Retrospective evaluation of the relationship between admission variables and brain herniation in dogs (2010-2019): 54 cases.

OBJECTIVE: To document the admission systolic blood pressure (SBP), heart rate (HR), and modified Glasgow coma scale (MGCS) score in dogs with and without brain herniation and to determine their relationship with brain herniation. DESIGN: Retrospective study between 2010 and 2019. SETTING: University veterinary teaching hospital. ANIMALS: Fifty-four client-owned dogs with brain herniation and 40 client-owned dogs as a control group, as determined on magnetic resonance imaging. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: SBP, HR, MGCS score, and outcome were extracted from medical records. MGCS score was retrospectively calculated based on initial neurological examination in dogs with adequate available information. Dogs with brain herniation had a significantly higher SBP (P = 0.0078), greater SBP-HR difference (P = 0.0006), and lower MGCS score (P < 0.0001) compared to control dogs. A cutoff value of an SBP ≥ 178 mm Hg, SBP-HR ≥ 60, and MGCS score ≤ 14 each provides a specificity of 90%-98%. A combination of an SBP > 140 mm Hg and HR < 80/min provided 24% sensitivity and 100% specificity to diagnose dogs with brain herniation (P < 0.0001). CONCLUSIONS: A high SBP, a greater difference between SBP and HR, a combination of higher SBP and lower HR, and a low MGCS score were associated with brain herniation in dogs presenting with neurological signs upon admission. Early recognition of these abnormalities may help veterinarians to suspect brain herniation and determine timely treatment.

The value of all-payer claims databases to states.

All-payer claims databases are being developed in states across the nation to fill gaps in information about the health care system. The value of such databases is becoming more apparent as these databases mature and are used more frequently to help states better understand their health care utilization and costs.

RNF4 and PLK1 are required for replication fork collapse in ATR-deficient cells.

The ATR-CHK1 axis stabilizes stalled replication forks and prevents their collapse into DNA double-strand breaks (DSBs). Here, we show that fork collapse in Atr-deleted cells is mediated through the combined effects the sumo targeted E3-ubiquitin ligase RNF4 and activation of the AURKA-PLK1 pathway. As indicated previously, Atr-deleted cells exhibited a decreased ability to restart DNA replication following fork stalling in comparison with control cells. However, suppression of RNF4, AURKA, or PLK1 returned the reinitiation of replication in Atr-deleted cells to near wild-type levels. In RNF4-depleted cells, this rescue directly correlated with the persistence of sumoylation of chromatin-bound factors. Notably, RNF4 repression substantially suppressed the accumulation of DSBs in ATR-deficient cells, and this decrease in breaks was enhanced by concomitant inhibition of PLK1. DSBs resulting from ATR inhibition were also observed to be dependent on the endonuclease scaffold protein SLX4, suggesting that RNF4 and PLK1 either help activate the SLX4 complex or make DNA replication fork structures accessible for subsequent SLX4-dependent cleavage. Thus, replication fork collapse following ATR inhibition is a multistep process that disrupts replisome function and permits cleavage of the replication fork.

Oncogenic stress sensitizes murine cancers to hypomorphic suppression of ATR.

Oncogenic Ras and p53 loss-of-function mutations are common in many advanced sporadic malignancies and together predict a limited responsiveness to conventional chemotherapy. Notably, studies in cultured cells have indicated that each of these genetic alterations creates a selective sensitivity to ataxia telangiectasia and Rad3-related (ATR) pathway inhibition. Here, we describe a genetic system to conditionally reduce ATR expression to 10% of normal levels in adult mice to compare the impact of this suppression on normal tissues and cancers in vivo. Hypomorphic suppression of ATR minimally affected normal bone marrow and intestinal homeostasis, indicating that this level of ATR expression was sufficient for highly proliferative adult tissues. In contrast, hypomorphic ATR reduction potently inhibited the growth of both p53-deficient fibrosarcomas expressing H-rasG12V and acute myeloid leukemias (AMLs) driven by MLL-ENL and N-rasG12D. Notably, DNA damage increased in a greater-than-additive fashion upon combining ATR suppression with oncogenic stress (H-rasG12V, K-rasG12D, or c-Myc overexpression), indicating that this cooperative genome-destabilizing interaction may contribute to tumor selectivity in vivo. This toxic interaction between ATR suppression and oncogenic stress occurred without regard to p53 status. These studies define a level of ATR pathway inhibition in which the growth of malignancies harboring oncogenic mutations can be suppressed with minimal impact on normal tissue homeostasis, highlighting ATR inhibition as a promising therapeutic strategy.