| 1. |
- Andersson, Claes, et al.
(författare)
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Assessment in vitro of interactions between anti-cancer drugs and noncancer drugs commonly used by cancer patients
- 2023
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Ingår i: Anti-Cancer Drugs. - : Lippincott Williams & Wilkins. - 0959-4973 .- 1473-5741. ; 34:1, s. 92-102
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Tidskriftsartikel (refereegranskat)abstract
- Cancer patients often suffer from cancer symptoms, treatment complications and concomitant diseases and are, therefore, often treated with several drugs in addition to anticancer drugs. Whether such drugs, here denoted as 'concomitant drugs', have anticancer effects or interact at the tumor cell level with the anticancer drugs is not very well known. The cytotoxic effects of nine concomitant drugs and their interactions with five anti-cancer drugs commonly used for the treatment of colorectal cancer were screened over broad ranges of drug concentrations in vitro in the human colon cancer cell line HCT116wt. Seven additional tyrosine kinase inhibitors were included to further evaluate key findings as were primary cultures of tumor cells from patients with colorectal cancer. Cytotoxic effects were evaluated using the fluorometric microculture cytotoxicity assay (FMCA) and interaction analysis was based on Bliss independent interaction analysis. Simvastatin and loperamide, included here as an opioid agonists, were found to have cytotoxic effects on their own at reasonably low concentrations whereas betamethasone, enalapril, ibuprofen, metformin, metoclopramide, metoprolol and paracetamol were inactive also at very high concentrations. Drug interactions ranged from antagonistic to synergistic over the concentrations tested with a more homogenous pattern of synergy between simvastatin and protein kinase inhibitors in HCT116wt cells. Commonly used concomitant drugs are mostly neither expected to have anticancer effects nor to interact significantly with anticancer drugs frequently used for the treatment of colorectal cancer.
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| 2. |
- Andersson, Claes, et al.
(författare)
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Mebendazole is unique among tubulin-active drugs in activating the MEK-ERK pathway
- 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
- We recently showed that the anti-helminthic compound mebendazole (MBZ) has immunomodulating activity in monocyte/macrophage models and induces ERK signalling. In the present study we investigated whether MBZ induced ERK activation is shared by other tubulin binding agents (TBAs) and if it is observable also in other human cell types. Curated gene signatures for a panel of TBAs in the LINCS Connectivity Map (CMap) database showed a unique strong negative correlation of MBZ with MEK/ERK inhibitors indicating ERK activation also in non-haematological cell lines. L1000 gene expression signatures for MBZ treated THP-1 monocytes also connected negatively to MEK inhibitors. MEK/ERK phosphoprotein activity testing of a number of TBAs showed that only MBZ increased the activity in both THP-1 monocytes and PMA differentiated macrophages. Distal effects on ERK phosphorylation of the substrate P90RSK and release of IL1B followed the same pattern. The effect of MBZ on MEK/ERK phosphorylation was inhibited by RAF/MEK/ERK inhibitors in THP-1 models, CD3/IL2 stimulated PBMCs and a MAPK reporter HEK-293 cell line. MBZ was also shown to increase ERK activity in CD4+ T-cells from lupus patients with known defective ERK signalling. Given these mechanistic features MBZ is suggested suitable for treatment of diseases characterized by defective ERK signalling, notably difficult to treat autoimmune diseases.
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| 3. |
- Babina, Arianne M., et al.
(författare)
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Rescue of Escherichia coli auxotrophy by de novo small proteins
- 2023
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Ingår i: eLIFE. - : eLife Sciences Publications Ltd. - 2050-084X. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Increasing numbers of small proteins with diverse physiological roles are being identified and characterized in both prokaryotic and eukaryotic systems, but the origins and evolution of these proteins remain unclear. Recent genomic sequence analyses in several organisms suggest that new functions encoded by small open reading frames (sORFs) may emerge de novo from noncoding sequences. However, experimental data demonstrating if and how randomly generated sORFs can confer beneficial effects to cells are limited. Here, we show that by upregulating hisB expression, de novo small proteins (<= 50 amino acids in length) selected from random sequence libraries can rescue Escherichia coli cells that lack the conditionally essential SerB enzyme. The recovered small proteins are hydrophobic and confer their rescue effect by binding to the 5 ' end regulatory region of the his operon mRNA, suggesting that protein binding promotes structural rearrangements of the RNA that allow increased hisB expression. This study adds RNA regulatory elements as another interacting partner for de novo proteins isolated from random sequence libraries and provides further experimental evidence that small proteins with selective benefits can originate from the expression of nonfunctional sequences.
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| 4. |
- Bergström, Ulf, et al.
(författare)
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Long-term decline in northern pike (Esox lucius L.) populations in the Baltic Sea revealed by recreational angling data
- 2022
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Ingår i: Fisheries Research. - : Elsevier BV. - 0165-7836 .- 1872-6763. ; 251
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Tidskriftsartikel (refereegranskat)abstract
- In the Baltic Sea, the large predatory fish northern pike (Esox lucius L.) is important for both recreational fisheries and ecosystem functioning. As existing fishery-independent surveys do not adequately monitor pike populations, a general lack of knowledge on population status and trends poses challenges for management. Here we use recreational angling data as an alternative method to describe pike population development along the Swedish Baltic Sea coast from 1938 onwards and assess the change over time in potential mortality factors by estimating harvest by fisheries and consumption by large predators. Data from a Swedish national register on trophy-sized pike (>12 kg) showed that numbers and maximum sizes peaked in 1990-1995, after which declines in both metrics are evident. In logbooks from a sport fishing club in the Stockholm archipelago, a simultaneous decrease in maximum sizes of pike was observed, together with a decrease in the total number of pike caught per fishing day. Jointly, these data indicate a decline in the abundance of large pike since around 1990. While commercial pike fisheries in the Baltic Sea have decreased continuously since the 1950s, recreational fishing increased after 1985, when Swedish coastal waters were made open access to anglers. The declines in large pike starting in the 1990s could, thus, have been driven by an increase in mortality from recreational fisheries, which at the time primarily practiced catch and kill. Since the 2000s, bag and slot length limits, spawning closures, and a general increase in catch-and-release fishing has reduced the landings of pike in recreational fisheries. Despite these fisheries regulations and higher release rates the decline in catches of large pike has continued, indicating an effect of other mortality factors. The strong growth of grey seal (Halichoerus grypus) and great cormorant (Phalacrocorax carbo sinensis) populations suggest that predation pressure on pike has increased over time. In the Stockholm archipelago these two predators were estimated to remove 5-18 times (range based on different diet composition estimates) more pike biomass than total fisheries landings in 2014-2017. To improve the situation for northern pike in the Baltic Sea managers need to consider both fisheries restrictions and measures to decrease predation pressure and increase recruitment. Catch data from recreational fisheries may be used to evaluate such management efforts by providing information on the population development of this keystone species.
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| 5. |
- Bi, Huijuan, et al.
(författare)
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A frame-shift mutation in COMTD1 is associated with impaired pheomelanin pigmentation in chicken
- 2023
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Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 19:4
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Tidskriftsartikel (refereegranskat)abstract
- The biochemical pathway regulating the synthesis of yellow/red pheomelanin is less well characterized than the synthesis of black/brown eumelanin. Inhibitor of gold (IG phenotype) is a plumage colour variant in chicken that provides an opportunity to further explore this pathway since the recessive allele (IG) at this locus is associated with a defect in the production of pheomelanin. IG/IG homozygotes display a marked dilution of red pheomelanin pigmentation, whilst black pigmentation (eumelanin) is only slightly affected. Here we show that a 2-base pair insertion (frame-shift mutation) in the 5th exon of the Catechol-O-methyltransferase containing domain 1 gene (COMTD1), expected to cause a complete or partial loss-of-function of the COMTD1 enzyme, shows complete concordance with the IG phenotype within and across breeds. We show that the COMTD1 protein is localized to mitochondria in pigment cells. Knockout of Comtd1 in a mouse melanocytic cell line results in a reduction in pheomelanin metabolites and significant alterations in metabolites of glutamate/glutathione, riboflavin, and the tricarboxylic acid cycle. Furthermore, COMTD1 overexpression enhanced cellular proliferation following chemical-induced transfection, a potential inducer of oxidative stress. These observations suggest that COMTD1 plays a protective role for melanocytes against oxidative stress and that this supports their ability to produce pheomelanin.
