Therapeutic vulnerability of multiple myeloma to MIR17PTi, a first-in-class inhibitor of pri-mir-17-92

The microRNA cluster miR-17-92 is oncogenic and represents a valuable therapeutic target in c-MYC (MYC)-driven malignancies. Here, we developed novel LNA gapmeR antisense oligonucleotides (ASOs) to induce RNase H-mediated degradation of MIR17HG primary transcripts and, consequently, to prevent biogenesis of miR-17-92 microRNAs (miR-17-92s). The leading LNA-ASO, named MIR17PTi, impaired proliferation of several cancer cell lines (n=48) established from both solid and hematologic tumors by on-target antisense activity, and more effectively as compared to miR-17-92s inhibitors. By focusing on multiple myeloma (MM), we found that MIR17PTi triggers apoptosis via impairment of homeostatic MYC/miR-17-92 feed-forward loops (FFLs) in patient-derived MM cells; and induced MYC-dependent synthetic lethality. We show that alteration of a BIM-centered FFL is instrumental for MIR17PTi to induce cytotoxicity in MM cells. MIR17PTi exerts strong in vivo anti-tumor activity in NOD-SCID mice bearing clinically relevant models of MM, with advantageous safety and pharmacokinetics profiles in non-human primates. Altogether, MIR17PTi is a novel pharmacological tool to be tested in early-phase clinical trials against MM and other MYC-driven malignancies

Drugging the lncRNA MALAT1 via LNA gapmeR ASO inhibits gene expression of proteasome subunits and triggers anti-multiple myeloma activity

The biological role and therapeutic potential of long non-coding RNAs (lncRNAs) in multiple myeloma (MM) are still to be investigated. Here, we studied the functional significance and the druggability of the oncogenic lncRNA MALAT1 in MM. Targeting MALAT1 by novel LNA-gapmeR antisense oligonucleotide antagonized MM cell proliferation and triggered apoptosis both in vitro and in vivo in a murine xenograft model of human MM. Of note, antagonism of MALAT1 downmodulated the two major transcriptional activators of proteasome subunit genes, namely NRF1 and NRF2, and resulted in reduced trypsin, chymotrypsin and caspase-like proteasome activities and in accumulation of polyubiquitinated proteins. NRF1 and NRF2 decrease upon MALAT1 targeting was due to transcriptional activation of their negative regulator KEAP1, and resulted in reduced expression of anti-oxidant genes and increased ROS levels. In turn, NRF1 promoted MALAT1 expression thus establishing a positive feedback loop. Our findings demonstrate a crucial role of MALAT1 in the regulation of the proteasome machinery, and provide proof-of-concept that its targeting is a novel powerful option for the treatment of MM

Selective targeting of IRF4 by synthetic microRNA-125b-5p mimics induces anti-multiple myeloma activity in vitro and in vivo

Interferon regulatory factor 4 (IRF4) is an attractive therapeutic target in multiple myeloma (MM). We here report that expression of IRF4 mRNA inversely correlates with microRNA (miR)-125b in MM patients. Moreover, we provide evidence that miR-125b is downregulated in TC2/3 molecular MM subgroups and in established cell lines. Importantly, constitutive expression of miR-125b-5p by lentiviral vectors or transfection with synthetic mimics impaired growth and survival of MM cells and overcame the protective role of bone marrow stromal cells (BMSCs) in vitro. Apoptotic and autophagy-associated cell death were triggered in MM cells upon miR-125b-5p ectopic expression. Importantly, we found that the anti-MM activity of miR-125b-5p was mediated via direct downregulation of IRF4 and its downstream effector BLIMP-1. Moreover, inhibition of IRF4 translated into downregulation of c-Myc, caspase-10 and cFlip, relevant IRF4-downstream effectors. Finally, in vivo intra-tumor or systemic delivery of formulated miR-125b-5p mimics against human MM xenografts in SCID/NOD mice induced significant anti-tumor activity and prolonged survival. Taken together, our findings provide evidence that miR-125b, differently from other hematologic malignancies, has tumor suppressor activity in MM. Furthermore, our data provide proof-of-concept that synthetic miR-125b-5p mimics are promising anti-MM agents to be validated in early clinical trials

Late-Proterozoic to Paleozoic history of the peri-Gondwana Calabria–Peloritani Terrane inferred from a review of zircon chronology

