Orthotopic induction of CH157MN convexity and skull base meningiomas into nude mice using stereotactic surgery and MRI characterization

Meningioma in vivo research is hampered by the difficulty of establishing an easy and reproducible orthotopic model able to mimic the characteristics of a human meningioma. Moreover, leptomeningeal dissemination and high mortality are often associated with such orthotopical models, making them useless for clinical translation studies. An optimized method for inducing meningiomas in nude mice at two different sites is described in this paper and the high reproducibility and low mortality of the models are demonstrated. Skull base meningiomas were induced in the auditory meatus and convexity meningiomas were induced on the brain surface of 23 and 24 nude mice, respectively. Both models led to the development of a mass easily observable by imaging methods. Dynamic contrast enhanced MRI was used as a tool to monitor and characterize the pathology onset and progression. At the end of the study, histology was performed to confirm the neoplastic origin of the diseased mass.

Role of phosphoinositide 3-kinase in the pathogenesis of acute pancreatitis

A large body of experimental and clinical data supports the notion that inflammation in acute pancreatitis has a crucial role in the pathogenesis of local and systemic damage and is a major determinant of clinical severity. Thus, research has recently focused on molecules that can regulate the inflammatory processes, such as phosphoinositide 3-kinases (PI3Ks), a family of lipid and protein kinases involved in intracellular signal transduction. Studies using genetic ablation or pharmacologic inhibitors of different PI3K isoforms, in particular the class I PI3Kδ and PI3Kγ, have contributed to a greater understanding of the roles of these kinases in the modulation of inflammatory and immune responses. Recent data suggest that PI3Ks are also involved in the pathogenesis of acute pancreatitis. Activation of the PI3K signaling pathway, and in particular of the class IB PI3Kγ isoform, has a significant role in those events which are necessary for the initiation of acute pancreatic injury, namely calcium signaling alteration, trypsinogen activation, and nuclear factor-κB transcription. Moreover, PI3Kγ is instrumental in modulating acinar cell apoptosis, and regulating local neutrophil infiltration and systemic inflammatory responses during the course of experimental acute pancreatitis. The availability of PI3K inhibitors selective for specific isoforms may provide new valuable therapeutic strategies to improve the clinical course of this disease. This article presents a brief summary of PI3K structure and function, and highlights recent advances that implicate PI3Ks in the pathogenesis of acute pancreatitis.

The power of microRNAs as diagnostic and prognostic biomarkers in liquid biopsies

In the last decades,progresses in medical oncology have ameliorated the treatment of patients and their outcome.However,further improvements are still necessary,in particular for certain types of tumors such as pancreatic,gastric,and lung cancer as well as acute myeloid leukemia where early detection and monitoring of the disease are crucial for final patient outcome.Liquid biopsy represents a great advance in the field because it is less invasive,less time-consuming,and safer compared to classical biopsies and it can be useful to monitor the evolution of the disease as well as the response of patients to therapy.Liquid biopsy allows the detection of circulating tumor cells,nucleic acids,and exosomes not only in blood but also in different biological fluids:urine,saliva,pleural effusions,cerebrospinal fluid,and stool.Among the potential biomarkers detectable in liquid biopsies,microRNAs(miRNAs)are gaining more and more attention,since they are easily detectable,quite stable in biological fluids,and show high sensitivity.Many data demonstrate that miRNAs alone or in combination with other biomarkers could improve the diagnostic and prognostic power for many different tumors.Despite this,standardization of methods,sample preparation,and analysis remain challenging and a huge effort should be made to address these issues before miRNA biomarkers can enter the clinic.This review summarizes the main findings in the field of circulating miRNAs in both solid and hematological tumors.

Pilot Study on the Intercalibration of a Categorisation System for FAlRer Digital Objects Related to Sensitive Data in the Life Sciences

Sharing sensitive data is a specific challenge for research infrastructures in the field of life sciences.For that reason a toolbox has been developed,providing resources for researchers who wish to share and use sensitive data,to support the workflows for handling these kinds of digital objects.Common and community approved annotations are required to be compliant with FAIR principles(Findability,Accessibility,Interoperability,Reusability).The toolbox makes use of a tagging(categorisation)system,allowing consistent labelling and categorisation of digital objects,in terms relevant to data sharing tasks and activities.A pilot study was performed within the Horizon 2020 project EOSC-Life,in which 2 experts from 6 life sciences research infrastructures were recruited to independently assign tags to the same set of 10 to 25 resources related to sensitive data management and data sharing(in total 110).Summary statistics of agreement and observer variation per research infrastructure are provided.The pilot study has shown that experts were able to attribute tags but in most cases with a considerable observer variation between experts.In the context of CWFR(Canonical Workflow Frameworks for Research),this indicates the necessity for careful definition,evaluation and validation of parameters and processes related to workflow descriptions.The results from this pilot study were used to tackle this issue by revising the categorisation system and providing an updated version.

The dark side of immunotherapy:pancreatic cancer

Since the journal Science deemed cancer immunotherapy as the“breakthrough of the year”in 2014,there has been an explosion of clinical trials involving immunotherapeutic approaches that,in the last decade-thanks also to the renaissance of the immunosurveillance theory(renamed the three Es theory)-have been continuously and successfully developed.In the latest update of the development of the immuno-oncology drug pipeline,published last November by Nature Review Drug Discovery,it was clearly reported that the immunoactive drugs under study almost doubled in just two years.Of the different classes of passive and active immunotherapies,“cell therapy”is the fastest growing.The aim of this review is to discuss the preclinical and clinical studies that have focused on different immuno-oncology approaches applied to pancreatic cancer,which we assign to the“dark side”of immunotherapy,in the sense that it represents one of the solid tumors showing less response to this type of therapeutic strategy.

Citron kinase interacts with LATS2 and inhibits its activity by occluding its hydrophobic phosphorylation motif

The inhibitory effect of large tumor suppressor kinase(LATS1/2)on the activity of the oncoprotein yes-associated protein(YAP)is crucial to maintain tissue homeostasis.Proteomic studies have identified several new regulators of this process.Recently,citron kinase(CIT)was listed as a potential binding candidate of Hippo-related components,suggesting a new connection between CIT and the Hippo pathway.Aside from CITs role in cytokinesis,the molecular crosstalk between CIT and the Hippo pathway is largely unknown.Here,we demonstrate a role for CIT as a scaffold protein Unking LATS2 and YAP.More importantly,CIT interacts with LATS2 to directly suppress LATS2 phosphorylation at the hydrophobic motif—targeted by MST1,leading to LATS2 inactivation and YAP activation.By studying their genetic interactions,we found that Sticky,the CIT homolog in Drosophila melanogaster,functions with Warts to control Drosophila eye development.Together,our study confirms citron kinase as a novel regulator of the Hippo pathway.