| 41. |
- Laryea, Daniel
(författare)
-
Preclinical Characterization in vivo and in vitro of Novel Agents for Cancer Chemotherapy : Studies on Benomyl, Carbendazim, Cryptolepine and Acriflavine
- 2010
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Preclinical methods for the identification and characterization of molecules for development into new cancer drugs were investigated. Based on repurposing, i.e. the exploration of currently prescribed drugs for new indications, and as a result of a new high throughput screening (HTS) approach, the benzimidazoles benomyl and carbendazim, the alkaloid cryptolepine and the acridine acriflavine were found interesting to characterize using these methods. In mice the benzimidazoles inhibited 3H-thymidine incorporation in tissues with high cell renewal, with benomyl being more active than carbendazim. They were rapidly absorbed with highest amounts seen in the liver, kidneys and gastro-intestinal lumen as evidenced from distribution of 14C-labeled drugs. In human tumour cell lines, the benzimidazoles showed a similar activity pattern but benomyl was more potent. This was true also in tumour cells from patients but carbendazim was relatively more active against solid tumours. Analyses of drug activity cross-resistance patterns and of drug activity – gene expression correlations in a cell line panel suggested multiple mechanisms of action for the benzimidazoles. Cryptolepine was widely distributed to tissues in vivo in the mice. It was more potent than the benzimidazoles in tumour cells, with highest activity in haematological malignancies but some patient samples of breast, colon and non small-cell lung cancer were sensitive. Cross-resistance analysis indicated cryptolepine to be a topoisomerase II inhibitor whereas drug activity – gene expression correlations suggested additional mechanisms of action. HTS on 2 000 molecules in colon cancer cell lines and normal cells identified acriflavine as a hit molecule, subsequently shown to have unprecedented activity against colorectal cancer tumour cells in patient tumour samples. Connectivity map analysis, based on drug induced gene expression perturbation patterns in a tumour cell line, indicated acriflavine to be a topoisomerase inhibitor, subsequently confirmed in a plasmid relaxation assay. In conclusion, repurposing of drugs and HTS using stringent activity criteria followed by preclinical characterization might contribute to more efficient development of new cancer drugs.
|
|
| 42. |
- Mattsson, Peter, et al.
(författare)
-
Physical fitness, but not muscle strength, is a risk factor for death in amyotrophic lateral sclerosis at an early age
- 2012
-
Ingår i: Journal of Neurology, Neurosurgery and Psychiatry. - : BMJ. - 0022-3050 .- 1468-330X. ; 83:4, s. 390-394
-
Tidskriftsartikel (refereegranskat)abstract
- Background Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disorder mainly characterised by motor symptoms. Extensive physical activity has been implicated in the aetiology of ALS. Differences in anthropometrics, physical fitness and isometric strength measured at 18-19 years were assessed to determine if they are associated with subsequent death in ALS. Method Data on body weight and height, physical fitness, resting heart rate and isometric strength measured at conscription were linked with data on death certificates in men born in 1951-1965 in Sweden (n=809 789). Physical fitness was assessed as a maximal test on an electrically braked bicycle ergometer. Muscle strength was measured as the maximal isometric strength in handgrip, elbow flexion and knee extension in standardised positions, using a dynamometer. Analyses were based on 684 459 (84.5%) men because of missing data. A matched case control study within this sample was performed. The population was followed until 31 December 2006, and 85 men died from ALS during this period. Results Weight adjusted physical fitness (W/kg), but not physical fitness per se, was a risk factor for ALS (OR 1.98, 95% CI 1.32 to 2.97), whereas resting pulse rate, muscle strength and other variables were not. Conclusions Physical fitness, but not muscle strength, is a risk factor for death at early age in ALS. This may indicate that a common factor underlies both fitness (W/kg) and risk of ALS.
|
|
| 43. |
- Mattsson, Susanne, et al.
(författare)
-
Internet-based stepped care with interactive support and cognitive behavioral therapy for reduction of anxiety and depressive symptoms in cancer : a clinical trial protocol
- 2013
-
Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 13, s. 414-
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Approximately 20-30% of patients with cancer experience a clinically relevant level of emotional distress in response to disease and treatment. This in itself is alarming but it is even more problematic because it is often difficult for physicians and nurses to identify cancer patients who experience clinically relevant levels of anxiety and depression symptoms. This can result in persistent distress and can cause human suffering as well as costs for individuals and to the community. Methods: Applying a multi-disciplinary and design-oriented approach aimed at attaining new evidence-based knowledge in basic and applied psychosocial oncology, this protocol will evaluate an intervention to be implemented in clinical practice to reduce cancer patient anxiety and depression. A prospective randomized design will be used. The overarching goal of the intervention is to promote psychosocial health among patients suffering from cancer by means of self-help programmes delivered via an Internet platform. Another goal is to reduce costs for individuals and society, caused by emotional distress in response to cancer. Following screening to detect levels of patient distress, patients will be randomized to standard care or a stepped care intervention. For patients randomized to the intervention, step 1 will consist of self-help material, a chat forum where participants will be able to communicate with each other, and a Frequently Asked Questions (FAQ) section where they can ask questions and get answers from an expert. Patients in the intervention group who still report symptoms of anxiety or depression after access to step 1 will be offered step 2, which will consist of cognitive behavioral therapy (CBT) administered by a personal therapist. The primary end point of the study is patients' levels of anxiety and depression, evaluated longitudinally during and after the intervention. Discussion: There is a lack of controlled studies of the psychological and behavioral processes involved in this type of intervention for anxiety and depressive disorders. Since anxiety and depressive symptoms are relatively common in patients with cancer and the availability of adequate support efforts is limited, there is a need to develop evidence-based stepped care for patients with cancer, to be delivered via the Internet.
