| 1. |
|
|
| 2. |
|
|
| 3. |
|
|
| 4. |
|
|
| 5. |
|
|
| 6. |
|
|
| 7. |
|
|
| 8. |
|
|
| 9. |
|
|
| 10. |
- Ademuyiwa, Adesoji O., et al.
(author)
-
Determinants of morbidity and mortality following emergency abdominal surgery in children in low-income and middle-income countries
- 2016
-
In: BMJ Global Health. - : BMJ Publishing Group Ltd. - 2059-7908. ; 1:4
-
Journal article (peer-reviewed)abstract
- Background: Child health is a key priority on the global health agenda, yet the provision of essential and emergency surgery in children is patchy in resource-poor regions. This study was aimed to determine the mortality risk for emergency abdominal paediatric surgery in low-income countries globally.Methods: Multicentre, international, prospective, cohort study. Self-selected surgical units performing emergency abdominal surgery submitted prespecified data for consecutive children aged <16 years during a 2-week period between July and December 2014. The United Nation's Human Development Index (HDI) was used to stratify countries. The main outcome measure was 30-day postoperative mortality, analysed by multilevel logistic regression.Results: This study included 1409 patients from 253 centres in 43 countries; 282 children were under 2 years of age. Among them, 265 (18.8%) were from low-HDI, 450 (31.9%) from middle-HDI and 694 (49.3%) from high-HDI countries. The most common operations performed were appendectomy, small bowel resection, pyloromyotomy and correction of intussusception. After adjustment for patient and hospital risk factors, child mortality at 30 days was significantly higher in low-HDI (adjusted OR 7.14 (95% CI 2.52 to 20.23), p<0.001) and middle-HDI (4.42 (1.44 to 13.56), p=0.009) countries compared with high-HDI countries, translating to 40 excess deaths per 1000 procedures performed.Conclusions: Adjusted mortality in children following emergency abdominal surgery may be as high as 7 times greater in low-HDI and middle-HDI countries compared with high-HDI countries. Effective provision of emergency essential surgery should be a key priority for global child health agendas.
|
|
| 11. |
|
|
| 12. |
- Blixt, L., et al.
(author)
-
Covid-19 in patients with chronic lymphocytic leukemia : clinical outcome and B- and T-cell immunity during 13 months in consecutive patients
- 2022
-
In: Leukemia. - : Springer Nature. - 0887-6924 .- 1476-5551. ; 36:2, s. 476-481
-
Journal article (peer-reviewed)abstract
- We studied clinical and immunological outcome of Covid-19 in consecutive CLL patients from a well-defined area during month 1–13 of the pandemic. Sixty patients (median age 71 y, range 43–97) were identified. Median CIRS was eight (4–20). Patients had indolent CLL (n = 38), had completed (n = 12) or ongoing therapy (n = 10). Forty-six patients (77%) were hospitalized due to severe Covid-19 and 11 were admitted to ICU. Severe Covid-19 was equally distributed across subgroups irrespective of age, gender, BMI, CLL status except CIRS (p < 0.05). Fourteen patients (23%) died; age ≥75 y was the only significant risk factor (p < 0.05, multivariate analysis with limited power). Comparing month 1–6 vs 7–13 of the pandemic, deaths were numerically reduced from 32% to 18%, ICU admission from 37% to 15% whereas hospitalizations remained frequent (86% vs 71%). Seroconversion occurred in 33/40 patients (82%) and anti-SARS-CoV-2 antibodies were detectable at six and 12 months in 17/22 and 8/11 patients, respectively. Most (13/17) had neutralizing antibodies and 19/28 had antibodies in saliva. SARS-CoV-2-specific T-cells (ELISpot) were detected in 14/17 patients. Covid-19 continued to result in high admission even among consecutive and young early- stage CLL patients. A robust and durable B and/or T cell immunity was observed in most convalescents.
|
|
| 13. |
|
|
| 14. |
- Daralnakhla, H, et al.