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| 6. |
- Byrgazov, Konstantin, et al.
(författare)
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Melphalan flufenamide inhibits osteoclastogenesis by suppressing proliferation of monocytes
- 2021
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Ingår i: Bone Reports. - : Elsevier. - 2352-1872. ; 15
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Tidskriftsartikel (refereegranskat)abstract
- Myeloma bone disease is a major complication in multiple myeloma affecting quality of life and survival. It is characterized by increased activity of osteoclasts, bone resorbing cells. Myeloma microenvironment promotes excessive osteoclastogenesis, a process of production of osteoclasts from their precursors, monocytes. The effects of two anti-myeloma drugs, melphalan flufenamide (melflufen) and melphalan, on the activity and proliferation of osteoclasts and their progenitors, monocytes, were assessed in this study. In line with previous research, differentiation of monocytes was associated with increased expression of genes encoding DNA damage repair proteins. Hence monocytes were more sensitive to DNA damage-causing alkylating agents than their differentiated progeny, osteoclasts. In addition, differentiated progeny of monocytes showed increased gene expression of immune checkpoint ligands which may potentially create an immunosuppressive microenvironment. Melflufen was ten-fold more active than melphalan in inhibiting proliferation of osteoclast progenitors. Furthermore, melflufen was also superior to melphalan in inhibition of osteoclastogenesis and bone resorption. These results demonstrate that melflufen may exert beneficial effects in patients with multiple myeloma such as reducing bone resorption and immunosuppressive milieu by inhibiting osteoclastogenesis.
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| 7. |
- Byrgazov, Konstantin, et al.
(författare)
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Targeting aggressive osteosarcoma with a peptidase-enhanced cytotoxic melphalan flufenamide
- 2020
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Ingår i: THERAPEUTIC ADVANCES IN MEDICAL ONCOLOGY. - : SAGE PUBLICATIONS LTD. - 1758-8340 .- 1758-8359. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Background: Low survival rates in metastatic high-grade osteosarcoma (HGOS) have remained stagnant for the last three decades. This study aims to investigate the role of aminopeptidase N (ANPEP) in HGOS progression and its targeting with a novel lipophilic peptidase-enhanced cytotoxic compound melphalan flufenamide (melflufen) in HGOS. Methods: Meta-analysis of publicly available gene expression datasets was performed to determine the impact ofANPEPgene expression on metastasis-free survival of HGOS patients. The efficacy of standard-of-care anti-neoplastic drugs and a lipophilic peptidase-enhanced cytotoxic conjugate melflufen was investigated in patient-derived HGOSex vivomodels and cell lines. The kinetics of apoptosis and necrosis induced by melflufen and doxorubicin were compared. Anti-neoplastic effects of melflufen were investigatedin vivo. Results: ElevatedANPEPexpression in diagnostic biopsies of HGOS patients was found to significantly reduce metastasis-free survival. In drug sensitivity assays, melflufen has shown an anti-proliferative effect in HGOSex vivosamples and cell lines, including those resistant to methotrexate, etoposide, doxorubicin, and PARP inhibitors. Further, HGOS cells treated with melflufen displayed a rapid induction of apoptosis and this sensitivity correlated with high expression ofANPEP. In combination treatments, melflufen demonstrated synergy with doxorubicin in killing HGOS cells. Finally, Melflufen displayed anti-tumor growth and anti-metastatic effectsin vivo. Conclusion: This study may pave the way for use of melflufen as an adjuvant to doxorubicin in improving the therapeutic efficacy for the treatment of metastatic HGOS.
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| 8. |
- Chemtob, Raphaelle A., et al.
(författare)
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Limited Distal Repair Results in Low Rates of Distal Events Following Surgery for Acute Type A Aortic Dissection
- 2023
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Ingår i: Seminars in Thoracic and Cardiovascular Surgery. - : Elsevier BV. - 1043-0679. ; 35:1, s. 7-15
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Tidskriftsartikel (refereegranskat)abstract
- To investigate mortality and reoperation rates following limited distal repair after acute type A aortic dissection (ATAAD) at a single medium volume institution. We analyzed all patients that underwent limited distal repair (ascending aortic or hemiarch replacement) following ATAAD between January 1998 and April 2020 at our institution. During the study period, 489 patients underwent ATAAD surgery, of which 457 (94%) underwent limited distal repair with a 30-day mortality of 12.9%. Among 30-day survivors, late follow-up was 97.7% complete with a mean follow-up of 6.0 ± 5.5 years. In all, 50 patients (11%) required a reoperation during the study period at a mean of 3.4 ± 3.4 years after initial repair, with a 30-day mortality of 12%. An aortic reoperation was required in 4.1 (2.0–6.1)%, 10.3 (7.1–13.6)%, 15.1 (10.9–19.4)%, and 18.0 (13.0–22.9)% of patients at 1, 5, 10, and 15 years. A distal reoperation was required in 3.0 (1.2–4.7)%, 8.0 (5.1–10.9)%, 10.3 (6.8–13.8)%, and 12.4 (8.2–16.5)% of patients and 4.4 (2.3–6.4)%, 10.4 (7.1–13.7)%, 13.9 (9.8–18.0)%, and 16.9 (12.0–21.9)% of patents had a distal event at 1, 5, 10, and 15 years, respectively. Limited distal repair with an ascending aortic or hemiarch replacement was associated with acceptable survival and rates of reoperations and distal events. Limited distal repair is a safe and feasible standard approach to ATAAD surgery at a medium-volume center.
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| 9. |
- Ede, Jacob, et al.
(författare)
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Carbon dioxide flooding to reduce postoperative neurological injury following surgery for acute type A aortic dissection : a prospective, randomised, blinded, controlled clinical trial, CARTA study protocol - objectives and design
- 2023
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Ingår i: BMJ Open. - 2044-6055. ; 13:5, s. 1-8
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Neurological complications after surgery for acute type A aortic dissection (ATAAD) increase patient morbidity and mortality. Carbon dioxide flooding is commonly used in open-heart surgery to reduce the risk of air embolism and neurological impairment, but it has not been evaluated in the setting of ATAAD surgery. This report describes the objectives and design of the CARTA trial, investigating whether carbon dioxide flooding reduces neurological injury following surgery for ATAAD. METHODS AND ANALYSIS: The CARTA trial is a single-centre, prospective, randomised, blinded, controlled clinical trial of ATAAD surgery with carbon dioxide flooding of the surgical field. Eighty consecutive patients undergoing repair of ATAAD, and who do not have previous neurological injuries or ongoing neurological symptoms, will be randomised (1:1) to either receive carbon dioxide flooding of the surgical field or not. Routine repair will be performed regardless of the intervention. The primary endpoints are size and number of ischaemic lesions on brain MRI performed after surgery. Secondary endpoints are clinical neurological deficit according to the National Institutes of Health Stroke Scale, level of consciousness using the Glasgow Coma Scale motor score, brain injury markers in blood after surgery, neurological function according to the modified Rankin Scale and postoperative recovery 3 months after surgery. ETHICS AND DISSEMINATION: Ethical approval has been granted by Swedish Ethical Review Agency for this study. Results will be disseminated through peer-reviewed media. TRIAL REGISTRATION NUMBER: NCT04962646.
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| 10. |
- Ede, Jacob, et al.
