Anti-VHL monoclonal antibody

Pulmonary surfactant protein A (SP-A) plays an important role in surfactant metabolism and lung innate immunity. In humans there are two proteins, SP-A1 and SP-A2, encoded by SFTPA1 and SFTPA2, respectively, which are produced by the alveolar type II cells (T2C). We sought to investigate the differential influence of SP-A1 and SP-A2 in T2C miRNome under oxidative stress (OxS). SP-A knock out (KO) and hTG male and female mice expressing SP-A1 or SP-A2 as well as gonadectomized (Gx) mice were exposed to O-3-induced oxidative stress (OxS) or filtered air (FA). Expression of miRNAs and mRNAs was measured in the T2C of experimental animals. (a) In SP-A1 males after normalizing to KO males, significant changes were observed in the miRNome in terms of sex-OxS effects, with 24 miRNAs being differentially expressed under OxS. (b) The mRNA targets of the dysregulated miRNAs included Ago2, Ddx20, Plcg2, Irs1, Elf2, Jak2, Map2k4, Bcl2, Ccnd1, and Vhl. We validated the expression levels of these transcripts, and observed that the mRNA levels of all of these targets were unaffected in SP-A1 T2C but six of these were significantly upregulated in the KO (except Bcl2 that was downregulated). (c) Gondadectomy had a major effect on the expression of miRNAs and in three of the mRNA targets (Irs1, Bcl2, and Vhl). Ccnd1 was upregulated in KO regardless of Gx. (d) The targets of the significantly changed miRNAs are involved in several pathways including MAPK signaling pathway, cell cycle, anti-apoptosis, and other. In conclusion, in response to OxS, SP-A1 and male hormones appear to have a major effect in the T2C miRNome.

Aim: Steroid sulfotransferase (SULT) plays physiological roles but its role in clear cell-renal cell carcinoma (ccRCC) remains unclear. We therefore investigated genetic alteration of steroid SULT genes in ccRCC. Results: Overexpression of any of SULT genes occurred in similar to 8% of ccRCC patients. Overexpression of steroid SULT genes was associated with worsened prognosis. Steroid SULT gene-upregulated ccRCC cases showed mutual exclusivity with mutations of VHL, SETD2 and PBRM1, and with focal deletions of 3p and 9p, respectively. Expressions of SULT genes were negatively correlated with that of VHL, SETD2 and PBRM1, respectively. While no cancer-intrinsic pathway was enriched, immune signatures were significantly enriched in SULT gene-overexpressed cases, resulting in significantly fewer infiltration of lymphocytes. Targeting SULT1B1 significantly inhibited growth of ccRCC cells. Conclusion: Steroid SULT genes were associated with worsened prognosis and with immune exclusion in ccRCC. Methods: In silico reproduction of TGGA and GTEx datasets was performed. Data were processed comprehensively using the platforms of cBioPotal, GEPIA, Human Protein Atlas, TIMER, respectively. Functional annotation was analyzed using platforms of NET-GE and GSEA, respectively. In vitro assays were performed for validation.