Risk factors and longitudinal regenerative outcomes of sinus membrane perforation during lateral window sinus floor elevation: A retrospective analysis up to 9 years.

BACKGROUND: Lateral-window sinus floor elevation (LSFE) is a reliable procedure to reconstruct the posterior maxilla for implant therapy. This retrospective study aimed to investigate risk factors associated with Schneiderian membrane perforation (SMP) occurrence during LSFE and longitudinal regenerative outcomes following LSFE up to 9 years. METHODS: Patients who had LSFE between 2010 and 2019 were included. All demographic and surgical-related data were retrieved from existing electronic health records. Radiographs were used to evaluate the vertical dimensional changes of ridge and graft materials and the potential anatomic factors of SMP. RESULTS: A total of 122 LSFE procedures in 99 patients were included in the study. Mean ridge height gain and graft shrinkages were 9.5 ± 3.47 and 1.57 ± 2.85 mm. The influence of the healing period on graft shrinkage showed a positive trend; the longer the healing period, the greater the graft shrinkage (p = 0.09). The pathology in the sinus showed a positive correlation with SMP (p = 0.07). However, other anatomical factors did not negatively impact SMP and subsequent ridge height gain (p > 0.05). CONCLUSIONS: With inherent limitation, the findings with up to 9 years of follow-up indicate a consistent ridge remodeling lasting for about 3 years after LSFE procedures. SMP or membrane thickening may not significantly affect the ridge gain following LSFE. The healing period had the most significant influence on graft shrinkage, showing that the longer the healing time between LSFE and implant placement, the greater the graft shrinkage.

Concerted roles of PTEN and ATM in controlling hematopoietic stem cell fitness and dormancy.

In order to sustain proficient life-long hematopoiesis, hematopoietic stem cells (HSCs) must possess robust mechanisms to preserve their quiescence and genome integrity. DNA-damaging stress can perturb HSC homeostasis by affecting their survival, self-renewal, and differentiation. Ablation of the kinase ataxia telangiectasia mutated (ATM), a master regulator of the DNA damage response, impairs HSC fitness. Paradoxically, we show here that loss of a single allele of Atm enhances HSC functionality in mice. To explain this observation, we explored a possible link between ATM and the tumor suppressor phosphatase and tensin homolog (PTEN), which also regulates HSC function. We generated and analyzed a knockin mouse line (PtenS398A/S398A), in which PTEN cannot be phosphorylated by ATM. Similar to Atm+/-, PtenS398A/S398A HSCs have enhanced hematopoietic reconstitution ability, accompanied by resistance to apoptosis induced by genotoxic stress. Single-cell transcriptomic analyses and functional assays revealed that dormant PtenS398A/S398A HSCs aberrantly tolerate elevated mitochondrial activity and the accumulation of reactive oxygen species, which are normally associated with HSC priming for self-renewal or differentiation. Our results unveil a molecular connection between ATM and PTEN, which couples the response to genotoxic stress and dormancy in HSCs.

Mutant ACVR1 Arrests Glial Cell Differentiation to Drive Tumorigenesis in Pediatric Gliomas.

Diffuse intrinsic pontine gliomas (DIPGs) are aggressive pediatric brain tumors for which there is currently no effective treatment. Some of these tumors combine gain-of-function mutations in ACVR1, PIK3CA, and histone H3-encoding genes. The oncogenic mechanisms of action of ACVR1 mutations are currently unknown. Using mouse models, we demonstrate that Acvr1G328V arrests the differentiation of oligodendroglial lineage cells, and cooperates with Hist1h3bK27M and Pik3caH1047R to generate high-grade diffuse gliomas. Mechanistically, Acvr1G328V upregulates transcription factors which control differentiation and DIPG cell fitness. Furthermore, we characterize E6201 as a dual inhibitor of ACVR1 and MEK1/2, and demonstrate its efficacy toward tumor cells in vivo. Collectively, our results describe an oncogenic mechanism of action for ACVR1 mutations, and suggest therapeutic strategies for DIPGs.