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Future directions and personalized medicine
Published in M. Alan Menter, Caitriona Ryan, Psoriasis, 2017
Two pharmacogenomic studies have demonstrated the effect of cyclosporine treatment on genetic expression in moderate-to-severe psoriasis.41,42 The first study investigated the genetic expression of 11 patients actively responding to cyclosporine therapy.41 RNA microarray analysis was performed on both blood and skin (lesional and nonlesional) samples at baseline and following 14 days of treatment. Cyclosporine downregulated the expression of 220 genes by 1.5-fold in the skin, more than 95% of which were associated with proinflammatory cells, keratinocytes, and fibroblasts. By contrast, there were no changes in the genetic expression in the peripheral blood at day 14. The expression of proinflammatory genes in skin lesions of the 11 patients was also analyzed using real-time polymerase chain reaction (RT-PCR) at baseline and periodically over 56 days. At day 14 of the treatment, there was downregulation of expression in genes coding for the type 1 helper T cell (Th1) pathway (p40, IFN-g Signal transducer and activator of transcription 1 [STAT1], Interferon regulatory factor 1, Chemokine [C-X-C motif] ligand 9 [CXCL9], interferon γ-induced protein 10, Interferon-induced GTP-binding protein Mx1) and the Th17 pathway (p19, IL-17, and IL-22 and downstream genes such as macrophage inflammatory protein-3 [MIP-3a], DefensinB-2 [DEFB-2], IL-1b, serpin family B member 3 [SERPINb3], and S100A12) in the skin.41 There was also a decrease in the production of TNF-α and inducible nitric oxide synthase (iNOS) from dendritic cells. When expression of genes in the skin was correlated to overall clinical score (using epidermal thickness, PASI, and K16 expression), IL-17 expression correlated best with the activity at day 14, whereas iNOS correlated best with long-term response. The second study examined the expression levels in genes upregulated in the skin of psoriasis patients following treatment with cyclosporine or recombinant IL-11.42 Microarray was used to compare genetic expression in lesional and nonlesional skin of eight patients compared with normal skin, showing 159 differentially expressed genes. Upregulation of genes encoding S100A12, ID4, metaxin [MTX], and heparin-binding protein17 [HBP17] occurred within 1 week of treatment, often preceding clinical improvement. Consequently cyclosporine, although potentially devastating in its side effects, could better be curtailed to patients whose genetic architecture affords them the benefits and response of cyclosporine without the associated toxicity.
Prostate cancer proteomics: clinically useful protein biomarkers and future perspectives
Published in Expert Review of Proteomics, 2018
Paula Intasqui, Ricardo P. Bertolla, Marcus Vinicius Sadi
Biomarkers of prostate cancer progression were also sought in the surrounding culture media (secretome) of 22Rv1 (primary prostate cancer, androgen-responsive cells) and PC3 cells, and compared to the secretome of PTN2 (normal prostatic cells) cells. Selected peptides were analyzed by Selected Reaction Monitoring (SRM). In this approach, seven proteins presented a highly increased expression (>5-fold) in the primary cancer secretome, compared to normal cells, such as the insulin-like growth factor-binding protein 2 (IGFBP2). On the other hand, four proteins were increased in the metastatic cancer secretome of both cell lines: prostate-associated microseminoprotein (MSMP), CLU, calsyntenin-1 (CLSTN1), and serum albumin (ALB) [32]. The surrounding cell media was again analyzed to compare different prostate cancer cell lines submitted to several cell culture perturbation conditions (hypoxia, redox imbalance, inflammation), mimicking the prostate cancer environment. This study identified filamin-A (FLNA) and filamin-B (FLNB), proteins involved with cell migration and vascular development, as the secretome proteins with the highest potential of having a causal relation with prostate cancer. FLNA and FLNB mRNA levels did not vary between cell lines or cancer aggressiveness/androgen dependency. Interestingly, when analyzing these proteins in plasma samples, a strong correlation between FLNA and FLNB levels in patients with BPH was observed, which is lost in patients with adenocarcinoma [33]. In the secretome of PC3 cells, proteins involved with lysine degradation and osteoclast differentiation were increased, regulated mainly by transforming growth factor (TGF) beta family proteins. In addition to these proteins, pentraxin-related protein PTX3 (PTX3), follistatin (FST), and serpin B3 (SERPINB3) were also suggested to play major roles in bone metastasis [34].
Impact of the biomarker enrichment strategy in drug development
Published in Expert Review of Molecular Diagnostics, 2020
Aline Bobato Lara Gongora, Leandro Jonata Carvalho Oliveira, Denis Leonardo Jardim
There are other biomarkers currently being studied, such as SERPINB3 or SERPINB4 mutations, SERPINB3 or SERPINB4 and gut microbial diversity as possible favorable predictive biomarkers. Mutations in STK11, B2M, JAK2, in the β -catenin pathway, TGF β have been investigated as negative predictive biomarkers [45].