Cdt2 is the substrate recognition adaptor of CRL4 Cdt2 E3 ubiquitin ligase complex and plays a pivotal role in the cell cycle by mediating the proteasomal degradation of Cdt1 (DNA replication licensing factor), p21 (cyclin-dependent kinase [CDK] inhibitor), and Set8 (histone methyltransferase) in S phase. Cdt2 itself is attenuated by SCF FbxO11 -mediated proteasomal degradation. Here, we report that 14-3-3 adaptor proteins interact with Cdt2 phosphorylated at threonine 464 (T464) and shield it from polyubiquitination and consequent proteasomal degradation. Depletion of 14-3-3 proteins promotes the interaction of FbxO11 with Cdt2. Overexpressing 14-3-3 proteins shields Cdt2 that has a phospho-mimicking mutation (T464D [change of T to D at position 464]) but not Cdt2(T464A) from ubiquitination. Furthermore, the delay of the cell cycle in the G 2 /M phase and decrease in cell proliferation seen upon depletion of 14-3-3γ is partly due to the accumulation of the CRL4 Cdt2 substrate, Set8 methyltransferase. Therefore, the stabilization of Cdt2 is an important function of 14-3-3 proteins in cell cycle progression.

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Background Treatment at high‐volume surgical facilities (HVSFs) provides a survival benefit for patients with head and neck squamous cell carcinomas (HNSCCs); however, it is unknown what role postoperative radiation therapy (PORT) plays in achieving the improved outcomes. Methods From the National Cancer Database, 6844 patients with locally advanced invasive HNSCCs of the oral cavity, oropharynx, larynx, and hypopharynx who underwent definitive surgery with PORT between 2004 and 2013 were identified. HVSFs were those in the top percentile for annual case volume during this period. Results The median follow‐up was 54 months. Compared with a lower volume surgical facility (LVSF), an HVSF improved 5‐year overall survival (OS; 57.7% at HVSFs vs 52.5% at LVSFs; P = .0003). Overall, 31.6% of the patients changed their radiation therapy (RT) facility after surgery, with this being more common at HVSFs (39.1% vs 28.9% at LVSFs; P < .001). Among those patients undergoing surgery at an HVSF, remaining at the same facility for RT improved 5‐year OS (63.1% vs 49.3% with a facility change; P < .0001). A propensity score–matched cohort of patients treated at HVSFs confirmed the improved 5‐year OS when patients remained at the treating HVSF for RT (59.2% vs 50.7% with a facility change; P = .005). In a multivariate analysis, treatment at an HVSF and remaining there for RT resulted in a reduced hazard of death (hazard ratio, 0.81; 95% confidence interval, 0.69‐0.94; P = .006). Conclusions The survival benefit associated with HVSFs persists only when patients remain at the facility for RT, and this suggests that facility specialization and/or high‐volume PORT may assist in driving the OS improvement.

BACKGROUND:The eighth edition of the AJCC Cancer Staging Manual (AJCC 8) incorporates depth of invasion (DOI) into the pathologic tumor (pT) classification and pathologic extranodal extension (pENE) into the pathologic nodal (pN) classification for oral cavity squamous cell carcinoma (OCSCC). This study evaluated the incidence and prognostic importance of stage migration as a result of these changes in the AJCC 8 staging system. METHODS: From the National Cancer Database, cohorts were identified from patients with OCSCC undergoing definitive surgery between 2004 and 2013 for pT (n = 7184), pN (n = 13,627), and pathologic stage (pStage) analysis (n = 5580). RESULTS: DOI and pENE were prognostic in all groups except for pN3 according to the seventh edition of the AJCC Cancer Staging Manual (AJCC 7). Upstaging was seen in 12.4% of patients for the pT classification, in 13.3% for the pN classification, and in 24.8% for the overall pStage grouping. Notably, upstaging led to similar or improved 5-year overall survival (OS) for every AJCC 8 pT/N classification except pStage IVB. Patients with AJCC 7 pT1 tumors that were upstaged to AJCC 8 pT3 tumors had improved OS in comparison with the remainder of the pT3 group (71.7% vs 43.7%; P < .0001). A multivariable analysis of upstaged pT3N0 patients demonstrated a reduced risk of death with the receipt of postoperative radiotherapy (PORT; hazard ratio, 0.56; 95% confidence interval, 0.33-0.95; P = .03). CONCLUSIONS: Upstaging is common in AJCC 8, and patients with upstaged tumors demonstrate improved survival; these factors should be kept in mind when one is interpreting data with the new staging system. PORT may reduce deaths among newly upstaged pT3N0 patients, and further study is needed in this area. Cancer 2019;125:2975-2983.

Aplastic anemia (AA) is a rare life-threatening disorder characterized by pancytopenia and a hypocellular bone marrow. 1 Pure red cell aplasia (PRCA) is a more limited marrow failure syndrome, with primary reduction in red blood cell production and virtual absence of marrow erythroid precursors. Although the etiology of immune-mediated marrow failure is complex, preceding viral infections have been associated with AA and PRCA, including parvovirus B19, cytomegalovirus, and Epstein-Barr virus. We present 6 cases of new-onset marrow failure (AA or PRCA) presumably associated with preceding severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.The records of patients treated for AA or PRCA at the University of Texas Southwestern, Parkland Hospital, the National Institutes of Health, and Mount Sinai were reviewed for SARS-CoV-2 infection. Six patients without prior hematologic diseases or SARS-CoV-2 vaccination were identified who had SARS-CoV-2 infection presumably before the diagnosis of AA or PRCA. This study was approved by the University of Texas Southwestern Medical Center Institutional Review Board (STU-2020-0832) and was performed according to the Declaration of Helsinki.