Dual PI3K/mTOR inhibition is required to effectively impair microenvironment survival signals in mantle cell lymphoma

Phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway activation contributes to mantle cell lymphoma (MCL) pathogenesis and drug resistance. Antitumor activity has been observed with mTOR inhibitors. However, they have shown limited clinical efficacy in relation to drug activation of feedback loops. Selective PI3K inhibition or dual PI3K/mTOR catalytic inhibition are different therapeutic approaches developed to achieve effective pathway blockage. Here, we have performed a comparative analysis of the mTOR inhibitor everolimus, the pan-PI3K inhibitor NVP-BKM120 and the dual PI3K/mTOR inhibitor NVP-BEZ235 in primary MCL cells. We found NVP-BEZ235 to be more powerful than everolimus or NVP-BKM120 in PI3K/Akt/mTOR signaling inhibition, indicating that targeting the PI3K/Akt/mTOR pathway at multiple levels is likely to be a more effective strategy for the treatment of MCL than single inhibition of these kinases. Among the three drugs, NVP-BEZ235 induced the highest change in gene expression profile. Functional validation demonstrated that NVP-BEZ235 inhibited angiogenesis, migration and tumor invasiveness in MCL cells. NVP-BEZ235 was the only drug able to block IL4 and IL6/STAT3 signaling which compromise the therapeutic effect of chemotherapy in MCL. Our findings support the use of the dual PI3K/mTOR inhibitor NVP-BEZ235 as a promising approach to interfere with the microenvironment-related processes in MCL

Some Directions for Performance Improvement of Li-Ion Batteries out of Usual Paths

Recent developments at IMN will be shared on several research directions out of usual paths for performance improvement of Li-ion batteries. We will focus on innovative surface modifications of electrode components, new electrode compositions and architectures, and failure mechanism upon cycling by in-depth characterization through coupled advanced spectroscopic techniques. A molecular grafting approach has been proposed as a way to modify the interfacial chemical reactivity of oxide materials, which is detrimental to their long-term energy storage properties as electrodes of Li-ion batteries. Surface derivatization of powder oxide materials such as Li1.2V3O8 and Li(Mn,Ni)2O4 was accomplished by in situ electrografting of a diazonium salt during Li-ion intercalation, leading to a covalently bonded organic multilayer. Charge transfer is not impeded, while electrolyte decomposition is inhibited thus increasing the cycle life and decreasing the self-discharge. Carbon additives of classical porous electrodes occupy a large volume fraction which is lost for charge storage. Redox functionalization of the surface of some carbon additives has been successfully achieved through non-covalent grafting chemistry using multi-redox pyrene molecules synthesized on purpose. Such functionalized carbon additives have been used to increase the stored energy and power of C-coated LFP porous electrodes. Thicker electrodes are needed for higher energy density Li-ion batteries. We evaluate different directions in order to design new innovative electrode architectures for such a purpose. Our grafting chemistry has been further developed to achieve molecular junctions between non-carbon-coated LFP and multiwall carbon nanotubes (MWCNT) using a designed thiophene-based conjugated molecule. The strategy enables original architecturing of the cathode of Li-ion batteries, with the individual MWCNT being electronically nanocontacted at the surface of LFP grains. This advancement leads to much higher specific capacity and better capacity retention for non calendared thick electrodes, for which the electronic wiring of the electroactive material grains is a critical issue. Another direction followed is the use of conducting polymer additives in porous electrodes, which are able to act as both conducting fillers and mechanical reinforcement materials. We have synthesized a new form of lithium doped PANI, the excellent properties of which in terms of specific capacity, stability on cycling and rate capability will be presented. The coating of bare LFP particles with thin layers of this new Li-doped PANI allows surpassing the performance of commercial carbon coated LFP thick electrodes. The role of this PANI additive into millimetric thick electrodes of NMC material will also be discussed. Future developments of higher energy density Si-based Li-ion batteries depend on the mastering of side reactions at the Si anode. We will compare the SEI composition and morphology at the Si surface upon cycling in half cell and full Li-ion cell configurations using a combination of 7Li, 19F MAS NMR, XPS, TOF-SIMS and STEM-EELS. The origin of the much faster aging of Si-based full cells versus half cells and future directions for improvement will be discusse

Working with Indigenous, local and scientific knowledge in assessments of nature and nature's linkages with people

Working with indigenous and local knowledge (ILK) is vital for inclusive assessments of nature and nature's linkages with people. Indigenous peoples' concepts about what constitutes sustainability, for example, differ markedly from dominant sustainability discourses. The Intergovernmental Platform on Biodiversity and Ecosystems Services (IPBES) is promoting dialogue across different knowledge systems globally. In 2017, member states of IPBES adopted an ILK Approach including: procedures for assessments of nature and nature's linkages with people; a participatory mechanism; and institutional arrangements for including indigenous peoples and local communities. We present this Approach and analyse how it supports ILK in IPBES assessments through: respecting rights; supporting care and mutuality; strengthening communities and their knowledge systems; and supporting knowledge exchange. Customary institutions that ensure the integrity of ILK, effective empowering dialogues, and shared governance are among critical capacities that enable inclusion of diverse conceptualizations of sustainability in assessments

Recombinant humanised anti-HER2/neu antibody (Herceptin®) induces cellular death of glioblastomas

