For millions of years, endogenous retroelements have remained transcriptionally silent within mammalian genomes by epigenetic mechanisms. Modern anticancer therapies targeting the epigenetic ...machinery awaken retroelement expression, inducing antiviral responses that eliminate tumors through mechanisms not completely understood. Here, we find that massive binding of epigenetically activated retroelements by RIG-I and MDA5 viral sensors promotes ATP hydrolysis and depletes intracellular energy, driving tumor killing independently of immune signaling. Energy depletion boosts compensatory ATP production by switching glycolysis to mitochondrial oxidative phosphorylation, thereby reversing the Warburg effect. However, hyperfunctional succinate dehydrogenase in mitochondrial electron transport chain generates excessive oxidative stress that unleashes RIP1-mediated necroptosis. To maintain ATP generation, hyperactive mitochondrial membrane blocks intrinsic apoptosis by increasing BCL2 dependency. Accordingly, drugs targeting BCL2 family proteins and epigenetic inhibitors yield synergistic responses in multiple cancer types. Thus, epigenetic therapy kills cancer cells by rewiring mitochondrial metabolism upon retroelement activation, which primes mitochondria to apoptosis by BH3-mimetics. SIGNIFICANCE: The state of viral mimicry induced by epigenetic therapies in cancer cells remodels mitochondrial metabolism and drives caspase-independent tumor cell death, which sensitizes to BCL2 inhibitor drugs. This novel mechanism underlies clinical efficacy of hypomethylating agents and venetoclax in acute myeloid leukemia, suggesting similar combination therapies for other incurable cancers.
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According to preliminary data, seroconversion after mRNA SARS‐CoV‐2 vaccination might be unsatisfactory in Kidney Transplant Recipients (KTRs). However, it is unknown if seronegative patients develop ...at least a cellular response that could offer a certain grade of protection against SARS‐CoV‐2. To answer this question, we prospectively studied 148 recipients of either kidney (133) or kidney‐pancreas (15) grafts with assessment of IgM/IgG spike (S) antibodies and ELISpot against the nucleocapside (N) and the S protein at baseline and 2 weeks after receiving the second dose of the mRNA‐1273 (Moderna) vaccine. At baseline, 31 patients (20.9%) had either IgM/IgG or ELISpot positivity and were considered to be SARS‐CoV‐2‐pre‐immunized, while 117 (79.1%) patients had no signs of either cellular or humoral response and were considered SARS‐CoV‐2‐naïve. After vaccination, naïve patients who developed either humoral or cellular response were finally 65.0%, of which 29.9% developed either IgG or IgM and 35.0% S‐ELISpot positivity. Factors associated with vaccine unresponsiveness were diabetes and treatment with antithymocytes globulins during the last year. Side effects were consistent with that of the pivotal trial and no DSAs developed after vaccination. In conclusion, mRNA‐1273 SARS‐CoV‐2 vaccine elicits either cellular or humoral response in almost two thirds of KTRs.
Stable kidney or kidney‐pancreas transplant recipients exhibit lower than expected rates of cellular and humoral responses to the
Non-invasive scoring systems (NSS) are used to identify patients with non-alcoholic fatty liver disease (NAFLD) who are at risk of advanced fibrosis, but their reliability in predicting long-term ...outcomes for hepatic/extrahepatic complications or death and their concordance in cross-sectional and longitudinal risk stratification remain uncertain.
The most common NSS (NFS, FIB-4, BARD, APRI) and the Hepamet fibrosis score (HFS) were assessed in 1,173 European patients with NAFLD from tertiary centres. Performance for fibrosis risk stratification and for the prediction of long-term hepatic/extrahepatic events, hepatocarcinoma (HCC) and overall mortality were evaluated in terms of AUC and Harrell’s c-index. For longitudinal data, NSS-based Cox proportional hazard models were trained on the whole cohort with repeated 5-fold cross-validation, sampling for testing from the 607 patients with all NSS available.
Cross-sectional analysis revealed HFS as the best performer for the identification of significant (F0-1 vs. F2-4, AUC = 0.758) and advanced (F0-2 vs. F3-4, AUC = 0.805) fibrosis, while NFS and FIB-4 showed the best performance for detecting histological cirrhosis (range AUCs 0.85-0.88). Considering longitudinal data (follow-up between 62 and 110 months), NFS and FIB-4 were the best at predicting liver-related events (c-indices>0.7), NFS for HCC (c-index = 0.9 on average), and FIB-4 and HFS for overall mortality (c-indices >0.8). All NSS showed limited performance (c-indices <0.7) for extrahepatic events.
