Inhibitors of mutant isocitrate dehydrogenase (mIDH) 1 and 2 cancer-associated enzymes prevent the accumulation of the oncometabolite d-2-hydroxyglutarate (2-HG) and are under clinical investigation ...for the treatment of several cancers harboring an IDH mutation. Herein, we describe the discovery of vorasidenib (AG-881), a potent, oral, brain-penetrant dual inhibitor of both mIDH1 and mIDH2. X-ray cocrystal structures allowed us to characterize the compound binding site, leading to an understanding of the dual mutant inhibition. Furthermore, vorasidenib penetrates the brain of several preclinical species and inhibits 2-HG production in glioma tissue by >97% in an orthotopic glioma mouse model. Vorasidenib represents a novel dual mIDH1/2 inhibitor and is currently in clinical development for the treatment of low-grade mIDH glioma.
A number of human cancers harbor somatic point mutations in the genes encoding isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2). These mutations alter residues in the enzyme active sites and confer ...a gain-of-function in cancer cells, resulting in the accumulation and secretion of the oncometabolite (R)-2-hydroxyglutarate (2HG). We developed a small molecule, AGI-6780, that potently and selectively inhibits the tumor-associated mutant IDH2/R140Q. A crystal structure of AGI-6780 complexed with IDH2/R140Q revealed that the inhibitor binds in an allosteric manner at the dimer interface. The results of steady-state enzymology analysis were consistent with allostery and slow-tight binding by AGI-6780. Treatment with AGI-6780 induced differentiation of TF-1 erythroleukemia and primary human acute myelogenous leukemia cells in vitro. These data provide proof-of-concept that inhibitors targeting mutant IDH2/R140Q could have potential applications as a differentiation therapy for cancer.
The clinical significance of magnetic resonance imaging (MRI) changes after radiation therapy (RT) in children with ependymoma is not well defined. We compared imaging changes following proton beam ...radiation therapy (PBRT) to those after photon-based intensity modulated RT (IMRT).
Seventy-two patients with nonmetastatic intracranial ependymoma who received postoperative RT (37 PBRT, 35 IMRT) were analyzed retrospectively. MRI images were reviewed by 2 neuroradiologists.
Sixteen PBRT patients (43%) developed postradiation MRI changes at 3.8 months (median) with resolution by 6.1 months. Six IMRT patients (17%) developed changes at 5.3 months (median) with 8.3 months to resolution. Mean age at radiation was 4.4 and 6.9 years for PBRT and IMRT, respectively (P = .06). Age at diagnosis (>3 years) and time of radiation (≥3 years) was associated with fewer imaging changes on univariate analysis (odds ratio OR: 0.35, P = .048; OR: 0.36, P = .05). PBRT (compared to IMRT) was associated with more frequent imaging changes, both on univariate (OR: 3.68, P = .019) and multivariate (OR: 3.89, P = .024) analyses. Seven (3 IMRT, 4 PBRT) of 22 patients with changes had symptoms requiring intervention. Most patients were treated with steroids; some PBRT patients also received bevacizumab and hyperbaric oxygen therapy. None of the IMRT patients had lasting deficits, but 2 patients died from recurrent disease. Three PBRT patients had persistent neurological deficits, and 1 child died secondarily to complications from radiation necrosis.
Postradiation MRI changes are more common with PBRT and in patients less than 3 years of age at diagnosis and treatment. It is difficult to predict causes for development of imaging changes that progress to clinical significance. These changes are usually self-limiting, but some require medical intervention, especially those involving the brainstem.
Controlled alignment of long DNA nanofibers is challenging. This communication reports a method to align human genomic DNA with nearly unlimited length using lithographically produced micro-patterns ...of self-assembled monolayers (SAMs) with positively charged terminal groups. The micro-patterns act as local DNA reservoirs to supply DNAs for nanofiber formation, and can also stretch and align DNA nanofibers to form an ordered array by controlling the dewetting profile. By reducing the size and inter-patch distance of a micro-patch, a nearly uniform array of long DNA nanofibers can be patterned over a large area. A controlled motion of a DNA containing droplet allows for free patterning of DNA nanofibers and production of complex structures without a transfer process. Bending of DNA nanofibers due to local distortion of the contact line bridges more adjacent micro-patches and increases the chance of producing continuous nanofibers. The interplay between surface tension and electrostatic attraction of positively charged micro-patterns allows the production of long DNA nanofibers in a simple yet powerful way.
A novel single-layer structured triboelectric generator (TEG) is proposed with a hybrid mix of carbon nanotube (CNT) and silk. Here, the mixing of two materials in liquid phase for proven effective ...power generation is shown. In this research, CNT provides the function of conductivity, whereas silk fibroin forms the main triboelectric generation material that is uniformly mixed with CNT, to achieve a conductive film with superior electric power generation capability. The newly proposed TEG shows very good electrical performance and great potential in simplifying TEG's structure and manufacturing process, enhancing their feasibility in future wearable applications.