(författare)
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Radiological properties of neurological injury following acute type A aortic dissection repair
- 2023
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Ingår i: JTCVS Open. - 2666-2736. ; 15, s. 38-60
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The study objective was to assess the radiological properties of acute type A aortic dissection–related neurological injuries and identify predictors of neurological injury. Methods: Our single-center, retrospective, observational study included all patients who underwent acute type A aortic dissection repair between January 1998 and December 2021. Multivariable analyses and Cox regression were performed to identify predictors of embolic lesions, watershed lesions, neurological injury, 30-day mortality, and late mortality. Results: A total of 538 patients were included. Of these, 120 patients (22.3%) experienced postoperative neurological injury; 74 patients (13.8%) had postoperative stroke, and 36 patients (6.8%) had postoperative coma. The 30-day mortality was 22.7% in the neurological injury group versus 5.8% in the no neurological injury group (P < .001). We identified several independent predictors of neurological injury. Cerebral malperfusion (odds ratio, 2.77; 95% confidence interval, 1.53-5.00), systemic hypotensive shock (odds ratio, 1.97; 95% confidence interval, 1.13-3.43), and aortic arch replacement (odds ratio, 3.08; 95% confidence interval, 1.17-8.08) predicted embolic lesions. Diabetes mellitus (odds ratio, 5.35; 95% confidence interval, 1.85-15.42), previous cardiac surgery (odds ratio, 8.62; 95% confidence interval, 1.47-50.43), duration of hypothermic circulatory arrest (odds ratio, 1.05; 95% confidence interval, 1.01-1.08), cardiopulmonary bypass time (odds ratio, 1.01; 95% confidence interval, 1.00-1.01), ascending aortic/arch cannulation (odds ratio, 5.68; 95% confidence interval, 1.88-17.12), and left ventricular cannulation (odds ratio, 17.81; 95% confidence interval, 1.69-188.01) predicted watershed lesions. Retrograde cerebral perfusion (odds ratio, 0.28; 95% confidence interval, 0.01-0.84) had a protective effect against watershed lesions. Conclusions: In this study, we demonstrated that the radiological features of neurological injury may be as important as clinical characteristics in understanding the pathophysiology and causality behind neurological injury related to acute type A aortic dissection repair.
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| 11. |
- Ede, Jacob, et al.
(författare)
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Retrograde cerebral perfusion reduces embolic and watershed lesions after acute type a aortic dissection repair with deep hypothermic circulatory arrest
- 2024
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Ingår i: Journal of Cardiothoracic Surgery. - : BioMed Central (BMC). - 1749-8090. ; 19:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: To assess whether retrograde cerebral perfusion reduces neurological injury and mortality in patients undergoing surgery for acute type A aortic dissection.Methods: Single-center, retrospective, observational study including all patients undergoing acute type A aortic dissection repair with deep hypothermic circulatory arrest between January 1998 and December 2022 with or without the adjunct of retrograde cerebral perfusion. 515 patients were included: 257 patients with hypothermic circulatory arrest only and 258 patients with hypothermic circulatory arrest and retrograde cerebral perfusion. The primary endpoints were clinical neurological injury, embolic lesions, and watershed lesions. Multivariable logistic regression was performed to identify independent predictors of the primary outcomes. Survival analysis was performed using Kaplan-Meier estimates.Results: Clinical neurological injury and embolic lesions were less frequent in patients with retrograde cerebral perfusion (20.2% vs. 28.4%, p = 0.041 and 13.7% vs. 23.4%, p = 0.010, respectively), but there was no significant difference in the occurrence of watershed lesions (3.0% vs. 6.1%, p = 0.156). However, after multivariable logistic regression, retrograde cerebral perfusion was associated with a significant reduction of clinical neurological injury (OR: 0.60; 95% CI 0.36–0.995, p = 0.049), embolic lesions (OR: 0.55; 95% CI 0.31–0.97, p = 0.041), and watershed lesions (OR: 0.25; 95%CI 0.07–0.80, p = 0.027). There was no significant difference in 30-day mortality (12.8% vs. 11.7%, p = ns) or long-term survival between groups.Conclusion: In this study, we showed that the addition of retrograde cerebral perfusion during hypothermic circulatory arrest in the setting of acute type A aortic dissection repair reduced the risk of clinical neurological injury, embolic lesions, and watershed lesions.
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| 12. |
- Ek, Frida, 1993-
(författare)
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Quiescent cancer cells : Three-dimensional cell models for evaluation of new therapeutics
- 2022
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Inadequate metabolic conditions in solid tumors lead to the formation of quiescent cancer cells that are suspended in a transient cell cycle arrest. When conditions change, quiescent cancer cells can re-enter the cell cycle and cause recurrence. Drug screening efforts have revealed mitochondrial oxidative phosphorylation as a unique metabolic dependency in quiescent cancer cells. The anthelmintic drug nitazoxanide is an inhibitor of oxidative phosphorylation and preferentially active against quiescent cancer cells in multicellular tumor spheroids. In this thesis, we employed current and developed new models of quiescent cancer cells and applied live cell imaging for improved preclinical evaluation of cancer drugs in hepatocellular and colorectal carcinoma cell lines. As part of this work, a new assay to measure mitochondrial membrane potential in three-dimensional cell models was developed, an application of the JC-1 assay, and we demonstrated that the preferential activity against quiescent cancer cells of nitazoxanide is shared by two kinase inhibitors: sorafenib and regorafenib. The sensitivity of quiescent cancer cells to nitazoxanide, sorafenib, and regorafenib correlated with the disruption of the mitochondrial membrane potential. Nitazoxanide and sorafenib, in combination, caused an additive decrease in viability, mitochondrial membrane potential, and colony regrowth capacity. Furthermore, we developed a quiescent hollow fiber assay and implemented an improved analysis using live cell imaging and adenosine triphosphate analysis. Hypoxia and cancer cell quiescence were enriched in hollow fiber macrocapsules over time, and the culture conditions affected nitazoxanide sensitivity. Additionally, we used basement membrane extract gel to support cell growth in hollow fiber macrocapsules and implanted macrocapsules in mice. We observed that the in vivo environment was favorable to cell growth. Through this characterization of the quiescent hollow fiber assay, we were able to outline important paths for future research.
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| 13. |
- Guné, Henrik, et al.
(författare)
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Impact of ABO blood group on bleeding complications after surgery for acute type A aortic dissection
- 2021
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Ingår i: Blood Coagulation and Fibrinolysis. - 1473-5733. ; 32:4, s. 253-258
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Tidskriftsartikel (refereegranskat)abstract
- Excessive bleeding is a serious complication associated with impaired survival after surgery for acute type A aortic dissection (ATAAD). Different ABO blood groups are associated with variable levels of circulating von Willebrand factor and therefore potentially altered risks of surgical haemorrhage. The current study aimed to assess the impact of blood group on bleeding complications after ATAAD surgery. This was a retrospective cohort study including 336 patients surgically treated for ATAAD between January 2004 and January 2019. Patients with blood group O were compared with non-O patients. In total, 152 blood group O patients were compared with 184 non-O patients. There were no differences in rates of massive bleeding (27.0 vs. 25.5%, P = 0.767) or re-exploration for bleeding (16.4 vs. 13.0%, P = 0.379) in blood group O and non-O patients, respectively. Median chest tube output 12 h after surgery was 520 ml (350-815 ml) in blood group O and 490 ml (278-703 ml) in non-O patients (P = 0.229). Blood group O patients received more fibrinogen concentrate (6.1 ± 4.0 vs. 4.9 ± 3.3 g, P = 0.023) but administered units of packed red blood cells [5 (2-8) vs. 4 (2-9) U, P = 0.736], platelets [4 (2-4) vs. 3 (2-5) U, P = 0.521] or plasma [4 (1-7) vs. 4 (0-7) U, P = 0.562] were similar. This study could not demonstrate any association between blood group and bleeding after surgery for ATAAD. It cannot be ruled out that potential differences were levelled out by blood group O patients receiving significantly more fibrinogen concentrate.
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| 14. |
- Hartmann, Rafael, et al.
(författare)
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Rational Design of Azastatin as a Potential ADC Payload with Reduced Bystander Killing.
- 2020
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Ingår i: ChemMedChem. - : Wiley. - 1860-7179 .- 1860-7187. ; 15:24, s. 2500-2512
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Tidskriftsartikel (refereegranskat)abstract
- Auristatins are a class of ultrapotent microtubule inhibitors, whose growing clinical popularity in oncology is based upon their use as payloads in antibody-drug conjugates (ADCs). The most widely utilized auristatin, MMAE, has however been shown to cause apoptosis in non-pathological cells proximal to the tumour ("bystander killing"). Herein, we introduce azastatins, a new class of auristatin derivatives encompassing a side chain amine for antibody conjugation. The synthesis of Cbz-azastatin methyl ester, which included the C2-elongation and diastereoselective reduction of two proteinogenic amino acids as key transformations, was accomplished in 22 steps and 0.76 % overall yield. While Cbz-protected azastatin methyl ester (0.13-3.0 nM) inhibited proliferation more potently than MMAE (0.47-6.5 nM), removal of the Cbz-group yielded dramatically increased IC50 -values (9.8-170 nM). We attribute the reduced apparent cytotoxicity of the deprotected azastatin methyl esters to a lack of membrane permeability. These results clearly establish the azastatins as a novel class of cytotoxic payloads ideally suited for use in next-generation ADC development.