Overall, NFS, HFS and FIB-4 outperformed APRI and BARD for both cross-sectional identification of fibrosis and prediction of long-term outcomes, confirming that they are useful tools for the clinical management of patients with NAFLD at increased risk of fibrosis and liver-related complications or death.
Non-invasive scoring systems are increasingly being used in patients with non-alcoholic fatty liver disease to identify those at risk of advanced fibrosis and hence clinical complications. Herein, we compared various non-invasive scoring systems and identified those that were best at identifying risk, as well as those that were best for the prediction of long-term outcomes, such as liver-related events, liver cancer and death.
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•Different non-invasive scoring systems (NSS) have been proposed to stratify patients according to the risk of advanced fibrosis.•In the cross-sectional analysis, HFS showed the best performance for the identification of advanced fibrosis.•NFS and FIB-4 showed the best performance for the detection of histological cirrhosis.•After a median follow-up of ~7 years, NFS, HFS and FIB-4 performed similarly well for the prediction of HCC and overall mortality.•All NSS had limited performance for extrahepatic events, although those incorporating diabetes performed slightly better.
Tumor extracellular vesicles (EVs) mediate the communication between tumor and stromal cells mostly to the benefit of tumor progression. Notably, tumor EVs travel in the bloodstream, reach distant ...organs, and locally modify the microenvironment. However, visualizing these events in vivo still faces major hurdles. Here, we describe an approach for tracking circulating tumor EVs in a living organism: we combine chemical and genetically encoded probes with the zebrafish embryo as an animal model. We provide a first description of tumor EVs’ hemodynamic behavior and document their intravascular arrest. We show that circulating tumor EVs are rapidly taken up by endothelial cells and blood patrolling macrophages and subsequently stored in degradative compartments. Finally, we demonstrate that tumor EVs activate macrophages and promote metastatic outgrowth. Overall, our study proves the usefulness and prospects of zebrafish embryo to track tumor EVs and dissect their role in metastatic niches formation in vivo.
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•MemBright allows for bright and specific staining of EVs•The zebrafish embryo allows tracking of tumor EVs at high spatiotemporal resolution•Circulating tumor EVs are mostly taken up by endothelial cells and patrolling macrophages•Zebrafish melanoma EVs favor metastatic outgrowth in zebrafish embryos
Tumor extracellular vesicles (EVs) promote tumor progression. However, their behavior in body fluids remains mysterious. Hyenne et al. show that the zebrafish embryo can be used to track and assess the function of circulating tumor EVs in vivo and provide a high-resolution description of their dissemination and uptake.
The historical lack of preclinical models reflecting the genetic heterogeneity of multiple myeloma (MM) hampers the advance of therapeutic discoveries. To circumvent this limitation, we screened mice ...engineered to carry eight MM lesions (NF-κB, KRAS, MYC, TP53, BCL2, cyclin D1, MMSET/NSD2 and c-MAF) combinatorially activated in B lymphocytes following T cell-driven immunization. Fifteen genetically diverse models developed bone marrow (BM) tumors fulfilling MM pathogenesis. Integrative analyses of ∼500 mice and ∼1,000 patients revealed a common MAPK-MYC genetic pathway that accelerated time to progression from precursor states across genetically heterogeneous MM. MYC-dependent time to progression conditioned immune evasion mechanisms that remodeled the BM microenvironment differently. Rapid MYC-driven progressors exhibited a high number of activated/exhausted CD8
T cells with reduced immunosuppressive regulatory T (T
) cells, while late MYC acquisition in slow progressors was associated with lower CD8
T cell infiltration and more abundant T
cells. Single-cell transcriptomics and functional assays defined a high ratio of CD8
T cells versus T
cells as a predictor of response to immune checkpoint blockade (ICB). In clinical series, high CD8
T/T
cell ratios underlie early progression in untreated smoldering MM, and correlated with early relapse in newly diagnosed patients with MM under Len/Dex therapy. In ICB-refractory MM models, increasing CD8
T cell cytotoxicity or depleting T
cells reversed immunotherapy resistance and yielded prolonged MM control. Our experimental models enable the correlation of MM genetic and immunological traits with preclinical therapy responses, which may inform the next-generation immunotherapy trials.
