[A multivariate model for predicting induction response and prognosis in core binding factor acute myeloid leukemia].

Objective: To evaluate the efficacy and prognostic factors in core binding factor (CBF) acute myeloid leukemia (AML) under current therapy modalities, therefore optimizing the treatment strategies. Methods: Standard cytological and immune methods including next generation sequencing (NGS) were used for risk stratification. Complete remission (CR) rate, disease-free survival (DFS) and overall survival (OS) were assessed by multivariate Logistic and Cox regression models in a total of 206 adults (aged 16-65 years) with CBF-AML, including 152 AML patients with t(8;21) and 54 with inv(16). Results: The CR rate of inv(16) patients after first course was 54/54(100%), significantly higher than that of t(8;21) patients [127/147(86.4%), P=0.005]. The fusion transcript level and KIT mutation were independent factors related to CR rate in t(8;21) patients (P=0.044 and 0.027; respectively). DFS and OS in inv(16) patients tended to be more superior than that in t(8;21) patients (P=0.066 for DFS; P=0.306 for OS; respectively). Multivariate Cox identified negative expression of CD(19) and female gender the independent predictors of inferior DFS in t(8;21) patients (P=0.000 for CD(19); P=0.006 for sex; respectively). Analysis of combining CD(19) with gender indicated that females/CD(1)(9-)subpopulation had significantly poor DFS than did males/CD(19)(+) ones (Bonferroni-P<0.000 01). The number of mutations in each patient, FLT3-ITD and additional karyotype abnormalities did not affect CR rate and DFS (all P>0.05). Conclusions: Patients with inv(16) have better induction response than those with t(8;21). High level of fusion transcripts and positive KIT mutation are associated with low CR rate in t(8;21) patients. Negative CD(19) expression and female gender are independent predictors of inferior DFS in t(8;21) patients.

TNF alpha inhibits myogenic differentiation of C2C12 cells through NF-κB activation and impairment of IGF-1 signaling pathway.

Cachexia or muscle wasting is a common condition that occurs in many chronic diseases. The wasting conditions are characterized by increased levels of TNF-α which was also known as cachectin in the past. But how TNF-α exerts its cachetic effects remains controversial. To clarify this issue, we investigated the impact of TNF-α on C2C12 cell myogenic differentiation. Our results demonstrate that myotube formation was completely inhibited by TNF-α when added to differentiating C2C12 myoblasts. The inhibitory effect of TNF-α on differentiation was accompanied by activation of NF-κB and down regulation of myogenin and Akt. Importantly, TNF-α's effect on differentiation was abolished when IGF-1 was added to the culture. IGF-1 treatment also inhibited NF-κB reporter activity and restored Akt levels. Our data suggest that TNF-α inhibits myogenic differentiation through NF-κB activation and impairment of IGF-1 signaling pathway. The reversal of TNF-α induced inhibition of myogenesis by IGF-1 may have significant therapeutic potential.

Bortezomib inhibits C2C12 growth by inducing cell cycle arrest and apoptosis.

Proteosome inhibitors such as bortezomib (BTZ) have been used to treat muscle wasting in animal models. However, direct effect of BTZ on skeletal muscle cells has not been reported. In the present study, our data showed that C2C12 cells exhibited a dose-dependent decrease in cell viability in response to increasing concentrations of BTZ. Consistent with the results of cell viability, Annexin V/PI analysis showed a significant increase in apoptosis after exposing the cells to BTZ for 24h. The detection of cleaved caspase-3 further confirmed apoptosis. The apoptosis induced by BTZ was associated with reduced expression of p-ERK. Cell cycle analysis revealed that C2C12 cells underwent G2/M cell cycle arrest when incubated with BTZ for 24h. Furthermore, BTZ inhibited formation of multinucleated myotubes. The inhibition of myotube formation was accompanied by decreased expression of Myogenin. Our data suggest that BTZ induces cell death and inhibits differentiation of C2C12 cells at clinically relevant doses.

Felodipine downregulates serum interleukin-18 levels in rats with fructose-induced metabolic syndrome.

OBJECTIVE: Human studies suggest that calcium-channel blockers have cardiovascular protection besides reducing blood pressure, and interleukin-18 (IL-18) levels which are elevated in obese population are associated with metabolic syndrome (MetS). The purpose of this research was to study the change of serum IL-18 levels and the effect of felodipine on it in high-fructose diet-fed rats. METHODS: In this research, 30 Wistar male rats were randomized into 3 groups. A control group (no.=12) was fed with normal feeds, and high-fructose diet was given to a fructose group and a flodioine group (no.=9 in each group). All animals were fed for a period of 32 weeks, during which body weight and systolic blood pressure (BP) were measured once every 4 weeks. Felodipine (5 mg/kg/d) was then administered by gavage daily for 6 weeks to the felodipine group. Before and after treatment with felodipine, fasting plasma lipid, blood glucose, plasma insulin, and serum IL-18 were detected. RESULTS: Body weight, systolic BP, triglycerides, fasting insulin, and the R-value of homeostasis model (HOMA-R) were significantly increased in high-fructose rats (p<0.01). Serum IL-18 levels were elevated and had significant positive correlation with HOMA-R in rats with fructose-induced MetS (p<0.01). We also found that felodipine may decrease HOMA-R and serum IL-18 levels besides reducing blood pressure (p<0.05, p<0.01). CONCLUSION: IL-18 plays an important role in the development of MetS, while felodipine exerts an anti-inflammatory effect on rats with fructose-induced MetS by downregulating serum IL-18 levels.

Oxidative dna damage of lymphocytes in peripheral blood and ascites in cancer patients.

BACKGROUND: Patients with malignant ascites (ma) usually experience poor quality of life, and treatment of this symptom remains a challenge. Oxidative stress, which can cause oxidative damage to dna, plays a pivotal role in carcinogenesis; however, the relationship between oxidative stress and dna damage to tumour-associated lymphocytes (tals) in ma is unclear. METHODS: We measured the total antioxidant capacity (tac) of plasma and ma supernatant in 31 cancer patients with ma, and we used a comet assay to assess dna damage to both peripheral blood mononuclear cells (pbmcs) and tals. Measurements in age- and sex-matched healthy volunteers were used as controls. RESULTS: The tac of plasma was remarkably lower in cancer patients (9.73 ± 1.96 U/mL) than in healthy control subjects (11.31 ± 1.50 U/mL, p < 0.001). The tac of ma supernatant (6.34 ± 1.57 U/mL) was significantly lower than that of plasma in cancer patients (7.42 ± 1.36 U/mL, p < 0.001). The comet percentage of pbmcs was higher in cancer patients (17.26% ± 6.04%) than in healthy control subjects (9.44% ± 4.47%, p < 0.01). In cancer patients, the comet percentage of tals (36.14% ± 17.85%) was significantly higher than that of pbmcs (17.26% ± 6.04%, p < 0.001). In cancer patients with ma, negative correlations were observed between plasma tac and dna damage to pbmcs (r = -0.505, p = 0.004) and between the tac of ma supernatant and the comet percentage of tals (r = -0.588, p = 0.001). CONCLUSIONS: Results indicate the presence of significant oxidative damage to the dna of lymphocytes in peripheral blood and ascites from patients with ma, being especially higher in the cells from ascites. The lower tac of ma supernatant may be related to a higher degree of dna damage to tals. The present study suggests that an oxidant-antioxidant imbalance may be one of the mechanisms leading to the dna damage detected in peripheral blood and local tals in patients with ma, which may provide a novel approach to the treatment of ma.