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Purpose@#Oligometastatic non–small cell lung cancer (NSCLC) patients have been increasingly regarded as a distinct group that could benefit from local treatment to achieve a better clinical outcome. However, current definitions of oligometastasis are solely numerical, which are imprecise because of ignoring the biological heterogeneity caused by genomic characteristics. Our study aimed to profile the molecular alterations of oligometastatic NSCLC and elucidate its potential difference from polymetastasis. @*Materials and Methods@#We performed next-generation sequencing to analyze tumors and paired peripheral blood from 77 oligometastatic and 21 polymetastatic NSCLC patients to reveal their genomic characteristics and assess the genetic heterogeneity. @*Results@#We found ERBB2, ALK, MLL4, PIK3CB, and TOP2A were mutated at a significantly lower frequency in oligometastasis compared with polymetastasis. EGFR and KEAP1 alterations were mutually exclusive in oligometastatic group. More importantly, oligometastasis has a unique significant enrichment of apoptosis signaling pathway. In contrast to polymetastasis, a highly enriched COSMIC signature 4 and a special mutational process, COSMIC signature 14, were observed in the oligometastatic cohort. According to OncoKB database, 74.03% of oligometastatic NSCLC patients harbored at least one actionable alteration. The median tumor mutation burden of oligometastasis was 5.00 mutations/Mb, which was significantly associated with smoking, DNA damage repair genes, TP53 mutation, SMARCA4 mutation, LRP1B mutation, ABL1 mutation. @*Conclusion@#Our results shall help redefine oligometastasis beyond simple lesion enumeration that will ultimately improve the selection of patients with real oligometastatic state and optimize personalized cancer therapy for oligometastatic NSCLC.
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Objective:To investigate clinical outcome and the risk factors for death in acute pancreatitis (AP) patients complicated with acute kidney injury (AKI).Methods:The clinical data of 232 AP patients complicated with AKI admitted to the Center of Severe Pancreatitis of Jinling Hospital Affiliated to Nanjing University School of Medicine from January 2016 to December 2020 were retrospectively analyzed. Patients were divided into survival group ( n=162) and death group ( n=70) based on the survival status. The two groups' clinical characteristics, biochemical indexes, and renal function indexes were compared. Univariate analysis and multivariate logistic regression analysis were used to analyze the independent risk factors for death in AP patients complicated with AKI. Results:Sixteen patients(6.9%) among the 232 had AKI Ⅰ, 15(6.5%) had AKI Ⅱ, and 201(86.6%) had AKI Ⅲ. Forty-one patients (17.7%) became AKI with a disease course <7 days, 184 patients (79.3%) gradually progressed to acute kidney disease with a disease course of 7-90 days, and 7 patients (3.0%) eventually progressed to chronic kidney disease with a disease course >90 days. Renal replacement treatment (RRT) was administered in 179 patients (77.2%), lasting an average of 14 (7-25) days. 138 patients (59.5%) had their renal function recovered while they were hospitalized, including 9 patients (6.5%) who did so within 7 days, 69 patients (50.0%) within 30 days, and 127 patients (92.0%) within 90 days. The average recovery time was 16 (7-28) days. Seventy patients (30.2%) died during hospitalization, including 8(3.5%) within 7 days, 42(18.1%) within 30 days, and 68(29.3%) within 90 days. Univariate analysis revealed that the proportions of biliary etiology, neutrophil to lymphocyte ratio (NLR), serum cystatin C, sequential organ failure assessment(SOFA) score, AKI Ⅲ proportion, number of patients undergoing RRT, and duration of AKI were significantly higher in the death group compared to the survival group. The number of patients complicated by infected pancreatic necrosis (IPN) and having surgical intervention was also significantly greater than that in the survival group, while the proportion of patients whose renal function recovered was much lower than that in the survival group. The differences were all statistically significant (all P value <0.05). Multivariate logistic analysis showed that SOFA( OR=1.182, 95% CI 1.000-1.396, P=0.049), and IPN( OR=8.403, 95% CI 3.748-18.838, P<0.001) were independent risk factors for death. Conclusions:SOFA score and IPN at admission were independent risk factors for death in AP patients with AKI. Vigilance should be given as soon as possible to improve the outcome of patients through clinical intervention.
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Retinoid X receptor α (RXRα) and its N-terminally truncated version tRXRα play important roles in tumorigenesis, while some RXRα ligands possess potent anti-cancer activities by targeting and modulating the tumorigenic effects of RXRα and tRXRα. Here we describe NSC-640358 (N-6), a thiazolyl-pyrazole derived compound, acts as a selective RXRα ligand to promote TNFα-mediated apoptosis of cancer cell. N-6 binds to RXRα and inhibits the transactivation of RXRα homodimer and RXRα/TR3 heterodimer. Using mutational analysis and computational study, we determine that Arg316 in RXRα, essential for 9-cis-retinoic acid binding and activating RXRα transactivation, is not required for antagonist effects of N-6, whereas Trp305 and Phe313 are crucial for N-6 binding to RXRα by forming extra π-π stacking interactions with N-6, indicating a distinct RXRα binding mode of N-6. N-6 inhibits TR3-stimulated transactivation of Gal4-DBD-RXRα-LBD by binding to the ligand binding pocket of RXRα-LBD, suggesting a strategy to regulate TR3 activity indirectly by using small molecules to target its interacting partner RXRα. For its physiological activities, we show that N-6 strongly inhibits tumor necrosis factor α (TNFα)-induced AKT activation and stimulates TNFα-mediated apoptosis in cancer cells in an RXRα/tRXRα dependent manner. The inhibition of TNFα-induced tRXRα/p85α complex formation by N-6 implies that N-6 targets tRXRα to inhibit TNFα-induced AKT activation and to induce cancer cell apoptosis. Together, our data illustrate a new RXRα ligand with a unique RXRα binding mode and the abilities to regulate TR3 activity indirectly and to induce TNFα-mediated cancer cell apoptosis by targeting RXRα/tRXRα.