| 1. |
- Gad, Helge, et al.
(författare)
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MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool
- 2014
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Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 508:7495, s. 215-221
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Tidskriftsartikel (refereegranskat)abstract
- Cancers have dysfunctional redox regulation resulting in reactive oxygen species production, damaging both DNA and free dNTPs. The MTH1 protein sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, we show that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, resulting in DNA damage and cell death. We validate MTH1 as an anticancer target in vivo and describe small molecules TH287 and TH588 as first-in-class nudix hydrolase family inhibitors that potently and selectively engage and inhibit the MTH1 protein in cells. Protein co-crystal structures demonstrate that the inhibitors bindin the active site of MTH1. The inhibitors cause incorporation of oxidized dNTPs in cancer cells, leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse xenografts. This study exemplifies the non-oncogene addiction concept for anticancer treatment and validates MTH1 as being cancer phenotypic lethal.
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| 4. |
- Gustafsson, Oscar, et al.
(författare)
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Long-wavelength infrared quantum-dot based interband photodetectors
- 2011
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Ingår i: Infrared physics & technology. - : Elsevier BV. - 1350-4495 .- 1879-0275. ; 54:3, s. 287-291
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Tidskriftsartikel (refereegranskat)abstract
- We report on the design and fabrication of (Al)GaAs(Sb)/InAs tensile strained quantum-dot (QD) based detector material for thermal infrared imaging applications in the long-wavelength infrared (LWIR) regime. The detection is based on transitions between confined dot states and continuum states in a type-II band lineup, and we therefore refer to it as a dot-to-bulk (D2B) infrared photodetector with expected benefits including long carrier lifetime due to the type-II band alignment, suppressed Shockley-Read-Hall generation-recombination due to the relatively large-bandgap matrix material, inhibited Auger recombination processes due to the tensile strain and epitaxial simplicity. Metal-organic vapor-phase epitaxy was used to grow multiple (Al)GaAs(Sb) QD layers on InAs substrates at different QD nominal thicknesses, compositions, doping conditions and multilayer periods, and the material was characterized using atomic force and transmission electron microscopy, and Fourier-transform infrared absorption spectroscopy. Dot densities up to 1 x 10(11) cm(-2), 1 x 10(12) cm(-2) and 3 x 10(10) cm(-2) were measured for GaAs, AlGaAs and GaAsSb QDs, respectively. Strong absorption in GaAs, AlGaAs and GaAsSb multilayer QD samples was observed in the wavelength range 6-12 mu m. From the wavelength shift in the spectral absorption for samples with varying QD thickness and composition it is believed that the absorption is due to an intra- valance band transition. From this it is possible to estimate the type-II inter-band transition wavelength, thereby suggesting that (Al)GaAs(Sb) QD/InAs heterostructures are suitable candidates for LWIR detection and imaging.
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| 5. |
- Eriksson, Anna, et al.
(författare)
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The novel tyrosine kinase inhibitor AKN-028 has significant antileukemic activity in cell lines and primary cultures of acute myeloid leukemia
- 2012
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Ingår i: Blood Cancer Journal. - : Springer Science and Business Media LLC. - 2044-5385. ; 2, s. e81-
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Tidskriftsartikel (refereegranskat)abstract
- Aberrantly expressed tyrosine kinases have emerged as promising targets for drug development in acute myeloid leukemia (AML). We report that AKN-028, a novel tyrosine kinase inhibitor (TKI), is a potent FMS-like receptor tyrosine kinase 3 (FLT3) inhibitor (IC50=6 nM), causing dose-dependent inhibition of FLT3 autophosphorylation. Inhibition of KIT autophosphorylation was shown in a human megakaryoblastic leukemia cell line overexpressing KIT. In a panel of 17 cell lines, AKN-028 showed cytotoxic activity in all five AML cell lines included. AKN-028 triggered apoptosis in MV4-11 by activation of caspase 3. In primary AML samples (n=15), AKN-028 induced a clear dose-dependent cytotoxic response (mean IC50 1 μM). However, no correlation between antileukemic activity and FLT3 mutation status, or to the quantitative expression of FLT3, was observed. Combination studies showed synergistic activity when cytarabine or daunorubicin was added simultaneously or 24 h before AKN-028. In mice, AKN-028 demonstrated high oral bioavailability and antileukemic effect in primary AML and MV4-11 cells, with no major toxicity observed in the experiment. In conclusion, AKN-028 is a novel TKI with significant preclinical antileukemic activity in AML. Possible sequence-dependent synergy with standard AML drugs and good oral bioavailability has made it a candidate drug for clinical trials (ongoing).
