| 1. |
- Clemedson, Cecilia, et al.
(författare)
-
Development of an in vitro test battery for the estimation of acute human systemic toxicity : An outline of the EDIT project. Evaluation-guided Development of New In Vitro Test Batteries
- 2002
-
Ingår i: ATLA (Alternatives to Laboratory Animals). - 0261-1929. ; 30:3, s. 313-321
-
Tidskriftsartikel (refereegranskat)abstract
- The aim of the Evaluation-guided Development of new In Vitro Test Batteries (EDIT) multicentre programme is to establish and validate in vitro tests relevant to toxicokinetics and for organ-specific toxicity, to be incorporated into optimal test batteries for the estimation of human acute systemic toxicity. The scientific basis of EDIT is the good prediction of human acute toxicity obtained with three human cell line tests (R(2) = 0.77), in the Multicentre Evaluation of In Vitro Cytotoxicity (MEIC) programme. However, the results from the MEIC study indicated that at least two other types of in vitro test ought to be added to the existing test battery to improve the prediction of human acute systemic toxicity - to determine key kinetic events (such as biotransformation and passage through biological barriers), and to predict crucial organ-specific mechanisms not covered by the tests in the MEIC battery. The EDIT programme will be a case-by-case project, but the establishment and validation of new tests will be carried through by a common, step-wise procedure. The Scientific Committee of the EDIT programme defines the need for a specific set of toxicity or toxicokinetic data. Laboratories are then invited to perform the defined tests in order to provide the "missing" data for the EDIT reference chemicals. The results obtained will be evaluated against the MEMO (the MEIC Monograph programme) database, i.e. against human acute systemic lethal and toxicity data. The aim of the round-table discussions at the 19th Scandinavian Society for Cell Toxicology (SSCT) workshop, held in Ringsted, Denmark on 6-9 September 2001, was to identify which tests are the most important for inclusion in the MEIC battery, i.e. which types of tests the EDIT programme should focus on. It was proposed that it is important to include in vitro methods for various kinetic events, such as biotransformation, absorption in the gut, passage across the blood-brain barrier, distribution volumes, protein binding, and renal clearance/accumulation. Models for target organ toxicity were also discussed. Because several of the outlier chemicals (paracetamol, digoxin, malathion, nicotine, paraquat, atropine and potassium cyanide) in the MEIC in vivo-in vitro evaluation have a neurotoxic potential, it was proposed that the development within the EDIT target organ programme should initially be focused on the nervous system.
|
|
| 2. |
- Gunst, Jesper D., et al.
(författare)
-
Efficacy of the TMPRSS2 inhibitor camostat mesilate in patients hospitalized with Covid-19-a double-blind randomized controlled trial
- 2021
-
Ingår i: eClinicalMedicine. - : Elsevier. - 2589-5370. ; 35
-
Tidskriftsartikel (refereegranskat)abstract
- Background: The trans-membrane protease serine 2 (TMPRSS2) is essential for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cell entry and infection. Efficacy and safety of TMPRSS2 inhibitors in patients with coronavirus disease 2019 (Covid-19) have not been evaluated in randomized trials.Methods: We conducted an investigator-initiated, double-blind, randomized, placebo-controlled multicenter trial in patients hospitalized with confirmed SARS-CoV-2 infection from April 4, to December 31, 2020. Within 48 h of admission, participants were randomly assigned in a 2:1 ratio to receive the TMPRSS2 inhibitor camostat mesilate 200 mg three times daily for 5 days or placebo. The primary outcome was time to discharge or clinical improvement measured as ≥2 points improvement on a 7-point ordinal scale. Other outcomes included 30-day mortality, safety and change in oropharyngeal viral load. ClinicalTrials.gov Identifier: NCT04321096. EudraCT Number: 2020-001,200-42.Findings: 137 patients were assigned to receive camostat mesilate and 68 to placebo. Median time to clinical improvement was 5 days (interquartile range [IQR], 3 to 7) in the camostat group and 5 days (IQR, 2 to 10) in the placebo group (P = 0·31). The hazard ratio for 30-day mortality in the camostat compared with the placebo group was 0·82 (95% confidence interval [CI], 0·24 to 2·79; P = 0·75). The frequency of adverse events was similar in the two groups. Median change in viral load from baseline to day 5 in the camostat group was -0·22 log10 copies/mL (p <0·05) and -0·82 log10 in the placebo group (P <0·05).Interpretation: Under this protocol, camostat mesilate treatment was not associated with increased adverse events during hospitalization for Covid-19 and did not affect time to clinical improvement, progression to ICU admission or mortality.
|
|
| 3. |
- Jønsson, Knud A, et al.