(author)
-
Lipophilic Peptide Dendrimers for Delivery of Splice-Switching Oligonucleotides
- 2021
-
In: Pharmaceutics. - : MDPI AG. - 1999-4923. ; 13:1
-
Journal article (peer-reviewed)abstract
- Non-viral transfection reagents are continuously being developed in attempt to replace viral vectors. Among those non-viral vectors, dendrimers have gained increasing interest due to their unique molecular structure and multivalency. However, more improvements are still needed to achieve higher efficacy and lower toxicity. In this study, we have examined 18 peptide dendrimers conjugated to lipophilic moieties, such as fatty acids or hydrophobic amino acids, that were previously explored for siRNA. Reporter cells were employed to investigate the transfection of single strand splice-switching oligonucleotides (ONs) using these peptide dendrimers. Luciferase level changes reflecting efficiency varied with amino acid composition, stereochemistry, and complexation media used. 3rd generation peptide dendrimers with D-amino acid configuration were superior to L-form. Lead formulations with 3rd generation, D-amino acid peptide dendrimers increased the correction level of the delivered ON up to 93-fold over untreated HeLa Luc/705 cells with minimal toxicity. To stabilize the formed complexes, Polyvinyl alcohol 18 (PVA18) polymer was added. Although PVA18 addition increased activity, toxicity when using our best candidates G 2,3KL-(Leu)4 (D) and G 2,3KL-diPalmitamide (D) was observed. Our findings demonstrate the potential of lipid-conjugated, D-amino acid-containing peptide dendrimers to be utilized as an effective and safe delivery vector for splice-switching ONs.
|
|
| 15. |
- Estupinan, HY, et al.
(author)
-
BTK gatekeeper residue variation combined with cysteine 481 substitution causes super-resistance to irreversible inhibitors acalabrutinib, ibrutinib and zanubrutinib
- 2021
-
In: Leukemia. - : Springer Science and Business Media LLC. - 1476-5551 .- 0887-6924. ; 35:85, s. 1317-1329
-
Journal article (peer-reviewed)abstract
- Irreversible inhibitors of Bruton tyrosine kinase (BTK), pioneered by ibrutinib, have become breakthrough drugs in the treatment of leukemias and lymphomas. Resistance variants (mutations) occur, but in contrast to those identified for many other tyrosine kinase inhibitors, they affect less frequently the “gatekeeper” residue in the catalytic domain. In this study we carried out variation scanning by creating 11 substitutions at the gatekeeper amino acid, threonine 474 (T474). These variants were subsequently combined with replacement of the cysteine 481 residue to which irreversible inhibitors, such as ibrutinib, acalabrutinib and zanubrutinib, bind. We found that certain double mutants, such as threonine 474 to isoleucine (T474I) or methionine (T474M) combined with catalytically active cysteine 481 to serine (C481S), are insensitive to ≥16-fold the pharmacological serum concentration, and therefore defined as super-resistant to irreversible inhibitors. Conversely, reversible inhibitors showed a variable pattern, from resistance to no resistance, collectively demonstrating the structural constraints for different classes of inhibitors, which may affect their clinical application.
|
|
| 16. |
- Estupinan, HY, et al.
(author)
-
Comparative Analysis of BTK Inhibitors and Mechanisms Underlying Adverse Effects
- 2021
-
In: Frontiers in cell and developmental biology. - : Frontiers Media SA. - 2296-634X. ; 9, s. 630942-
-
Journal article (peer-reviewed)abstract
- The cytoplasmic protein-tyrosine kinase BTK plays an essential role for differentiation and survival of B-lineage cells and, hence, represents a suitable drug target. The number of BTK inhibitors (BTKis) in the clinic has increased considerably and currently amounts to at least 22. First-in-class was ibrutinib, an irreversible binder forming a covalent bond to a cysteine in the catalytic region of the kinase, for which we have identified 228 active trials listed atClinicalTrials.gov. Next-generation inhibitors, acalabrutinib and zanubrutinib, are approved both in the United States and in Europe, and zanubrutinib also in China, while tirabrutinib is currently only registered in Japan. In most cases, these compounds have been used for the treatment of B-lymphocyte tumors. However, an increasing number of trials instead addresses autoimmunity and inflammation in multiple sclerosis, rheumatoid arthritis, pemphigus and systemic lupus erythematosus with the use of either irreversibly binding inhibitors, e.g., evobrutinib and tolebrutinib, or reversibly binding inhibitors, like fenebrutinib. Adverse effects (AEs) have predominantly implicated inhibition of other kinases with a BTKi-binding cysteine in their catalytic domain. Analysis of the reported AEs suggests that ibrutinib-associated atrial fibrillation is caused by binding to ERBB2/HER2 and ERBB4/HER4. However, the binding pattern of BTKis to various additional kinases does not correlate with the common assumption that skin manifestations and diarrhoeas are off-target effects related to EGF receptor inhibition. Moreover, dermatological toxicities, diarrhoea, bleedings and invasive fungal infections often develop early after BTKi treatment initiation and subsequently subside. Conversely, cardiovascular AEs, like hypertension and various forms of heart disease, often persist.
