Serum and Bile Lipids in Young Women with Radiolucent Gallstones

To investigate the relationship between blood and bile lipids, serum cholesterol, high density lipoprotein cholesterol, and triglycerides were correlated with cholesterol saturation index of bile in 21 women-10 with radiolucent gallstones and 11 without stones. All of the women had regular menstrual cycles, were normolipidemic, and on a hospital diet. On the same morning, blood and the darkest duodenal bile were taken after cholecystokinin (CCK) stimulation. Standard laboratory procedures were used to analyze serum and bile lipids. We found: 1) statistically significant (t test, p less than 0.05) but only slight hypercholesterolemia (+ 12%) in patients with gallstones; 2) a negative correlation of serum cholesterol with cholesterol saturation index of bile, both in the control group (r = -0.654, p less than 0.05) and in gallstone patients (r = -0.665, p less than 0.05); 3) a correlation of high density lipoprotein cholesterol with cholesterol saturation index only in normal women (r = -0.619, p less than 0.05); 4) conversely, a correlation of triglycerides with the same index in only gallstone patients (r = 0.641, p less than 0.05). With the stepwise multiple regression analysis (independent variables: diagnosis of gallstones, serum cholesterol, HDL cholesterol, triglycerides; dependent variable: biliary cholesterol saturation index), only gallstone diagnosis and serum cholesterol influenced significantly (F test, p less than 0.05) the biliary cholesterol saturation index. These findings suggest that young women with radiolucent gallstones are slightly hypercholesterolemic, that in women both with and without gallstones there is a negative correlation between serum cholesterol and biliary cholesterol saturation, but women with gallstones have a higher cholesterol saturation index of the bile than women without gallstones with the same level of cholesterol in the blood.     

miR-15b/16-2 deletion promotes B-cell malignancies

The central role of the microRNA (miR) 15a/16-1 cluster in B-cell oncogenesis has been extensively demonstrated, with over two-thirds of B-cell chronic lymphocytic leukemia characterized by the deletion of the miR-15a/16-1 locus at 13q14. Despite the well-established understanding of the molecular mechanisms occurring during miR-15a/16-1 dysregulation, the oncogenic role of other miR-15/16 family members, such as the miR-15b/16-2 cluster (3q25), is still far from being elucidated. Whereas miR-15a is highly similar to miR-15b, miR-16-1 is identical to miR-16-2; thus, it could be speculated that both clusters control a similar set of target genes and may have overlapping functions. However, the biological role of miR-15b/16-2 is still controversial. We generated miR-15b/16-2 knockout mice to better understand the cluster’s role in vivo. These mice developed B-cell malignancy by age 15–18 mo with a penetrance of 60%. At this stage, mice showed significantly enlarged spleens with abnormal B cell-derived white pulp enlargement. Flow cytometric analysis demonstrated an expanded CD19+ CD5+ population in the spleen of 40% knockout mice, a characteristic of the chronic lymphocytic leukemia-associated phenotype found in humans. Of note, miR-15b/16-2 modulates the CCND2 (Cyclin D2), CCND1 (Cyclin D1), and IGF1R (insulin-like growth factor 1 receptor) genes involved in proliferation and antiapoptotic pathways in mouse B cells. These results are the first, to our knowledge, to suggest an important role of miR-15b/16-2 loss in the pathogenesis of B-cell chronic lymphocytic leukemia.MicroRNAs (miRNAs) are a class of small noncoding RNAs that modulate gene expression in many physiological and pathological conditions (1). Altered miRNA expression has been reported in several human cancers, and miRNA expression profiles vary according to the considered tumor (2).A role for miRNAs in tumorigenesis and progression was originally documented for the miR-15/16 family (2–5). This group of miRNAs encompasses the miR-15a/16-1 cluster (on chromosome 13q14,) the miR-15b/16-2 cluster (on chromosome 3q25), and the miR-195/497 cluster (on chromosome 17p13).The role of the miR-15a/16-1 cluster in B-cell pathology has been extensively demonstrated (5). The deletion of the miR-15a/16-1 cluster has been reported in over two-thirds of B-cell chronic lymphocytic leukemias (B-CLLs) (5). Our group has demonstrated that the loss of miR-15a/16-1 expression induces higher levels of the antiapoptotic proteins BCL2 and myeloid cell leukemia sequence 1 (BCL2-related) (MCL1) (3, 6). Moreover, this deletion promotes mature B-cell expansion by deregulating the transition from G1 to S phase (7).On the other hand, the biological role of miR-15b/16-2 is still controversial, as this cluster has been reported to behave as either a tumor suppressor [acute promyelocytic leukemia (8, 9) and osteosarcoma (10)] or an oncogene [melanoma (11), up-regulated in the plasma of colorectal cancer (12) and head and neck carcinoma (13)].Because the miR-15a/16-1 and miR-15b/16-2 clusters share miRNAs that are highly similar or, in the case of miR-16, identical, it is possible that they control a similar set of target genes and have overlapping functions.To better characterize the role of miR-15b/16-2 in tumorigenesis and tumor progression, we generated a conventional miR-15b/16-2 knockout mouse model. By the age of 15–18 mo, miR-15b/16-2 knockout mice developed lymphoproliferative disorders closely resembling human B-CLL, with diffuse lymph node enlargement and severe splenomegaly due to the expansion of a CD19+ CD5+ double positive population of neoplastic B cells.