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| 15. |
- Karlsson, Henning, et al.
(författare)
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Selective radiosensitization by nitazoxanide of quiescent clonogenic colon cancer tumour cells
- 2022
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Ingår i: Oncology Letters. - : Spandidos Publications. - 1792-1074 .- 1792-1082. ; 23:4
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Tidskriftsartikel (refereegranskat)abstract
- Nitazoxanide is a Food and Drug Administration-approved antiprotozoal drug recently demonstrated to be selectively active against quiescent and glucose-deprived tumour cells. This drug also has several characteristics that suggest its potential as a radiosensitizer. The present study aimed to investigate the interaction between nitazoxanide and radiation on human colon cancer cells cultured as monolayers, and to mimic key features of solid tumours in patients, as spheroids, as well as in xenografts in mice. In the present study, colon cancer HCT116 green fluorescent protein (GFP) cells were exposed to nitazoxanide, radiation or their combination. Cell survival was analysed by using total cell kill and clonogenic assays. DNA double-strand breaks were evaluated in the spheroid experiments, and HCT116 GFP cell xenograft tumours in mice were used to investigate the effect of nitazoxanide and radiation in vivo. In the clonogenic assay, nitazoxanide synergistically and selectively sensitized cells grown as spheroids to radiation. However, this was not observed in cells cultured as monolayers, as demonstrated in the total cell kill assays, and much less with the clinically established sensitizer 5-fluorouracil. The sensitizing effect from nitazoxanide was confirmed via spheroid gamma-H2A histone family member X staining. Nitazoxanide and radiation alone similarly inhibited the growth of HCT116 GFP cell xenograft tumours in mice with no evidence of synergistic interaction. In conclusion, nitazoxanide selectively targeted quiescent glucose-deprived tumour cells and sensitized these cells to radiation in vitro. Nitazoxanide also inhibited tumour growth in vivo. Thus, nitazoxanide is a candidate for repurposing into an anticancer drug, including its use as a radiosensitizer.
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| 16. |
- Karlsson, Stefan, et al.
(författare)
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Model-based Automated Testing of Mobile Applications : An Industrial Case Study
- 2021
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Ingår i: Proceedings. - 9781665444569 ; , s. 130-137
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Konferensbidrag (refereegranskat)abstract
- Automatic testing of mobile applications has been a well-researched area in recent years. However, testing in industry is still a very manual practice, as research results have not been fully transferred and adopted. Considering mobile applications, manual testing has the additional burden of adequate testing posed by a large number of available devices and different configurations, as well as the maintenance and setup of such devices.In this paper, we propose and evaluate the use of a model-based test generation approach, where generated tests are executed on a set of cloud-hosted real mobile devices. By using a model-based approach we generate dynamic, less brittle, and implementation simple test cases. The test execution on multiple real devices with different configurations increase the confidence in the implementation of the system under test. Our evaluation shows that the used approach produces a high coverage of the parts of the application related to user interactions. Nevertheless, the inclusion of external services in test generation is required in order to additionally increase the coverage of the complete application. Furthermore, we present the lessons learned while transferring and implementing this approach in an industrial context and applying it to the real product.
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| 17. |
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| 18. |
- Kases, Katharina, et al.
(författare)
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The RNA-binding protein ZC3H11A interacts with the nuclear poly(A)-binding protein PABPN1 and alters polyadenylation of viral transcripts
- 2023
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Ingår i: Journal of Biological Chemistry. - : Elsevier. - 0021-9258 .- 1083-351X. ; 299:8
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Tidskriftsartikel (refereegranskat)abstract
- Nuclear mRNA metabolism is regulated by multiple proteins, which either directly bind to RNA or form multiprotein complexes. The RNA-binding protein ZC3H11A is involved in nuclear mRNA export, NF-kappa B signaling, and is essential during mouse embryo development. Furthermore, previous studies have shown that ZC3H11A is important for nuclear-replicating viruses. However, detailed biochemical characterization of the ZC3H11A protein has been lacking. In this study, we established the ZC3H11A protein interactome in human and mouse cells. We demonstrate that the nuclear poly(A)-binding protein PABPN1 interacts specifically with the ZC3H11A protein and controls ZC3H11A localization into nuclear speckles. We report that ZC3H11A specifically interacts with the human adenovirus type 5 (HAdV-5) capsid mRNA in a PABPN1dependent manner. Notably, ZC3H11A uses the same zinc finger motifs to interact with PABPN1 and viral mRNA. Further, we demonstrate that the lack of ZC3H11A alters the polyadenylation of HAdV-5 capsid mRNA. Taken together, our results suggest that the ZC3H11A protein may act as a novel regulator of polyadenylation of nuclear mRNA.
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| 19. |
- Larsson, Mårten, et al.
(författare)
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A prospective, controlled study on the utility of rotational thromboelastometry in surgery for acute type A aortic dissection
- 2022
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- To evaluate the hemostatic system with ROTEM in patients undergoing surgery for acute type aortic dissection (ATAAD) using elective aortic procedures as controls. This was a prospective, controlled, observational study. The study was performed at a tertiary referral center and university hospital. Twenty-three patients with ATAAD were compared to 20 control patients undergoing elective surgery of the ascending aorta or the aortic root. ROTEM (INTEM, EXTEM, HEPTEM and FIBTEM) was tested at 6 points in time before, during and after surgery for ATAAD or elective aortic surgery. The ATAAD group had an activated coagulation coming into the surgical theatre. The two groups showed activation of both major coagulation pathways during surgery, but the ATAAD group consistently had larger deficiencies. Reversal of the coagulopathy was successful, although none of the groups reached elective baseline until postoperative day 1. ROTEM did not detect low levels of clotting factors at heparin reversal nor low levels of platelets. This study demonstrated that ATAAD is associated with a coagulopathic state. Surgery causes additional damage to the hemostatic system in ATAAD patients as well as in patients undergoing elective surgery of the ascending aorta or the aortic root. ROTEM does not adequately catch the full coagulopathy in ATAAD. A transfusion protocol in ATAAD should be specifically created to target this complex coagulopathic state and ROTEM does not negate the need for routine laboratory tests.
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| 20. |
- Larsson, Mårten, et al.
(författare)
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The effect of postoperative anticoagulation on false lumen patency after surgery for acute type A aortic dissection
- 2021
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Ingår i: Journal of Cardiothoracic Surgery. - : Springer Science and Business Media LLC. - 1749-8090. ; 16:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Patent false lumen has been shown to have a negative impact on prognosis after surgery for acute type A aortic dissection (ATAAD). We aimed to assess the effect of postoperative anticoagulation on false lumen patency and clinical outcomes in relation to false lumen status. Methods: Postoperative computed tomographies of 156 patients undergoing ATAAD DeBakey type I surgery were retrospectively evaluated for false lumen patency. The patients were divided into groups determined by anticoagulation treatment at discharge. Uni- and multivariable logistic regression was used for analysing the effect of anticoagulation on the false lumen, and Kaplan–Meier estimates were used to assess the association of a patent false lumen with the incidence of reoperation and long-term survival. Results: A patent false lumen was present in 81% of the patients. Postoperative anticoagulants were not associated with a patent false lumen (p = 0.48) in univariable analysis. In multivariable analysis, both hemiarch replacement (OR 0.15, CI95% 0.05–0.49, p = 0.001) and the use of betablockers had a protective effect (OR 0.29, CI95% 0.10–0.85, p = 0.023). The Kaplan–Meier estimates for survival and the composite endpoint of survival and freedom from distal reintervention indicated no difference in outcome between patients in regard to anticoagulation treatment (survival p = 0.43, composite p = 0.82) or false lumen status (survival p = 0.21, composite p = 0.09). Conclusion: This study could not show negative effects from the postoperative use of anticoagulants on false lumen status, nor that false lumen patency was associated with poorer prognosis. A hemiarch procedure was shown to be associated with reduced risk of false lumen patency.
