MSN8C: A Promising Candidate for Antitumor Applications as a Novel Catalytic Inhibitor of Topoisomerase II.

MSN8C, an analog of mansonone E, has been identified as a novel catalytic inhibitor of human DNA topoisomerase II that induces tumor regression and differs from VP-16(etoposide). Treatment with MSN8C showed significant antiproliferative activity against eleven human tumor cell lines in vitro. It was particularly effective against the HL-60/MX2 cell line, which is resistant to Topo II poisons. The resistance factor (RF) of MSN8C for Topo II in HL-60/MX2 versus HL-60 was 1.7, much lower than that of traditional Topo II poisons. Furthermore, in light of its potent antitumor efficacy and low toxicity, as demonstrated in the A549 tumor xenograft model, MSN8C has been identified as a promising candidate for antitumor applications.

Design and Synthesis of Bouchardatine Derivatives as a Novel AMP-Activated Protein Kinase Activator for the Treatment of Colorectal Cancer.

Metabolic reprogramming is a crucial hallmark of tumorigenesis. Modulating the reprogrammed energy metabolism is an attractive anticancer therapeutic strategy. We previously found a natural product, bouchardatine, modulated aerobic metabolism and inhibited proliferation in the colorectal cancer cell (CRC). Herein, we designed and synthesized a new series of bouchardatine derivatives to discover more potential modulators. We applied the dual-parametric high-content screening (HCS) to evaluate their AMP-activated protein kinase (AMPK) modulation and CRC proliferation inhibition effect simultaneously. And we found their antiproliferation activities were highly correlated to AMPK activation. Among them, 18a was identified with nanomole-level antiproliferation activities against several CRCs. Interestingly, the evaluation found that 18a selectively upregulated oxidative phosphorylation (OXPHOS) and inhibited proliferation by modulating energy metabolism. Additionally, this compound effectively inhibited the RKO xenograft growth along with AMPK activation. In conclusion, our study identified 18a as a promising candidate for CRC treatment and suggested a novel anti-CRC strategy by AMPK activating and OXPHOS upregulating.

The association between sleep duration, quality, and nonalcoholic fatty liver disease: A cross-sectional study.

Sleep can affect nonalcoholic fatty liver disease (NAFLD). We investigated the association between sleep duration, sleep quality, and NAFLD. From January to December 2018, 1,073 patients (age: 37.94 ± 10.88, Body Mass Index (BMI): 22.85 ± 3.27) were enrolled. Pittsburgh Sleep Quality Index Questionnaire and Munich Chronotype Questionnaire were used to assess sleep duration, quality, and habits. Ultrasonography was used to diagnose NAFLD. Multivariate logistic regression models were used to calculate the odds ratio (OR) and 95% confidence interval (CI) of the risk of NAFLD by different types of sleep duration and sleep quality. No significant differences in sleep time, sleep quality, and sleep habits between the NAFLD and the non-NAFLD groups were observed (P > 0.05). There was no correlation between sleep duration and NAFLD in the whole cohort. After adjusting for age, exercise, fasting plasma glucose, and BMI, the group with long sleep duration showed a decreased risk of NAFLD in men (OR = 0.01, 95% CI: 0.001-0.27, P = 0.032). However, in all four adjusted models, no correlation between sleep duration, quality, and NAFLD was found in women. In conclusion, sleep duration was significantly and negatively associated with NAFLD in men but not women. Prospective studies are required to confirm this association.

Imaging ocular water inflow in the mouse with deuterium oxide MRI.

Abnormal intraocular fluid flow or clearance is involved with a variety of eye diseases such as glaucoma and diabetic retinopathy, but measurement of water exchange dynamics in the vitreous and aqueous remain challenging. 2H MRI can be used to image deuterium oxide (D2O) as a tracer, but the signal-to-noise ratio for deuterium is low due to its low concentration, which has hampered its application to imaging the eye. To overcome this challenge, we investigated the feasibility of direct D2O MRI to measure water dynamics in the mouse eye. The balanced steady-state free precession (bSSFP) sequence provided substantially higher signal-to-noise ratio for imaging D2O in fluid compared to standard gradient echo and spin echo sequences. bSSFP allowed dynamic imaging of intraocular water inflow in the mouse with 41 s temporal resolution. The inflow rate in the vitreous was found to be faster than in the aqueous. These studies demonstrate the feasibility of in vivo imaging of water inflow dynamics into the both the vitreous and aqueous in mice, which could be useful in studies of abnormal fluid exchange in rodent models of eye disease.

