Many diabetic patients remain undiagnosed, and oral findings may offer an unrealized opportunity for the identification of affected individuals unaware of their condition. We recruited 601 individuals who presented for care at a dental clinic, were ≥40 years old, if non-Hispanic white, and ≥30 years old, if Hispanic or non-white, and had never been told they have pre-diabetes or diabetes. Those with at least one self-reported diabetes risk factor (N=535) received a periodontal examination and a point-of-care hemoglobin A1c (HbA1c) test. A fasting plasma glucose (FPG) test was used as the study outcome, signifying potential diabetes or pre-diabetes. Performance characteristics of simple models of dysglycemia (FPG≥100 mg/dL) identification were evaluated and optimal cut-offs identified. A model including only two dental variables had an estimated area under the receiver operating characteristic curve (AUC) of 0.65. The addition of a point-of-care HbA1c test improved the AUC to 0.79 (p<0.001). The presence of ≥26% deep pockets or ≥4 missing teeth correctly identified 73% of true cases; the addition of an HbA1c≥5.7% increased correct identification to 92%. Analysis of our data suggests that oral healthcare professionals have the opportunity to identify unrecognized diabetes and pre-diabetes in dental patients and refer them to a physician for further evaluation and care.

In addition to allelic mutations, cancers are known to harbor alterations in their chromatin landscape. Here, we show that genomic ablation of Smurf2, a HECT-domain E3 ubiquitin ligase, results in dysregulation of DNA damage response and genomic stability, culminating to increased susceptibility to various types of cancers in aged mice. We demonstrate that Smurf2 regulates histone H2B monoubiquitination as well as histone H3 tri-methylation at K4 and K79 by targeting RNF20 to proteasomal degradation in both mouse and human cells. We further show that Smurf2 and RNF20 are co-localized at the γ-H2AX foci of double-stranded DNA breaks in the nucleus. Thus, Smurf2 has a tumor suppression function that normally maintains genomic stability by controlling the epigenetic landscape of histone modifications through RNF20.

SUMMARY Here, we report that kinase-dead IKKα knock-in mice develop spontaneous lung squamous cell carcinomas (SCCs) associated with IKKα downregulation and marked pulmonary inflammation. IKKα reduction upregulated the expression of p63, Trim29, and keratin 5 (K5), which serve as diagnostic markers for human lung SCCs. IKKαlowK5+p63hi cell expansion and SCC formation were accompanied by inflammation-associated deregulation of oncogenes, tumor suppressors, and stem cell regulators. Reintroducing transgenic K5.IKKα, depleting macrophages, and reconstituting irradiated mutant animals with WT bone marrow (BM) prevented SCC development, suggesting that BM-derived IKKα-mutant macrophages promote the transition of IKKαlowK5+p63hi cells to tumor cells. This mouse model resembles human lung SCCs, sheds light on the mechanisms underlying lung malignancy development, and identifies targets for therapy of lung SCCs.