Cranial nerve VI palsy in chronic sphenoid sinusitis.

Sphenoid sinusitis is a rare disease associated with life-threatening complications that can be avoided with early recognition and timely treatment. Here, we present a case of a woman in her 80s admitted for symptomatic anaemia likely secondary to a gastrointestinal bleed with left cranial nerve (CN) VI palsy incidentally discovered on physical examination. CT and MRI were suggestive of chronic left sphenoid sinusitis with possible involvement of the left cavernous sinus. Surgical treatment was deferred due to high cardiac risk for perioperative mortality and recent ischaemic stroke. Despite antibiotic treatment, the patient's CN VI palsy remained unchanged. This report contributes to the current understanding of sphenoid sinusitis by presenting a complex case of chronic sphenoid sinusitis in which urgent surgical intervention was deferred due to the patient's multiple comorbidities. Furthermore, it highlighted the importance of the CN examination and imaging modalities in diagnosing sphenoid sinusitis.

Loss of PBRM1 Alters Promoter Histone Modifications and Activates ALDH1A1 to Drive Renal Cell Carcinoma.

Subunits of SWI/SNF chromatin remodeling complexes are frequently mutated in human malignancies. The PBAF complex is composed of multiple subunits, including the tumor-suppressor protein PBRM1 (BAF180), as well as ARID2 (BAF200), that are unique to this SWI/SNF complex. PBRM1 is mutated in various cancers, with a high mutation frequency in clear cell renal cell carcinoma (ccRCC). Here, we integrate RNA-seq, histone modification ChIP-seq, and ATAC-seq data to show that loss of PBRM1 results in de novo gains in H3K4me3 peaks throughout the epigenome, including activation of a retinoic acid biosynthesis and signaling gene signature. We show that one such target gene, ALDH1A1, which regulates a key step in retinoic acid biosynthesis, is consistently upregulated with PBRM1 loss in ccRCC cell lines and primary tumors, as well as non-malignant cells. We further find that ALDH1A1 increases the tumorigenic potential of ccRCC cells. Using biochemical methods, we show that ARID2 remains bound to other PBAF subunits after loss of PBRM1 and is essential for increased ALDH1A1 after loss of PBRM1, whereas other core SWI/SNF components are dispensable, including the ATPase subunit BRG1. In total, this study uses global epigenomic approaches to uncover novel mechanisms of PBRM1 tumor suppression in ccRCC. IMPLICATIONS: This study implicates the SWI/SNF subunit and tumor-suppressor PBRM1 in the regulation of promoter histone modifications and retinoic acid biosynthesis and signaling pathways in ccRCC and functionally validates one such target gene, the aldehyde dehydrogenase ALDH1A1.