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Background Recent studies demonstrated that engagement of sodium glucose transporter 1 (SGLT-1) by orally administered D-glucose protects the intestinal mucosa from lipopolysaccharide (LPS)-induced injury. We tested whether SGLT-1 engagement might protect the intestinal mucosa from doxorubicin (DXR)- and 5-fluorouracil (5-FU)-induced injury in animal models mimicking acute or chronic mucositis. Methods Mice were treated intraperitoneally with DXR, alone or in combination with 5-FU, and orally with BLF501, a glucose-derived synthetic compound with high affinity for SGLT-1. Intestinal mucosal epithelium integrity was assessed by histological analysis, cellular proliferation assays, real-time PCR gene expression assays and Western blot assays. Student’s t-test (paired two-tailed) and χ2 analyses were used for comparisons between groups. Differences were considered significant at p Results BLF501 administration in mice treated with DXR and/or 5-FU decreased the injuries to the mucosa in terms of epithelial integrity and cellular proliferative ability. Co-treatment with BLF501 led to a normal expression and distribution of both zonula occludens-1 (ZO-1) and beta-catenin, which were underexpressed after treatment with either chemotherapeutic agent alone. BLF501 administration also restored normal expression of caspase-3 and ezrin/radixin/moesin (ERM), which were overexpressed after treatment with DXR and 5-FU. In SGLT1-/- mice, BLF501 had no detectable effects. BLF501 administration in wild-type mice with growing A431 tumors did not modify antitumor activity of DXR. Conclusions BLF501-induced protection of the intestinal mucosa is a promising novel therapeutic approach to reducing the severity of chemotherapy-induced mucositis.

Adoptive cell transfer therapy (ACT) holds a highly promising treatment for metastatic melanoma patients. ACT involves the ex vivo expansion of autologous antitumor reactive tumor infiltrating lymphocytes and their reinfusion into lymphodepleted patients, accompanied by IL-2 administration. ACT demonstrates objective clinical responsiveness in 40-50% patients, including 10-21% complete responses. However, the mechanisms underlying the observed inter-individual variability in response to this type of therapy are not well understood. We applied whole genome-wide association study (GWAS) using Illumina OmniQuad 1M SNP bead array and expanded the SNP coverage to 33M by imputation against International HapMap and 1,000 genomes data sets. The analysis was performed in 208 TIL or PBMC samples undergone adoptive therapy or high does IL-2 therapy at the Surgery Branch, NCI. Comparisons between patients experiencing a complete responder (CR, n=30) versus those suffering progression of disease (PD, n=108) excluding the reminder partial responder patients identified 140 independent association SNPs which covers 14 functional known genes at a threshold p-value < 1 x 10-5. Within the chromosomal crossover range (1000Kb), we observed possible association with 405 annotated genes. The strongest signal was rs11587096, rs4506458 on chromosome 1 and rs7894773, rs7070986 at chromosome 10. Several genes at those loci had known immunological function. Those include TLR5, MIA3, TAF1A, DUSP10, DISP1, HHIPL2, MAF177B and EIF3a, FAM45A, SFXN4, GRK5, RGS10, TIAL1, BAG3, INPPF5 AND SEC23IP on chromosome 1 and 10 respectively. Possible functional impact of the significant SNP on chromosome 10 at transcript level was further validated by analyzing encoded gene exons using Fluidigm technology. In conclusion, we have identified different loci associated with clinic outcome by GWAS study suggesting that genetic predisposition is one of the important component determine immune responsiveness.