| 1. |
- 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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| 2. |
- Forslund, Marina
(författare)
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A nutrition intervention in men with prostate cancer : Exploring effects on bowel symptoms from radiotherapy, patient experience, and nutrient intake
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Objective The main objective of this thesis was to explore the effects of a nutrition intervention on acute and late bowel symptoms in men with localised prostate cancer treated with pelvic radiotherapy (study I), participants’ experiences from receiving the nutrition intervention (study II), and associations with nutrient intakes (study III).Methods A total of 180 men with localised prostate cancer referred to curative radiotherapy targeting the prostate gland and pelvic lymph nodes were recruited to the trial. The participants were randomised to standard care plus a nutrition intervention aiming to modify fibre and lactose intakes (NIG; n=92) or standard care alone (SCG; n=88). Data on bowel symptoms and dietary intake were collected pre-treatment and at seven time points during a 26-month study period. Analyses of the effects of the nutrition intervention on bowel symptoms were conducted for the acute phase (up to 2 months post radiotherapy), and the late phase (7 to 24 months post radiotherapy). Semi-structured interviews were conducted with 15 participants from the NIG to explore experiences of the nutrition intervention.Results The nutrition intervention was associated with statistically significantly, but not clinically significantly, less bother from blood in stools and flatulence during the acute phase. The nutrition intervention was also associated with more bloated abdomen during the late phase (Study I). Social support, contributing to the greater good, prior knowledge, dietary information, and a small need for change facilitated adherence. While feeling limited, wanting to decide for themselves, the timing of the intervention, unmet expectations, and loss of motivation were described as barriers for adherence (Study II). A greater reduction of lactose was associated with decreased intake of calcium at the end of the radiotherapy period. A more modified fibre intake during the radiotherapy period was associated with increased vitamin C, but decreased selenium intake (Study III).Conclusions The effects from the nutrition intervention were small and inconclusive and do not support routine dietary advice aiming to modify fibre and lactose intakes as a mean to substantially reduce adverse effects from pelvic radiotherapy. Tailored nutritional interventions based on individual preferences, prior knowledge, and context, could enhance adherence. There were few associations between modified fibre and lactose intakes and nutrient intakes, thus, no recommendations can be made on whether such dietary advice should continue to be provided to men with prostate cancer undergoing pelvic radiotherapy.
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| 3. |
- Forslund, Marina, et al.
(författare)
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Effects of a nutrition intervention on acute and late bowel symptoms and health-related quality of life up to 24 months post radiotherapy in patients with prostate cancer : a multicentre randomised controlled trial.
- 2020
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Ingår i: Supportive Care in Cancer. - : Springer Nature. - 0941-4355 .- 1433-7339. ; 28:7, s. 3331-3342
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Radiotherapy to the prostate gland and pelvic lymph nodes may cause acute and late bowel symptoms and diminish quality of life. The aim was to study the effects of a nutrition intervention on bowel symptoms and health-related quality of life, compared with standard care.Methods: Patients were randomised to a nutrition intervention (n = 92) aiming to replace insoluble fibres with soluble and reduce intake of lactose, or a standard care group (n = 88) who were recommended to maintain their habitual diet. Bowel symptoms, health-related quality of life and intake of fibre and lactose-containing foods were assessed up to 24 months after radiotherapy completion. Multiple linear regression was used to analyse the effects of the nutrition intervention on bowel symptoms during the acute (up to 2 months post radiotherapy) and the late (7 to 24 months post radiotherapy) phase.Results: Most symptoms and functioning worsened during the acute phase, and improved during the late phase in both the intervention and standard care groups. The nutrition intervention was associated with less blood in stools (p = 0.047), flatulence (p = 0.014) and increased loss of appetite (p = 0.018) during the acute phase, and more bloated abdomen in the late phase (p = 0.029). However, these associations were clinically trivial or small.Conclusions: The effect of the nutrition intervention related to dietary fibre and lactose on bowel symptoms from pelvic RT was small and inconclusive, although some minor and transient improvements were observed. The results do not support routine nutrition intervention of this type to reduce adverse effects from pelvic radiotherapy.
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| 4. |
- Forslund, Marina, et al.