|
|
| 17. |
|
|
| 18. |
- Fröjdh, Erik, et al.
(author)
-
Depth of interaction and bias voltage dependence of the spectral response in a pixellated CdTe detector operating in time-over-threshold mode subjected to monochromatic X-rays
- 2012
-
In: Journal of Instrumentation. - 1748-0221. ; 7:3, s. Art. no. C03002-
-
Journal article (peer-reviewed)abstract
- High stopping power is one of the most important figures of merit for X-ray detectors. CdTe is a promising material but suffers from: material defects, non-ideal charge transport and long range X-ray fluorescence. Those factors reduce the image quality and deteriorate spectral information. In this project we used a monochromatic pencil beam collimated through a 20Όm pinhole to measure the detector spectral response in dependance on the depth of interaction. The sensor was a 1mm thick CdTe detector with a pixel pitch of 110Όm, bump bonded to a Timepix readout chip operating in Time-Over-Threshold mode. The measurements were carried out at the Extreme Conditions beamline I15 of the Diamond Light Source. The beam was entering the sensor at an angle of ∌20 degrees to the surface and then passed through ∌25 pixels before leaving through the bottom of the sensor. The photon energy was tuned to 77keV giving a variation in the beam intensity of about three orders of magnitude along the beam path. Spectra in Time-over-Threshold (ToT) mode were recorded showing each individual interaction. The bias voltage was varied between -30V and -300V to investigate how the electric field affected the spectral information. For this setup it is worth noticing the large impact of fluorescence. At -300V the photo peak and escape peak are of similar height. For high bias voltages the spectra remains clear throughout the whole depth but for lower voltages as -50V, only the bottom part of the sensor carries spectral information. This is an effect of the low hole mobility and the longer range the electrons have to travel in a low field. © 2012 IOP Publishing Ltd and Sissa Medialab srl.
|
|
| 19. |
- Fröjdh, Erik, et al.
(author)
-
Probing Defects in a Small Pixellated CdTe Sensor Using an Inclined Mono Energetic X-Ray Micro Beam
- 2013
-
In: IEEE Transactions on Nuclear Science. - 0018-9499 .- 1558-1578. ; 60:4, s. 2864-2869
-
Journal article (peer-reviewed)abstract
- High quantum efficiency is important in X-ray imaging applications. This means using high-Z sensor materials. Unfortunately many of these materials suffer from defects that cause non-ideal charge transport. In order to increase the understanding of these defects, we have mapped the 3D response of a number of defects in two 1 mm thick CdTe sensors with different pixel sizes (55 mu m and 110 mu m) using a monoenergetic microbeam at 79 keV. The sensors were bump bonded to Timepix read out chips. Data was collected in photon counting as well as time-over-thresholdmode. The time-over-thresholdmode is a very powerful tool to investigate charge transport properties and fluorescence in pixellated detectors since the signal from the charge that each photon deposits in each pixel can be analyzed. Results show distorted electrical field around the defects, indications of excess leakage current and large differences in behavior between electron collection and hole collection mode. The experiments were carried out on the Extreme Conditions Beamline I15 at Diamond Light Source.
|
|
| 20. |
|
|
| 21. |
|
|
| 22. |
|
|
| 23. |
|
|
| 24. |
- Hande, M, et al.