The bridging integrator 1 (BIN1) tumor suppressor encodes multiple alternatively spliced isoforms implicated in DNA repair, cell-cycle control, apoptosis and membrane dynamics. BIN1 attenuation has ...been reported in several solid tumors; however, the role of BIN1 in lymphomagenesis remains unexplored. We recently demonstrated that BIN1 transcript levels are significantly downregulated in CD4(+)CD7(-) Sezary cells from patients with Sezary syndrome (SS), a subtype of cutaneous T-cell lymphoma (CTCL). We have now demonstrated that restored BIN1 expression in CTCL cells leads to a significant reduction in cell proliferation, an increase in spontaneous and Fas/Fas ligand (Fas/FasL)-induced apoptosis in vitro and inhibition of tumorigenic activity of CTCL cells in vivo. Interestingly, restoration of BIN1 expression in CTCL cells downregulates the expression of c-FLIP, an important inhibitor of Fas/FasL-mediated apoptosis, and activates the caspase cascade; these phenotypes can be rescued by knockdown of BIN1. Importantly, significantly reduced BIN1 expression and increased c-FLIP expression are observed in primary CTCL patient samples, and high BIN1 and low c-FLIP mRNA levels correlate with better survival rate in SS patients. These results indicate that BIN1 regulates Fas/FasL-mediated apoptosis through c-FLIP and that BIN1 deficiency may have an important role in CTCL pathogenesis by causing apoptosis resistance. Thus BIN1 and c-FLIP represent potential therapeutic targets in CTCL.
Purpose: To study the sensitivity of dose calculation to CT number in Hounsfield units (HU) in three heterogeneity dose correction algorithms. Methods: A set of 24×16×20 cm3 ellipse cylinder phantom ...was created with smooth HU distribution (HU range −810, 1000) in Eclipse treatment planning system. Three heterogeneity dose corrected algorithms, Modified Batho (MB), Batho Power Law (BPL) and Equivalent TAR (eTAR), were applied for dose calculation with 6MV and SAD setup. The dose difference was evaluated by comparing the dose calculated at HU=0 (water) phantom with other HU value phantoms which all had same setup and fixed 100 MU delivered to each one of them for 1) three algorithms, 2) different field size, and 3) different depth. A set of double straight lines, percentage_dose_correction = slope*HU, was calculated based on the least squares error method to best fit the percentage dose correction vs. HU in HU<0 and HU>0 ranges for every algorithm and parameter date set. Results and Conclusion: 1) A straight line fitted very well with every percentage dose correction vs. HU data set (the straight line coefficient of determination: r2>0.995). An over all average slope was −0.021 (standard deviation σ=0.0032) in HU<0 and −0.011 (σ=0.0017) in HU>0 regions. The dose correction showed more sensitive to HU in HU<0 than in HU>0 region. This was caused by the slope difference in HU to electron density conversion curve. 2) As irradiated field size increased, the sensitivity of dose correction to HU decreased in MB. 3) The dose correction sensitivity to HU was proportional to the calculated depth in MB. 4) BPL showed a least dose correction sensitivity to HU comparing with other two algorithms which was nearly 25% lower than MB and eTAB in HU<0 range, and 25% lower than MB and 14% lower than eTAB in HU>0 range.
Isocitrate dehydrogenase-1 (IDH1) R132 mutations occur in glioma, but their physiological significance is unknown. Here we describe the generation and characterization of brain-specific Idh1 R132H ...conditional knock-in (KI) mice. Idh1 mutation results in hemorrhage and perinatal lethality. Surprisingly, intracellular reactive oxygen species (ROS) are attenuated in Idh1-KI brain cells despite an apparent increase in the NADP(+)/NADPH ratio. Idh1-KI cells also show high levels of D-2-hydroxyglutarate (D2HG) that are associated with inhibited prolyl-hydroxylation of hypoxia-inducible transcription factor-1α (Hif1α) and up-regulated Hif1α target gene transcription. Intriguingly, D2HG also blocks prolyl-hydroxylation of collagen, causing a defect in collagen protein maturation. An endoplasmic reticulum (ER) stress response induced by the accumulation of immature collagens may account for the embryonic lethality of these mutants. Importantly, D2HG-mediated impairment of collagen maturation also led to basement membrane (BM) aberrations that could play a part in glioma progression. Our study presents strong in vivo evidence that the D2HG produced by the mutant Idh1 enzyme is responsible for the above effects.
Liquid-liquid phase separation (LLPS) represents a major physiochemical principle to organize intracellular membrane-less structures. Studies with non-segmented negative-sense (NNS) RNA viruses have ...uncovered a key role of LLPS in the formation of viral inclusion bodies (IBs), sites of viral protein concentration in the cytoplasm of infected cells. These studies further reveal the structural and functional complexity of viral IB factories and provide a foundation for their future research. Herein, we review the literature leading to the discovery of LLPS-driven formation of IBs in NNS RNA virus-infected cells and the identification of viral scaffold components involved, and then outline important questions and challenges for IB assembly and disassembly. We discuss the functional implications of LLPS in the life cycle of NNS RNA viruses and host responses to infection. Finally, we speculate on the potential mechanisms underlying IB maturation, a phenomenon relevant to many human diseases.
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