|
|
| 44. |
- Månsson, Christopher, et al.
(författare)
-
Safety and Preliminary Efficacy of Ultrasound-guided Percutaneous Irreversible Electroporation for Treatment of Localized Pancreatic Cancer
- 2014
-
Ingår i: Anticancer Research. - 0250-7005 .- 1791-7530. ; 34:1A, s. 289-293
-
Tidskriftsartikel (refereegranskat)abstract
- Background:Irreversible electroporation (IRE) is a local tumor treatment. Thin needles are placed percutaneously around the tumor under ultrasound guidance. Short pulses of direct current sent through the tissue irreversibly increase cell membrane permeability leading to cell death. We report a phase I study assessing the safety of ultrasound guided percutaneous IRE in patients with localized pancreatic cancer (LPC).Patients and Methods:Five patients (three males) with LPC, judged unsuitable for surgery, chemotherapy, or non-resectable after standard oncological treatment, were treated with IRE. The treatment was given under general anesthesia with muscle relaxation.Results:No serious treatment-related adverse events were observed. There was no 30-day mortality. One patient went on to laparotomy and had a R0 pancreaticoduodenectomy with portal vein resection. Six months after the treatment, two patients had no signs of recurrence on computed tomography or contrast-enhanced ultrasound.Conclusion: IRE for LPC can be safely performed percutaneously under ultrasound guidance, with promising initial results regarding efficacy.
|
|
| 45. |
- Neiman, Maja, et al.
(författare)
-
Selectivity analysis of single binder assays used in plasma protein profiling
- 2013
-
Ingår i: Proteomics. - : Wiley. - 1615-9853 .- 1615-9861. ; 13:23-24, s. 3406-3410
-
Tidskriftsartikel (refereegranskat)abstract
- The increasing availability of antibodies toward human proteins enables broad explorations of the proteomic landscape in cells, tissues, and body fluids. This includes assays with antibody suspension bead arrays that generate protein profiles of plasma samples by flow cytometer analysis. However, antibody selectivity is context dependent so it is necessary to corroborate on-target detection over off-target binding. To address this, we describe a concept to directly verify interactions from antibody-coupled beads by analysis of their eluates by Western blots and MS. We demonstrate selective antibody binding in complex samples with antibodies toward a set of chosen proteins with different abundance in plasma and serum, and illustrate the need to adjust sample and bead concentrations accordingly. The presented approach will serve as an important tool for resolving differential protein profiles from antibody arrays within plasma biomarker discoveries.
|
|
| 46. |
|
|
| 47. |
- Nygren, Peter, et al.
(författare)
-
Repositioning of the anthelmintic drug mebendazole for the treatment for colon cancer
- 2013
-
Ingår i: Journal of Cancer Research and Clinical Oncology. - : Springer Science and Business Media LLC. - 0171-5216 .- 1432-1335. ; 139:12, s. 2133-2140
-
Tidskriftsartikel (refereegranskat)abstract
- In the present study, we screened a compound library containing 1,600 clinically used compounds with the aim to identify compounds, which potentially could be repositioned for colon cancer therapy. Two established colon cancer cell lines were tested using the fluorometric microculture cytotoxicity assay (FMCA). For compound comparison connectivity map (CMAP) analysis, NCI 60 data mining and protein kinase binding measurements were performed. Sixty-eight compounds were defined as hits with activity in both of these cell lines (< 40 % cell survival compared with control) at 10 mu M drug concentration. Analysis of chemical similarity of the hit compounds revealed several distinct clusters, among them the antiparasitic benzimidazole group. Two of these compounds, mebendazole (MBZ) and albendazole (ABZ) are registered for human use. Data from the NCI 60 cell line panel revealed only modest correlation between MBZ and ABZ, indicating differences in mechanism of action. This was further supported when gene expression signatures were compared in the CMAP database; ABZ ranked very low when MBZ was used as the query signature. Furthermore, MBZ, but not ABZ, was found to significantly interact with several protein kinases including BCR-ABL and BRAF. Analysis of the diagnosis-specific activity of MBZ showed activity in 80 % of the colon cancer cell lines in the NCI 60 panel. Three additional colon cancer cell lines and three cell models with non-malignant phenotypes were subsequently tested, confirming selective colon cancer activity of MBZ. MBZ seemingly has repositioning potential for colorectal cancer therapy.
|
|
| 48. |
- Palm, Maria E, et al.