(author)
-
Oligonucleotide⁻Palladacycle Conjugates as Splice-Correcting Agents
- 2019
-
In: Molecules (Basel, Switzerland). - : MDPI AG. - 1420-3049. ; 24:6
-
Journal article (peer-reviewed)abstract
- 2’-O-Methylribo phosphorothioate oligonucleotides incorporating cyclopalladated benzylamine conjugate groups at their 5’-termini have been prepared and their ability to hybridize with a designated target sequence was assessed by conventional UV melting experiments. The oligonucleotides were further examined in splice-switching experiments in human cervical cancer (HeLa Luc/705), human liver (HuH7_705), and human osteosarcoma (U-2 OS_705) reporter cell lines. Melting temperatures of duplexes formed by the modified oligonucleotides were approximately 5 °C lower than melting temperatures of the respective unmodified duplexes. The cyclopalladated oligonucleotides functioned as splice-correcting agents in the HeLa Luc/705 cell line somewhat more efficiently than their unmodified counterparts. Furthermore, the introduction of this chemical modification did not induce toxicity in cells. These results demonstrate the feasibility of using covalently metalated oligonucleotides as therapeutic agents.
|
|
| 25. |
|
|
| 26. |
|
|
| 27. |
- Maneuski, D., et al.
(author)
-
Imaging and spectroscopic performance studies of pixellated CdTe Timepix detector
- 2012
-
In: Journal of Instrumentation. - 1748-0221. ; 7:1, s. Art. no. C01038-
-
Journal article (peer-reviewed)abstract
- In this work the results on imaging and spectroscopic performances of 14 × 14 × 1 mm CdTe detectors with 55 × 55Όm and 110 × 110Όm pixel pitch bump-bonded to a Timepix chip are presented. The performance of the 110 × 110Όm pixel detector was evaluated at the extreme conditions beam line I15 of the Diamond Light Source. The energy of X-rays was set between 25 and 77 keV. The beam was collimated through the edge slits to 20Όm FWHM incident in the middle of the pixel. The detector was operated in the time-over-threshold mode, allowing direct energy measurement. Energy in the neighbouring pixels was summed for spectra reconstruction. Energy resolution at 77 keV was found to be ΔE/E = 3.9%. Comparative imaging and energy resolution studies were carried out between two pixel size detectors with a fluorescence target X-ray tube and radioactive sources. The 110 × 110Όm pixel detector exhibited systematically better energy resolution in comparison to 55 × 55Όm. An imaging performance of 55 × 55Όm pixellated CdTe detector was assessed using the Modulation Transfer Function (MTF) technique and compared to the larger pixel. A considerable degradation in MTF was observed for bias voltages below -300 V. Significant room for improvement of the detector performance was identified both for imaging and spectroscopy and is discussed. © 2012 IOP Publishing Ltd and SISSA.
|
|
| 28. |
|
|
| 29. |
- Naeem, Aishath, et al.
(author)
-
Pirtobrutinib targets BTK C481S in ibrutinib-resistant CLL but second-site BTK mutations lead to resistance
- 2023
-
In: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 7:9, s. 1929-1943
-
Journal article (peer-reviewed)abstract
- Covalent inhibitors of Bruton tyrosine kinase (BTK) have transformed the therapy of chronic lymphocytic leukemia (CLL), but continuous therapy has been complicated by the development of resistance. The most common resistance mechanism in patients whose disease progresses on covalent BTK inhibitors (BTKis) is a mutation in the BTK 481 cysteine residue to which the inhibitors bind covalently. Pirtobrutinib is a highly selective, noncovalent BTKi with substantial clinical activity in patients whose disease has progressed on covalent BTKi, regardless of BTK mutation status. Using in vitro ibrutinib-resistant models and cells from patients with CLL, we show that pirtobrutinib potently inhibits BTK-mediated functions including B-cell receptor (BCR) signaling, cell viability, and CCL3/CCL4 chemokine production in both BTK wild-type and C481S mutant CLL cells. We demonstrate that primary CLL cells from responding patients on the pirtobrutinib trial show reduced BCR signaling, cell survival, and CCL3/CCL4 chemokine secretion. At time of progression, these primary CLL cells show increasing resistance to pirtobrutinib in signaling inhibition, cell viability, and cytokine production. We employed longitudinal whole-exome sequencing on 2 patients whose disease progressed on pirtobrutinib and identified selection of alternative-site BTK mutations, providing clinical evidence that secondary BTK mutations lead to resistance to noncovalent BTKis.
|
|
| 30. |
- Nikravesh, Abbas, et al.
