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Medical Schoolhttps://deepblue.lib.umich.edu/bitstream/2027.42/149436/1/VinayGuduguntla_1.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149436/2/VinayGuduguntla_2.docxhttps://deepblue.lib.umich.edu/bitstream/2027.42/149436/3/VinayGuduguntla_3.doc

Opposing Tumor-Promoting and -Suppressive Functions of Rictor/mTORC2 Signaling in Adult Glioma and Pediatric SHH Medulloblastoma.

Most human cancers arise from stem and progenitor cells by the sequential accumulation of genetic and epigenetic alterations, while cancer modeling typically requires simultaneous multiple oncogenic events. Here, we show that a single p53 mutation, despite causing no defect in the mouse brain, promoted neural stem and progenitor cells to spontaneously accumulate oncogenic alterations, including loss of multiple chromosomal (chr) regions syntenic to human chr10 containing Pten, forming malignant gliomas with PI3K/Akt activation. Rictor/mTORC2 loss inhibited Akt signaling, greatly delaying and reducing glioma formation by suppressing glioma precursors within the subventricular zone stem cell niche. Rictor/mTORC2 loss delayed timely differentiation of granule cell precursors (GCPs) during cerebellar development, promoting sustained GCP proliferation and medulloblastoma formation, which recapitulated critical features of TP53 mutant sonic hedgehog (SHH) medulloblastomas with GLI2 and/or N-MYC amplification. Our study demonstrates that Rictor/mTORC2 has opposing functions in neural stem cells and GCPs in the adult and the developing brain, promoting malignant gliomas and suppressing SHH-medulloblastoma formation, respectively

Variation in Cardiac Rehabilitation Participation During Aortic Valve Replacement Episodes of Care

Background: Despite reported benefit in the setting of aortic valve replacement (AVR), cardiac rehabilitation (CR) utilization remains low, with few studies evaluating hospital and patient-level variation in CR participation. We explored determinants of CR variability during AVR episodes of care: transcatheter aortic valve replacement (TAVR) and surgical aortic valve replacement (SAVR). Methods: A cohort of 10,124 AVR episodes of care (TAVR n=5,121 from 24 hospitals; SAVR n=5,003 from 32 hospitals) were identified from the Michigan Value Collaborative statewide multipayer registry (2015 to 2019). CR enrollment was defined as the presence of a single professional or facility claim within 90 days of discharge: 93797, 93798, G0422, G0423. Annual trends and hospital variation in CR were described for TAVR, SAVR, and all AVR. Multilevel logistic regression was used to estimate effects of predictors and hospital risk-adjusted rates of CR enrollment. Results: Overall, 4,027 (39.8%) patients enrolled in CR, with significant differences by treatment strategy: SAVR=50.9%, TAVR=28.9% (p\u3c0.001). CR use after SAVR was significantly higher than after TAVR and increased over time for both modalities (p\u3c0.001). There were significant differences in CR enrollment across age, gender, payer, and some comorbidities (p\u3c.05). At the hospital-level, CR participation rates for all AVR varied 10-fold (4.8% to 68.7%) and were moderately correlated between SAVR and TAVR (Pearson r=0.56, p\u3c0.01). Conclusions: Substantial variation exists in CR participation during AVR episodes of care across hospitals. However, within-hospital CR participation rates were significantly correlated across treatment strategies. These findings suggest that CR participation is the product of hospital-specific practice patterns. Identifying hospital practices associated with higher CR participation can help assist future quality improvement efforts to increase CR use after AVR

Opposing Tumor-Promoting and -Suppressive Functions of Rictor/mTORC2 Signaling in Adult Glioma and Pediatric SHH Medulloblastoma

Summary: Most human cancers arise from stem and progenitor cells by the sequential accumulation of genetic and epigenetic alterations, while cancer modeling typically requires simultaneous multiple oncogenic events. Here, we show that a single p53 mutation, despite causing no defect in the mouse brain, promoted neural stem and progenitor cells to spontaneously accumulate oncogenic alterations, including loss of multiple chromosomal (chr) regions syntenic to human chr10 containing Pten, forming malignant gliomas with PI3K/Akt activation. Rictor/mTORC2 loss inhibited Akt signaling, greatly delaying and reducing glioma formation by suppressing glioma precursors within the subventricular zone stem cell niche. Rictor/mTORC2 loss delayed timely differentiation of granule cell precursors (GCPs) during cerebellar development, promoting sustained GCP proliferation and medulloblastoma formation, which recapitulated critical features of TP53 mutant sonic hedgehog (SHH) medulloblastomas with GLI2 and/or N-MYC amplification. Our study demonstrates that Rictor/mTORC2 has opposing functions in neural stem cells and GCPs in the adult and the developing brain, promoting malignant gliomas and suppressing SHH-medulloblastoma formation, respectively. : Hyperactivation of PI3K/AKT signaling is frequently observed in adult glioblastomas (GBMs), whereas sonic hedgehog-subgroup medulloblastomas (SHH-MBs) in children rarely exhibit AKT activation. Using a genetically engineered mouse model of malignant brain tumor, Akgül et al. show that Rictor/mTORC2 loss inhibits Akt signaling, which delays p53-mutant-driven malignant gliomas, while promoting SHH-MBs. Keywords: glioblastoma, medulloblastoma, Rictor, mammalian target of rapamycin complex 2, mTORC2, Pten, p53, phosphatidylinositol 3-kinase pathway, PI3K, Ak