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| 6. |
- Genovese, Giulio, et al.
(författare)
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Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence.
- 2014
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Ingår i: The New England journal of medicine. - 1533-4406 .- 0028-4793. ; 371:26, s. 2477-87
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Tidskriftsartikel (refereegranskat)abstract
- Cancers arise from multiple acquired mutations, which presumably occur over many years. Early stages in cancer development might be present years before cancers become clinically apparent.
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| 7. |
- Heijl, Caroline, et al.
(författare)
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Incidence of malignancy in patients treated for antineutrophil cytoplasm antibody-associated vasculitis: follow-up data from European Vasculitis Study Group clinical trials.
- 2011
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 70, s. 1415-1421
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: /st> Because standard immunosuppressive treatment for antineutrophil cytoplasm antibody-associated vasculitis (AAV) (granulomatosis with polyangiitis (Wegener's) (GPA) and microscopic polyangiitis (MPA)) has been associated with a significant risk of developing cancer, the cancer incidence of treated AAV patients was assessed. METHODS: /st> This analysis concerned 535 patients with newly diagnosed AAV from 15 countries who had been enrolled between 1995 and 2002 in four European clinical trials. Over the period 2004-7, study participants' follow-up events were updated, including cancers diagnosed. Age, sex and area-standardised incidence ratios (SIR) and their 95% CI were calculated by linkage to five national cancer databases. RESULTS: /st> During the 2650 person-years' observation period, 50 cancers were diagnosed in 46 patients. SIR (95% CI) were 1.58 (1.17 to 2.08) for cancers at all sites, 1.30 (0.90 to 1.80) for cancers at all sites excluding non-melanoma skin cancer (NMSC), 2.41 (0.66 to 6.17) for bladder cancer, 3.23 (0.39 to 11.65) for leukaemia, 1.11 (0.03 to 6.19) for lymphoma and 2.78 (1.56 to 4.59) for NMSC. Subgroup SIR for cancers at all sites were 1.92 (1.31 to 2.71) for GPA and 1.20 (0.71 to 1.89) for MPA. CONCLUSIONS: /st> Cancer rates for AAV patients treated with conventional immunosuppressive therapy exceeded those expected for the general population. This cancer excess was largely driven by an increased incidence of NMSC. The smaller cancer risk magnitude in this cohort, compared with previous studies, might reflect less extensive use of cyclophosphamide in current treatment protocols. Longer follow-up data are warranted to appraise the risk of developing cancers later during the course of AAV.
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| 8. |
- Höglund, Andreas, 1980-, et al.
(författare)
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Therapeutic implications for the induced levels of Chk1 in Myc- expressing cancer cells
- 2011
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Ingår i: Clinical Cancer Research. - Philadelphia : Association for Cancer Research. - 1078-0432 .- 1557-3265. ; 17:22, s. 7067-7079
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: The transcription factor c-Myc (or "Myc") is a master regulator of pathways driving cell growth and proliferation. MYC is deregulated in many human cancers, making its downstream target genes attractive candidates for drug development. We report the unexpected finding that B-cell lymphomas from mice and patients exhibit a striking correlation between high levels of Myc and checkpoint kinase 1 (Chk1). Experimental Design: By in vitro cell biology studies as well as preclinical studies using a genetically engineered mouse model, we evaluated the role of Chk1 in Myc-overexpressing cells. Results: We show that Myc indirectly induces Chek1 transcript and protein expression, independently of DNA damage response proteins such as ATM and p53. Importantly, we show that inhibition of Chk1, by either RNA interference or a novel highly selective small molecule inhibitor, results in caspase-dependent apoptosis that affects Myc-overexpressing cells in both in vitro and in vivo mouse models of B-cell lymphoma. Conclusion: Our data suggest that Chk1 inhibitors should be further evaluated as potential drugs against Myc-driven malignancies such as certain B-cell lymphoma/leukemia, neuroblastoma, and some breast and lung cancers. Clin Cancer Res; 17(22); 7067-79. (C) 2011 AACR.
