NOTCH1 mutations occur in approximately 10% of patients with chronic lymphocytic leukemia (CLL). However, the relationship between the genetic aberrations and tumor cell drug resistance or disease progression remains unclear. Frameshift deletions were detected by gene sequencing in the NOTCH1 PEST domain in three naive CLL patients. These mutations were associated with chromosomal abnormalities including trisomy 12 or 13q deletion. Of note, one of the patients developed Richter’s transformation during FCR treatment. Immunofluorescent and western blot analyses revealed a markedly higher intracellular domain of NOTCH (ICN) expression in the mutated cells compared with their unmutated counterparts and normal CD19+ B lymphocytes (P<0.01 and P<0.001, respectively). In addition, strong DNA-κB binding activities were observed in the mutant cells by gel shift assays. RT-PCR analysis revealed elevated RelA mRNA expression in the mutant cells, while RelB levels were variable. Reduced levels of RelA and RelB mRNA were observed in unmutated CLL and normal B cells. Compared to unmutated CLL and normal B cells, increased apoptosis occurred in the mutant cells in the presence of GSI (ICN inhibitor) and PDTC (NF-κB inhibitor), particularly under the synergistic effects of the two drugs (P=0.03). Moreover, IKKα and IKKβ, the active components in the NF-κB pathway, were markedly inhibited following prolonged treatment with GSI and PDTC. These results suggested that NOTCH1 mutations constitutively activate the NF-κB signaling pathway in CLL, which is likely related to ICN overexpression, indicating NOTCH1 and NF-κB as potential therapeutic targets in the treatment of CLL.

Background. Legumain is related to carotid atherosclerotic plaques and may be a new biomarker of carotid atherosclerosis. However, the association between legumain and peripheral artery disease (PAD) of lower extremity has been less studied. This study is aimed at exploring the potential link between legumain and PAD in patients with type 2 diabetes mellitus (T2DM). Methods. A cross-sectional study was conducted on 483 hospitalized T2DM patients. The serum legumain level was measured by a sandwich enzyme-linked immunosorbent assay. PAD was evaluated by color Doppler sonography. The association between legumain and PAD was tested by logistic regression. The predictive power of legumain for PAD was evaluated with the receiver-operating-characteristic (ROC) curve. Results. Overall, 201 (41.6%) patients suffered from PAD. Patients with PAD had significantly higher serum legumain level than those without PAD [11.9 (6.3, 17.9) μg/L vs. 7.6 (3.2, 14.2) μg/L, p < 0.001 ]. Logistic regression showed that a higher serum legumain level was independently associated with a greater risk of PAD in T2DM patients [adjusted odds ratio (aOR): 1.03; 95% confidence interval (CI): 1.01-1.06]. The area under the ROC curve was 0.634 (95% CI, 0.585 to 0.684). Conclusion. High serum legumain level was significantly correlated with an increased risk of PAD in T2DM patients.

Abstract.The majority of patients with chronic lymphocytic leukemia (CLL) are not cured by traditional chemotherapy. One possible explanation for this is that the microenvironment protects CLL cells from both spontaneous-and cytotoxic-mediated apoptosis. The present study was designed to investigate the mechanisms accounting for these effects, since this information is crucial to understanding CLL physiopathology and identifying potential treatment targets. The CLL cell line L1210 and primary CLL cells were cultured under different conditions: With serum, cyclophosphamide (CTX), or with monolayers and conditioned medium (CM) from the stromal cell line HESS-5. Apoptosis, Hes family BHLH transcription factor 1 (HES-1) gene and protein expression, and histone H3K27me3 DNA demethylation were determined. Co-culture of L1210 cells with HESS-5 cells significantly inhibited serum deprivation-and CTX-induced apoptosis of leukemia cells, and resulted in a significant increase in short-term proliferation. Soluble factors in the CM from HESS-5 cells had a negligible effect. The HESS-5 cell-mediated inhibition of apoptosis of CLL cells was associated with increased HES-1 expression and hypomethylation of the H3K27me3 gene in the leukemia cells. These results indicate that stromal cells enhance the survival of CLL cells by regulating the HES-1 gene and protein expression, as well as H3K27me3 DNA demethylation, and suggest that specific interactions between stromal and leukemia cells may enhance the resistance of leukemia cells to chemotherapy.

Background Adropin, a newly‑identified energy homeostasis protein, has been implicated in the maintenance of metabolic homeostasis and insulin sensitivity. This study attempts to measure the association between serum adropin and carotid atherosclerosis in patients with type 2 diabetes mellitus (T2DM). Methods This cross‑sectional study was performed in 503 hospitalized patients with T2DM.Serum adropin level was measured by a sandwich enzyme-linked immunosorbent assay. The carotid atherosclerosis was assessed by color Doppler sonography. The association between adropin and carotid atherosclerotic plaque was tested by logistic regression model. The effect of adropin on carotid intimal-medial thickness (CIMT) was estimated using linear regression model. Results Overall, 280 (55.7%) patients had carotid atherosclerotic plaque. The risk of carotid atherosclerotic plaque decreased with the increment of serum adropin level (adjusted odds ratio [aOR], 0.90; 95%CI: 0.81–0.99) in patients with T2DM. Serum adropin (Standardized β = − 0.006, p = 0.028) was also independently protective factor for CIMT in patients with T2DM. Conclusion In patients with T2DM, high serum adropin level was correlated with a decreased risk of carotid atherosclerosis in T2DM patients. Low circulating level of adropin may promote carotid atherosclerosis.