| 1. |
- Niklasson, Mia, et al.
(författare)
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Membrane-Depolarizing Channel Blockers Induce Selective Glioma Cell Death by Impairing Nutrient Transport and Unfolded Protein/Amino Acid Responses
- 2017
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Ingår i: Cancer Research. - : AMER ASSOC CANCER RESEARCH. - 0008-5472 .- 1538-7445. ; 77:7, s. 1741-1752
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Tidskriftsartikel (refereegranskat)abstract
- Glioma-initiating cells (GIC) are considered the underlying cause of recurrences of aggressive glioblastomas, replenishing the tumor population and undermining the efficacy of conventional chemotherapy. Here we report the discovery that inhibiting T-type voltage-gated Ca2+ and KCa channels can effectively induce selective cell death of GIC and increase host survival in an orthotopic mouse model of human glioma. At present, the precise cellular pathways affected by the drugs affecting these channels are unknown. However, using cell-based assays and integrated proteomics, phosphoproteomics, and transcriptomics analyses, we identified the downstreamsignaling events these drugs affect. Changes in plasma membrane depolarization and elevated intracellular Na+, which compromised Na+-dependent nutrient transport, were documented. Deficits in nutrient deficit acted in turn to trigger the unfolded protein response and the amino acid response, leading ultimately to nutrient starvation and GIC cell death. Our results suggest new therapeutic targets to attack aggressive gliomas.
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| 2. |
- Al-Amin, Rasel A., Researcher, 1983-, et al.
(författare)
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Monitoring drug–target interactions through target engagement-mediated amplification on arrays and in situ
- 2022
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Ingår i: Nucleic Acids Research. - : Oxford University Press. - 0305-1048 .- 1362-4962. ; 50:22, s. e129-e129
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Tidskriftsartikel (refereegranskat)abstract
- Drugs are designed to bind their target proteins in physiologically relevant tissues and organs to modulate biological functions and elicit desirable clinical outcomes. Information about target engagement at cellular and subcellular resolution is therefore critical for guiding compound optimization in drug discovery, and for probing resistance mechanisms to targeted therapies in clinical samples. We describe a target engagement-mediated amplification (TEMA) technology, where oligonucleotide-conjugated drugs are used to visualize and measure target engagement in situ, amplified via rolling-circle replication of circularized oligonucleotide probes. We illustrate the TEMA technique using dasatinib and gefitinib, two kinase inhibitors with distinct selectivity profiles. In vitro binding by the dasatinib probe to arrays of displayed proteins accurately reproduced known selectivity profiles, while their differential binding to fixed adherent cells agreed with expectations from expression profiles of the cells. We also introduce a proximity ligation variant of TEMA to selectively investigate binding to specific target proteins of interest. This form of the assay serves to improve resolution of binding to on- and off-target proteins. In conclusion, TEMA has the potential to aid in drug development and clinical routine by conferring valuable insights in drug–target interactions at spatial resolution in protein arrays, cells and in tissues.
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| 3. |
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| 4. |
- Birznieks, Ingvars, et al.
(författare)
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Encoding of direction of fingertip forces by human tactile afferents
- 2001
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Ingår i: Journal of Neuroscience. - : Society for Neuroscience. - 0270-6474 .- 1529-2401. ; 21:20, s. 8222-8237
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Tidskriftsartikel (refereegranskat)abstract
- In most manipulations, we use our fingertips to apply time-varying forces to the target object in controlled directions. Here we used microneurography to assess how single tactile afferents encode the direction of fingertip forces at magnitudes, rates, and directions comparable to those arising in everyday manipulations. Using a flat stimulus surface, we applied forces to a standard site on the fingertip while recording impulse activity in 196 tactile afferents with receptive fields distributed over the entire terminal phalanx. Forces were applied in one of five directions: normal force and forces at a 20 degrees angle from the normal in the radial, distal, ulnar, or proximal directions. Nearly all afferents responded, and the responses in most slowly adapting (SA)-I, SA-II, and fast adapting (FA)-I afferents were broadly tuned to a preferred direction of force. Among afferents of each type, the preferred directions were distributed in all angular directions with reference to the stimulation site, but not uniformly. The SA-I population was biased for tangential force components in the distal direction, the SA-II population was biased in the proximal direction, and the FA-I population was biased in the proximal and radial directions. Anisotropic mechanical properties of the fingertip and the spatial relationship between the receptive field center of the afferent and the stimulus site appeared to influence the preferred direction in a manner dependent on afferent type. We conclude that tactile afferents from the whole terminal phalanx potentially contribute to the encoding of direction of fingertip forces similar to those that occur when subjects manipulate objects under natural conditions.
