[The Mechanism of Artesunate Combined with Cytarabine and/or Daunorubicin on the Apoptosis of MV4-11 MLL-rearranged Acute Myeloid Leukemia Cell Line].

OBJECTIVE: To investigate the effect and mechanism of artesunate (ARTS) combined with cytarabine(Ara-C) and/or daunorubicin (DNR) on the proliferation and apoptosis of MV4-11 human mixed-lineage leukemia rearranged（MLL-r） acute myeloid leukemia (AML) cell line. METHODS: CCK-8 assay was used to detect the proliferation effect of individual or in combination of ARTS, DNR, Ara-C on MV4-11 cells. The IC50 of ARTS, DNR and Ara-C was calculated separately. The cell apoptosis and expression of receptors DR4 and DR5 were detected by flow cytometry. Western blot was used to detect the expression of Caspase-3 and Caspase-9 in each groups. RESULTS: The inhibition effect of ARTS, Ara-C and DNR on the proliferation of MV4-11 were all dose-dependently (r=0.99, 0.90 and 0.97, respectively). The IC50 of ARTS, Ara-C and DNR on MV4-11 for 48 hours were 0.31 µg/ml, 1.43 µmol/L and 22.47 nmol/L, respectively. At the dose of ARTS 0.3 µg/ml， Ara-C 1.0 µmol/L and DNR 15 nmol/L, the proliferation rate for 48 hours of the tri-combination treatment was significantly lower than that of the bi-combination treatment, while both were significantly lower than that of the individual treatment (all P＜0.05). In terms of bi-combination treatment, the cells proliferation rate for 48 hours of the ARTS+Ara-C group was significantly lower than that of the ARTS+DNR group, while both were significantly lower than that of the Ara-C+DNR group (all P＜0.05). The cooperativity index (CI) of bi- and tri-combination treatment were all less than 1. After 48 hours of drug action, the cell apoptosis rate of the ARTS+DNR+Ara-C group was significantly higher than that of the Ara-C+DNR group, while both were significantly higher than that of the ARTS+DNR group (all P＜0.05). Meanwhile, the was no statistical difference between the cells apoptotic rate of the ARTS+DNR+Ara-C group and the ARTS+Ara-C group (P>0.05). The expression of DR4 and DR5 also showed no difference between control group and drug group. Compared with the DNR+Ara-C group, the expressions of Caspase-3 were significantly down-regulated in both the ARTS+DNR+Ara-C group and the ARTS+Ara-C group (all P＜0.05). The down-regulation of Caspase-3 expression was the most significantly in the combination group of three drugs, while the Caspase-9 expressions in different groups showed no apparent change. CONCLUSION: The in vitro study showed that tri-combination of ARTS+Ara-C+DNR and bi-combination of ARTS+Ara-C could inhibit the proliferation and promote apoptosis of MV4-11 cell line. The inhibition effect of these two combinations were significantly superior to that of the traditional Ara-C+DNR treatment. The mechanism underlying this finding may be identified by the down regulation of Caspase-3, while no altered expression was observed of Caspase-9, DR4 and DR5.

Combined clinical parameters improve the diagnostic efficacy of 18F-FDG PET/CT in patients with fever of unknown origin (FUO) and inflammation of unknown origin (IUO): A prospective study in China.

OBJECTIVES: To improve the diagnostic efficacy of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) for Chinese patients with fever of unknown origin (FUO) and inflammation of unknown origin (IUO), with combined clinical parameters. MATERIALS AND METHODS: FUO/IUO patients who underwent a standard diagnostic work-up and 18F-FDG PET/CT scanning were enrolled and divided into a local uptake lesion subgroup and a non-specific abnormal uptake subgroup. Beneficial clinical parameters for improving the diagnostic efficacy of PET/CT were identified. RESULTS: From January 2014 to January 2019, 253 FUO/IUO patients were studied. In total, 147 patients had local uptake lesions and 106 patients had non-specific abnormal uptake. In the local uptake lesion group, the positioning accuracy of PET/CT was 37.2% in grades 1 and 2, and 66.3% in grades 3 and 4. With the following combination of clinical parameters, the positioning accuracy increased to 75.0% and 90.0%, respectively: time from admission to performing PET/CT scanning <6.5 days and C-reactive protein level >95 mg/l. In the non-specific abnormal uptake group, the combination of sex (male), bicytopenia, and lactic dehydrogenase improved the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for diagnosing malignancy from 64.3%, 69%, 60%, and 72.7%, respectively, to 83.3%, 81%, 81.4%, and 82.9%, respectively. With the combination of sex (male), white blood count, serum ferritin level, and hepatosplenomegaly, the infection prediction model had a sensitivity, specificity, PPV, and NPV of 78%, 76.2%, 76.6%, and 77.6%, respectively. CONCLUSIONS: Combined clinical parameters improved the localization diagnostic value of 18F-FDG PET/CT in the local uptake lesion subgroup and the etiological diagnostic value in the non-specific abnormal uptake subgroup.

A Diagnostic Tool for Identification of Etiologies of Fever of Unknown Origin in Adult Patients.

The diagnosis and treatment of fever of unknown origin (FUO) are huge challenges to clinicians. Separating the etiologies of FUO into infectious and non-infectious disease is conducive to clinical physicians not only on making decisions rapidly concerning the prescription of suitable antibiotics but also on further analysis of the final diagnosis. In order to develop and validate a diagnostic tool to efficiently distinguish the etiologies of adult FUO patients as infectious or non-infectious disease, FUO patients from the departments of infectious disease and internal medicine in three Chinese tertiary hospitals were enrolled retrospectively and prospectively. By using polynomial logistic regression analysis, the diagnostic formula and the associated scoring system were developed. The variables included in this diagnostic formula were from clinical evaluations and common laboratory examinations. The proposed tool could discriminate infectious and non-infectious causes of FUO with an area under receiver operating characteristic curve (AUC) of 0.83, sensitivity of 0.80 and specificity of 0.75. This diagnosis tool could predict the infectious and non-infectious causes of FUO in the validation cohort with an AUC of 0.79, sensitivity of 0.79 and specificity of 0.70. The results suggested that this diagnostic tool could be a reliable tool to discriminate between infectious and non-infectious causes of FUO.

Establishment of a Predictive Model Related to Pathogen Invasion for Infectious Diseases and Its Diagnostic Value in Fever of Unknown Origin.

The present study aimed to establish a list of parameters indicative of pathogen invasion and develop a predictive model to distinguish the etiologies of fever of unknown origin (FUO) into infectious and non-infectious causes. From January 2014 to September 2017, 431 patients with FUO were prospectively enrolled in the study population. This study established a list of 26 variables from the following 4 aspects: host factors, epidemiological factors, behavioral factors, and iatrogenic factors. Predefined predicted variables were included in a multivariate logistic regression analysis to develop a predictive model. The predictive model and the corresponding scoring system were developed using data from the confirmed diagnoses and 9 variables were eventually identified. These factors were incorporated into the predictive model. This model discriminated between infectious and non-infectious causes of FUO with an AUC of 0.72, sensitivity of 0.71, and specificity of 0.63. The predictive model and corresponding scoring system based on factors concerning pathogen invasion appear to be reliable screening tools to discriminate between infectious and non-infectious causes of FUO.