(författare)
-
Cisplatin binds human copper chaperone Atox1 and promotes unfolding in vitro.
- 2011
-
Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 108:17, s. 6951-6
-
Tidskriftsartikel (refereegranskat)abstract
- Cisplatin (cisPt), Pt(NH(3))(2)Cl(2), is a cancer drug believed to kill cells via DNA binding and damage. Recent work has implied that the cellular copper (Cu) transport machinery may be involved in cisPt cell export and drug resistance. Normally, the Cu chaperone Atox1 binds Cu(I) via two cysteines and delivers the metal to metal-binding domains of ATP7B; the ATP7B domains then transfer the metal to the Golgi lumen for loading on cuproenzymes. Here, we use spectroscopic methods to test if cisPt interacts with purified Atox1 in solution in vitro. We find that cisPt binds to Atox1's metal-binding site regardless of the presence of Cu or not: When Cu is bound to Atox1, the near-UV circular dichroism signals indicate Cu-Pt interactions. From NMR data, it is evident that cisPt binds to the folded protein. CisPt-bound Atox1 is however not stable over time and the protein begins to unfold and aggregate. The reaction rates are limited by slow cisPt dechlorination. CisPt-induced unfolding of Atox1 is specific because this effect was not observed for two unrelated proteins that also bind cisPt. Our study demonstrates that Atox1 is a candidate for cisPt drug resistance: By binding to Atox1 in the cytoplasm, cisPt transport to DNA may be blocked. In agreement with this model, cell line studies demonstrate a correlation between Atox1 expression levels, and cisplatin resistance.
|
|
| 49. |
- Pettersson, Anna, et al.
(författare)
-
Effects of a dietary intervention on gastrointestinal symptoms after prostate cancer radiotherapy : Long-term results from a randomized controlled trial
- 2014
-
Ingår i: Radiotherapy and Oncology. - : Elsevier BV. - 0167-8140 .- 1879-0887. ; 113:2, s. 240-247
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND PURPOSE:To evaluate the long-term effects of dietary intervention on gastrointestinal symptoms after highly dose-escalated radiotherapy for localized prostate cancer, using boost with protons or high-dose-rate brachytherapy.MATERIALS AND METHODS:Patients were randomized to an intervention group (n=64) advised to reduce insoluble dietary fiber and lactose intake, or to a standard care group (n=66) advised to continue their usual diet. Gastrointestinal symptoms, other domains of health-related quality of life (HRQOL), and dietary intake were evaluated for ⩽24months post-radiotherapy with the European Organization for Research and Treatment of Cancer quality-of-life questionnaires QLQ-C30 and QLQ-PR25, Gastrointestinal Side Effects Questionnaire, and Food Frequency Questionnaire. The effect of the intervention on gastrointestinal symptoms was evaluated using generalized estimating equations.RESULTS:Dietary intervention had no obvious effect on long-term gastrointestinal symptoms or HRQOL. The intervention group markedly reduced their dietary fiber and lactose intake during radiotherapy, but adherence tended to decline over time. The vast majority of long-term gastrointestinal symptoms were reported as 'a little', with a noticeable difference from pre-treatment only for unintentional stool leakage, limitations on daily activities, and mucus discharge.CONCLUSION:Long-term gastrointestinal symptoms were predominantly mild, and dietary intervention was not superior to a usual diet in preventing these symptoms.
|
|
| 50. |
- Pinto, Dalila, et al.
(författare)
-
Functional impact of global rare copy number variation in autism spectrum disorders.
- 2010
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 466:7304, s. 368-372
-
Tidskriftsartikel (refereegranskat)abstract
- The autism spectrum disorders (ASDs) are a group of conditions characterized by impairments in reciprocal social interaction and communication, and the presence of restricted and repetitive behaviours. Individuals with an ASD vary greatly in cognitive development, which can range from above average to intellectual disability. Although ASDs are known to be highly heritable ( approximately 90%), the underlying genetic determinants are still largely unknown. Here we analysed the genome-wide characteristics of rare (<1% frequency) copy number variation in ASD using dense genotyping arrays. When comparing 996 ASD individuals of European ancestry to 1,287 matched controls, cases were found to carry a higher global burden of rare, genic copy number variants (CNVs) (1.19 fold, P = 0.012), especially so for loci previously implicated in either ASD and/or intellectual disability (1.69 fold, P = 3.4 x 10(-4)). Among the CNVs there were numerous de novo and inherited events, sometimes in combination in a given family, implicating many novel ASD genes such as SHANK2, SYNGAP1, DLGAP2 and the X-linked DDX53-PTCHD1 locus. We also discovered an enrichment of CNVs disrupting functional gene sets involved in cellular proliferation, projection and motility, and GTPase/Ras signalling. Our results reveal many new genetic and functional targets in ASD that may lead to final connected pathways.
|
|