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| 9. |
- Lehmann, S, et al.
(författare)
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Continuing high early death rate in acute promyelocytic leukemia: a population-based report from the Swedish Adult Acute Leukemia Registry.
- 2011
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Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 1476-5551 .- 0887-6924. ; 25:7, s. 1128-34
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Tidskriftsartikel (refereegranskat)abstract
- Our knowledge about acute promyelocytic leukemia (APL) patients is mainly based on data from clinical trials, whereas population-based information is scarce. We studied APL patients diagnosed between 1997 and 2006 in the population-based Swedish Adult Acute Leukemia Registry. Of a total of 3897 acute leukemia cases, 3205 (82%) had non-APL acute myeloid leukemia (AML) and 105 (2.7%) had APL. The incidence of APL was 0.145 per 100,000 inhabitants per year. The median age at the time of diagnosis was 54 years; 62% were female and 38% male. Among younger APL patients, female sex predominated (89% of patients <40 years). Of the 105 APL patients, 30 (29%) died within 30 days (that is, early death (ED)) (median 4 days) and 28 (26%) within 14 days from diagnosis. In all, 41% of the EDs were due to hemorrhage; 35% of ED patients never received all-trans-retinoic acid treatment. ED rates increased with age but more clearly with poor performance status. ED was also associated with high white blood cells, lactate dehydrogenase, creatinine, C-reactive protein and low platelet count. Of non-ED patients, 97% achieved complete remission of which 16% subsequently relapsed. In total, 62% are still alive at 6.4 years median follow-up. We conclude that ED rates remain very high in an unselected APL population.
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| 10. |
- Paredes, J. A., et al.
(författare)
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Gene Expression Deregulation in Postnatal Skeletal Muscle of TK2 Deficient Mice Reveals a Lower Pool of Proliferating Myogenic Progenitor Cells
- 2013
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:1, s. e53698-
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Tidskriftsartikel (refereegranskat)abstract
- Loss of thymidine kinase 2 (TK2) causes a heterogeneous myopathic form of mitochondrial DNA (mtDNA) depletion syndrome (MDS) in humans that predominantly affects skeletal muscle tissue. In mice, TK2 deficiency also affects several tissues in addition to skeletal muscle, including brain, heart, adipose tissue, kidneys and causes death about 3 weeks after birth. We analysed skeletal muscle and heart muscle tissues of Tk2 knockout mice at postnatal development phase and observed that TK2 deficient pups grew slower and their skeletal muscles appeared significantly underdeveloped, whereas heart was close to normal in size. Both tissues showed mtDNA depletion and mitochondria with altered ultrastructure, as revealed by transmission electron microscopy. Gene expression microarray analysis showed a strong down-regulation of genes involved in cell cycle and cell proliferation in both tissues, suggesting a lower pool of undifferentiated proliferating cells. Analysis of isolated primary myoblasts from Tk2 knockout mice showed slow proliferation, less ability to differentiate and signs of premature senescence, even in absence of mtDNA depletion. Our data demonstrate that TK2 deficiency disturbs myogenic progenitor cells function in postnatal skeletal muscle and we propose this as one of the causes of underdeveloped phenotype and myopathic characteristic of the TK2 deficient mice, in addition to the progressive mtDNA depletion, mitochondrial damage and respiratory chain deficiency in post-mitotic differentiated tissue.
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