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| 5. |
- Diwakarla, Shanti, et al.
(författare)
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Aryl Sulfonamide Inhibitors of Insulin-Regulated Aminopeptidase Enhance Spine Density in Primary Hippocampal Neuron Cultures
- 2016
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Ingår i: ACS Chemical Neuroscience. - : American Chemical Society (ACS). - 1948-7193. ; 7:10, s. 1383-1392
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Tidskriftsartikel (refereegranskat)abstract
- The zinc metallopeptidase insulin regulated aminopeptidase (IRAP), which is highly expressed in the hippocampus and other brain regions associated with cognitive function, has been identified as a high-affinity binding site of the hexapeptide angiotensin IV (Ang IV). This hexapeptide is thought to facilitate learning and memory by binding to the catalytic site of IRAP to inhibit its enzymatic activity. In support of this hypothesis, low molecular weight, nonpeptide specific inhibitors of TRAP have been shown to enhance memory in rodent models. Recently, it was demonstrated that linear and macrocyclic Ang IV-derived peptides can alter the shape and increase the number of dendritic spines in hippocampal cultures, properties associated with enhanced cognitive performance. After screening a library of 10 500 drug like substances for their ability to inhibit IRAP, we identified a series of low molecular weight aryl sulfonamides, which exhibit no structural similarity to Ang IV, as moderately potent IRAP inhibitors:A structural and biological characterization of three of these aryl sulfonamides was performed. Their binding modes to human IRAP were explored by docking calculations combined with molecular dynamics simulations and binding affinity estimations using the linear interaction energy method. Two alternative binding modes emerged from this analysis, both of which correctly rank the ligands according to their experimental binding affinities for this series of compounds. Finally, we show that two of these drug-like IRAP inhibitors can alter dendritic spine morphology and increase spine density in primary cultures of hippocampal neurons.
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| 6. |
- Gad, Helge, et al.
(författare)
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MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool
- 2014
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Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 508:7495, s. 215-221
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Tidskriftsartikel (refereegranskat)abstract
- Cancers have dysfunctional redox regulation resulting in reactive oxygen species production, damaging both DNA and free dNTPs. The MTH1 protein sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, we show that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, resulting in DNA damage and cell death. We validate MTH1 as an anticancer target in vivo and describe small molecules TH287 and TH588 as first-in-class nudix hydrolase family inhibitors that potently and selectively engage and inhibit the MTH1 protein in cells. Protein co-crystal structures demonstrate that the inhibitors bindin the active site of MTH1. The inhibitors cause incorporation of oxidized dNTPs in cancer cells, leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse xenografts. This study exemplifies the non-oncogene addiction concept for anticancer treatment and validates MTH1 as being cancer phenotypic lethal.
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| 7. |
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| 8. |
- Jenmalm, Per, et al.
(författare)
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Lighter or heavier than predicted : neural correlates of corrective mechanisms during erroneously programmed lifts
- 2006
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Ingår i: Journal of Neuroscience. - Bethesda, Md. : Society for Neuroscience. - 0270-6474 .- 1529-2401. ; 26:35, s. 9015-9021
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Tidskriftsartikel (refereegranskat)abstract
- A central concept in neuroscience is that the CNS signals the sensory discrepancy between the predicted and actual sensory consequences of action. It has been proposed that the cerebellum and parietal cortex are involved in this process. A discrepancy will trigger preprogrammed corrective responses and update the engaged sensorimotor memories. Here we use functional magnetic resonance imaging with an event-related design to investigate the neuronal correlates of such discrepancies. Healthy adults repeatedly lifted an object between their right index fingers and thumbs, and on some lifting trials, the weight of the object was unpredictably changed between light (230 g) and heavy (830 g). Regardless of whether the weight was heavier or lighter than predicted, activity was found in the right inferior parietal cortex (supramarginal gyrus). This suggests that this region is involved in the comparison of the predicted and actual sensory input and the updating of the sensorimotor memories. When the object was lighter or heavier than predicted, two different types of preprogrammed force corrections occurred. There was a slow force increase when the weight of the object was heavier than predicted. This corrective response was associated with activity in the left primary motor and somatosensory cortices. The fast termination of the excessive force when the object was lighter than predicted activated the right cerebellum. These findings show how the parietal cortex, cerebellum, and motor cortex are involved in the signaling of the discrepancy between predicated and actual sensory feedback and the associated corrective mechanisms.
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| 9. |
- Llona-Minguez, Sabin, et al.