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| 21. |
- Lu, Xi, et al.
(författare)
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Cell-lineage controlled epigenetic regulation in glioblastoma stem cells determines functionally distinct subgroups and predicts patient survival
- 2022
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- The epigenetic regulation of glioblastoma stem cell (GSC) function remains poorly understood. Here, the authors compare the chromatin accessibility landscape of GSC cultures from mice and patients and suggest that the epigenome of GSCs is cell lineage-regulated and could predict patient survival. There is ample support for developmental regulation of glioblastoma stem cells. To examine how cell lineage controls glioblastoma stem cell function, we present a cross-species epigenome analysis of mouse and human glioblastoma stem cells. We analyze and compare the chromatin-accessibility landscape of nine mouse glioblastoma stem cell cultures of three defined origins and 60 patient-derived glioblastoma stem cell cultures by assay for transposase-accessible chromatin using sequencing. This separates the mouse cultures according to cell of origin and identifies three human glioblastoma stem cell clusters that show overlapping characteristics with each of the mouse groups, and a distribution along an axis of proneural to mesenchymal phenotypes. The epigenetic-based human glioblastoma stem cell clusters display distinct functional properties and can separate patient survival. Cross-species analyses reveals conserved epigenetic regulation of mouse and human glioblastoma stem cells. We conclude that epigenetic control of glioblastoma stem cells primarily is dictated by developmental origin which impacts clinically relevant glioblastoma stem cell properties and patient survival.
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| 22. |
- Mansoori, Sharmineh, et al.
(författare)
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A phase 2a clinical study on the safety and efficacy of individualized dosed mebendazole in patients with advanced gastrointestinal cancer
- 2021
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Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Mebendazole is used extensively for treatment of local gut helminthic and invasive echinococcus infections. Anticancer effects of mebendazole have been shown in experimental cancer models and in case studies in patients with advanced cancer. Given these observations, the aims of this study were to investigate safety and efficacy of individualized dosed mebendazole in the cancer indication. Patients with treatment refractory gastrointestinal cancer were treated with individualized dose adjusted mebendazole up to 4 g/day to target a serum concentration of 300 ng/ml. Efficacy and safety were assessed by CT-scans, clinical surveillance and blood sampling. Eleven patients were included in the study and 10 started the treatment phase. Two patients stopped treatment prior to and the remaining eight after tumour evaluation by CT-scan at 8 weeks, all due to progressive disease. Four patients also fulfilled criteria suggested for hyperprogression. Only five patients reached the target serum-mebendazole concentration. No severe adverse effects were observed. Individualized dose adjusted mebendazole is safe and well tolerated in patients with advanced cancer but all patients experienced rapid progressive disease. New approaches such as prodrug development and combination with other anticancer drugs seem needed for further exploration of mebendazole as an anticancer drug.
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| 23. |
- Naboulsi, Rakan
(författare)
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Animal genomics – gene discovery and gene characterization
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis involves two projects. The aim in the first project was to identify genomic regions associated with spontaneous autoimmune thyroiditis (SAT), which is a hereditary autoimmune disease that affects the obese strain (OS) of chicken, an animal model for human Hashimoto’s thyroiditis (HT). In the second project, we study ZBED6, a highly conserved protein unique to placental mammals. Here we explore the functional significance of ZBED6 in general, and its effect on the regulation of Igf2 and miR483 in specific. To identify genomic regions predisposing to SAT, a nine-generation intercross between OS and their wild ancestor, the red junglefowl (RJF), was previously generated. In paper I, we developed a cell-based assay to phenotype the F9 chickens by measuring the TSH levels in their serum. We found that 1) SAT is similar to HT in the sense that the serum-TSH levels increase in affected individuals, and 2) that TSH levels in SAT-affected chickens starts to increase after 20 weeks of age. In paper II, a whole genome sequencing experiment was performed to compare a healthy and a severely SAT-affected groups of chicken. This analysis revealed 12 genomic loci to be significantly different between the two groups. In the second project, we utilized a mouse myoblast cell line, C2C12, to characterize the function of ZBED6. In paper III, we affect ZBED6 function, by either mutating its binding site in Igf2 (Igf2dGGCT), or by completely knocking it out (Zbed6-/-). Functional analysis of the mutant cells revealed that ZBED6 overexpression induces cell cycle arrest and apoptosis, that ZBED6 directly affects mitochondrial activity, and that ZBED6 in myoblast cells mainly exerts its effect through regulating Igf2. In paper IV, we use ZBED6 knock-out and knock-in mice to investigate the effect of ZBED6 on the regulation of miRNA expression. We found that ZBED6 is not a general regulator for miRNA, with the exception of miR483, which exists in an intron of Igf2. Thereafter, we generated miR483-/- cells, using the Igf2dGGCT cell line. In this analysis we found that the main function of miR483 in myoblast cells is to regulate the expression of Igf2, and that ZBED6 partially regulates Igf2 through regulating miR483.
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| 24. |
- Naboulsi, Rakan, et al.
(författare)
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ZBED6 regulates Igf2 expression partially through its regulation of miR483 expression
- 2021
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Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- The expression of Igf2 in mammals shows a complex regulation involving multiple promoters and epigenetic mechanisms. We previously identified a novel regulatory mechanism based on the interaction between the transcriptional factor ZBED6 and Igf2 intron. Disruption of the ZBED6-Igf2 interaction leads to a dramatic up-regulation of IGF2 expression postnatally. In the current study we characterize an additional layer of regulation involving miR483 encoded by another Igf2 intron. We found a highly significant up-regulation of miR483 expression when the ZBED6-Igf2 axis is disrupted in transgenic mice. Furthermore, CRISPR/Cas9 mediated knock-out of miR483 in C2C12 myoblast cells, both wild-type and cells with disrupted ZBED6-Igf2 axis (Igf2(dGGCT)), resulted in down-regulation of Igf2 expression and a reduced proliferation rate. This was further validated using miR483 mimics and inhibitors. RNA-seq analysis revealed a significant enrichment of genes involved in the PI3K-Akt signaling pathway among genes down-regulated in miR483(-/-) cells, including Igf2 down-regulation. The opposite pattern was observed in Igf2(dGGCT) cells, where Igf2 is up-regulated. Our data suggest a positive feedback between miR483 and Igf2 promoter activity, strongly affecting how ZBED6 controls Igf2 expression in various cell types.
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| 25. |
- Narbe, Ulrik, et al.
(författare)
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The distribution of circulating tumor cells is different in metastatic lobular compared to ductal carcinoma of the breast –long term prognostic significant
- 2020
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Ingår i: Cells. - : MDPI AG. - 2073-4409. ; 9:7
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Tidskriftsartikel (refereegranskat)abstract
- Background: Invasive lobular carcinoma (ILC) has distinguishing features when compared to invasive ductal carcinoma of no special type (NST). In this study, we explored the distributional and prognostic characteristics of circulating tumor cells (CTCs) in metastatic ILC and NST. Materials and methods: Patients were included in an observational trial (ClinicalTrials.gov NCT01322893) with ILC (n = 28) and NST (n = 111). CTC count (number/7.5 mL blood) was evaluated with serial sampling (CellSearch). The primary endpoint was progression-free survival (PFS). Results: The CTC counts were higher in ILC (median 70) than in NST cases (median 2) at baseline (p < 0.001). The evidence for ≥5 CTCs as a prognostic factor for PFS in ILC was weak, but stronger with higher cut-offs (CTC ≥ 20: hazard ratio (HR) 3.0, p = 0.01) (CTC ≥ 80: HR 3.6, p = 0.004). In NST, however, the prognostic effect of CTCs ≥5 was strong. Decline in CTC count from baseline to three months was associated with improved prognosis in ILC and NST. Conclusions: The number of CTCs is higher in ILC than in NST, implying that a higher CTC cut-off could be considered for ILC when applying the CellSearch technique.
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| 26. |
- Nyberg, Frida, et al.
