| 1. |
- Ali, Zaheer, et al.
(författare)
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Zebrafish patient-derived xenograft models predict lymph node involvement and treatment outcome in non-small cell lung cancer
- 2022
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Ingår i: Journal of Experimental & Clinical Cancer Research. - : BMC. - 1756-9966. ; 41:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Accurate predictions of tumor dissemination risks and medical treatment outcomes are critical to personalize therapy. Patient-derived xenograft (PDX) models in mice have demonstrated high accuracy in predicting therapeutic outcomes, but methods for predicting tumor invasiveness and early stages of vascular/lymphatic dissemination are still lacking. Here we show that a zebrafish tumor xenograft (ZTX) platform based on implantation of PDX tissue fragments recapitulate both treatment outcome and tumor invasiveness/dissemination in patients, within an assay time of only 3 days. Methods Using a panel of 39 non-small cell lung cancer PDX models, we developed a combined mouse-zebrafish PDX platform based on direct implantation of cryopreserved PDX tissue fragments into zebrafish embryos, without the need for pre-culturing or expansion. Clinical proof-of-principle was established by direct implantation of tumor samples from four patients. Results The resulting ZTX models responded to Erlotinib and Paclitaxel, with similar potency as in mouse-PDX models and the patients themselves, and resistant tumors similarly failed to respond to these drugs in the ZTX system. Drug response was coupled to elevated expression of EGFR, Mdm2, Ptch1 and Tsc1 (Erlotinib), or Nras and Ptch1 (Paclitaxel) and reduced expression of Egfr, Erbb2 and Foxa (Paclitaxel). Importantly, ZTX models retained the invasive phenotypes of the tumors and predicted lymph node involvement of the patients with 91% sensitivity and 62% specificity, which was superior to clinically used tests. The biopsies from all four patient tested implanted successfully, and treatment outcome and dissemination were quantified for all patients in only 3 days. Conclusions We conclude that the ZTX platform provide a fast, accurate, and clinically relevant system for evaluation of treatment outcome and invasion/dissemination of PDX models, providing an attractive platform for combined mouse-zebrafish PDX trials and personalized medicine.
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| 2. |
- Glerup, Rie, et al.
(författare)
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Multiplex proteomics as risk predictor of infection in patients treated with hemodialysis-A prospective multicenter study
- 2022
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Ingår i: Hemodialysis International. - : John Wiley & Sons. - 1492-7535 .- 1542-4758. ; 26:2, s. 191-201
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Tidskriftsartikel (refereegranskat)abstract
- Introduction Severe infection is a major problem in hemodialysis patients. Multiplex proteomics might reveal novel insights into disease mechanisms increasing the risk of infection and might also be used as a risk prediction tool. The aims of this study were (1) to evaluate associations between 92 proteins assessed by a proximity extension assay and the development of severe infection in patients on hemodialysis and (2) to develop a risk prediction model for severe infection using prespecified clinical variables and proteomics. Methods Prospective, observational multicenter cohort study with 5-year follow-up. Patients receiving in-center hemodialysis in five facilities in Denmark were included. The primary composite endpoint was death caused by infection, bacteremia, and infections requiring hospitalization of at least 2 days or prolonging a hospital stay. Findings Of 331 patients included 210 patients reached the primary endpoint during follow-up. In adjusted Cox regression analyses, 14 plasma proteins were associated with severe infection. Correcting for multiple testing revealed only cathepsin-L1 and interleukin-6 significantly associated with the primary outcome. Cathepsin-L1-hazard ratio: 1.64 (95% confidence interval [CI] 1.24-2.17) and interleukin-6-hazard ratio: 1.16 (95% CI 1.05-1.29). Apparent C-statistics of the risk prediction model using clinical variables was 0.605, addition of cathepsin-L1 and interleukin-6 to the model improved discrimination slightly: C = 0.625. Discussion Proteomic profiling identified cathepsin-L1 and interleukin-6 as markers for infectious risk in hemodialysis patients. Further studies are needed to replicate the results and to examine possible causality. The developed risk prediction models need considerable improvement before implementation in clinical practice is meaningful.