(författare)
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Experiences of a nutrition intervention : A qualitative study within a randomised controlled trial in men undergoing radiotherapy for prostate cancer
- 2020
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Ingår i: Nutrition & Dietetics. - : Wiley. - 1446-6368 .- 1747-0080. ; 77:2, s. 223-230
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Tidskriftsartikel (refereegranskat)abstract
- AIM: Men with prostate cancer undergoing radiotherapy may experience acute and late bowel symptoms. Nutrition interventions have shown some benefits, however, adherence tends to decline over time. Qualitative studies, carried out after an intervention, are important to help explain trial results. The aim of the present study was to explore patient experience of participating in a nutrition intervention in a randomised controlled trial, with a focus on facilitators and barriers to adherence.METHODS: Semistructured interviews were conducted with 15 men with prostate cancer recruited from a randomised controlled trial on a nutrition intervention during radiotherapy. Interviews were analysed with content analysis with an inductive approach.RESULTS: The informants were motivated to make dietary changes to avoid bowel symptoms. Social support, a feeling of contributing to the greater good, prior knowledge, dietary information and a small need for behaviour change facilitated adherence. Feeling limited, wanting to decide for themselves, the timing of the intervention, unmet expectations of dietary advice and loss of motivation, were described as barriers for adherence.CONCLUSIONS: Future nutrition intervention trials may benefit from involving significant others to a greater degree, as well as offering pre-set recipes and strategies to manage social events, and more sessions with the dietitian for patients in need of more support. Tailored interventions based on the individual's preferences, context and prior knowledge about food may further facilitate adherence.
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| 5. |
- Hauffman, Anna, et al.
(författare)
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Cocreated internet-based stepped care for individuals with cancer and concurrent symptoms of anxiety and depression : Results from the U-CARE AdultCan randomized controlled trial
- 2020
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Ingår i: Psycho-Oncology. - : John Wiley & Sons. - 1057-9249 .- 1099-1611. ; 29:12, s. 2012-2018
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Tidskriftsartikel (refereegranskat)abstract
- Objective The aim was to evaluate the effects of cocreated internet-based stepped care (iCAN-DO) on anxiety, depression, posttraumatic stress, and health-related quality of life (HRQoL) in individuals with cancer and self-reported anxiety and/or depression symptoms, compared with standard care.Methods Clinically recruited individuals with breast, colorectal, or prostate cancer underwent online screening with the Hospital Anxiety and Depression Scale (HADS). Those with anxiety and/or depression symptoms (>7 on any of the HADS subscales) were randomized to iCAN-DO or standard care. iCAN-DO comprised psychoeducation and self-care strategies (step 1) and internet-based cognitive behavioral therapy (iCBT, step 2). Data were collected before randomization and at 1, 4, 7, and 10 months and analyzed with intention-to-treat regression analysis and randomization tests.Results Online screening identified 245 (27%) of 909 individuals who reported anxiety and/or depression symptoms. They were randomized to iCAN-DO (n = 124) or standard care (n = 121). Of them 49% completed the 10-month assessment, and in the iCAN-DO group 85% accessed step 1 and 13% underwent iCBT. iCAN-DO decreased the levels of symptoms of depression (−0.54, 95% confidence interval: −1.08 to −0.01, P < .05) and the proportion of individuals with symptoms of depression (P < .01) at 10 months, compared with standard care, according to HADS. There were no significant effects on anxiety, posttraumatic stress, or HRQoL.Conclusion Internet-based stepped care improves symptoms of depression in individuals with cancer. Further studies are needed to gain knowledge on how to optimize and implement internet-based support in oncology care.