(author)
-
Antisense PNA Accumulates in Escheria coli and mediates a Long Post-antibiotic Effect
- 2008
-
In: Molecular Therapy. - : Elsevier BV. - 1525-0016 .- 1525-0024. ; 15:8, s. 1537-1542
-
Journal article (peer-reviewed)abstract
- Antisense agents that target growth-essential genes display surprisingly potent bactericidal properties. In particular, peptide nucleic acid (PNA) and phosphorodiamidate morpholino oligomers linked to cationic carrier peptides are effective in time kill assays and as inhibitors of bacterial peritonitis in mice. It is unclear how these relatively large antimicrobials overcome stringent bacterial barriers and mediate killing. Here we determined the transit kinetics of peptide–PNAs and observed an accumulation of cell-associated PNA in Escherichia coli and slow efflux. An inhibitor of drug efflux pumps did not alter peptide–PNA potency, indicating a lack of active efflux from cells. Consistent with cell retention, the post-antibiotic effect (PAE) of the anti-acyl carrier protein (acpP) peptide–PNA was greater than 11 hours. Bacterial cell accumulation and a long PAE are properties of significant interest for antimicrobial development.
|
|
| 31. |
- Nizami, Abdul-Sattar, et al.
(author)
-
Waste biorefineries : enabling circular economies in developing countries
- 2017
-
In: Bioresource Technology. - : Elsevier. - 0960-8524 .- 1873-2976. ; 241, s. 1101-1117
-
Journal article (peer-reviewed)abstract
- This paper aims to examine the potential of waste biorefineries in developing countries as a solution to current waste disposal problems and as facilities to produce fuels, power, heat, and value-added products. The waste in developing countries represents a significant source of biomass, recycled materials, chemicals, energy, and revenue if wisely managed and used as a potential feedstock in various biorefinery technologies such as fermentation, anaerobic digestion (AD), pyrolysis, incineration, and gasification. However, the selection or integration of biorefinery technologies in any developing country should be based on its waste characterization. Waste biorefineries if developed in developing countries could provide energy generation, land savings, new businesses and consequent job creation, savings of landfills costs, GHG emissions reduction, and savings of natural resources of land, soil, and groundwater. The challenges in route to successful implementation of biorefinery concept in the developing countries are also presented using life cycle assessment (LCA) studies. (C) 2017 Elsevier Ltd. All rights reserved.
|
|
| 32. |
- Pabon-Martinez, YV, et al.
(author)
-
LNA effects on DNA binding and conformation: from single strand to duplex and triplex structures
- 2017
-
In: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7:1, s. 11043-
-
Journal article (peer-reviewed)abstract
- The anti-gene strategy is based on sequence-specific recognition of double-strand DNA by triplex forming (TFOs) or DNA strand invading oligonucleotides to modulate gene expression. To be efficient, the oligonucleotides (ONs) should target DNA selectively, with high affinity. Here we combined hybridization analysis and electrophoretic mobility shift assay with molecular dynamics (MD) simulations to better understand the underlying structural features of modified ONs in stabilizing duplex- and triplex structures. Particularly, we investigated the role played by the position and number of locked nucleic acid (LNA) substitutions in the ON when targeting a c-MYC or FXN (Frataxin) sequence. We found that LNA-containing single strand TFOs are conformationally pre-organized for major groove binding. Reduced content of LNA at consecutive positions at the 3′-end of a TFO destabilizes the triplex structure, whereas the presence of Twisted Intercalating Nucleic Acid (TINA) at the 3′-end of the TFO increases the rate and extent of triplex formation. A triplex-specific intercalating benzoquinoquinoxaline (BQQ) compound highly stabilizes LNA-containing triplex structures. Moreover, LNA-substitution in the duplex pyrimidine strand alters the double helix structure, affecting x-displacement, slide and twist favoring triplex formation through enhanced TFO major groove accommodation. Collectively, these findings should facilitate the design of potent anti-gene ONs.
|
|
| 33. |
|
|
| 34. |
|
|
| 35. |
|
|
| 36. |
|
|
| 37. |
|
|
| 38. |
|
|
| 39. |
|
|
| 40. |
- Saher, O, et al.