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| 3. |
- Grinderslev, Jakob B., et al.
(författare)
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Polymorphism and solid solutions of trimethylammonium monocarboranes
- 2022
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Ingår i: Dalton Transactions. - : Royal Society of Chemistry (RSC). - 1477-9226 .- 1477-9234. ; 51:41, s. 15806-15815
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Tidskriftsartikel (refereegranskat)abstract
- Metal closo-boranes have recently received significant attention as solid-state electrolytes due to their high thermal and electrochemical stability, and the weak interaction between the cat- and anion, facilitating fast ionic conductivity. Here we report a synthesis method for obtaining a novel mixed closo-carborane compound, [NH(CH3)3][(CB8H9)0.26(CB9H10)0.66(CB11H12)0.08]. The crystal structures are investigated for [NH(CH3)3][CB9H10] and [NH(CH3)3][(CB8H9)0.26(CB9H10)0.66(CB11H12)0.08], revealing that the latter forms a solid solution isostructural to [NH(CH3)3][CB9H10]. The compounds exhibit polymorphism as a function of temperature, and we report the discovery of four polymorphs of [NH(CH3)3][CB9H10] and four isostructural solid solution [NH(CH3)3][(CB8H9)0.26(CB9H10)0.66(CB11H12)0.08], along with a high-temperature decomposition intermediate of the latter. The α-polymorph is an ordered structure, with increasing amounts of disorder for the β- and γ-polymorphs, while the high temperature δ- and ϵ-polymorphs at T > 476 K are fully disordered on both the cation and anion site. These new compounds may be used as precursors for new types of solid-state ionic conductors.
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| 4. |
- Oliva, Delmy, et al.
(författare)
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Opposing inflammatory biomarker responses to sleep disruption in cancer patients before and during oncological therapy
- 2022
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Ingår i: Frontiers in Neuroscience. - : Frontiers Media S.A.. - 1662-4548 .- 1662-453X. ; 16
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundSleep disruption is known to be highly prevalent in cancer patients, aggravated during oncological treatment and closely associated with reduced quality of life, therapeutic outcome and survival. Inflammatory factors are associated with sleep disruption in healthy individuals and cancer patients, but heterogeneity and robustness of inflammatory factors associated with sleep disruption and how these are affected by oncological therapy remain poorly understood. Furthermore, due to the complex crosstalk between sleep-, and therapy-associated factors, including inflammatory factors, there are currently no established biomarkers for predicting sleep disruption in patients undergoing oncological therapy. MethodsWe performed a broad screen of circulating biomarkers with immune-modulating or endocrine functions and coupled these to self-reported sleep quality using the Medical Outcomes Study (MOS) sleep scale. Ninety cancer patients with gastrointestinal, urothelial, breast, brain and tonsillar cancers, aged between 32 and 86 years, and scheduled for adjuvant or palliative oncological therapy were included. Of these, 71 patients were evaluable. Data was collected immediately before and again 3 months after onset of oncological therapy. ResultsSeventeen among a total of 45 investigated plasma proteins were found to be suppressed in cancer patients exhibiting sleep disruption prior to treatment onset, but this association was lost following the first treatment cycle. Patients whose sleep quality was reduced during the treatment period exhibited significantly increased plasma levels of six pro-inflammatory biomarkers (IL-2, IL-6, IL-12, TNF-a, IFN-g, and GM-CSF) 3 months after the start of treatment, whereas biomarkers with anti-inflammatory, growth factor, immune-modulatory, or chemokine functions were unchanged. ConclusionOur work suggests that biomarkers of sleep quality are not valid for cancer patients undergoing oncological therapy if analyzed only at a single timepoint. On the other hand, therapy-associated increases in circulating inflammatory biomarkers are closely coupled to reduced sleep quality in cancer patients. These findings indicate a need for testing of inflammatory and other biomarkers as well as sleep quality at multiple times during the patient treatment and care process.