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| 6. |
- Hauffman, Anna
(författare)
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Internet-based Psychosocial Support : Design, Effects and User Experience in the Cancer Setting
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background and Aim Being diagnosed with cancer is often described as a major loss of control leading to severe psychological distress and symptoms of anxiety and depression can continue to affect the individual in the long term. The cancer and its treatment may influence all dimensions of health, thus the psychosocial support provided needs to be multifaceted and easy accessed. Internet-based interventions may be one way to provide such support, but evidence is limited. This thesis aimed to investigate the design, effects, and experiences of internet-based psychosocial support in cancer.Methods and Results Study 1 encompassed a co-creation development process resulting in the interactive support provided as the first step in an internet-based stepped care intervention (iCAN-DO). The effects of iCAN-DO were investigated in a randomised controlled trial, targeting individuals newly diagnosed with cancer and concurrent self-reported symptoms of anxiety and depression (according to the Hospital Anxiety and Depression Scale). Step 1 had a psycho-educative content involving self-care strategies and was available to the intervention group during the ten-month study period. Step 2 comprised a guided internet-based cognitive behavior therapy (iCBT) program and was offered those without improvement in anxiety and depression after using Step 1. The results showed that iCAN-DO improved symptoms of depression compared with standard care, while symptoms of anxiety were largely unaffected. Most participants used Step 1, while only a few used Step 2.In Study 2, aspects of usefulness, relevance, and usability in iCAN-DO were explored through qualitative interviews, analysed using content analysis. Results showed that standard healthcare did not meet the individuals' needs and iCAN-DO was used as complement, providing access to relevant, trustworthy information and support. Usability was affected by the perceived usefulness and ease of use of the intervention, as well as by the user´s circumstances in life and consequences of the cancer. The co-creation process in the development of Step 1 added relevance, but both steps 1 and 2 would have gained from being provided earlier, integrated into standard healthcare and more adaptable to the individual.Conclusion The thesis concluded that the internet-based intervention had positive effects on symptoms of depression in individuals newly diagnosed with cancer. Individuals with cancer experience several unmet needs in standard healthcare and since psycho-educative support including self-care advice seems feasible in this group, efforts are needed to incorporate internet-based support in regular oncology care. Since the intervention did not target all symptoms (i.e. anxiety) further research is needed on how to enhance efficacy and how to make iCBT more feasible for this group.
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| 7. |
- Månsson, Christopher, Läkarexamen, 1977-, et al.
(författare)
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Ultrasound-guided Percutaneous Irreversible Electroporation for Treatment of Locally Recurrent Pancreatic Cancer After Surgical Resection
- 2020
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Ingår i: Anticancer Research. - : INT INST ANTICANCER RESEARCH. - 0250-7005 .- 1791-7530. ; 40:5, s. 2771-2775
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Tidskriftsartikel (refereegranskat)abstract
- Background/Aim: Irreversible electroporation (IRE) has recently been used as an experimental treatment for cancers including locally advanced pancreatic cancer. There is very limited data on IRE in pancreatic cancer that is locally recurrent after surgical resection. The aim of this study was to evaluate the safety and efficacy of IRE in this setting.Patients and Methods: Ten patients with locally recurrent pancreatic cancer without distant metastases after surgical resection were included and treated with ultrasound-guided percutaneous IRE.Results: Two patients had severe complications, of whom one died. Median disease-free survival was 3.3 months and overall median survival after IRE and resection was 16.5 and 42.7 months, respectively. Two patients are alive 42.1 and 23.9 months after the IRE without signs of local recurrence.Conclusion: Percutaneous IRE in locally recurrent pancreatic cancer following curative resection is feasible, but should be regarded as a high-risk procedure that, at present, cannot be recommended outside of clinical trials. Further research is needed to select patients who might benefit from this treatment.
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| 8. |
- Nygren, Jens M., 1976-, et al.
