrate for thioredoxin reductase1. MSC is metabolized to MS by β-elimination activity, and this can be used as a substrate for TrxR1, which is monitored spectrophotometrically by the oxidation of NADPH. Overexpression of KYAT1 may be an advantage in exploring the anti-tumor property of MSC, as it plays an important role in MSC metabolism. Both metabolites of MSC (MSP and MS) play critical roles in anti-tumor activity. MSP is known to inhibit HDAC activity, while MS has been shown to increase the formation of ROS and induce redox imbalance in the tumor. We used therapeutic mRNA techniques to induce KYAT1 expression using a lipid nanoparticle (LNPs)-based delivery system in hepatocellular carcinoma (HCC) cells. the addition of antisense microRNA122 (HCC-specific) with KYAT1mRNA showed precise targeting of HCC cells. Our results demonstrate successful targeted therapy in HCC cells with MSC. The choice of the model system is very important in drug screening. Cell culture, 2D and 3D models are widely used, but the reproducibility is very low when transferred to in vivo. Our group has established an ex vivo slice culture model for pancreatic ductal adenocarcinoma (PDAC). We used this ex vivo model to test the anti-cancer properties of sodium selenite and MSC. Our results, both by histology and transcriptomics data, show that sodium selenite at a concentration of 15 μM (concentration below MTD in humans) exhibited pronounced anti-tumor activity by targeting multiple hallmark genes that support cancer growth and progression. In this work, we have shown that redox-active selenium compounds as potential anti-cancer agents by (1) mechanisms to facilitate uptake by altering the expression of SLC7A11 (xCT) through small-molecule pharmacological compounds, (2) increasing the metabolizing enzymes (KYAT1) using different methods and targeted therapy (3) used different model (ex vivo) to mimic the in vivo settings.
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| 7. |
- Teotia, Arun K., et al.
(författare)
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Exosome-Functionalized Ceramic Bone Substitute Promotes Critical-Sized Bone Defect Repair in Rats
- 2021
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Ingår i: ACS Applied Bio Materials. - : American Chemical Society (ACS). - 2576-6422. ; 4:4, s. 3716-3726
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Tidskriftsartikel (refereegranskat)abstract
- Ceramic biomaterials are promising alternatives to bone autografts. However, limited bioactivity affects their performance. Therefore, bioactive molecules and cells are often added to enhance their performance. Exosomes have emerged as cell-secreted vesicles, delivering proteins, lipids, and nucleic acids in a paracrine/endocrine fashion. We studied two complementary aspects required for exosome activity/therapy using purified exosomes: first, the intracellular uptake of labeled exosomes and second, the influence of delivered exosomes on cell behavior. Origin-specific differences in the characteristics of purified exosomes, quantification of time-dependent intracellular uptake of PKH-26-labeled exosomes by mesenchymal stem cells (MSCs) and preosteoblasts, and influence on cell behavior were evaluated. Furthermore, exosomes from osteoblasts and MSCs cultured under normal and osteogenic environments were isolated. There is little data available on the concentration and dose of exosomes required for bone regeneration. Therefore, equal amounts of quantified exosomes were implanted in vivo in rat tibia critical defects using a calcium sulfate-nano-hydroxyapatite nanocement (NC) bone filler as the carrier. Bone regeneration was quantified using micro-computed tomography and histology. Along with inducing early maturation and mineral deposition by primary preosteoblasts in vitro, exosome treatment also demonstrated a positive effect on bone mineralization in vivo. Our study concludes that providing a local delivery of exosomes loaded onto a slowly resorbing NC bone filler can provide a potential alternate to autografts as a bone substitute.
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