Xu, Hongyan

Abstract Iron (Fe) overload is not rare among sickle cell disease (SCD) patients. It results from either chronic transfusions for primary or secondary stroke prevention, or more commonly sporadic, mostly unnecessary transfusions and are associated with significant morbidity, secondary to hepatic, cardiac and renal Fe deposition. Previous studies at our Center showed that 12% of the adult SCD population had Fe overload, and vast majority of these (80%) resulted from episodic transfusions (Son et al, 2013). Subsequent studies showed that the Fe regulatory peptide, hepcidin was appropriately upregulated in SCD subjects with Fe overload, and the plasma levels of the glycoprotein hormone erythroferrone (ERFE) was not as high as that found in patients with transfusion dependent beta thalassemia (TDT) due to the absence of significant ineffective erythropoiesis in SCD (Thawer et al, 2017, Mangaonkar et al, Brit. J. Haematol, 2020). We report on the utilization and outcomes in Fe overloaded SCD patients who were prescribed the oral chelating agent deferasirox. 22 patients were prescribed deferasirox; median age was 38, 12 female 10 male. 21 had Hb SS, and 1 had s-b 0 thalassemia. Deferasirox dose ranged from 720-2500 mg/day (12 to 28 mg/Kg/day). Nonadherence was ascertained by patients' own admission. Figures 1-3 show the pre and post ferritin levels in subjects who were on deferasirox, and in controls; patients who took deferasirox had a more pronounced decrease in their ferritin (p=.004 vs p=.74). Although hepatic MRI for liver iron content (LIC) was not available on all patients, in those who underwent MRI there was a correlation between LIC and serum ferritin obtained at close temporal proximity (Fig. 4). Most common side effects of deferasirox were gastrointestinal (abdominal pain, nausea, vomiting, diarrhea), which were seen less commonly with the newer oral formulation (Jadenu). Several conclusions can be drawn from our observation on relatively small number of patients: 1) Deferasirox is effective in decreasing Fe overload as shown by serum ferritin levels 2) Second generation of oral deferasirox is better tolerated, and therefore is associated with improved adherence, 3) Documentation of a decrease in LIC with chelation will be important for the reversal of Fe induced organ damage, and 4) Parallel studies of the levels of Fe regulatory peptides hepcidin and erythroferrone (ERFE) will clarify the effect of chelation therapy on biomarkers of Fe metabolism. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Background: Anaplastic thyroid carcinoma (ATC) accounts for only 3% of thyroid cancers, yet strikingly, it accounts for almost 40% of thyroid cancer deaths. Currently, no effective therapies exist. In an effort to identify ATC-specific therapeutic targets, we analyzed global gene expression data from multiple studies to identify ATC-specific dysregulated genes. Methods: The National Center for Biotechnology Information Gene Expression Omnibus database was searched for high-throughput gene expression microarray studies from human ATC tissue along with normal thyroid and/or papillary thyroid cancer (PTC) tissue. Gene expression levels in ATC were compared with normal thyroid or PTC using seven separate comparisons, and an ATC-specific gene set common in all seven comparisons was identified. We investigated these genes for their biological functions and pathways. Results: There were three studies meeting inclusion criteria, (including 32 ATC patients, 69 PTC, and 75 normal). There were 259 upregulated genes and 286 downregulated genes in ATC with at least two-fold change in all seven comparisons. Using a five-fold filter, 36 genes were upregulated in ATC, while 40 genes were downregulated. Of the 10 top globally upregulated genes in ATC, 4/10 ( MMP1 , ANLN , CEP55 , and TFPI2 ) are known to play a role in ATC progression; however, 6/10 genes ( TMEM158 , CXCL5 , E2F7 , DLGAP5 , MME , and ASPM ) had not been specifically implicated in ATC. Similarly, 3/10 ( SFTA3 , LMO3 , and C2orf40 ) of the most globally downregulated genes were novel in this context, while 7/10 genes ( SLC26A7 , TG , TSHR , DUOX2 , CDH1 , PDE8B , and FOXE1 ) have been previously identified in ATC. We experimentally validated a significant correlation for seven transcription factors ( KLF16 , SP3 , ETV6 , FOXC1 , SP1 , EGFR1 , and MAFK ) with the ATC-specific genes using microarray analysis of ATC cell lines. Ontology clustering of globally altered genes revealed that “mitotic cell cycle” is highly enriched in the globally upregulated gene set (44% of top upregulated genes, p -value <10 −30 ). Conclusions: By focusing on globally altered genes, we have identified a set of consistently altered biological processes and pathways in ATC. Our data are consistent with an important role for M-phase cell cycle genes in ATC, and may provide direction for future studies to identify novel therapeutic targets for this disease.