Predicting the spatio-temporal response of recurrent glioblastoma treated with rhenium-186 labelled nanoliposomes.

Rhenium-186 (186Re) labeled nanoliposome (RNL) therapy for recurrent glioblastoma patients has shown promise to improve outcomes by locally delivering radiation to affected areas. To optimize the delivery of RNL, we have developed a framework to predict patient-specific response to RNL using image-guided mathematical models. Methods: We calibrated a family of reaction-diffusion type models with multi-modality imaging data from ten patients (NCR01906385) to predict the spatio-temporal dynamics of each patient's tumor. The data consisted of longitudinal magnetic resonance imaging (MRI) and single photon emission computed tomography (SPECT) to estimate tumor burden and local RNL activity, respectively. The optimal model from the family was selected and used to predict future growth. A simplified version of the model was used in a leave-one-out analysis to predict the development of an individual patient's tumor, based on cohort parameters. Results: Across the cohort, predictions using patient-specific parameters with the selected model were able to achieve Spearman correlation coefficients (SCC) of 0.98 and 0.93 for tumor volume and total cell number, respectively, when compared to the measured data. Predictions utilizing the leave-one-out method achieved SCCs of 0.89 and 0.88 for volume and total cell number across the population, respectively. Conclusion: We have shown that patient-specific calibrations of a biology-based mathematical model can be used to make early predictions of response to RNL therapy. Furthermore, the leave-one-out framework indicates that radiation doses determined by SPECT can be used to assign model parameters to make predictions directly following the conclusion of RNL treatment. Statement of Significance: This manuscript explores the application of computational models to predict response to radionuclide therapy in glioblastoma. There are few, to our knowledge, examples of mathematical models used in clinical radionuclide therapy. We have tested a family of models to determine the applicability of different radiation coupling terms for response to the localized radiation delivery. We show that with patient-specific parameter estimation, we can make accurate predictions of future glioblastoma response to the treatment. As a comparison, we have shown that population trends in response can be used to forecast growth from the moment the treatment has been delivered.In addition to the high simulation and prediction accuracy our modeling methods have achieved, the evaluation of a family of models has given insight into the response dynamics of radionuclide therapy. These dynamics, while different than we had initially hypothesized, should encourage future imaging studies involving high dosage radiation treatments, with specific emphasis on the local immune and vascular response.

IG1, a Mansonone F Analog, Exhibits Antibacterial Activity against Staphylococcus aureus by Potentially Impairing Cell Wall Synthesis and DNA Replication.

Infection caused by Staphylococcus aureus, especially methicillin-resistant S. aureus (MRSA), is very common in communities and hospitals, which poses a great challenge to human health. Therefore, increasing attention has been paid to finding effective antimicrobial agents. Mansonone F is a natural compound which has an oxaphenalene skeleton and anti-S. aureus activity, but its sources are limited and its synthesis is difficult. Thus, IG1, a C9-substituent mansonone F analog, was assessed for its activity against Staphylococcus aureus and its mechanism of action was investigated. Antimicrobial susceptibility assays showed that IG1 has strong antibacterial activity against S. aureus, including MRSA, with minimum inhibitory concentrations (MICs) ranging from 0.5 to 2 µg/mL, which were very close to those of vancomycin, and these changed little, even with an increase in the amount of the inoculum. To further explore the antibacterial properties of IG1, time-kill experiments were conducted. Compared with vancomycin and moxifloxacin, treatment with different concentrations of IG1 reduced the viability of organisms in a very similar manner and the reduction was not significant, which indicated that IG1 is a potentially strong anti-S. aureus agent. Finally, the antibacterial mechanism was analyzed, with flow cytometric analysis revealing that IG1 treatment resulted in a time-dependent decrease in the DNA content of S. aureus. Transmission electron microscopy (TEM) analysis showed that very few dividing cells could be found and the cell wall was damaged in the field of IG1-treated cells. These results indicate that IG1 is a potential new antibacterial agent against S. aureus, including MRSA.

Circulating metabolites associated with tumor hypoxia and early response to treatment in bevacizumab-refractory glioblastoma after combined bevacizumab and evofosfamide.