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| 5. |
- Reimer, Lasse, et al.
(författare)
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Low dose DMSO treatment induces oligomerization and accelerates aggregation of α-synuclein
- 2022
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Dimethyl sulfoxide (DMSO) is a highly utilized small molecule that serves many purposes in scientific research. DMSO offers unique polar, aprotic and amphiphilic features, which makes it an ideal solvent for a wide variety of both polar and nonpolar molecules. Furthermore, DMSO is often used as a cryoprotectant in cell-based research. However, recent reports suggest that DMSO, even at low concentration, might interfere with important cellular processes, and cause macromolecular changes to proteins where a shift from α-helical to β-sheet structure can be observed. To investigate how DMSO might influence current research, we assessed biochemical and cellular impacts of DMSO treatment on the structure of the aggregation-prone protein α-synuclein, which plays a central role in the etiology of Parkinson’s disease, and other brain-related disorders, collectively termed the synucleinopathies. Here, we found that addition of DMSO increased the particle-size of α-synuclein, and accelerated the formation of seeding-potent fibrils in a dose-dependent manner. These fibrils made in the presence of DMSO were indistinguishable from fibrils made in pure PBS, when assessed by proteolytic digestion, cytotoxic profile and their ability to seed cellular aggregation of α-synuclein. Moreover, as evident through binding to the MJFR-14-6-4-2 antibody, which preferentially recognizes aggregated forms of α-synuclein, and a bimolecular fluorescence complementation assay, cells exposed to DMSO experienced increased aggregation of α-synuclein. However, no observable α-synuclein abnormalities nor differences in neuronal survival were detected after oral DMSO-treatment in either C57BL/6- or α-synuclein transgenic F28 mice. In summary, we demonstrate that low concentrations of DMSO makes α-synuclein susceptible to undergo aggregation both in vitro and in cells. This may affect experimental outcomes when studying α-synuclein in the presence of DMSO, and should call for careful consideration when such experiments are planned.
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| 6. |
- Xie, Sisi, et al.
(författare)
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Dietary ketone body-escalated histone acetylation in megakaryocytes alleviates chemotherapy-induced thrombocytopenia
- 2022
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Ingår i: Science Translational Medicine. - : AMER ASSOC ADVANCEMENT SCIENCE. - 1946-6234 .- 1946-6242. ; 14:673
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Tidskriftsartikel (refereegranskat)abstract
- Chemotherapy-induced thrombocytopenia (CIT) is a severe complication in patients with cancer that can lead to impaired therapeutic outcome and survival. Clinically, therapeutic options for CIT are limited by severe adverse effects and high economic burdens. Here, we demonstrate that ketogenic diets alleviate CIT in both animals and humans without causing thrombocytosis. Mechanistically, ketogenic diet-induced circulating beta-hydroxybutyrate (beta-OHB) increased histone H3 acetylation in bone marrow megakaryocytes. Gain- and loss-of-function experiments revealed a distinct role of 3-beta-hydroxybutyrate dehydrogenase (BDH)-mediated ketone body metabolism in promoting histone acetylation, which promoted the transcription of platelet biogenesis genes and induced thrombocytopoiesis. Genetic depletion of the megakaryocyte-specific ketone body transporter monocarboxylate transporter 1 (MCT1) or pharmacological targeting of MCT1 blocked beta-OHB-induced thrombocytopoiesis in mice. A ketogenesis-promoting diet alleviated CIT in mouse models. Moreover, a ketogenic diet modestly increased platelet counts without causing thrombocytosis in healthy volunteers, and a ketogenic lifestyle inversely correlated with CIT in patients with cancer. Together, we provide mechanistic insights into a ketone body-MCT1-BDH-histone acetylation-platelet biogenesis axis in megakaryocytes and propose a non-toxic, low-cost dietary intervention for combating CIT.
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