(author)
-
Sugar and Polymer Excipients Enhance Uptake and Splice-Switching Activity of Peptide-Dendrimer/Lipid/Oligonucleotide Formulations
- 2019
-
In: Pharmaceutics. - : MDPI AG. - 1999-4923. ; 11:12
-
Journal article (peer-reviewed)abstract
- Non-viral transfection vectors are commonly used for oligonucleotide (ON) delivery but face many challenges before reaching the desired compartments inside cells. With the support of additional compounds, it might be more feasible for a vector to endure the barriers and achieve efficient delivery. In this report, we screened 18 different excipients and evaluated their effect on the performance of peptide dendrimer/lipid vector to deliver single-stranded, splice-switching ONs under serum conditions. Transfection efficiency was monitored in four different reporter cell lines by measuring splice-switching activity on RNA and protein levels. All reporter cell lines used had a mutated human β-globin intron 2 sequence interrupting the luciferase gene, which led to an aberrant splicing of luciferase pre-mRNA and subsidence of luciferase protein translation. In the HeLa Luc/705 reporter cell line (a cervical cancer cell line), the lead excipients (Polyvinyl derivatives) potentiated the splice-switching activity up to 95-fold, compared to untreated cells with no detected cytotoxicity. Physical characterization revealed that lead excipients decreased the particle size and the zeta potential of the formulations. In vivo biodistribution studies emphasized the influence of formulations as well as the type of excipients on biodistribution profiles of the ON. Subsequently, we suggest that the highlighted impact of tested excipients would potentially assist in formulation development to deliver ON therapeutics in pre-clinical and clinical settings.
|
|
| 41. |
- Saidas Nair, K, et al.
(author)
-
Alteration of the serine protease PRSS56 causes angle-closure glaucoma in mice and posterior microphthalmia in humans and mice
- 2011
-
In: NATURE GENETICS. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 43:6, s. 579-U118
-
Journal article (peer-reviewed)abstract
- Angle-closure glaucoma (ACG) is a subset of glaucoma affecting 16 million people(1-3). Although 4 million people are bilaterally blind from ACG(4,5), the causative molecular mechanisms of ACG remain to be defined. High intraocular pressure induces glaucoma in ACG. High intraocular pressure traditionally was suggested to result from the iris blocking or closing the angle of the eye, thereby limiting aqueous humor drainage. Eyes from individuals with ACG often have a modestly decreased axial length, shallow anterior chamber and relatively large lens, features that predispose to angle closure(6). Here we show that genetic alteration of a previously unidentified serine protease (PRSS56) alters axial length and causes a mouse phenotype resembling ACG. Mutations affecting this protease also cause a severe decrease of axial length in individuals with posterior microphthalmia. Together, these data suggest that alterations of this serine protease may contribute to a spectrum of human ocular conditions including reduced ocular size and ACG.
|
|
| 42. |
|
|
| 43. |
|
|
| 44. |
|
|
| 45. |
|
|
| 46. |
|
|
| 47. |
- Smith, CIE, et al.