Glioblastomas (GBM) are the most common and aggressive form of primary malignant brain tumor in the adult population, and, despite modern therapies, patients often develop recurrent disease, and the disease remains incurable with median survival below 2 years. Resistance to bevacizumab is driven by hypoxia in the tumor and evofosfamide is a hypoxia-activated prodrug, which we tested in a phase 2, dual center (University of Texas Health Science Center in San Antonio and Dana Farber Cancer Institute) clinical trial after bevacizumab failure. Tumor hypoxic volume was quantified by 18F-misonidazole PET. To identify circulating metabolic biomarkers of tumor hypoxia in patients, we used a high-resolution liquid chromatography-mass spectrometry-based approach to profile blood metabolites and their specific enantiomeric forms using untargeted approaches. Moreover, to evaluate early response to treatment, we characterized changes in circulating metabolite levels during treatment with combined bevacizumab and evofosfamide in recurrent GBM after bevacizumab failure. Gamma aminobutyric acid, and glutamic acid as well as its enantiomeric form D-glutamic acid all inversely correlated with tumor hypoxia. Intermediates of the serine synthesis pathway, which is known to be modulated by hypoxia, also correlated with tumor hypoxia (phosphoserine and serine). Moreover, following treatment, lactic acid was modulated by treatment, likely in response to a hypoxia mediated modulation of oxidative vs glycolytic metabolism. In summary, although our results require further validation in larger patients' cohorts, we have identified candidate metabolic biomarkers that could evaluate the extent of tumor hypoxia and predict the benefit of combined bevacizumab and evofosfamide treatment in GBM following bevacizumab failure.

Effects of Grain Refinement and Thermal Aging on Atomic Scale Local Structures of Ultra-Fine Explosives by X-ray Total Scattering.

The atomic scale local structures affect the initiation performance of ultra-fine explosives according to the stimulation results of hot spot formation. However, the experimental characterization of local structures in ultra-fine explosives has been rarely reported, due to the difficulty in application of characterization methods having both high resolution in and small damage to unstable organic explosive materials. In this work, X-ray total scattering was explored to investigate the atomic scale local distortion of two widely applicable ultra-fine explosives, LLM-105 and HNS. The experimental spectra of atomic pair distribution function (PDF) derived from scattering results were fitted by assuming rigid ring structures in molecules. The effects of grain refinement and thermal aging on the atomic scale local structure were investigated, and the changes in both the length of covalent bonds have been identified. Results indicate that by decreasing the particle size of LLM-105 and HNS from hundreds of microns to hundreds of nanometers, the crystal structures remain, whereas the molecular configuration slightly changes and the degree of structural disorder increases. For example, the average length of covalent bonds in LLM-105 reduces from 1.25 Å to 1.15 Å, whereas that in HNS increases from 1.25 Å to 1.30 Å, which is possibly related to the incomplete crystallization process and internal stress. After thermal aging of ultra-fine LLM-105 and HNS, the degree of structural disorder decreases, and the distortion in molecules formed in the synthesis process gradually healed. The average length of covalent bonds in LLM-105 increases from 1.15 Å to 1.27 Å, whereas that in HNS reduces from 1.30 Å to 1.20 Å. The possible reason is that the atomic vibration in the molecule intensifies during the heat aging treatment, and the internal stress was released through changes in molecular configuration, and thus the atomic scale distortion gradually heals. The characterization method and findings in local structures obtained in this work may pave the path to deeply understand the relationship between the defects and performance of ultra-fine explosives.

Discovery of a Novel G-Quadruplex and Histone Deacetylase (HDAC) Dual-Targeting Agent for the Treatment of Triple-Negative Breast Cancer.

The development of triple-negative breast cancer (TNBC) is highly associated with G-quadruplex (G4); thus, targeting G4 is a potential strategy for TNBC therapy. Because concomitant histone deacetylases (HDAC) inhibition could amplify the impact of G4-targeting compounds, we designed and synthesized two novel series of G4/HDAC dual-targeting compounds by connecting the zinc-binding pharmacophore of HDAC inhibitors to the G4-targeting isaindigotone scaffold (1). Among the new compounds, a6 with the potent HDAC inhibitory and G4 stabilizing activity could induce more DNA G4 formation than SAHA and 1 in TNBC cells. Remarkably, a6 caused more G4-related DNA damage and G4-related differentially expressed genes, consistent with its effect on disrupting the cell cycle, invasion, and glycolysis. Furthermore, a6 significantly suppresses the proliferation of various TNBC cells and the MDA-MB-231 xenograft model without evident toxicity. Our study suggests a novel strategy for TNBC therapeutics through dual-targeting HDAC and G4.

