RESUMEN
Background: Previous research showed that 5-hydroxytryptophan (5HTP), a metabolic precursor of serotonin, reduces allergic lung inflammation by inhibiting eosinophil migration across endothelial monolayers. Objective: It is unknown if serotonin receptors are involved in mediating this 5HTP function or if serotonin receptor (HTR) single nucleotide polymorphisms (SNPs) associate with lung function in humans. Methods: Serotonin receptor subtypes were assessed by qPCR, western blot, confocal microscopy, pharmacological inhibitors and siRNA knockdown. HTR SNPs were assessed in two cohorts. Results: Pharmacological inhibition or siRNA knockdown of the serotonin receptors HTR1A or HTR1B in endothelial cells abrogated the inhibitory effects of 5HTP on eosinophil transendothelial migration. In contrast, eosinophil transendothelial migration was not inhibited by siRNA knockdown of HTR1A or HTR1B in eosinophils. Surprisingly, these HTRs were intracellular in endothelial cells and an extracellular supplementation with serotonin did not inhibit eosinophil transendothelial migration. This is consistent with the inability of serotonin to cross membranes, the lack of selective serotonin reuptake receptors on endothelial cells, and the studies showing minimal impact of selective serotonin reuptake inhibitors on asthma. To extend our HTR studies to humans with asthma, we examined the CHIRAH and GALA cohorts for HTR SNPs that affect HTR function or are associated with behavior disorders. A polygenic index of SNPs in HTRs was associated with lower lung function in asthmatics. Conclusions: Serotonin receptors mediate 5HTP inhibition of transendothelial migration and HTR SNPs associate with lower lung function. These results may serve to aid in design of novel interventions for allergic inflammation.
RESUMEN
Sertoli-Leydig cell tumors (SLCT) are a rare form of sex cord stromal tumors. DICER1 germline mutations have been identified in a portion of these cases. We report a 15-year-old individual who presented to a well-child visit with secondary amenorrhea and subjective observations of a deepening voice and broadening shoulders. Elevations were noted in serum testosterone, inhibin B, androstenedione, and DHEA. Pelvic ultrasound and magnetic resonance imaging (MRI) revealed a left ovarian complex lesion measuring 5.8 x 5.5 x 4.6 cm. A laparoscopic unilateral salpingo-oophorectomy was performed with negative pelvic washings and a diagnosis of stage 1A, poorly differentiated/grade 3 SLCT of the ovary. Somatic and germline testing both demonstrated DICER1 pathologic variations. Adjuvant chemotherapy with cisplatin/etoposide/ifosfamide (PEI) was completed under the care of pediatric oncology, and this patient is now undergoing surveillance with no signs of recurrence. DICER1 Syndrome is associated with multiple tumors, including SLCT, pleuropulmonary blastoma (PPB), cystic sarcomas, and Wilms tumor among others. Patients with SLCT found to have a DICER1 mutation should undergo genetic testing and cancer screening, which may help to identify neoplasms associated with the DICER1 mutation at an early stage. This case will serve as a useful addition to the literature and review suggested pre-operative, operative, and surveillance guidelines.