U–Pb analyses of zircon from ten samples of augen gneisses, eight mafic and intermediate metaigneous rocks and six metasediments from some tectonic domains along the Calabria–Peloritani Terrane (Southern Italy) contribute to knowledge of peri-Gondwanan evolution from Late-Proterozoic to Paleozoic times. All samples were equilibrated under amphibolite to granulite facies metamorphism during the Variscan orogeny. The zircon grains of all considered samples preserve a Proterozoic memory suggestive of detrital, metamorphic and igneous origin. The available data fit a frame involving: (1) Neoproterozoic detrital input from cratonic areas of Gondwana; (2) Pan-African/Cadomian assemblage of blocks derived from East and West African Craton; (3) metamorphism and bimodal magmatism between 535 and 579 Ma, within an active margin setting; (4) rifting and opening of Ordovician basins fed by detrital input from the assembled Cadomian blocks. The Paleozoic basins evolved through sedimentation, metamorphism and magmatism during the Variscan orogeny involving Palaeozoic and pre-Paleozoic blocks. The Proterozoic zircon records decidedly decrease in the high grade metamorphic rocks affected by Variscan pervasive partial melting. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s40064-016-1839-8) contains supplementary material, which is available to authorized users

Laparoscopic right hemicolectomy: a SICE (Società Italiana di Chirurgia Endoscopica e Nuove tecnologie) network prospective study on the approach to right colon lymphadenectomy in Italy: is there a standard?—CoDIG 2 (ColonDx Italian Group)

Background: Colon cancer is a disease with a worldwide spread. Surgery is the best option for the treatment of advanced colon cancer, but some aspects are still debated, such as the extent of lymphadenectomy. In Japanese guidelines, the gold standard was D3 dissection to remove the central lymph nodes (203, 213, and 223), but in 2009, Hoenberger et al. introduced the concept of complete mesocolic excision, in which surgical dissection follows the embryological planes to remove the mesentery entirely to prevent leakage of cancer cells and collect more lymph nodes. Our study describes how lymphadenectomy is currently performed in major Italian centers with an unclear indication on the type of lymphadenectomy that should be performed during right hemicolectomy (RH). Methods: CoDIG 2 is an observational multicenter national study that involves 76 Italian general surgery wards highly specialized in colorectal surgery. Each center was asked not to modify their usual surgical and clinical practices. The aim of the study was to assess the preference of Italian surgeons on the type of lymphadenectomy to perform during RH and the rise of any new trends or modifications in habits compared to the findings of the CoDIG 1 study conducted 4 years ago. Results: A total of 788 patients were enrolled. The most commonly used surgical technique was laparoscopic (82.1%) with intracorporeal (73.4%), side-to-side (98.7%), or isoperistaltic (96.0%) anastomosis. The lymph nodes at the origin of the vessels were harvested in an inferior number of cases (203, 213, and 223: 42.4%, 31.1%, and 20.3%, respectively). A comparison between CoDIG 1 and CoDIG 2 showed a stable trend in surgical techniques and complications, with an increase in the robotic approach (7.7% vs. 12.3%). Conclusions: This analysis shows how lymphadenectomy is performed in Italy to achieve oncological outcomes in RH, although the technique to achieve a higher lymph node count has not yet been standardized. Trial registration (ClinicalTrials.gov) ID: NCT05943951

Contrasting styles of (U)HP rock exhumation along the Cenozoic Adria-Europe plate boundary (Western Alps, Calabria, Corsica)

Since the first discovery of ultrahigh pressure (UHP) rocks 30 years ago in the Western Alps, the mechanisms for exhumation of (U)HP terranes worldwide are still debated. In the western Mediterranean, the presently accepted model of synconvergent exhumation (e.g., the channel-flow model) is in conflict with parts of the geologic record. We synthesize regional geologic data and present alternative exhumation mechanisms that consider the role of divergence within subduction zones. These mechanisms, i.e., (i) the motion of the upper plate away from the trench and (ii) the rollback of the lower plate, are discussed in detail with particular reference to the Cenozoic Adria-Europe plate boundary, and along three different transects (Western Alps, Calabria-Sardinia, and Corsica-Northern Apennines). In the Western Alps, (U)HP rocks were exhumed from the greatest depth at the rear of the accretionary wedge during motion of the upper plate away from the trench. Exhumation was extremely fast, and associated with very low geothermal gradients. In Calabria, HP rocks were exhumed from shallower depths and at lower rates during rollback of the Adriatic plate, with repeated exhumation pulses progressively younging toward the foreland. Both mechanisms were active to create boundary divergence along the Corsica-Northern Apennines transect, where European southeastward subduction was progressively replaced along strike by Adriatic northwestward subduction. The tectonic scenario depicted for the Western Alps trench during Eocene exhumation of (U)HP rocks correlates well with present-day eastern Papua New Guinea, which is presented as a modern analog of the Paleogene Adria-Europe plate boundary

The Use of DInSAR Data for the Analysis of Building Damage Induced by Slow-Moving Landslides

The paper aims at checking the contribution that DInSAR data, processed via different algorithms, can provide to the analysis of damages recorded to buildings located in slow-moving landslide affected areas. For this purpose, an urban area in Calabria region, southern Italy, was selected due to the availability of both DInSAR data since 1992 and historic information concerning damage data recorded via municipal ordinances. The combination of DInSAR data and the results of supplementary damage surveys allowed the preliminary investigation of a cause (maximum velocity)-effect (damage) relationship which, once validated, can be valuably used for damage analysis and forecasting