Discovery of Quinacrine as a Potent Topo II and Hsp90 Dual-Target Inhibitor, Repurposing for Cancer Therapy.

Topo II and Hsp90 are promising targets. In this study, we first verified the structural similarities between Topo IIα ATPase and Hsp90α N-ATPase. Subsequently, 720 compounds from the Food and Drug Administration (FDA) drug library and kinase library were screened using the malachite green phosphate combination with the Topo II-mediated DNA relaxation and MTT assays. Subsequently, the antimalarial drug quinacrine was found to be a potential dual-target inhibitor of Topo II and Hsp90. Mechanistic studies showed that quinacrine could specifically bind to the Topo IIα ATPase domain and inhibit the activity of Topo IIα ATPase without impacting DNA cleavage. Furthermore, our study revealed that quinacrine could bind Hsp90 N-ATPase and inhibit Hsp90 activity. Significantly, quinacrine has broad antiproliferation activity and remains sensitive to the multidrug-resistant cell line MCF-7/ADR and the atypical drug-resistant tumor cell line HL-60/MX2. Our study identified quinacrine as a potential dual-target inhibitor of Topo II and Hsp90, depending on the ATP-binding domain, positioning it as a hit compound for further structural modification.

Design, Synthesis, and Evaluation of New Sugar-Substituted Imidazole Derivatives as Selective c-MYC Transcription Repressors Targeting the Promoter G-Quadruplex.

c-MYC is a key driver of tumorigenesis. Repressing the transcription of c-MYC by stabilizing the G-quadruplex (G4) structure with small molecules is a potential strategy for cancer therapy. Herein, we designed and synthesized 49 new derivatives by introducing carbohydrates to our previously developed c-MYC G4 ligand 1. Among these compounds, 19a coupled with a d-glucose 1,2-orthoester displayed better c-MYC G4 binding, stabilization, and protein binding disruption abilities than 1. Our further evaluation indicated that 19a blocked c-MYC transcription by targeting the promoter G4, leading to c-MYC-dependent cancer cell death in triple-negative breast cancer cell MDA-MB-231. Also, 19a significantly inhibited tumor growth in the MDA-MB-231 mouse xenograft model accompanied by c-MYC downregulation. Notably, the safety of 19a was dramatically improved compared to 1. Our findings indicated that 19a could become a promising anticancer candidate, which suggested that introducing carbohydrates to improve the G4-targeting and antitumor activity is a feasible option.

A novel HSF1 activator ameliorates non-alcoholic steatohepatitis by stimulating mitochondrial adaptive oxidation.

BACKGROUND AND PURPOSE: Non-alcoholic steatohepatitis (NASH) is the more severe form of metabolic associated fatty liver disease (MAFLD) and no pharmacological treatment as yet been approved. Identification of novel therapeutic targets and their agents is critical to overcome the current inadequacy of drug treatment for NASH. EXPERIMENTAL APPROACH: The correlation between heat shock factor 1 (HSF1) levels and the development of NASH and the target genes of HSF1 in hepatocyte were investigated by chromatin-immunoprecipitation sequencing. The effects and mechanisms of SYSU-3d in alleviating NASH were examined in relevant cell models and mouse models (the Ob/Ob mice, high-fat and high-cholesterol diet and the methionine-choline deficient diet-fed mice). The actions of SYSU-3d in vivo were evaluated. KEY RESULTS: HSF1 is progressively reduced with mitochondrial dysfunction in NASH pathogenesis and activation of this transcription factor by its newly identified activator SYSU-3d effectively inhibited all manifestations of NASH in mice. When activated, the phosphorylated HSF1 (Ser326) translocated to nucleus and bound to the promoter of PPARγ coactivator-1α (PGC-1α) to induce mitochondrial biogenesis. Thus, increasing mitochondrial adaptive oxidation and inhibiting oxidative stress. The deletion of HSF1 and PGC-1α or recovery of HSF1 in HSF1-deficiency cells showed the HSF1/PGC-1α pathway was mainly responsible for the anti-NASH effects of SYSU-3d independent of AMP-activated protein kinase (AMPK). CONCLUSION AND IMPLICATIONS: Activation of HSF1 is a practical therapeutic approach for NASH treatment via the HSF1/PGC-1α/mitochondrial pathway and SYSU-3d can be considered as a potential candidate for the treatment of NASH.