(författare)
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Sorafenib and nitazoxanide disrupt mitochondrial function and inhibit regrowth capacity in three-dimensional models of hepatocellular and colorectal carcinoma
- 2022
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Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Quiescent cancer cells in malignant tumors can withstand cell-cycle active treatment and cause cancer spread and recurrence. Three-dimensional (3D) cancer cell models have led to the identification of oxidative phosphorylation (OXPHOS) as a context-dependent vulnerability. The limited treatment options for advanced hepatocellular carcinoma (HCC) and colorectal carcinoma (CRC) metastatic to the liver include the multikinase inhibitors sorafenib and regorafenib. Off-target effects of sorafenib and regorafenib are related to OXPHOS inhibition; however the importance of this feature to the effect on tumor cells has not been investigated in 3D models. We began by assessing global transcriptional responses in monolayer cell cultures, then moved on to multicellular tumor spheroids (MCTS) and tumoroids generated from a CRC patient. Cells were treated with chemotherapeutics, kinase inhibitors, and the OXPHOS inhibitors. Cells grown in 3D cultures were sensitive to the OXPHOS inhibitor nitazoxanide, sorafenib, and regorafenib and resistant to other multikinase inhibitors and chemotherapeutic drugs. Furthermore, nitazoxanide and sorafenib reduced viability, regrowth potential and inhibited mitochondrial membrane potential in an additive manner at clinically relevant concentrations. This study demonstrates that the OXPHOS inhibition caused by sorafenib and regorafenib parallels 3D activity and can be further investigated for new combination strategies.
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| 27. |
- Rafati, Nima, et al.
(författare)
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Reconstruction of the birth of a male sex chromosome present in Atlantic herring
- 2020
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : National Academy Of Sciences. - 0027-8424 .- 1091-6490. ; 117:39, s. 24359-24368
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Tidskriftsartikel (refereegranskat)abstract
- The mechanisms underlying sex determination are astonishingly plastic. Particularly the triggers for the molecular machinery, which recalls either the male or female developmental program, are highly variable and have evolved independently and repeatedly. Fish show a huge variety of sex determination systems, including both genetic and environmental triggers. The advent of sex chromosomes is assumed to stabilize genetic sex determination. However, because sex chromosomes are notoriously cluttered with repetitive DNA and pseudogenes, the study of their evolution is hampered. Here we reconstruct the birth of a Y chromosome present in the Atlantic herring. The region is tiny (230 kb) and contains only three intact genes. The candidate male-determining gene BMPR1BBY encodes a truncated form of a BMP1B receptor, which originated by gene duplication and translocation and underwent rapid protein evolution. BMPR1BBY phosphorylates SMADs in the absence of ligand and thus has the potential to induce testis formation. The Y region also contains two genes encoding subunits of the sperm-specific Ca2+ channel CatSper required for male fertility. The herring Y chromosome conforms with a characteristic feature of many sex chromosomes, namely, suppressed recombination between a sex-determining factor and genes that are beneficial for the given sex. However, the herring Y differs from other sex chromosomes in that suppression of recombination is restricted to an ∼500-kb region harboring the male-specific and sex-associated regions. As a consequence, any degeneration on the herring Y chromosome is restricted to those genes located in the small region affected by suppressed recombination.
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| 28. |
- Selvin, Tove, et al.
(författare)
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Immuno-oncological effects of standard anticancer agents and commonly used concomitant drugs : an in vitro assessment
- 2024
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Ingår i: BMC Pharmacology & Toxicology. - : BioMed Central (BMC). - 2050-6511. ; 25:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundIt has become evident in the field of oncology that the outcome of medical treatment is influenced by the combined effect exerted on both cancer- and immune cells. Therefore, we evaluated potential immunological effects of 46 standard anticancer agents and 22 commonly administered concomitant non-cancer drugs.MethodsWe utilized a miniaturized in vitro model system comprised of fluorescently labeled human colon and lung cancer cell lines grown as monocultures and co-cultured with activated peripheral blood mononuclear cells (PBMCs). The Bliss Independence Model was then applied to detect antagonism and synergy between the drugs and activated immune cells.ResultsAmong the standard anticancer agents, tyrosine kinase inhibitors (TKIs) stood out as the top inducers of both antagonism and synergy. Ruxolitinib and dasatinib emerged as the most notably antagonistic substances, exhibiting the lowest Bliss scores, whereas sorafenib was shown to synergize with activated PBMCs. Most concomitant drugs did not induce neither antagonism nor synergy. However, the statins mevastatin and simvastatin were uniquely shown to synergize with activated PBMC at all tested drug concentrations in the colon cancer model.ConclusionWe utilized a miniaturized tumor-immune model to enable time and cost-effective evaluation of a broad panel of drugs in an immuno-oncology setting in vitro. Using this approach, immunomodulatory effects exerted by TKIs and statins were identified.
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| 29. |
- Selvin, Tove, et al.
(författare)
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Phenotypic screening platform identifies statins as enhancers of immune cell-induced cancer cell death.
- 2023
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Ingår i: BMC cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- High-throughput screening (HTS) of small molecule drug libraries has greatly facilitated the discovery of new cancer drugs. However, most phenotypic screening platforms used in the field of oncology are based solely on cancer cell populations and do not allow for the identification of immunomodulatory agents.We developed a phenotypic screening platform based on a miniaturized co-culture system with human colorectal cancer- and immune cells, providing a model that recapitulates part of the tumor immune microenvironment (TIME) complexity while simultaneously being compatible with a simple image-based readout. Using this platform, we screened 1,280 small molecule drugs, all approved by the Food and Drug Administration (FDA), and identified statins as enhancers of immune cell-induced cancer cell death.The lipophilic statin pitavastatin had the most potent anti-cancer effect. Further analysis demonstrated that pitavastatin treatment induced a pro-inflammatory cytokine profile as well as an overall pro-inflammatory gene expression profile in our tumor-immune model.Our study provides an in vitro phenotypic screening approach for the identification of immunomodulatory agents and thus addresses a critical gap in the field of immuno-oncology. Our pilot screen identified statins, a drug family gaining increasing interest as repurposing candidates for cancer treatment, as enhancers of immune cell-induced cancer cell death. We speculate that the clinical benefits described for cancer patients receiving statins are not simply caused by a direct effect on the cancer cells but rather are dependent on the combined effect exerted on both cancer and immune cells.
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| 30. |
- Selvin, Tove
(författare)
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Preclinical tumor-immune modeling : For the identification of immunomodulatory drugs
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- For a long time, the field of cancer research was dominated by a tumor cell-centric view. That, however, changed once it became recognized that medical cancer treatment is largely influenced by the combined effect exerted on both cancer and immune cells. In this work, we aimed to develop and apply preclinical model systems for the identification and evaluation of immunomodulatory anti-cancer agents. In Paper I, we employed single-cell RNA sequencing (scRNA-seq) to investigate immunological effects of trifluridine (FTD), a nucleoside analogue used for the treatment of colorectal cancer (CRC). The study revealed that while FTD induces immunogenic cell death (ICD), it may also attenuate T cell-mediated antitumor responses. In paper II and III, we developed and applied a phenotypic screening platform based on a miniaturized tumor-immune model. In paper II, aiming to identify immunological effects of clinical relevance and provide a reference point for screening novel compound libraries, the model system was used to assess a broad panel of standard anticancer agents. In paper III, the platform was used to screen a drug library containing 1280 small molecule drugs, all approved by the FDA or other agencies. Using this approach, statins were identified as enhancers of immune cell-mediated cancer cell killing. Finally, in paper IV, we developed the immuno-oncology hollow fiber assay (HFA) with the goal of bridging the gap between cell based in vitro assays and more complex mouse models for evaluation of immuno-oncological agents. The HFA is an in vivo assay in which semipermeable fibers are filled with cancer cells and implanted in rodents. We further developed the HFA to incorporate both cancer and immune cells. This novel assay demonstrated the potential to capture immune-mediated cancer cell killing in vivo within a matter of days. Collectively, this work provides a research approach for immuno-oncology drug screening, in vitro validation, and initial in vivo evaluation.
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| 31. |
- Selvin, Tove, et al.
