miR-28-based combination therapy impairs aggressive B cell lymphoma growth by rewiring DNA replication.

Diffuse large B cell lymphoma (DLBCL) is the most common aggressive B cell lymphoma and accounts for nearly 40% of cases of B cell non-Hodgkin lymphoma. DLBCL is generally treated with R-CHOP chemotherapy, but many patients do not respond or relapse after treatment. Here, we analyzed the therapeutic potential of the tumor suppressor microRNA-28 (miR-28) for DLBCL, alone and in combination with the Bruton's tyrosine kinase inhibitor ibrutinib. Combination therapy with miR-28 plus ibrutinib potentiated the anti-tumor effects of monotherapy with either agent by inducing a specific transcriptional cell-cycle arrest program that impairs DNA replication. The molecular actions of miR-28 and ibrutinib synergistically impair DNA replication by simultaneous inhibition of origin activation and fork progression. Moreover, we found that downregulation of the miR-28-plus-ibrutinib gene signature correlates with better survival of ABC-DLBCL patients. These results provide evidence for the effectiveness of a new miRNA-based ibrutinib combination therapy for DLBCL and unveil the miR-28-plus-ibrutinib gene signature as a new predictor of outcome in ABC-DLBCL patients.

Individualisation of radiation protection recommendations for patients treated with [177Lu]Lu-DOTA-TATE.

BACKGROUND: As for any other nuclear medicine treatment, patients treated with [177Lu]Lu-DOTA-TATE should be given some radiation protection recommendations after being discharged to limit the dose received by family members and public. The restriction periods will depend on the remaining activity at the time of discharge, the washout rate and patients' personal conditions. The activity in patients' whole-body follows a bi-exponential behaviour. At the time of discharge only the first part of the time-activity curve is known. However, the second phase of the bi-exponential curve should be known to individualize the time of restrictions. The main purpose of this prospective study was to establish a simple method for calculating the restriction periods based on measurements taken before discharge. METHODS: The whole-body time-activity curve was calculated for 20 patients from dose-rate measurements performed during the first week post-administration. An effective decay time [Formula: see text] was calculated from a mono-exponential fit performed with the 6 h and 24 h measurements and compared with the effective decay time [Formula: see text] obtained from the mono-exponential fit performed with the 24 h, 48 h and 168 h measurements. The differences between them were calculated and the 95th percentile of these differences was used as a correction factor for [Formula: see text]. A modified effective decay [Formula: see text] was obtained by adding the correction factor to [Formula: see text] and the restriction periods for each patient was calculated. The whole body activity washout between the first and the fourth treatment cycles of 16 patients was also compared. RESULTS: The comparison of the whole-body activity curves between the first and the fourth cycle of the treatment for 16 patients would indicate that the recommendations on radiation protection determined from the first cycle could reasonably be used for the remaining cycles in most patients. The values of [Formula: see text] and [Formula: see text] obtained for the 20 patients were significantly different. The 95th percentile of the differences between [Formula: see text] and [Formula: see text] was 46 h, which is thus the time to be added to [Formula: see text] so as to determine the restriction periods. CONCLUSIONS: The proposed method makes it possible to calculate the restriction periods for patients treated with [177Lu]Lu-DOTA-TATE before they leave the hospital in a conservative and individualized way.

microRNA Fine-Tuning of the Germinal Center Response.

Germinal centers (GCs) are complex multicellular structures in which antigen-specific B cells undergo the molecular remodeling that enables the generation of high-affinity antibodies and the differentiation programs that lead to the generation of plasma-antibody-secreting cells and memory B cells. These reactions are tightly controlled by a variety of mechanisms, including the post-transcriptional control of gene expression by microRNAs (miRNAs). Through the development of animal models with B cell-specific modified miRNA expression, we have contributed to the understanding of the role of miRNAs in the regulation of GC responses and in B cell neoplasia. Here, we review recent advances in the understanding of the role of miRNAs in the regulation of B cell and T follicular helper physiology during the GC response and in the diseases associated to GC response dysregulation.

miRNA-Based Therapies in B Cell Non-Hodgkin Lymphoma.

Non-Hodgkin lymphoma (NHL) is a diverse class of hematological cancers, many of which arise from germinal center (GC)-experienced B cells. Thus GCs, the sites of antibody affinity maturation triggered during immune responses, also provide an environment that facilitates B cell oncogenic transformation. miRNAs provide attractive and mechanistically different strategies to treat these malignancies based on their potential for simultaneous modulation of multiple targets. Here, we discuss the scientific rationale for miRNA-based therapeutics in B cell neoplasias and review recent advances that may help establish a basis for novel candidate miRNA-based therapies for B cell-NHL (B-NHL).

Proteasome versus Thioredoxin Reductase Competition as Possible Biological Targets in Antitumor Mixed Thiolate-Dithiocarbamate Gold(III) Complexes.

New mixed gold(III) derivatives with dithiocarbamate and thiolate ligands have been synthesized and characterized. They display high anticancer activity against colon cancer cell lines without affecting to differentiated enterocytes, high stability in phosphate-buffered saline solution, and resistance to gold reduction in the presence of reducing agents in the majority of the derivatives. Some of them show interaction with thioredoxin reductase as derived from in vitro analysis and computational studies. However, a competition between this enzyme and proteasome is detected in cells, which is corroborated by the determination of proteasomal chymotrypsin-like activity inhibition. In addition, some of these dithiocarbamate gold(III) derivatives reduce cell viability and proliferation by intrinsic apoptotic pathway, with changes in mitochondrial membrane potential, cytochrome c release and caspase-3 activation. Consequently, our results show new complexes with proteasome as possible target in colorectal cancer.