(författare)
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Examining the Ethical Implications of Health Care Technology Described in US and Swedish PhD Dissertations : Protocol for a Scoping Review
- 2020
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Ingår i: JMIR Research Protocols. - Toronto : J M I R Publications Inc.. - 1929-0748. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: The development of new biomedical technologies is accelerating at an unprecedented speed. These new technologies will undoubtedly bring solutions to long-standing problems and health conditions. However, they will likely also have a shadow side in the form of unintended effects or ethical implications accompanying them. It may be presumed that the research behind new technologies has been evaluated from an ethical perspective; however, the evidence that this has been done is scant.Objective: The objective of this study is to gain an understanding, if and how PhD dissertations focused on health technologies describe actual or possible ethical issues resulting from their research.Methods: The purpose of scoping reviews is to map a topic in the literature comprehensively and systematically to identify gaps in the literature or identify key evidence. The search strategy for this protocol will include electronic databases including ProQuest, Medline/Pubmed, Diva, SwePub and LIBRIS. Searches will be limited to PhD dissertations published in the US and Sweden in the last ten years. The study will be mapped in five stages: 1) identifying the research question, 2) identifying relevant studies, 3) study selection, 4) retrieving and charting the data, and 5) collating, summarizing and reporting the results.Results: The findings of this study will indicate if and how researchers, PhD students and their supervisors, are considering ethics in their studies, including both research ethics and the ethical implications of their work. The findings can guide researchers in determining gaps and shortcomings in current doctoral education and offer a foundation to adjusting doctoral research education.Conclusions: In a society where technology and research are advancing at speeds unknown to us before, we need to find new and more efficient ways to consider ethical issues and address them in a timelier manner. This study will offer an understanding of how ethics is currently being integrated into US and Swedish PhD dissertations and inform the future direction of ethics education at a doctoral level. © Jens M. Nygren, Hans-Peter de Ruiter. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 22.01.2020.
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| 9. |
- Rendo, Verónica, et al.
(författare)
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Exploiting loss of heterozygosity for allele-selective colorectal cancer chemotherapy
- 2020
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Allelic losses occurring in cancer cells have been suggested as potential targets for therapy. Here, the authors show how recurring loss of heterozygosity of a drug metabolic gene in colorectal cancers can be exploited using a low molecular weight compound. Cancer chemotherapy targeting frequent loss of heterozygosity events is an attractive concept, since tumor cells may lack enzymatic activities present in normal constitutional cells. To find exploitable targets, we map prevalent genetic polymorphisms to protein structures and identify 45 nsSNVs (non-synonymous small nucleotide variations) near the catalytic sites of 17 enzymes frequently lost in cancer. For proof of concept, we select the gastrointestinal drug metabolic enzyme NAT2 at 8p22, which is frequently lost in colorectal cancers and has a common variant with 10-fold reduced activity. Small molecule screening results in a cytotoxic kinase inhibitor that impairs growth of cells with slow NAT2 and decreases the growth of tumors with slow NAT2 by half as compared to those with wild-type NAT2. Most of the patient-derived CRC cells expressing slow NAT2 also show sensitivity to 6-(4-aminophenyl)-N-(3,4,5-trimethoxyphenyl)pyrazin-2-amine (APA) treatment. These findings indicate that the therapeutic index of anti-cancer drugs can be altered by bystander mutations affecting drug metabolic genes.
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| 10. |
- Schulte, T., et al.
(författare)
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Assigned NMR backbone resonances of the ligand-binding region domain of the pneumococcal serine-rich repeat protein (PsrP-BR) reveal a rigid monomer in solution
- 2020
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Ingår i: Biomolecular NMR Assignments. - : Springer. - 1874-2718 .- 1874-270X.
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Tidskriftsartikel (refereegranskat)abstract
- The pneumococcal serine rich repeat protein (PsrP) is displayed on the surface of Streptococcus pneumoniae with a suggested role in colonization in the human upper respiratory tract. Full-length PsrP is a 4000 residue-long multi-domain protein comprising a positively charged functional binding region (BR) domain for interaction with keratin and extracellular DNA during pneumococcal adhesion and biofilm formation, respectively. The previously determined crystal structure of the BR domain revealed a flat compressed barrel comprising two sides with an extended β-sheet on one side, and another β-sheet that is distorted by loops and β-turns on the other side. Crystallographic B-factors indicated a relatively high mobility of loop regions that were hypothesized to be important for binding. Furthermore, the crystal structure revealed an inter-molecular β-sheet formed between edge strands of two symmetry-related molecules, which could promote bacterial aggregation during biofilm formation. Here we report the near complete 15N/13C/1H backbone resonance assignment of the BR domain of PsrP, revealing a secondary structure profile that is almost identical to the X-ray structure. Dynamic 15N-T1, T2 and NOE data suggest a monomeric and rigid structure of BR with disordered residues only at the N- and C-termini. The presented peak assignment will allow us to identify BR residues that are crucial for ligand binding.
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