(författare)
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Single-cell transcriptional pharmacodynamics of trifluridine in a tumor-immune model
- 2022
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 12
-
Tidskriftsartikel (refereegranskat)abstract
- Understanding the immunological effects of chemotherapy is of great importance, especially now that we have entered an era where ever-increasing pre-clinical and clinical efforts are put into combining chemotherapy and immunotherapy to combat cancer. Single-cell RNA sequencing (scRNA-seq) has proved to be a powerful technique with a broad range of applications, studies evaluating drug effects in co-cultures of tumor and immune cells are however scarce. We treated a co-culture comprised of human colorectal cancer (CRC) cells and peripheral blood mononuclear cells (PBMCs) with the nucleoside analogue trifluridine (FTD) and used scRNA-seq to analyze posttreatment gene expression profiles in thousands of individual cancer and immune cells concurrently. ScRNA-seq recapitulated major mechanisms of action previously described for FTD and provided new insight into possible treatment-induced effects on T-cell mediated antitumor responses.
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| 32. |
- Steinmetz, Julia, et al.
(författare)
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Descriptive Proteome Analysis to Investigate Context-Dependent Treatment Responses to OXPHOS Inhibition in Colon Carcinoma Cells Grown as Monolayer and Multicellular Tumor Spheroids
- 2020
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Ingår i: ACS Omega. - : American Chemical Society (ACS). - 2470-1343. ; 5:28, s. 17242-17254
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Tidskriftsartikel (refereegranskat)abstract
- We have previously identified selective upregulation of the mevalonate pathway genes upon inhibition of oxidative phosphorylation (OXPHOS) in quiescent cancer cells. Using mass spectrometry-based proteomics, we here investigated whether these responses are corroborated on the protein level and whether proteomics could yield unique insights into context-dependent biology. HCT116 colon carcinoma cells were cultured as monolayer cultures, proliferative multicellular tumor spheroids (P-MCTS), or quiescent (Q:MCTS) multicellular tumor spheroids and exposed to OXPHOS inhibitors: nitazoxanide, FCCP, oligomycin, and salinomycin or the HMG-CoA-reductase inhibitor simvastatin at two different doses for 6 and 24 h. Samples were processed using an in-depth bottom-up proteomics workflow resulting in a total of 9286 identified protein groups. Gene set enrichment analysis showed profound differences between the three cell systems and confirmed differential enrichment of hypoxia, OXPHOS, and cell cycle progression-related protein responses in P-MCTS and QMCTS. Treatment experiments showed that the observed drug-induced alterations in gene expression of metabolically challenged cells are not translated directly to the protein level, but the results reaffirmed OXPHOS as a selective vulnerability of quiescent cancer cells. This work provides rationale for the use of deep proteome profiling to identify context-dependent treatment responses and encourages further studies investigating metabolic processes that could be co-targeted together with OXPHOS to eradicate quiescent cancer cells.
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| 33. |
- Tarle, Magnus, et al.
(författare)
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A World Model Based Reinforcement Learning Architecture for Autonomous Power System Control
- 2021
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Ingår i: 2021 IEEE International Conference on Communications, Control, and Computing Technologies for Smart Grids (SmartGridComm). - : IEEE. ; , s. 364-370
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Konferensbidrag (refereegranskat)abstract
- Renewable generation is leading to rapidly shifting power flows and it is anticipated that traditional power system control may soon be inadequate to cope with these fluctuations. Traditional control include human-in-the-loop-control schemes while more autonomous control methods can be categorized into Wide-Area Monitoring, Protection and Control systems (WAMPAC). Within this latter group of more advanced systems, reinforcement learning (RL) is a potential candidate to facilitate power system control facing these new challenges. In this paper we demonstrate how a model based reinforcement learning (MBRL) algorithm, which learns and uses an internal model of the world, can be used for autonomous power system control. The proposed RL agent, called the World Model for Autonomous Power System Control (WMAP), includes a safety shield to minimize risk of poor decisions at high uncertainty. The shield can be configured to permit WMAP to take actions with the condition that WMAP asks for guidance, e.g. from a human operator, when in doubt. As an alternative, WMAP could be run in full decision support mode which would require the operator to take all the active decisions. A case study is performed on a IEEE 14-bus system where WMAP is setup to control setpoints of two FACTS devices to emulate grid stability improvements. Results show that improved grid stability is achieved using WMAP while staying within voltage limits. Furthermore, a disastrous situation is avoided when WMAP asks for help in a test scenario event that it had not been trained for.
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| 34. |
- Tarle, Magnus, et al.
(författare)
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Safe Reinforcement Learning for Mitigation of Model Errors in FACTS Setpoint Control
- 2023
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Ingår i: 2023 International Conference on Smart Energy Systems and Technologies, SEST 2023. - : Institute of Electrical and Electronics Engineers (IEEE).
-
Konferensbidrag (refereegranskat)abstract
- The application of closed-loop control using model-based approaches in wide area monitoring protection and control is limited. Challenges of model-based approaches include engineering complexity, model errors and convergence issues. In particular, as the grid is evolving e.g. with the expansion of renewables and distributed generation, maintaining an updated network model without model errors is onerous. Promising alternatives to model-based approaches are data-driven control architectures based on reinforcement learning (RL). In this work we study safe RL to confront safety concerns with data-driven approaches. In a case study on the IEEE 14-bus and IEEE 57-bus systems, accumulated constraint violations are investigated for a model-free RL agent and a model-based RL agent. These agents are compared against a model-based optimal controller subject to model errors. Our findings suggest that RL could be considered for optimizing voltage and current setpoints in systems where model errors include topological errors.
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| 35. |
- Teurneau-Hermansson, Karl, et al.
(författare)
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Mortality after non-surgically treated acute type A aortic dissection is higher than previously reported
- 2024
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Ingår i: European Journal of Cardio-Thoracic Surgery. - 1010-7940. ; 65:2
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: It has been commonly accepted that untreated acute type A aortic dissection (ATAAD) results in an hourly mortality rate of 1–2% during the 1st 24 h after symptom onset. The data to support this statement rely solely on patients who have been denied surgical treatment after reaching surgical centres. The objective was to perform a total review of non-surgically treated (NST) ATAAD and provide contemporary mortality data. METHODS: This was a regional, retrospective, observational study. All patients receiving one of the following diagnoses: International Classification of Diseases (ICD)-9 4410, 4411, 4415, 4416 or ICD-10 I710, I711, I715, I718 in an area of 1.9 million inhabitants in Southern Sweden during a period of 23 years (January 1998 to November 2021) were retrospectively screened. The search was conducted using all available medical registries so that every patient diagnosed with ATAAD in our region was identified. The charts and imaging of each screened patient were subsequently reviewed to confirm or discard the diagnosis of ATAAD. RESULTS: Screening identified 2325 patients, of whom 184 NST ATAAD patients were included. The mortality of NST ATAAD was 47.3 ± 4.4%, 55.0 ± 4.4%, 76.7 ± 3.7% and 83.9 ± 4.3% at 24 h, 48 h, 14 days and 1 year, respectively. The hourly mortality rate during the 1st 24 h after symptom onset was 2.6%. CONCLUSIONS: This study observed higher mortality than has previously been reported. It emphasizes the need for timely diagnosis, swift management and emergent surgical treatment for patients suffering an acute type A aortic dissection.
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| 36. |
- Teurneau-Hermansson, Karl, et al.
(författare)
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S100B predicts neurological injury and 30-day mortality following surgery for acute type A aortic dissection : an observational cohort study
- 2023
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Ingår i: Journal of Cardiothoracic Surgery. - : Springer Science and Business Media LLC. - 1749-8090. ; 18:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Neurological injuries are frequent following Acute Type A Aortic Dissection (ATAAD) repair occurring in 4–30% of all patients. Our objective was to study whether S100B can predict neurological injury following ATAAD repair. Methods: This was a single-center, retrospective, observational study. The study included all patients that underwent ATAAD repair at our institution between Jan 1998 and Dec 2021 and had recorded S100B-values. The primary outcome measure was neurological injury, defined as focal neurological deficit or coma diagnosed by clinical assessment with or without radiological confirmation and with a symptom duration of more than 24 h. Secondary outcome measure was 30-day mortality. Results: 538 patients underwent surgery during the study period and 393 patients, had recorded S100B-values. The patients had a mean age of 64.4 ± 11.1 years and 34% were female. Receiver operating characteristic curve for S100B 24 h postoperatively yielded area under the curve 0.687 (95% CI 0.615–0.759) and best Youden’s index corresponded to S100B 0.225 which gave a sensitivity of 60% and specificity of 75%. Multivariable logistic regression identified S100B ≥ 0.23 μg/l at 24 h as an independent predictor for neurological injury (OR 4.71, 95% CI 2.59–8.57; p < 0.01) along with preoperative cerebral malperfusion (OR 4.23, 95% CI 2.03–8.84; p < 0.01) as well as an independent predictor for 30-day mortality (OR 4.57, 95% CI 1.18–11.70; p < 0.01). Conclusions: We demonstrated that S100B, 24 h after surgery is a strong independent predictor for neurological injury and 30-day mortality after ATAAD repair. Trial registration: As this was a retrospective observational study it was not registered.
