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- Liddelow, S. A., et al.
(författare)
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Mechanisms That Determine the Internal Environment of the Developing Brain: A Transcriptomic, Functional and Ultrastructural Approach
- 2013
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 8:7
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Tidskriftsartikel (refereegranskat)abstract
- We provide comprehensive identification of embryonic (E15) and adult rat lateral ventricular choroid plexus transcriptome, with focus on junction-associated proteins, ionic influx transporters and channels. Additionally, these data are related to new structural and previously published permeability studies. Results reveal that most genes associated with intercellular junctions are expressed at similar levels at both ages. In total, 32 molecules known to be associated with brain barrier interfaces were identified. Nine claudins showed unaltered expression, while two claudins (6 and 8) were expressed at higher levels in the embryo. Expression levels for most cytoplasmic/regulatory adaptors (10 of 12) were similar at the two ages. A few junctional genes displayed lower expression in embryos, including 5 claudins, occludin and one junctional adhesion molecule. Three gap junction genes were enriched in the embryo. The functional effectiveness of these junctions was assessed using blood-delivered water-soluble tracers at both the light and electron microscopic level: embryo and adult junctions halted movement of both 286Da and 3kDa molecules into the cerebrospinal fluid (CSF). The molecular identities of many ion channel and transporter genes previously reported as important for CSF formation and secretion in the adult were demonstrated in the embryonic choroid plexus (and validated with immunohistochemistry of protein products), but with some major age-related differences in expression. In addition, a large number of previously unidentified ion channel and transporter genes were identified for the first time in plexus epithelium. These results, in addition to data obtained from electron microscopical and physiological permeability experiments in immature brains, indicate that exchange between blood and CSF is mainly transcellular, as well-formed tight junctions restrict movement of small water-soluble molecules from early in development. These data strongly indicate the brain develops within a well-protected internal environment and the exchange between the blood, brain and CSF is transcellular and not through incomplete barriers.
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| 2. |
- Juliusson, Gunnar, et al.
(författare)
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Increased remissions from one course for intermediate-dose cytosine arabinoside and idarubicin in elderly acute myeloid leukaemia when combined with cladribine. A randomized population-based phase II study
- 2003
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Ingår i: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 123:5, s. 810-818
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Tidskriftsartikel (refereegranskat)abstract
- Cladribine has single-drug activity in acute myeloid leukaemia (AML), and may enhance the formation of the active metabolite (ara-CTP) of cytosine arabinoside (ara-C). To evaluate the feasibility of adding intermittent cladribine to intermediate-dose ara-C (1 g/m(2)/2 h) b.i.d. for 4 d with idarubicin (CCI), we performed a 2:1 randomized phase II trial in AML patients aged over 60 years. Primary endpoints were time to recovery from cytopenia and need for supportive care following the first course. Sixty-three patients (median 71 years, range 60-84 years) were included, constituting 72% of all eligible patients. Toxicity was limited, with no differences between the treatment arms. The early toxic death rate was 11%. The median time to recovery from neutropenia and thrombocytopenia was 22 and 17 d from the start of course no. 1, respectively, and the requirement for platelet and red cell transfusions was four and eight units respectively. Patients had a median of 8 d with fever over 38degreesC, and 17 d with intravenous antibiotic treatment. The overall complete remission (CR) rate was 62%, with 51% CR from one course of CCI in comparison with 35% for the two-drug therapy (P = 0.014). The median survival with a 2-year follow-up was 14 months, and the 2-year survival was over 30%, with no differences between the treatment arms. Considering the median age and our population-based approach, the overall results are encouraging.
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| 5. |
- Mollgard, L, et al.
(författare)
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The FLT3 inhibitor PKC412 in combination with cytostatic drugs in vitro in acute myeloid leukemia
- 2008
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Ingår i: Cancer Chemotherapy and Pharmacology. - : Springer Science and Business Media LLC. - 0344-5704 .- 1432-0843. ; 62:3, s. 439-448
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Tidskriftsartikel (refereegranskat)abstract
- An internal tandem duplication of FLT3 (FLT3/ITD) occurs in approximately 25% of newly diagnosed AML. PKC412 inhibits the growth of leukemic cell lines with FLT3 mutations such as the MV4-11. This study evaluated the in vitro effects of the combination of PKC412 and ara-C or daunorubicin, studying the effect of co-incubation, pre-incubation and sequential incubation of the drugs in patient samples and cell lines. Thirty-three patients with AML were included. Two cell lines were studied; MV4-11 that expresses the FLT3/ITD and HL-60 that does not. In the patient cells PKC412 exerted its effect at concentrations between 0.1 and 2.0 muM. For MV4-11 cells concentrations down to 1 nM were effective. In patient samples, the results of co-incubation of PKC412 with ara-C were synergistic in 5%, additive in 67%, sub additive in 17% and antagonistic in 11% of the cases. In patient cells, incubations with ara-C and PKC412 resulted in synergistic effects in 17% of the FLT3/ITD positive samples compared to 0% synergistic in the FLT3/ITD negative samples (p < 0.01). Antagonistic effects were more common in the FLT3/ITD negative samples. The timing of the drugs had little impact on the effect. In cell lines, antagonistic effects were seen frequently in HL-60 (90%) and less so in MV4-11 (60%) regardless of sequence or timing of the drugs. The combination of daunorubicin and PKC412 resulted in more synergistic and less antagonistic effects compared to combinations with ara-C, in both patient material and cell lines. The combination of Lonafarnib, a farnesyl-transferase inhibitor (FTI) and PKC412 had additive and synergistic effects in both FLT3/ITD positive and negative cell lines. In conclusion, the combination of PKC412 together with chemotherapeutic drugs is more effective in FLT3/ITD positive AML cells. Antagonistic effects can be seen, especially in patient samples without FLT3/ITD. Also, the combination of PKC412 and the farnesylinhibitor lonafarnib should be further explored.
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