Glioblastoma multiforme (GBM) remains the most devastating primary tumour in neuro-oncology. Targeting of the human epithelial receptor type 2 (HER2)-neu receptor by specific antibodies is a recent well-established therapy for breast tumours. Human epithelial receptor type 2/neu is a transmembrane tyrosine/kinase receptor that appears to be important for the regulation of cancer growth. Human epithelial receptor type 2/neu is not expressed in the adult central nervous system, but its expression increases with the degree of astrocytoma anaplasia. The specificity of HER2/neu for tumoral astrocytomas leads us to study in vitro treatment of GBM with anti-HER2/neu antibody. We used human GBM cell lines expressing HER2/neu (A172 express HER2/neu more than U251MG) or not (U87MG) and monoclonal humanised antibody against HER2/neu (Herceptin®). Human epithelial receptor type 2/neu expression was measured by immunohistochemistry and flow cytometry. Direct antibody effect, complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity were evaluated by different cytometric assays. We have shown, for the first time, the ability of anti-HER2/neu antibodies to induce apoptosis and cellular-dependent cytotoxicity of HER2/neu-expressing GBM cell lines. The results decreased from A172 to U251 and were negative for U87MG, in accordance with the decreasing density of HER2/neu receptors

Synergistic anti-tumor activity of acadesine (AICAR) in combination with the anti-CD20monoclonal antibody rituximab in in vivo and in vitro models of mantle cell lymphoma

Mantle cell lymphoma (MCL) is considered one of the most challenging lymphoma, with limited responses to current therapies. Acadesine, a nucleoside analogue has shown antitumoral effects in different preclinical cancer models as well as in a recent phase I/II clinical trial conducted in patients with chronic lymphocytic leukemia. Here we observed that acadesine exerted a selective antitumoral activity in the majority of MCL cell lines and primary MCL samples, independently of adverse cytogenetic factors. Moreover, acadesine was highly synergistic, both in vitro and in vivo, with the anti-CD20 monoclonal antibody rituximab, commonly used in combination therapy for MCL. Gene expression profiling analysis in harvested tumors suggested that acadesine modulates immune response, actin cytoskeleton organization and metal binding, pointing out a substantial impact on metabolic processes by the nucleoside analog. Rituximab also induced changes on metal binding and immune responses.The combination of both drugs enhanced the gene signature corresponding to each single agent, showing an enrichment of genes involved in inflammation, metabolic stress, apoptosis and proliferation. These effects could be important as aberrant apoptotic and proinflammatory pathways play a significant role in the pathogenesis of MCL. In summary, our results suggest that acadesine exerts a cytotoxic effect in MCL in combination with rituximab, by decreasing the proliferative and survival signatures of the disease, thus supporting the clinical examination of this strategy in MCL patients

Neurobiol Aging

GRN mutations are frequent causes of familial frontotemporal degeneration. Although there is no clear consensual threshold, plasma progranulin levels represent an efficient biomarker for predicting GRN mutations when decreased. We evaluated plasma levels to determine whether it could also predict age at onset, clinical phenotype, or disease progression in 160 GRN carriers. Importantly, progranulin levels were influenced by gender, with lower levels in male than in female patients in our study. Although we found no correlation with age at onset or with clinical phenotype, we confirmed that decreased level predicts GRN mutations, even in presymptomatic carriers more than four decades before disease onset. We also provided first evidence for the stability of levels throughout longitudinal trajectory in carriers, over a 4-year time span. Finally, we confirmed that progranulin levels constitute a reliable, cost-effective marker, suitable as a screening tool in patients with familial frontotemporal degeneration, and more broadly in patients without family history or with atypical presentations who are less likely to be referred for molecular diagnosis

Biocultural approaches to pollinator conservation

Pollinators underpin sustainable livelihoods that link ecosystems, spiritual and cultural values, and customary governance systems with indigenous peoples and local communities (IPLC) across the world. Biocultural diversity is a short-hand term for this great variety of people-nature interlinkages that have developed over time in specific ecosystems. Biocultural approaches to conservation explicitly build on the conservation practices inherent in sustaining these livelihoods. We used the Conceptual Framework of the Intergovernmental Platform on Biodiversity and Ecosystem Services to analyse the biocultural approaches to pollinator conservation by indigenous peoples and local communities globally. The analysis identified biocultural approaches to pollinators across all six elements of the Conceptual Framework, with conservation-related practices occurring in sixty countries, in all continents except Antarctica. Practices of IPLC that are significant for biocultural approaches to pollinator conservation can be grouped into three categories: the practice of valuing diversity and fostering biocultural diversity; landscape management practices; and diversified farming systems. Particular IPLCs may use some or all of these practices. Policies that recognise customary tenure over traditional lands, strengthen Indigenous and Community Conserved Areas, promote heritage listing and support diversified farming within a food sovereignty approach, are among several identified that strengthen biocultural approaches to pollinator conservation, and thereby deliver mutual benefits for pollinators and people

The IPBES Conceptual Framework - connecting nature and people

The first public product of the Intergovernmental Platform on Biodiversity and Ecosystem Services (IPBES) is its Conceptual Framework. This conceptual and analytical tool, presented here in detail, will underpin all IPBES functions and provide structure and comparability to the syntheses that IPBES will produce at different spatial scales, on different themes, and in different regions. Salient innovative aspects of the IPBES Conceptual Framework are its transparent and participatory construction process and its explicit consideration of diverse scientific disciplines, stakeholders, and knowledge systems, including indigenous and local knowledge. Because the focus on co-construction of integrative knowledge is shared by an increasing number of initiatives worldwide, this framework should be useful beyond IPBES, for the wider research and knowledge-policy communities working on the links between nature and people, such as natural, social and engineering scientists, policy-makers at different levels, and decision-makers in different sectors of society