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Background Pituitary adenomas (PA) are the second most common intracranial tumors and are classified according to hormone they produce, and the transcription factors they express. The majority of PA occur sporadically, and their molecular pathogenesis is incompletely understood. Methods Here we performed transcriptome and proteome analysis of tumors derived from POU1F1 (GH-, TSH-, and PRL-tumors, N = 16), NR5A1 (gonadotropes and null cells adenomas, n = 17) and TBX19 (ACTH-tumors, n = 6) lineages as well as from silent ACTH-tumors (n = 3) to determine expression of kinases, cyclins, CDKs and CDK inhibitors. Results The expression profiles of genes encoding kinases were distinctive for each of the three PA lineage: NR5A1-derived tumors showed upregulation of ETNK2 and PIK3C2G and alterations in MAPK, ErbB and RAS signaling, POU1F1-derived adenomas showed upregulation of PIP5K1B and NEK10 and alterations in phosphatidylinositol, insulin and phospholipase D signaling pathways and TBX19-derived adenomas showed upregulation of MERTK and STK17B and alterations in VEGFA-VEGFR, EGF-EGFR and Insulin signaling pathways. In contrast, the expression of the different genes encoding cyclins, CDK and CDK inhibitors among NR5A1-, POU1F1- and TBX19-adenomas showed only subtle differences. CDK9 and CDK18 were upregulated in NR5A1-adenomas, whereas CDK4 and CDK7 were upregulated in POUF1-adenomas. Conclusions The kinome of PA clusters these lesions into three distinct groups according to the transcription factor that drives their terminal differentiation. And these complexes could be harnessed as molecular therapy targets.

Pituitary adenomas (PA) are the second most common intracranial tumors. These neoplasms are classified according to the hormone they produce. The majority of PA occur sporadically, and their molecular pathogenesis is incompletely understood. The present transcriptomic and methylomic analysis of PA revealed that they segregate into three molecular clusters according to the transcription factor driving their terminal differentiation. First cluster, driven by NR5A1, consists of clinically non-functioning PA (CNFPA), comprising gonadotrophinomas and null cell; the second cluster consists of clinically evident ACTH adenomas and silent corticotroph adenomas, driven by TBX19; and the third, POU1F1-driven TSH-, PRL- and GH-adenomas, segregated together. Genes such as CACNA2D4, EPHA4 and SLIT1, were upregulated in each of these three clusters, respectively. Pathway enrichment analysis revealed specific alterations of these clusters: calcium signaling pathway in CNFPA; renin-angiotensin system for ACTH-adenomas and fatty acid metabolism for the TSH-, PRL-, GH-cluster. Non-tumoral pituitary scRNAseq data confirmed that this clustering also occurs in normal cytodifferentiation. Deconvolution analysis identify potential mononuclear cell infiltrate in PA consists of dendritic, NK and mast cells. Our results are consistent with a divergent origin of PA, which segregate into three clusters that depend on the specific transcription factors driving late pituitary cytodifferentiation.

Background To estimate the incremental cost-effectiveness ratio (ICER) of the use of continuous subcutaneous insulin infusion (CSII) therapy versus multiple daily injections (MDI) therapy in adult patients with type 1 diabetes (T1D) at the Mexican Institute of Social Security (IMSS). Methods An analysis was developed using the internationally validated Core Diabetes Model (CDM) with which the incidence and progression of acute and chronic complications and the mortality of T1D was simulated throughout life. The baseline characteristics of the simulated cohorts were obtained from Mexican T1D adult patients aged ≥ 18 years that received care at two national IMSS medical centres in 2016. In the base case, the costs of the complications and treatment of the disease with both therapies were estimated in Mexican currency from the perspective of the institution, using Diagnosis Related Groups for outpatient and inpatient care. Utilities were taken from the international bibliography. In a secondary analysis, indirect costs were included using a human capital approach. The model used a lifetime time horizon, and a discount rate of 5% was applied for health outcomes and costs. A one-way sensitivity analysis was conducted on key variables and patient sub-groups; uncertainty was evaluated using a Cost-Effectiveness Acceptability Curve. Results The average age of the cohort was 32 years, with diabetes duration of 19 years, an average HbA1c of 9.2%; 29% were men. A gain of 0.614 Quality Adjusted Life Years (QALYs) was estimated with the use of CSII therapy. The estimated ICER was MXN$478,020 per QALY in the base case, and MXN$369,593 when indirect costs were considered. The sensitivity analysis showed that, in adult patients with HbA1c > 9.0%, the ICER was MXN$262,237. Conclusions This is the first economic evaluation study that compares CSII therapy versus MDI therapy for T1D adult patients in Mexico. The insulin pump therapy can be considered cost-effective in the context of the IMSS when considering a threshold of three GDPs per capita with 43.9% probability. Results improve substantially when patients have an HbA1c above 9%.