(författare)
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Discovery of the First Potent and Selective Inhibitors of Human dCTP Pyrophosphatase 1
- 2016
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 59:3, s. 1140-1148
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Tidskriftsartikel (refereegranskat)abstract
- The dCTPase pyrophosphatase 1 (dCTPase) regulates the intracellular nucleotide pool through hydrolytic degradation of canonical and noncanonical nucleotide triphosphates (dNTPs). dCTPase is highly expressed in multiple carcinomas and is associated with cancer cell sternness. Here we report on the development of the first potent and selective dCTPase inhibitors that enhance the cytotoxic effect of cytidine analogues in leukemia cells. Boronate 30 displays a promising in vitro ADME profile, including plasma and mouse microsomal half-lives, aqueous solubility, cell permeability and CYP inhibition, deeming it a suitable compound for in vivo studies.
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| 10. |
- Llona-Minguez, Sabin, et al.
(författare)
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Identification of Triazolothiadiazoles as Potent Inhibitors of the dCTP Pyrophosphatase 1
- 2017
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 60:5, s. 2148-2154
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Tidskriftsartikel (refereegranskat)abstract
- The dCTP pyrophosphatase 1 (dCTPase) is involved in the regulation of the cellular dNTP pool and has been linked to cancer progression. Here we report on the discovery of a series of 3,6-disubstituted triazolothiadiazoles as potent dCTPase inhibitors. Compounds 16 and 18 display good correlation between enzymatic inhibition and target engagement, together with efficacy in a cellular synergy model, deeming them as a promising starting point for hit -to-lead development.
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| 11. |
- Mai, Xiaomei, 1969-, et al.
(författare)
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Asthma, lung function and allergy in 12-year-old children with very low birth weight : a prospective study
- 2003
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Ingår i: Pediatric Allergy and Immunology. - : Wiley. - 0905-6157 .- 1399-3038. ; 14:3, s. 184-192
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Tidskriftsartikel (refereegranskat)abstract
- We assessed the relationship between very low birth weight (VLBW) (≤1500 g) and the development of asthma, lung function and atopy. The study groups comprised 74 of all 86 (86%) VLBW and 64 of all 86 (74%) matched term children who were prospectively followed for 12 years. A questionnaire on asthmatic and allergic symptoms was completed and skin prick tests, spirometry and hypertonic saline provocation tests were performed at 12 years of age. Cytokine secretion was analysed in stimulated blood leukocyte cultures in 28 VLBW and 23 term children. A history of asthma was more frequent among the VLBW children, as compared with the term children at age 12 (22% vs. 9%, p = 0.046). Among the VLBW children, very preterm birth (gestational age: week 25 to 29) (RR 2.5, 95%CI 1.1–5.8), neonatal mechanical ventilation (RR 2.8, 95%CI 1.2–6.4) and neonatal oxygen supplementation (RR 4.3, 95%CI 1.3–14.0) were significantly associated with a history of asthma by the age of 12 years in univariate analyses. In multivariate logistic regression, neonatal oxygen supplementation ≥ 9 days was the only remaining significant risk factor for a history of asthma (adjusted OR 6.7, 95%CI 1.0–44). The VLBW children who required mechanical ventilation during the neonatal period were more likely to have bronchial hyperresponsiveness than those not requiring mechanical ventilation (60% vs. 28%, p = 0.050). The spirometric values were similar among the VLBW and the term children at 12 years. Very low birth weight was not significantly related to allergic rhinoconjunctivitis, eczema or positive skin prick tests. Furthermore, the levels of IL-4, IL-5 and IFN-γ in stimulated cell cultures were similar in the VLBW and the term children. A history of asthma by 12 years of age was twice as common among the VLBW as the term children, and neonatal oxygen supplementation seemed to be associated with the increased risk. Furthermore, mechanical ventilation during the neonatal period was associated with bronchial hyperresponsiveness at age 12. Very low birth weight per se was not, however, related to atopy.
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| 12. |
- Scherman, Peter, et al.
(författare)
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Three-year recurrence of Dupuytren’s contracture after needle fasciotomy and collagenase injection : a two-centre randomized controlled trial
- 2018
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Ingår i: Journal of Hand Surgery: European Volume. - : SAGE Publications. - 1753-1934 .- 2043-6289. ; 43:8, s. 836-840
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Tidskriftsartikel (refereegranskat)abstract
- Collagenase injection and needle fasciotomy have similar short-term outcomes in the treatment of Dupuytren’s contracture. The purpose of this study was to compare the recurrence rate of these two procedures 3 years after index treatment of primary disease. We enrolled 93 patients (96 rays) from a previous two-centre randomized controlled trial. The rays that had been retreated or showed an increase in the total passive extension deficit of 30° or more compared with 3 months after treatment were regarded as recurrences. Seventeen of 40 needle fasciectomies and 12 of 36 of collagenase injections had recurred. This difference was not statistically significant. We conclude that collagenase injection and needle fasciotomy have similar 3-year recurrence rates in the treatment of Dupuytren’s contracture. Level of evidence: I.