(författare)
-
Ecological and evolutionary determinants for the adaptive radiation of the Madagascan vangas.
- 2012
-
Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 109:17, s. 6620-5
-
Tidskriftsartikel (refereegranskat)abstract
- Adaptive radiation is the rapid diversification of a single lineage into many species that inhabit a variety of environments or use a variety of resources and differ in traits required to exploit these. Why some lineages undergo adaptive radiation is not well-understood, but filling unoccupied ecological space appears to be a common feature. We construct a complete, dated, species-level phylogeny of the endemic Vangidae of Madagascar. This passerine bird radiation represents a classic, but poorly known, avian adaptive radiation. Our results reveal an initial rapid increase in evolutionary lineages and diversification in morphospace after colonizing Madagascar in the late Oligocene some 25 Mya. A subsequent key innovation involving unique bill morphology was associated with a second increase in diversification rates about 10 Mya. The volume of morphospace occupied by contemporary Madagascan vangas is in many aspects as large (shape variation)--or even larger (size variation)--as that of other better-known avian adaptive radiations, including the much younger Galapagos Darwin's finches and Hawaiian honeycreepers. Morphological space bears a close relationship to diet, substrate use, and foraging movements, and thus our results demonstrate the great extent of the evolutionary diversification of the Madagascan vangas.
|
|
| 4. |
- López, Aida Rodríguez, et al.
(författare)
-
Autophagy-mediated control of ribosome homeostasis in oncogene-induced senescence
- 2023
-
Ingår i: Cell Reports. - 2211-1247. ; 42:11, s. 1-23
-
Tidskriftsartikel (refereegranskat)abstract
- Oncogene-induced senescence (OIS) is a persistent anti-proliferative response that acts as a barrier against malignant transformation. During OIS, cells undergo dynamic remodeling, which involves alterations in protein and organelle homeostasis through autophagy. Here, we show that ribosomes are selectively targeted for degradation by autophagy during OIS. By characterizing senescence-dependent alterations in the ribosomal interactome, we find that the deubiquitinase USP10 dissociates from the ribosome during the transition to OIS. This release of USP10 leads to an enhanced ribosome ubiquitination, particularly of small subunit proteins, including lysine 275 on RPS2. Both reinforcement of the USP10-ribosome interaction and mutation of RPS2 K275 abrogate ribosomal delivery to lysosomes without affecting bulk autophagy. We show that the selective recruitment of ubiquitinated ribosomes to autophagosomes is mediated by the p62 receptor. While ribophagy is not required for the establishment of senescence per se, it contributes to senescence-related metabolome alterations and facilitates the senescence-associated secretory phenotype.
|
|
| 5. |
- Våbenø, Jon, et al.
(författare)
-
Conformational restrictions in ligand binding to the human intestinal di-/tripeptide transporter: implications for design of hPEPT1 targeted prodrugs.
- 2005
-
Ingår i: Bioorganic & medicinal chemistry. - : Elsevier BV. - 0968-0896. ; 13:6, s. 1977-88
-
Tidskriftsartikel (refereegranskat)abstract
- The aim of the present study was to develop a computational method aiding the design of dipeptidomimetic pro-moieties targeting the human intestinal di-/tripeptide transporter hPEPT1. First, the conformation in which substrates bind to hPEPT1 (the bioactive conformation) was identified by conformational analysis and 2D dihedral driving analysis of 15 hPEPT1 substrates, which suggested that psi(1) approximately 165 degrees , omega(1) approximately 180 degrees , and phi(2) approximately 280 degrees were descriptive of the bioactive conformation. Subsequently, the conformational energy required to change the peptide backbone conformation (DeltaE(bbone)) from the global energy minimum conformation to the identified bioactive conformation was calculated for 20 hPEPT1 targeted model prodrugs with known K(i) values. Quantitatively, an inverse linear relationship (r(2)=0.81, q(2)=0.80) was obtained between DeltaE(bbone) and log1/K(i), showing that DeltaE(bbone) contributes significantly to the experimentally observed affinity for hPEPT1 ligands. Qualitatively, the results revealed that compounds classified as high affinity ligands (K(i)<0.5 mM) all have a calculated DeltaE(bbone)<1 kcal/mol, whereas medium and low-affinity compounds (0.5 mM
|
|
