Most human cancers develop from stem and progenitor cell populations through the sequential accumulation of various genetic and epigenetic alterations. Cancer stem cells have been identified from medulloblastoma (MB), but a comprehensive understanding of MB stemness, including the interactions between the tumor immune microenvironment and MB stemness, is lacking. Here, we employed a trained stemness index model based on an existent one‐class logistic regression (OCLR) machine‐learning method to score MB samples; we then obtained two stemness indices, a gene expression‐based stemness index (mRNAsi) and a DNA methylation‐based stemness index (mDNAsi), to perform an integrated analysis of MB stemness in a cohort of primary cancer samples (n = 763). We observed an inverse trend between mRNAsi and mDNAsi for MB subgroup and metastatic status. By applying the univariable Cox regression analysis, we found that mRNAsi significantly correlated with overall survival (OS) for all MB patients, whereas mDNAsi had no significant association with OS for all MB patients. In addition, by combining the Lasso‐penalized Cox regression machine‐learning approach with univariate and multivariate Cox regression analyses, we identified a stemness‐related gene expression signature that accurately predicted survival in patients with Sonic hedgehog (SHH) MB. Furthermore, positive correlations between mRNAsi and prognostic copy number aberrations in SHH MB, including MYCN amplifications and GLI2 amplifications, were detected. Analyses of the immune microenvironment revealed unanticipated correlations of MB stemness with infiltrating immune cells. Lastly, using the Connectivity Map, we identified potential drugs targeting the MB stemness signature. Our findings based on stemness indices might advance the development of objective diagnostic tools for quantitating MB stemness and lead to novel biomarkers that predict the survival of patients with MB or the efficacy of strategies targeting MB stem cells.

Background Distinctive from their normal counterparts, cancer cells exhibit unique metabolic dependencies on glutamine to fuel anabolic processes. Specifically, pancreatic ductal adenocarcinoma (PDAC) cells rely on an unconventional metabolic pathway catalyzed by aspartate transaminase 1 (GOT1) to rewire glutamine metabolism and support nicotinamide adenine dinucleotide phosphate (NADPH) production. Thus, the important role of GOT1 in energy metabolism and Reactive Oxygen Species (ROS) balance demonstrates that targeting GOT1 may serve as an important therapeutic target in PDAC. Methods To assay the binding affinity between Aspulvinone O (AO) and GOT1 proteins, the virtual docking, microscale thermophoresis (MST), cellular thermal shift assay (CETSA) and drug affinity responsive target stability (DARTS) methods were employed. GOT1 was silenced in several PDAC cell lines. The level of OCR and ECR were assayed by seahorse. To evaluate the in vivo anti-tumor efficacy of AO, the xenograft model was built in CB17/scid mouse. Results Screening of an in-house natural compound library identified the AO as a novel inhibitor of GOT1 and repressed glutamine metabolism, which sensitizes PDAC cells to oxidative stress and suppresses cell proliferation. Virtual docking analysis suggested that AO could bind to the active site of GOT1 and form obvious hydrophobic interaction with Trp141 together with hydrogen bonds with Thr110 and Ser256. Further in vitro validation, including MST, CETSA and DARTS, further demonstrated the specific combining capacity of AO. We also show that the selective inhibition of GOT1 by AO significantly reduces proliferation of PDAC in vitro and in vivo. Conclusions Taken together, our findings identify AO as a potent bioactive inhibitor of GOT1 and a novel anti-tumour agent for PDAC therapy. Electronic supplementary material The online version of this article (10.1186/s12964-019-0425-4) contains supplementary material, which is available to authorized users.

While halogenated nucleosides are used as common anticancer and antiviral drugs, naturally occurring halogenated nucleosides are rare. Adechlorin (ade) is a 2′‐chloro nucleoside natural product first identified from Actinomadura sp. ATCC 39365. However, the installation of chlorine in the ade biosynthetic pathway remains elusive. Reported herein is a Fe2+‐α‐ketoglutarate halogenase AdeV that can install a chlorine atom at the C2′ position of 2′‐deoxyadenosine monophosphate to afford 2′‐chloro‐2′‐deoxyadenosine monophosphate. Furthermore, 2′,3′‐dideoxyadenosine‐5′‐monophosphate and 2′‐deoxyinosine‐5′‐monophosphate can also be converted, albeit 20‐fold and 2‐fold, respectively, less efficiently relative to the conversion of 2′‐deoxyadenosine monophosphate. AdeV represents the first example of a Fe2+‐α‐ketoglutarate‐dependent halogenase that converts nucleotides into chlorinated analogues.

A bioflocculant produced by B. licheniformis was investigated with regard to a low-cost culture medium and its industrial application. Molasses replaced sucrose as the sole carbon source in bioflocculant fermentation. The optimum low-cost culture medium was determined to be composed of 20 g/L molasses, 0.4 g/L urea, 0.4 g/L NaCl, 0.2 g/L KH2PO4, 1.6 g/L K2HPO4, and 0.2 g/L MgSO4. The bioflocculant from B. licheniformis was then applied to treat sugarcane-neutralizing juice to remove colloids, suspended particles, and coloring matters in a sugar refinery factory. The optimal operation conditions were a bioflocculant dosage of 21 U/mL, pH 7.3 and a heating temperature of 100A degrees C. The color and turbidity of the sugarcane juice reached IU 1267 and IU 206, respectively, after clarification with the bioflocculant; these values were almost the same as those acquired following treatment with polyacrylamide (PAM), the most widely applied flocculant in sugar industries. These results suggest the great potential for use of bioflocculants in the sugar refinery process.Ministry of Science and Technology of the People's Republic of China [2009EG111023]; Fujian Development and Reform Commission [[2010]983]; Shenzhen Key Laboratory of Microbial Genetic Engineerin

Alloying noble metals with non-noble metals enables high activity while reducing the cost of electrocatalysts in fuel cells. However, under fuel cell operating conditions, state-of-the-art oxygen reduction reaction alloy catalysts either feature high atomic percentages of noble metals (>70%) with limited durability or show poor durability when lower percentages of noble metals (<50%) are used. Here we demonstrate a highly-durable alloy catalyst derived by alloying PtPd (<50%) with 3d-transition metals (Cu, Ni or Co) in ternary compositions. The origin of the high durability is probed by in-situ/operando high-energy synchrotron X-ray diffraction coupled with pair distribution function analysis of atomic phase structures and strains, revealing an important role of realloying in the compressively-strained single-phase alloy state despite the occurrence of dealloying. The implication of the finding, a striking departure from previous perceptions of phase-segregated noble metal skin or complete dealloying of non-noble metals, is the fulfilling of the promise of alloy catalysts for mass commercialization of fuel cells.