Background: Laboratory risk indicator for necrotizing fasciitis (LRINEC score) is a simple laboratory tool used to distinguish between necrotizing soft-tissue infections (NSTI) and other soft-tissue infections. A LRINEC score of ‡6 is considered as denoting a high risk of necrotizing fasciitis. A certain LRINEC score might also be associated with mortality and other outcomes of patients with NSTI. Methods: A review of the medical charts of patients was carried out. The study sites were one tertiary academic centre and one community, university-affiliated hospital. All adult patients with necrotizing soft-tissue infections from 2002 to 2005 were selected then LRINEC scores were calculated for each patient. We enrolled patients where there was sufficient information to determine that the LRINEC score was either <6 or ‡6. Results: A total of two hundred and nine patients were enrolled and analysed. The overall mortality rate was 33 of 209 (15.8%) and amputation rate was 55 of 209 (26.3%). The amputation rates were defined as numbers of patients who received amputation divided by numbers of total patients. Enrolled patients were divided into two groups. Group I was those whose LRINEC score was <6 and group II was those whose LRINEC score was ‡6. Significant differences in mortality rate (P = 0.04) and amputation rate (P = 0.002) were noted between two groups. Conclusion: The LRINEC score is associated with the outcomes of patients with NSTI. Patients with a LRINEC score of ‡6 have a higher rate of both mortality and amputation.

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Background T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive disease with a high risk of induction failure and poor outcomes, with relapse due to drug resistance. Recent studies show that bromodomains and extra-terminal (BET) protein inhibitors are promising anti-cancer agents. ARV-825, comprising a BET inhibitor conjugated with cereblon ligand, was recently developed to attenuate the growth of multiple tumors in vitro and in vivo. However, the functional and molecular mechanisms of ARV-825 in T-ALL remain unclear. This study aimed to investigate the therapeutic efficacy and potential mechanism of ARV-825 in T-ALL. Methods Expression of the BRD4 were determined in pediatric T-ALL samples and differential gene expression after ARV-825 treatment was explored by RNA-seq and quantitative reverse transcription-polymerase chain reaction. T-ALL cell viability was measured by CCK8 assay after ARV-825 administration. Cell cycle was analyzed by propidium iodide (PI) staining and apoptosis was assessed by Annexin V/PI staining. BRD4, BRD3 and BRD2 proteins were detected by western blot in cells treated with ARV-825. The effect of ARV-825 on T-ALL cells was analyzed in vivo. The functional and molecular pathways involved in ARV-825 treatment of T-ALL were verified by western blot and chromatin immunoprecipitation (ChIP). Results BRD4 expression was higher in pediatric T-ALL samples compared with T-cells from healthy donors. High BRD4 expression indicated a poor outcome. ARV-825 suppressed cell proliferation in vitro by arresting the cell cycle and inducing apoptosis, with elevated poly-ADP ribose polymerase and cleaved caspase 3. BRD4, BRD3, and BRD2 were degraded in line with reduced cereblon expression in T-ALL cells. ARV-825 had a lower IC50 in T-ALL cells compared with JQ1, dBET1 and OTX015. ARV-825 perturbed the H3K27Ac-Myc pathway and reduced c-Myc protein levels in T-ALL cells according to RNA-seq and ChIP. In the T-ALL xenograft model, ARV-825 significantly reduced tumor growth and led to the dysregulation of Ki67 and cleaved caspase 3. Moreover, ARV-825 inhibited cell proliferation by depleting BET and c-Myc proteins in vitro and in vivo. Conclusions BRD4 indicates a poor prognosis in T-ALL. The BRD4 degrader ARV-825 can effectively suppress the proliferation and promote apoptosis of T-ALL cells via BET protein depletion and c-Myc inhibition, thus providing a new strategy for the treatment of T-ALL.