(author)
-
Therapeutic Oligonucleotides: State of the Art
- 2019
-
In: Annual review of pharmacology and toxicology. - : Annual Reviews. - 1545-4304 .- 0362-1642. ; 59, s. 605-630
-
Journal article (peer-reviewed)abstract
- Oligonucleotides (ONs) can interfere with biomolecules representing the entire extended central dogma. Antisense gapmer, steric block, splice-switching ONs, and short interfering RNA drugs have been successfully developed. Moreover, antagomirs (antimicroRNAs), microRNA mimics, aptamers, DNA decoys, DNAzymes, synthetic guide strands for CRISPR/Cas, and innate immunity-stimulating ONs are all in clinical trials. DNA-targeting, triplex-forming ONs and strand-invading ONs have made their mark on drug development research, but not yet as medicines. Both design and synthetic nucleic acid chemistry are crucial for achieving biologically active ONs. The dominating modifications are phosphorothioate linkages, base methylation, and numerous 2′-substitutions in the furanose ring, such as 2′-fluoro, O-methyl, or methoxyethyl. Locked nucleic acid and constrained ethyl, a related variant, are bridged forms where the 2′-oxygen connects to the 4′-carbon in the sugar. Phosphorodiamidate morpholino oligomers, carrying a modified heterocyclic backbone ring, have also been commercialized. Delivery remains a major obstacle, but systemic administration and intrathecal infusion are used for treatment of the liver and brain, respectively.
|
|
| 48. |
- T, Schleyer, et al.
(author)
-
Advancing oral medicine through informatics and information technology: a proposed framework and strategy.
- 2011
-
In: Oral diseases. - : Wiley. - 1354-523X. ; 17:Suppl 1, s. 85-94
-
Research review (peer-reviewed)abstract
- Abstract The implementation of information technology in healthcare is a significant focus for many nations around the world. However, information technology support for clinical care, research and education in oral medicine is currently poorly developed. This situation hampers our ability to transform oral medicine into a 'learning healthcare discipline' in which the divide between clinical practice and research is diminished and, ultimately, eliminated. This paper reviews the needs of and requirements for information technology support of oral medicine and proposes an agenda designed to meet those needs. For oral medicine, this agenda includes analyzing and reviewing current clinical and documentation practices, working toward progressively standardizing clinical data, and helping define requirements for oral medicine systems. IT professionals can contribute by conducting baseline studies about the use of electronic systems, helping develop controlled vocabularies and ontologies, and designing, implementing, and evaluating novel systems centered on the needs of clinicians, researchers and educators. Successfully advancing IT support for oral medicine will require close coordination and collaboration among oral medicine professionals, information technology professionals, system vendors, and funding agencies. If current barriers and obstacles are overcome, practice and research in oral medicine stand ready to derive significant benefits from the application of information technology.
|
|
| 49. |
- Umek, T., et al.
(author)
-
Oligonucleotides Targeting DNA Repeats Downregulate Huntingtin Gene Expression in Huntington's Patient-Derived Neural Model System
- 2021
-
In: Nucleic Acid Therapeutics. - : Mary Ann Liebert Inc. - 2159-3337 .- 2159-3345. ; 31:6, s. 443-456
-
Journal article (peer-reviewed)abstract
- Huntington's disease (HD) is one of the most common, dominantly inherited neurodegenerative disorders. It affects the striatum, cerebral cortex, and other subcortical structures leading to involuntary movement abnormalities, emotional disturbances, and cognitive impairments. HD is caused by a CAG center dot CTG trinucleotide-repeat expansion in exon 1 of the huntingtin (HTT) gene leading to the formation of mutant HTT (mtHTT) protein aggregates. Besides the toxicity of the mutated protein, there is also evidence that mtHTT transcripts contribute to the disease. Thus, the reduction of both mutated mRNA and protein would be most beneficial as a treatment. Previously, we designed a novel anti-gene oligonucleotide (AGO)-based strategy directly targeting the HTT trinucleotide-repeats in DNA and reported downregulation of mRNA and protein in HD patient fibroblasts. In this study, we differentiate HD patient-derived induced pluripotent stem cells to investigate the efficacy of the AGO, a DNA/Locked Nucleic Acid mixmer with phosphorothioate backbone, to modulate HTT transcription during neural in vitro development. For the first time, we demonstrate downregulation of HTT mRNA following both naked and magnetofected delivery into neural stem cells (NSCs) and show that neither emergence of neural rosette structures nor self-renewal of NSCs is compromised. Furthermore, the inhibition potency of both HTT mRNA and protein without off-target effects is confirmed in neurons. These results further validate an anti-gene approach for the treatment of HD.
|
|
| 50. |
|
|