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| 37. |
- Wisén, Niclas, et al.
(författare)
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Are Peacekeeping Missions Inevitably Stressful?
- 2021
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Ingår i: Scandinavian Journal of Military Studies. - : Scandinavian Military Studies. - 2596-3856. ; 4:1, s. 210-219
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Tidskriftsartikel (refereegranskat)
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| 38. |
- Wisén, Niclas, et al.
(författare)
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Is conduct after capture training sufficiently stressful?
- 2022
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Ingår i: Frontiers in Psychology. - : Frontiers Media SA. - 1664-1078. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Conduct after capture (CAC) training is for personnel at risk of being captured. To be effective, it needs to be stressful. But how do we know if it is stressful enough? This study uses biomarkers and cognitive measures to evaluate CAC. Soldiers undergoing CAC were measured by the stress hormone cortisol from saliva samples at baseline and during training. The training consisted of being taken capture and put through a number of realistic and threatening scenarios, targeting survival strategies taught in the preceding week. Between scenarios, the trainees were held in a holding cell where they were monitored by a guard. The saliva samples were taken in conjunction with the scenarios. The whole training took place over a period of ~24 h. Cognitive performance was measured at baseline and after training. Three groups took part Group A (n = 20) was taken after 48 h of intense tasks leaving them in a poor resting state. Group B (n = 23) was well rested at CAC onset. Group C (n = 10) was part of a survival, evasion, resistance, and escape (SERE) instructor course. The CAC training was the same for all groups. Group A exhibited a high increase in cortisol during CAC, compared to baseline levels were multiple times as high as “expected” values. Group B exhibited elevated levels slightly lower than those of group A, they also “dropped” to “normal” levels during the latter part of the exercise. Group C displayed the least increase with only slightly elevated levels. CAC training is stressful and cortisol levels were elevated enough to satisfy the prerequisite for effective stress inoculation. No cognitive performance drop could be identified; however, several participants “froze” during the exercise due to intensive stress.
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| 39. |
- Wisén, Niclas, et al.
(författare)
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Measuring the impact of operational stress : The relevance of assessing stress-related health across the deployment cycle
- 2023
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Ingår i: Military medicine. - : Oxford University Press (OUP). - 0026-4075 .- 1930-613X. ; 188:7-8, s. 2126-2132
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Mental health issues from intense or prolonged stress are a common concern in regard to military deployment. Deployments can objectively vary in stress exposure, but it is the individuals' perception of that stress that affects sustainability, mental health, and combat fitness, which calls for the need of a protocol to evaluate and maintain a current estimation of stress impact. So, how can we assess the impact of stressors during different phases of deployment?Materials and methods: We used three psychological self-rating forms, the PSS14-Perceived Stress Scale, SMBM-Shirom Melamed Burnout Measure, and KSQ-Karolinska Sleep Questionnaire, to measure the impact of stress before (T1), during (T2), and at homecoming (T3). We also wanted to see if T1 or T2 results could predict T3 results to be able to better prepare the homecoming program.The forms were handed out to Swedish soldiers deployed in Mali in 2017. The forms were collected as a way to assess the status of the mental health load at three timepoints based on the personnel function as a way to assess the current "psychological fitness level".Results: The results show that stress measured using PSS14 was high at homecoming. The same result was observed for SMBM. No measures from T1 or T2 could however predict the T3 results.Conclusions: Taken together, we found that screening of all contingent staff is relatively easy and provides personnel with relevant data on mental health and stress at the current time. We also found that test results correlated between T1 and T2 but not with T3. This indicates that there might be different stressors that affect staff at different timepoints.
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| 40. |
- Younis, Shady, et al.
(författare)
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Ablation of ZC3H11A causes early embryonic lethality and dysregulation of metabolic processes
- 2023
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences (PNAS). - 0027-8424 .- 1091-6490. ; 120:23
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Tidskriftsartikel (refereegranskat)abstract
- ZC3H11A (zinc finger CCCH domain-containing protein 11A) is a stress-induced mRNA-binding protein required for efficient growth of nuclear-replicating viruses. The cellular functions of ZC3H11A during embryonic development are unknown. Here, we report the generation and phenotypic characterization ofZc3h11a knockout (KO) mice. Heterozygous null Zc3h11a mice were born at the expected frequency without distinguishable phenotypic differences compared with wild-type mice. In contrast, homozygous null Zc3h11a mice were missing, indicating that Zc3h11a is crucial for embryonic viability and survival. Zc3h11a -/- embryos were detected at the expected Mendelian ratios up to late preimplantation stage (E4.5). However, phenotypic characterization at E6.5 revealed degeneration of Zc3h11a( -/-) embryos, indicating developmental defects around the time of implantation. Transcriptomic analyses documented a dysregulation of glycolysis and fatty acid metabolic pathways in Zc3h11a(-/-) embryos at E4.5. Proteomic analysis indicated a tight interaction between ZC3H11A and mRNA-export proteins in embryonic stem cells. CLIP-seq analysis demonstrated that ZC3H11A binds a subset of mRNA transcripts that are critical for metabolic regulation of embryonic cells. Furthermore, embryonic stem cells with an induced deletion of Zc3h11a display an impaired differentiation toward epiblast-like cells and impaired mitochondrial membrane potential. Altogether, the results show that ZC3H11A is participating in export and posttranscriptional regulation of selected mRNA transcripts required to maintain metabolic processes in embryonic cells. While ZC3H11A is essential for the viability of the early mouse embryo, inactivation of Zc3h11a expression in adult tissues using a conditional KO did not lead to obvious phenotypic defects.
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| 41. |
- Younis, Shady, et al.
(författare)
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The importance of the ZBED6-IGF2 axis for metabolic regulation in mouse myoblast cells
- 2020
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Ingår i: The FASEB Journal. - 0892-6638 .- 1530-6860. ; 34:8, s. 10250-10266
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Tidskriftsartikel (refereegranskat)abstract
- The transcription factor ZBED6 acts as a repressor of Igf2 and affects directly or indirectly the transcriptional regulation of thousands of genes. Here, we use gene editing in mouse C2C12 myoblasts and show that ZBED6 regulates Igf2 exclusively through its binding site 5'-GGCTCG-3' in intron 1 of Igf2. Deletion of this motif (Igf2ΔGGCT ) or complete ablation of Zbed6 leads to ~20-fold upregulation of the IGF2 protein. Quantitative proteomics revealed an activation of Ras signaling pathway in both Zbed6-/- and Igf2ΔGGCT myoblasts, and a significant enrichment of mitochondrial membrane proteins among proteins showing altered expression in Zbed6-/- myoblasts. Both Zbed6-/- and Igf2ΔGGCT myoblasts showed a faster growth rate and developed myotube hypertrophy. These cells exhibited an increased O2 consumption rate, due to IGF2 upregulation. Transcriptome analysis revealed ~30% overlap between differentially expressed genes in Zbed6-/- and Igf2ΔGGCT myotubes, with an enrichment of upregulated genes involved in muscle development. In contrast, ZBED6-overexpression in myoblasts led to cell apoptosis, cell cycle arrest, reduced mitochondrial activities, and ceased myoblast differentiation. The similarities in growth and differentiation phenotypes observed in Zbed6-/- and Igf2ΔGGCT myoblasts demonstrates that ZBED6 affects mitochondrial activity and myogenesis largely through its regulation of IGF2 expression. This study adds new insights how the ZBED6-Igf2 axis affects muscle metabolism.
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