Trade policy and negotiations have lain at the heart of the Brexit process. Initial UK trade policy has been characterised by: (1) the need to limit the impact of changes in trading relations (mainly ...with the EU) to minimise challenges for businesses and the possibility of economic losses; (2) a strong ideological commitment to free trade, and related to that; (3) symbolic and 'placebo' actions designed to show that the UK can enact an independent trade policy. Negotiation of free trade agreements (FTAs), thus, became a priority of trade policy. This article explores how approaches to FTAs have evolved, focusing specifically on post-Brexit FTAs with Australasia. Overall, the desire to complete speedy agreements has at times trumped business and societal interests, and precluded the development of a coherent long-term UK FTA vision, revealing the symbolic motivation of being seen as 'delivering Brexit' behind the initial years of post-Brexit trade policy.
Chitosan-based nanocarriers have become one of the most intensively studied transmucosal nanometric drug delivery platforms. This is due to a number of factors, including their simple and mild ...preparation technique as well as their capacity to associate macromolecules and facilitate their transport across mucosal barriers. In this review, we first describe our contribution to the origin of chitosan nanocarriers in the mid 90s, and summarize the early work that has impacted the development of this delivery technology. Secondly, we present our perspective regarding the potential of chitosan nanocarriers for some relevant applications: (i) vaccination, (ii) transmucosal protein delivery and (iii) gene therapy. Finally, we offer our perspective on the plausible advances in this area in the near future.
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Edging closer towards developing air and moisture compatible polar organometallic chemistry, the chemoselective and ultrafast addition of a range of aryllithium reagents to nitriles has been ...accomplished by using glycerol as a solvent, at ambient temperature in the presence of air, establishing a novel sustainable access to aromatic ketones. Addition reactions occur heterogeneously (“on glycerol conditions”), where the lack of solubility of the nitriles in glycerol and the ability of the latter to form strong intermolecular hydrogen bonds seem key to favouring nucleophilic addition over competitive hydrolysis. Remarkably, PhLi exhibits a greater resistance to hydrolysis working “on glycerol” conditions than “on water”. Introducing glycerol as a new solvent in organolithium chemistry unlocks a myriad of opportunities for developing more sustainable, air and moisture tolerant main‐group‐metal‐mediated organic synthesis.
Hooked on glycerol! Using glycerol as a sustainable and green reaction medium enables the efficient chemoselective addition of aryllithium reagents to nitriles at room temperature in air, edging closer towards reaching air and moisture compatible polar organometallic chemistry.
-Single-spanning SARS-CoV-2 envelope (E) protein topology is a major determinant of protein quaternary structure and function.-Charged residues distribution in E protein sequences from highly ...pathogenic human coronaviruses (i.e., SARS-CoV, MERS-CoV and SARS-CoV-2) stabilize Ntout-Ctin membrane topology.-E protein sequence could have evolved to ensure a more robust membrane topology from MERS-CoV to SARS-CoV and SARS-CoV-2.
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In a previous work, it was shown that bicarbonate (one of the most important factors causing Fe chlorosis in Strategy I plants) can limit the expression of several genes involved in Fe acquisition. ...Hypoxia is considered another important factor causing Fe chlorosis, mainly on calcareous soils. However, to date it is not known whether hypoxia aggravates Fe chlorosis by affecting bicarbonate concentration or by specific negative effects on Fe acquisition. Results found in this work show that hypoxia, generated by eliminating the aeration of the nutrient solution, can limit the expression of several Fe acquisition genes in Fe‐deficient Arabidopsis, cucumber and pea plants, like the genes for ferric reductases AtFRO2, PsFRO1 and CsFRO1; iron transporters AtIRT1, PsRIT1 and CsIRT1; H+‐ATPase CsHA1; and transcription factors AtFIT, AtbHLH38, and AtbHLH39. Interestingly, the limitation of the expression of Fe‐acquisition genes by hypoxia did not occur in the Arabidopsis ethylene constitutive mutant ctr1, which suggests that the negative effect of hypoxia is related to ethylene, an hormone involved in the upregulation of Fe acquisition genes. As for hypoxia, results obtained by applying bicarbonate to the nutrient solution suggests that ethylene is also involved in its negative effect, since ACC (1‐aminocyclopropane‐1‐carboxylic acid; ethylene precursor) partially reversed the negative effect of bicarbonate on the expression of Fe acquisition genes. Taken together, the results obtained show that hypoxia and bicarbonate could induce Fe chlorosis by limiting the expression of Fe acquisition genes, probably because each factor negatively affects different steps of ethylene synthesis and/or signaling.
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