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| 13. |
- Schmitz, Christina, et al.
(författare)
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Brain activity during predictable and unpredictable weight changes when lifting objects.
- 2005
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Ingår i: Journal of Neurophysiology. - : American Physiological Society. - 0022-3077 .- 1522-1598. ; 93:3, s. 1498-509
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Tidskriftsartikel (refereegranskat)abstract
- When humans repetitively lift the same object, the fingertip forces are targeted to the weight of the object. The anticipatory programming of the forces depends on sensorimotor memory representations that provide information on the object weight. In the present study, we investigate the neural substrates of these sensorimotor memory systems by recording the neural activity during predictable or unpredictable changes in the weight of an object in a lifting task. An unpredictable change in weight leads to erroneous programming of the fingertip forces. This triggers corrective mechanisms and an update of the sensorimotor memories. In the present fMRI study, healthy right-handed subjects repetitively lifted an object between right index finger and thumb. In the constant condition, which served as a control, the weight of the object remained constant (either 230 or 830 g). The weight alternated between 230 and 830 g during the regular condition and was irregularly changed between the two weights during the irregular condition. When we contrasted regular minus constant and irregular minus constant, we found activations in the right inferior frontal gyrus pars opercularis (area 44), the left parietal operculum and the right supramarginal gyrus. Furthermore, irregular was associated with stronger activation in the right inferior frontal cortex as compared with regular. Taken together, these results suggest that the updating of sensorimotor memory representations and the corrective reactions that occur when we manipulate different objects correspond to changes in synaptic activity in these fronto-parietal circuits.
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| 14. |
- Visnes, Torkild, et al.
(författare)
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Small-molecule inhibitor of OGG1 suppresses proinflammatory gene expression and inflammation
- 2018
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 362:6416, s. 834-
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Tidskriftsartikel (refereegranskat)abstract
- The onset of inflammation is associated with reactive oxygen species and oxidative damage to macromolecules like 7,8-dihydro-8-oxoguanine (8-oxoG) in DNA. Because 8-oxoguanine DNA glycosylase 1 (OGG1) binds 8-oxoG and because Ogg1-deficient mice are resistant to acute and systemic inflammation, we hypothesized that OGG1 inhibition may represent a strategy for the prevention and treatment of inflammation. We developed TH5487, a selective active-site inhibitor of OGG1, which hampers OGG1 binding to and repair of 8-oxoG and which is well tolerated by mice. TH5487 prevents tumor necrosis factor-alpha-induced OGG1-DNA interactions at guanine-rich promoters of proinflammatory genes. This, in turn, decreases DNA occupancy of nuclear factor kappa B and proinflammatory gene expression, resulting in decreased immune cell recruitment to mouse lungs. Thus, we present a proof of concept that targeting oxidative DNA repair can alleviate inflammatory conditions in vivo.
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| 15. |
- Åberg, Maria, et al.
(författare)
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Considerations in evaluating new treatment alternatives following peripheral nerve injuries : a prospective clinical study of methods used to investigate sensory, motor and functional recovery.
- 2007
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Ingår i: J Plast Reconstr Aesthet Surg. - : Elsevier BV. - 1748-6815. ; 60:2, s. 103-13
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Tidskriftsartikel (refereegranskat)abstract
- The current problem finding reliable and objective methods for evaluating results after peripheral nerve repair is a challenge when introducing new clinical techniques. The aim of this study was to obtain reference material and to evaluate the applicability of different tests used for clinical assessment after peripheral nerve injuries. Fifteen patients with a history of complete median nerve transsection and repair, and 15 healthy volunteers were included. Each subject was investigated using a battery of conventional and new tests for functional, sensory and motor recovery including questionnaires, clinical evaluations, neurophysiological and physiological findings. The results were statistically analysed and comparisons were made within the patient group and between patients and healthy volunteers using a 'per protocol' and an 'intention to treat' approach. Criteria for success were stipulated in order to be able to judge the usefulness of each method. The results showed that 19 of 34 variables, representing six of 16 methods, were not able to fulfil the criteria and were thus questionable for the evaluations of nerve repair in a clinical trial setting. However, 2pd, sensory recovery according to the non-modified British Medical Research Council, sensory neurography, manual muscle test, electromyography, questionnaires (i.e. DASH and the 4 question form) and performance tests (i.e. AMPS and Sollerman's subtests 4 and 8) did fulfil the criteria defined for being useful.
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