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Familial tooth agenesis (FTA) is one of the most common craniofacial anomalies in humans. Loss‐of‐function mutations in PAX9 and WNT10A have been known to cause FTA with various expressivity. In this study, we identified five FTA kindreds with novel PAX9 disease‐causing mutations: p.(Glu7Lys), p.(Val83Leu), p.(Pro118Ser), p.(Ser197Argfs*23), and c.771+4A>G. Concomitant PAX9 and WNT10A pathogenic variants found in two probands with severe phenotypes suggested an effect of mutational synergism. All overexpressed PAX9s showed proper nuclear localization, excepting the p.(Pro118Ser) mutant. Various missense mutations caused differential loss of PAX9 transcriptional ability. PAX9 overexpression in dental pulp cells upregulated LEF1 and AXIN2 expression, indicating a positive regulatory role for PAX9 in canonical Wnt signaling. Analyzing 176 cases with 63 different mutations, we observed a distinct pattern of tooth agenesis for PAX9‐associated FTA: Maxillary teeth are in general more frequently affected than mandibular ones. Along with all second molars, maxillary bicuspids and first molars are mostly involved, while maxillary lateral incisors and mandibular bicuspids are relatively less affected. Genotypically, missense mutations are associated with fewer missing teeth than frameshift and nonsense variants. This study significantly expands the phenotypic and genotypic spectrums of PAX9‐associated disorders and reveals a molecular mechanism of genetic synergism underlying FTA variable expressivity. [ABSTRACT FROM AUTHOR]

Background: Tooth loss, periodontal disease, dementia, and Alzheimer's disease share several risk factors in older adults. Several previous studies have reported positive associations between these dental problems and global cognitive defects. However, limited is known about the relationships among multiple dental/periodontal statuses and different cognitive domains. Method: This six‐year (2011‐2017) cohort study includes 515 older adults (65+). Global cognition was assessed by Montreal cognitive assessment‐Taiwan version (MoCA‐T). For cognitive domains, we used logical memory tests (immediate and delayed theme and free recall) in Wechsler Memory Scale‐Third Edition (WMS‐III) to assess memory. Trail Making Test A and B was used to assess attention and executive function, respectively. Digit span‐forward and backward was used to evaluate attention and working memory/short‐term memory, respectively. Verbal fluency tests were used to assess category/semantic fluency. A Z‐score was calculated for each cognitive domain‐specific test according to baseline mean and standard deviation. Oral health status includes tooth defect (dental caries, tooth wear, cervical abrasion, retained root or crown fracture), periodontal health (disease severity from healthy periodontal status, gingivitis to periodontitis), and arch integrity (no tooth loss nor retained root or crown fracture). Generalized linear mixed models were used to assess the associations above adjust important covariates. Result: At baseline, periodontitis was associated with poor performance in executive function [Trail Making Test A: b = ‐0.14, 95% confidence interval (CI) = ‐0.27 to ‐0.01]. The association between baseline severity of tooth defect and poor memory decreased (logical memory‐immediate theme recall: b = ‐0.05, 95% CI = ‐0.10 to ‐0.01); similarly finding was found for attention domain (digit span‐forward: b = ‐0.04, 95% CI = ‐0.07 to ‐0.001). At baseline, loss of arch integrity was associated with a better working memory/short‐term memory (digit span‐backward: β = 0.18, 95% CI = 0.01 to 0.36); as follow‐up time increased, this association decreased over six years (β = ‐0.04, 95% CI = ‐0.07 to ‐0.003). Conclusion: Periodontitis, tooth defects, or arch integrity was associated with poor performance of cognitive domains (memory, attention, and executive function) over time. A oral health evaluation may serve as predictors of the preclinical phase of dementia in its upcoming years. [ABSTRACT FROM AUTHOR]

Targeting the MEK/ ERK pathway has been viewed as a promising strategy for cancer therapy. However, MEK inhibition leads to the compensatory PI3K/ AKT activation and thus contributes to the desensitization of cancer cells to MEK inhibitors. The underlying molecular mechanism of this event is not yet understood. In this study, our data showed that the induction of Akt activity by MEK inhibitors was specifically observed in HER2-positive breast cancer cells. Silence of HER2, or overexpression of HER2 kinase-dead mutant, prevents the induction of Akt activation in response to MEK inhibition, indicating HER2 as a critical regulator for this event. Furthermore, HER2 Thr701 was demonstrated as a direct phosphorylation target of ERK1/2. Inhibition of this specific phosphorylation prolonged the dimerization of HER2 with EGFR in a clathrin-dependent manner, leading to the enhanced activation of HER2 and EGFR tyrosine kinase and their downstream Akt pathway. These results suggest that suppression of ERK-mediated HER2 Thr701 phosphorylation contributes to MEK inhibitor-induced Akt activation. [ABSTRACT FROM AUTHOR]