| 1. |
- Amare, Azmeraw T, et al.
(författare)
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Association of polygenic score and the involvement of cholinergic and glutamatergic pathways with lithium treatment response in patients with bipolar disorder.
- 2023
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Ingår i: Molecular psychiatry. - 1476-5578. ; 28, s. 5251-5261
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Tidskriftsartikel (refereegranskat)abstract
- Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental healthdisorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li+PGS) in patients with BD. To gain further insights into lithium's possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li+PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi+Gen: N=2367) and replicated in the combined PsyCourse (N=89) and BipoLife (N=102) studies. The associations of Li+PGS and lithium treatment response - defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P<0.05. Li+PGS was positively associated with lithium treatment response in the ConLi+Gen cohort, in both the categorical (P=9.8×10-12, R2=1.9%) and continuous (P=6.4×10-9, R2=2.6%) outcomes. Compared to bipolar patients in the 1st decile of the risk distribution, individuals in the 10th decile had 3.47-fold (95%CI: 2.22-5.47) higher odds of responding favorably to lithium. The results were replicated in the independent cohorts for the categorical treatment outcome (P=3.9×10-4, R2=0.9%), but not for the continuous outcome (P=0.13). Gene-based analyses revealed 36 candidate genes that are enriched in biological pathways controlled by glutamate and acetylcholine. Li+PGS may be useful in the development of pharmacogenomic testing strategies by enabling a classification of bipolar patients according to their response to treatment.
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| 2. |
- Chotteau, Veronique, 1963-, et al.
(författare)
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Study of Alternating Tangential Flow filtration for perfusion and harvest in Chinese Hamster Ovary cells cultivation
- 2010
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Ingår i: Proceedings of the Cell Culture Engineering Conference XII, April 25-30, 2010, Banff, Canada.
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Perfusion is a mode of operation where a continuous replacement of the conditioned medium by fresh medium is operated. It has the advantage of allowing high cell densities. This mode of operations is also required for some instable proteins since the cell-free supernatant containing the product of interest is immediately stored at low temperature where the proteolysis is not active. The ATF filtration device, Alternating Tangential Flow, has been designed to perfuse mammalian cell cultivation process and is used (or studied) nowadays for applications like perfusion, medium renewal, harvest, etc. The cell broth circulation back and forward in the filter prevents the filter clogging and the design ensures a low shear not damageable for the cells. A perfusion process operated by ATF filtration and using CHO cells producing a monoclonal antibody was developed in a 2 L bioreactor. The medium did not contain animal derived components. Cell densities above 40 x 106 cells/mL were obtained with a perfusion rate of 2 reactor volume/day. The highest cell density observed was 48 x 106 cells/mL. These high cell densities were challenging for the aeration. Pure oxygen aeration by large bubbles from an open tube resulted in satisfying oxygenation until 25 to 30 x 106 cells/mL but became limiting at higher cell densities due to the low kLa of these bubbles and the small liquid height. At higher cell densities, a porous sparger with pure oxygen was used either alone or in combination with the open tube aeration. Automatic delivery of antifoam C and pluronic counteracted the effect of small bubble foam deleterious for the cells. From an operation point-of-view, the perfusion operated by the ATF device was satisfying, without filter fouling, easy to operate and to adjust in comparison with other separation devices by filtration or acceleration. Finally harvesting by ATF filtration was evaluated in comparison with ‘one-way’ tangential flow filtration, TFF, on an IgG producing CHO fed-batch process produced in 2 L bioreactor. In both operation modes, ATF and TFF, filter fouling occurred after several minutes and the total process time was comparable but an important difference was that the viability drop obtained when using ATF was 15 % while it was 45 % using the TFF.
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| 3. |
- Delorme, Richard, et al.
(författare)
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No human tryptophan hydroxylase-2 gene R441H mutation in a large cohort of psychiatric patients and control subjects.
- 2006
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Ingår i: Biological Psychiatry. - : Elsevier BV. - 0006-3223. ; 60:2, s. 202-203
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: It was recently reported that a rare functional variant, R441H, in the human tryptophan hydroxylase-2 gene (hTPH2) could represent an important risk factor for unipolar major depression (UP) since it was originally found in 10% of UP patients (vs. 1.4% in control subjects). METHODS: We explored the occurrence of this variation in patients with affective disorders (n = 646), autism spectrum disorders (n = 224), and obsessive-compulsive disorder (OCD) (n = 201); in healthy volunteers with no psychiatric disorders (n = 246); and in an ethnic panel of control individuals from North Africa, Sub-Saharan Africa, India, China, and Sweden (n = 277). RESULTS: Surprisingly, we did not observe the R441H variant in any of the individuals screened (3188 independent chromosomes). CONCLUSIONS: Our results do not confirm the role of the R441H mutation of the hTPH2 gene in the susceptibility to UP. The absence of the variant from a large cohort of psychiatric patients and control subjects suggests that the findings reported in the original study could be due to a genotyping error or to stratification of the initial population reported. Additional data by other groups should contribute to the clarification of the discrepancy between our results and those previous published.
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