Screen for MicroRNA and Drug Interactions in Breast Cancer Cell Lines Points to miR-126 as a Modulator of CDK4/6 and PIK3CA Inhibitors.

Breast cancer (BC) represents the most common cancer in women worldwide. Due to its heterogeneous nature, breast cancer management might benefit from differential treatments toward personalized medicine. Additionally, drug resistance is a common phenomenon.

Loss of miR-204 expression is a key event in melanoma.

Cutaneous melanoma (CM) is a malignancy with increasing occurrence. Its microRNA repertoire has been defined in a number studies, leading to candidates for biological and clinical relevance: miR-200a/b/c, miR-203, miR-205, miR-204, miR-211, miR-23b and miR-26a/b. Our work was aimed to validate the role of these candidate miRNAs in melanoma, using additional patients cohorts and in vitro cultures.

An integrated genomic-transcriptomic approach supports a role for the proto-oncogene BCL3 in atherosclerosis.

Data with border-line statistical significance, copiously generated in genome-wide association studies of coronary artery disease (CAD), could include functionally relevant associations. We propose an integrated genomic and transcriptomic approach for unravelling new potential genetic signatures of atherosclerosis. Fifteen among 91 single nucleotide polymorphisms (SNPs) were first selected for association in a sex- and age-adjusted model by examining 510 patients with CAD and myocardial infarction and 388 subjects with normal coronary arteries (CAD-free) in the replication stages of a genome-wide association study.

Pluripotent stem cell miRNAs and metastasis in invasive breast cancer.

Background: The purpose of this study is to determine whether microRNA for pluripotent stem cells are also expressed in breast cancer and are associated with metastasis and outcome.

Methods: We studied global microRNA profiles during differentiation of human embryonic stem cells (n =26) and in breast cancer patients (n = 33) and human cell lines (n = 35). Using in situ hybridization, we then investigated MIR302 expression in 318 untreated breast cancer patients (test cohort, n = 22 and validation cohort, n = 296).

Next generation analysis of breast cancer genomes for precision medicine.

For many years breast cancer classification has been based on histology and immune-histochemistry. New techniques, more strictly related to cancer biology, partially succeeded in fractionating patients, correlated to survival and better predicted the patient response to therapy. Nowadays, great expectations arise from massive parallel or high throughput next generation sequencing.

Calmodulin expression distinguishes the smooth muscle cell population of human carotid plaque.

Several observations suggest the expansion of a distinct medial smooth muscle cell (SMC) subset in atherosclerosis and restenosis. We characterized the phenotypic features of SMC subsets in cultures derived from human carotid endarterectomy specimens. Specimens comprised an undiseased portion (thin intimal thickening with the underlying media) and a diseased portion (atherosclerotic plaque with the underlying media).

The MDM-2 antagonist nutlin-3 promotes the maturation of acute myeloid leukemic blasts.

The small-molecule inhibitor of murine double minute (MDM-2), Nutlin-3, induced variable apoptosis in primary acute myeloid leukemia (AML) blasts and promoted myeloid maturation of surviving cells, as demonstrated by analysis of CD11b and CD14 surface antigens and by morphologic examination. Although the best-characterized activity of Nutlin-3 is activation of the p53 pathway, Nutlin-3 induced maturation also in one AML sample characterized by p53 deletion, as well as in the p53(-/-) human myeloblastic HL-60 cell line. At the molecular level, the maturational activity of Nutlin-3 in HL-60 cells was accompanied by the induction of E2F1 transcription factor, and it was significantly counteracted by specific gene knockdown with small interfering RNA for E2F1.

TRAIL inhibits osteoclastic differentiation by counteracting RANKL-dependent p27Kip1 accumulation in pre-osteoclast precursors.

Experimental evidences indicate that the TNF family member TNF-related apoptosis inducing ligand (TRAIL) might be involved in modulating osteoclastic differentiation. The ability of recombinant soluble TRAIL to affect bone density in vivo was evaluated by using 4-week-old mice subcutaneously (s.c.

Synergistic cytotoxic activity of recombinant TRAIL plus the non-genotoxic activator of the p53 pathway nutlin-3 in acute myeloid leukemia cells.

To potentiate the response of acute myeloid leukemia (AML) to TRAIL cytotoxicity, we have adopted a strategy of combining nutlin-3, a potent non-genotoxic activator of the p53 pathway, with recombinant TRAIL. The rationale for using such a combination was that deletions and/or mutations of the p53 gene occur in only 5-10% of AML and that TRAIL and nutlin-3 activate the extrinsic and intrinsic pathways of apoptosis, respectively. TRAIL induced a rapid increase of apoptosis when added to OCI M4-type and MOLM M5-type AML cells, carrying a wild-type p53, as well as to NB4 M3-type AML, carrying a mutated p53.

Functional integrity of the p53-mediated apoptotic pathway induced by the nongenotoxic agent nutlin-3 in B-cell chronic lymphocytic leukemia (B-CLL).

Deletions and/or mutations of p53 are relatively rare and late events in the natural history of B-cell chronic lymphocytic leukemia (B-CLL). However, it is unknown whether p53 signaling is functional in B-CLL and if targeted nongenotoxic activation of the p53 pathway by using nutlin-3, a small molecule inhibitor of the p53/MDM2 interaction, is sufficient to kill B-CLL cells. In vitro treatment with nutlin-3 induced a significant cytotoxicity on primary CD19(+) B-CLL cells, but not on normal CD19(+) B lymphocytes, peripheral-blood mononuclear cells, or bone marrow hematopoietic progenitors.

Potential pathogenetic implications of cyclooxygenase-2 overexpression in B chronic lymphoid leukemia cells.

Evidence suggests that cyclooxygenase-2 (COX-2) increases tumorigenic potential by promoting resistance to apoptosis. Because B chronic lymphoid leukemia (B-CLL) cells exhibit a defective apoptotic response, we analyzed CD19(+) B lymphocytes purified from the peripheral blood of B-CLL patients. Microarray analysis showed a variable (up to 38-fold) increase in the steady-state mRNA levels of COX-2 in B-CLL lymphocytes compared with normal CD19(+) B lymphocytes.

Involvement of TRAIL/TRAIL-receptors in human intestinal cell differentiation.

Despite the fact that tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) and its receptors (TRAIL-Rs) are expressed in intestinal mucosa, little is known about the biological role of this system in intestinal cell physiology. The expression of surface TRAIL and TRAIL-R1, -R2, -R3, -R4 were examined by flow cytometry in the immortalized human cell line tsFHI under culture conditions promoting growth or growth arrest and expression of differentiated traits. A progressive increase of surface TRAIL expression paralleled tsFHI differentiation, consistently with immunohistochemistry analysis showing an increase of TRAIL immunostaining along the crypt-villus axis in normal jejuneal mucosa.