Predicting septic shock in patients with sepsis at emergency department triage using systolic and diastolic shock index.

INTRODUCTION: Identifying patients with at a high risk of progressing to septic shock is essential. Due to systemic vasodilation in the pathophysiology of septic shock, the use of diastolic blood pressure (DBP) has emerged. We hypothesized that the initial shock index (SI) and diastolic SI (DSI) at the emergency department (ED) triage can predict septic shock. METHOD: This observational study used the prospectively collected sepsis registry. The primary outcome was progression to septic shock. Secondary outcomes were the time to vasopressor requirement, vasopressor dose, and severity according to SI and DSI. Patients were classified by tertiles according to the first principal component of shock index and diastolic shock index. RESULTS: A total of 1267 patients were included in the analysis. The area under the receiver operating characteristic curve (AUC) for predicting progression to septic shock for DSI was 0.717, while that for SI was 0.707. The AUC for predicting progression to septic shock for DSI and SI were significantly higher than those for conventional early warning scores. Middle tertile showed adjusted Odd ratio (aOR) of 1.448 (95% CI 1.074-1.953), and that of upper tertile showed 3.704 (95% CI 2.299-4.111). CONCLUSION: The SI and DSI were significant predictors of progression to septic shock. Our findings suggest an association between DSI and vasopressor requirement. We propose stratifying lower tertile as being at low risk, middle tertile as being at intermediate risk, and upper tertile as being at high risk of progression to septic shock. This system can be applied simply at the ED triage.

LC3B upregulation by NANOG promotes immune resistance and stem-like property through hyperactivation of EGFR signaling in immune-refractory tumor cells.

Immune selection drives tumor cells to acquire refractory phenotypes. We previously demonstrated that cytotoxic T lymphocyte (CTL)-mediated immune pressure enriches NANOG+ tumor cells with stem-like and immune-refractory properties that make them resistant to CTLs. Here, we report that the emergence of refractory phenotypes is highly associated with an aberrant macroautophagic/autophagic state of the NANOG+ tumor cells and that the autophagic phenotype arises through transcriptional induction of MAP1LC3B/LC3B by NANOG. Furthermore, we found that upregulation of LC3B expression contributes to an increase in EGF secretion. The subsequent hyperactivation of EGFR-AKT signaling rendered NANOG+ tumor cells resistant to CTL killing. The NANOG-LC3B-p-EGFR axis was preserved across various types of human cancer and correlated negatively with the overall survival of cervical cancer patients. Inhibition of LC3B in immune-refractory tumor models rendered tumors susceptible to adoptive T-cell transfer, as well as PDCD1/PD-1 blockade, and led to successful, long-term control of the disease. Thus, our findings demonstrate a novel link among immune-resistance, stem-like phenotypes, and LC3B-mediated autophagic secretion in immune-refractory tumor cells, and implicate the LC3B-p-EGFR axis as a central molecular target for controlling NANOG+ immune-refractory cancer.Abbreviations: ACTB: actin beta; ATG7: autophagy related 7; BafA1: bafilomycin A1; CASP3: caspase 3; CFSE: carboxyfluorescein succinimidyl ester; ChIP: chromatin immunoprecipitation; CI: confidence interval; CIN: cervical intraepithelial neoplasia; CSC: cancer stem cell; CTL: cytotoxic T lymphocyte; EGF: epidermal growth factor; EGFR: epidermal growth factor receptor; FIGO: International Federation of Gynecology and Obstetrics; GFP: green fluorescent protein; GZMB: granzyme B; HG-CIN: high-grade CIN; IHC: immunohistochemistry; LG-CIN: low-grade CIN; LN: lymph node; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MCL1: myeloid cell leukemia sequence 1; MLANA/MART-1: melanoma antigen recognized by T cells 1; MUT: mutant; NANOG: Nanog homeobox; PDCD1/PD-1: programmed cell death 1; PMEL/gp100: premelanosome protein; RTK: receptor tyrosine kinase; TMA: tissue microarray; WT: wild type.