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ATM kinase is a tumor suppressor and a master regulator of the DNA damage response. Most cancer-associated alterations to ATM are missense mutations at the PI3-kinase regulatory domain (PRD) or the kinase domain. Expression of kinase-dead (KD) ATM protein solely accelerates lymphomagenesis beyond ATM loss. To understand how PRD suppresses lymphomagenesis, we introduced the cancer-associated PRD mutation R3008H (R3016 in mouse) into mice. R3008H abrogated DNA damage- and oxidative stress-induced activation of ATM without consistently affecting ATM protein stability and recruitment. In contrast to the early embryonic lethality of AtmKD/KD mice, AtmR3016H (AtmR/R) mice were viable, immunodeficient, and displayed spontaneous craniofacial abnormalities and delayed lymphomagenesis compared with Atm−/− controls. Mechanistically, R3008H rescued the tardy exchange of ATM-KD at DNA damage foci, indicating that PRD coordinates ATM activation with its exchange at DNA-breaks. Taken together, our results reveal a unique tumorigenesis profile for PRD mutations that is distinct from null or KD mutations.Significant:This study functionally characterizes the most common ATM missense mutation R3008H in cancer and identifies a unique role of PI3-kinase regulatory domain in ATM activation.

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Prevention of hypotension during the intra- and postoperative period is an important goal. Peripheral administration of low-concentration norepinephrine may be a safe and effective strategy to reduce the risk of hypotension.We conducted a 2-center, randomized pilot feasibility trial, with a target of 60 adult patients undergoing major noncardiac surgery. We randomized patients to receive a peripheral low-concentration (10 µg/mL) norepinephrine or placebo (saline 0.9%) infusion. The study drug infusion was titrated to achieve a minimum systolic blood pressure target, preselected within 10% of baseline value and within the range limit 100 to 120 mm Hg during surgery and for up to 4 or 24 hours postoperatively.We achieved a high consent rate (84%), successful study drug administration throughout surgery (98% of patients) and absence of unblinding. There were no important study drug-related adverse events. The average intraoperative systolic blood pressure was 120 ± 12.6 mm Hg in the norepinephrine group and 115 ± 14.9 mm Hg in the placebo group. The mean difference between the intraoperative systolic blood pressure achieved less the preselected minimum systolic blood pressure target was 10.0 ± 12.7 mm Hg in the norepinephrine group and 2.9 ± 14.7 mm Hg in the placebo group; difference in means, 7.1 (95% confidence interval, 0.2-14.0) mm Hg.A future large trial evaluating the effectiveness and safety of peripheral administration of low-concentration norepinephrine during the perioperative period is feasible, and likely to achieve a minimum systolic blood pressure threshold.

Discrimination is an urgent public health problem. A number of major cities and counties across the United States has declared racism a public health crisis. While there is a growing body of research on the discrimination-health connection, less is known regarding the social relational consequences of discrimination. The present study addresses this knowledge gap by investigating the relationship between discrimination, skin tone, and objective and subjective social isolation using a nationally representative sample of African Americans.This analysis was based upon the African American subsample (N = 3,570) of the National Survey of American Life. Discrimination was assessed with the Everyday Discrimination Scale. Objective and subjective isolation differentiated between respondents who were (a) socially isolated from both family and friends, (b) socially isolated from friends only, (c) socially isolated from family only, and (d) not socially isolated. Skin tone was self-reported. Multinomial logistic regression analyses were used to test the study hypotheses.The analyses indicated that more frequent discriminatory experiences were associated with increased risk for subjective and objective social isolation. Skin tone moderated the association between discrimination and subjective isolation; the discrimination-isolation relationship was stronger among participants with darker skin tones.These findings shed light on African Americans' nuanced experiences with discrimination and colorism. Further, the data demonstrate heterogeneity in the vulnerability to the adverse effects of discrimination within the African American population; the relationship between discrimination and subjective isolation was stratified by skin tone. This underscores the well-documented and persistent racialized social stratification system in the United States (PsycInfo Database Record (c) 2022 APA, all rights reserved).