Hyperthyroidism in gestational trophoblastic disease - a literature review.

OBJECTIVE: Gestational trophoblastic disease (GTD) is a group of pregnancy-related disorders that arise from abnormal proliferation of placental trophoblast. Some patients with GTD develop hyperthyroidism, a rare but potentially life-threatening complication requiring early detection and management. Existing literature on hyperthyroidism in GTD is scant. This review aims to analyse the epidemiology, pathophysiology and management of this phenomenon. METHODS: A comprehensive search of MEDLINE, EMBASE and Cochrane Library was performed to obtain articles that explored hyperthyroidism in GTD. A total of 405 articles were screened and 228 articles were considered for full-text review. We selected articles that explored epidemiology, pathophysiology and outcomes/management of hyperthyroidism in GTD. RESULTS: The pathophysiology of hyperthyroidism in GTD is well-investigated. Placental trophoblastic tissue secretes excessive hCG, which is structurally similar to thyroid stimulating hormone and also has enhanced thyrotropic activity compared to normal hCG. The incidence and prevalence of hyperthyroidism in GTD varies worldwide, with lower rates associated with high uptake of early antenatal screening and early GTD detection. No clear risk factors for hyperthyroidism in GTD were identified. While hyperthyroidism can be definitively managed with surgical evacuation of the uterus, severe complications associated with hyperthyroidism in GTD have been reported, including thyroid storm-induced multi-organ failure, ARDS, and pulmonary hypertension. CONCLUSION: Early detection of GTD is critical to prevent development of hyperthyroidism and its associated complications. Hyperthyroidism should be recognised as an important perioperative consideration for women undergoing surgery for GTD, and requires appropriate management. Future studies should explore risk factors for hyperthyroidism in GTD, which may facilitate earlier identification of high-risk women.

Drugging MYCN Oncogenic Signaling through the MYCN-PA2G4 Binding Interface.

MYCN is a major driver for the childhood cancer, neuroblastoma, however, there are no inhibitors of this target. Enhanced MYCN protein stability is a key component of MYCN oncogenesis and is maintained by multiple feedforward expression loops involving MYCN transactivation target genes. Here, we reveal the oncogenic role of a novel MYCN target and binding protein, proliferation-associated 2AG4 (PA2G4). Chromatin immunoprecipitation studies demonstrated that MYCN occupies the PA2G4 gene promoter, stimulating transcription. Direct binding of PA2G4 to MYCN protein blocked proteolysis of MYCN and enhanced colony formation in a MYCN-dependent manner. Using molecular modeling, surface plasmon resonance, and mutagenesis studies, we mapped the MYCN-PA2G4 interaction site to a 14 amino acid MYCN sequence and a surface crevice of PA2G4. Competitive chemical inhibition of the MYCN-PA2G4 protein-protein interface had potent inhibitory effects on neuroblastoma tumorigenesis in vivo. Treated tumors showed reduced levels of both MYCN and PA2G4. Our findings demonstrate a critical role for PA2G4 as a cofactor in MYCN-driven neuroblastoma and highlight competitive inhibition of the PA2G4-MYCN protein binding as a novel therapeutic strategy in the disease. SIGNIFICANCE: Competitive chemical inhibition of the PA2G4-MYCN protein interface provides a basis for drug design of small molecules targeting MYC and MYCN-binding partners in malignancies driven by MYC family oncoproteins.