Resting-State Functional Magnetic Resonance Imaging of Interhemispheric Functional Connectivity in Experimental Traumatic Brain Injury.

Although resting-state functional magnetic resonance imaging (rsfMRI) has the potential to offer insights into changes in functional connectivity networks after traumatic brain injury (TBI), there are few studies that examine the effects of moderate TBI for monitoring functional recovery in experimental TBI, and thus the neural correlates of brain recovery from moderate TBI remain incompletely understood. Non-invasive rsfMRI was used to longitudinally investigate changes in interhemispheric functional connectivity (IFC) after a moderate TBI to the unilateral sensorimotor cortex in rats (n = 9) up to 14 days. Independent component analysis of the rsfMRI data was performed. Correlations of rsfMRI sensorimotor networks were made with changes in behavioral scores, lesion volume, and T2- and diffusion-weighted images across time. TBI animals showed less localized rsfMRI patterns in the sensorimotor network compared to sham (n = 6) and normal (n = 5) animals. rsfMRI clusters in the sensorimotor network showed less bilateral symmetry compared to sham and normal animals, indicative of IFC disruption. With time after injury, many of the rsfMRI patterns in the sensorimotor network showed more bilateral symmetry, indicative of IFC recovery. The disrupted IFC in the sensorimotor and subsequent partial recovery showed a positive correlation with changes in behavioral scores. Overall, rsfMRI detected widespread disruption and subsequent recovery of IFC within the sensorimotor networks post-TBI, which correlated with behavioral changes. Therefore, rsfMRI offers the means to probe functional brain reorganization and thus has the potential to serve as an imaging marker to longitudinally stage TBI and monitor for novel treatments.

Gene Network Analysis of Hepatocellular Carcinoma Identifies Modules Associated with Disease Progression, Survival, and Chemo Drug Resistance.

BACKGROUND: Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality worldwide. HCC transcriptome has been extensively studied; however, the progress in disease mechanisms, prognosis, and treatment is still slow. METHODS: A rank-based module-centric workflow was introduced to analyze important modules associated with HCC development, prognosis, and drug resistance. The currently largest HCC cell line RNA-Seq dataset from the LIMORE database was used to construct the reference modules by weighted gene co-expression network analysis. RESULTS: Thirteen reference modules were identified with validated reproducibility. These modules were all associated with specific biological functions. Differentially expressed module analysis revealed the crucial modules during HCC development. Modules and hub genes are indicative of patient survival. Modules can differentiate patients in different HCC stages. Furthermore, drug resistance was revealed by drug-module association analysis. Based on differentially expressed modules and hub genes, six candidate drugs were screened. The hub genes of those modules merit further investigation. CONCLUSION: We proposed a reference module-based analysis of the HCC transcriptome. The identified modules are associated with HCC development, survival, and drug resistance. M3 and M6 may play important roles during HCV to HCC development. M1, M3, M5, and M7 are associated with HCC survival. High M4, high M9, low M1, and low M3 may be associated with dasatinib, doxorubicin, CD532, and simvastatin resistance. Our analysis provides useful information for HCC diagnosis and treatment.

Smart Host-Guest Energetic Material Constructed by Stabilizing Energetic Fuel Hydroxylamine in Lattice Cavity of 2,4,6,8,10,12-Hexanitrohexaazaisowurtzitane Significantly Enhanced the Detonation, Safety, Propulsion, and Combustion Performances.

The host-guest inclusion strategy has become a promising method for developing novel high-energy density materials (HEDMs). The selection of functional guest molecules was a strategic project, as it can not only enhance the detonation performance of host explosives but can also modify some of their suboptimal performances. Here, to improve the propulsion and combustion performances of 2,4,6,8,10,12-hexanitrohexaazaisowurtzitane (HNIW), a novel energetic-energetic host-guest inclusion explosive was obtained by incorporating energetic rocket fuel, hydroxylamine (HA), into the lattice cavities of HNIW. Based on their perfect space matching, the crystallographic density of HNIW-HA was determined to be 2.00 g/cm3 at 296 K, which has reached the gold standard regarding the density of HEDMs. HNIW-HA also showed higher thermal stability (Td = 245.9 °C) and safety (H50 = 16.8 cm) and superior detonation velocity (DV = 9674 m/s) than the ε-HNIW. Additionally, because of the excellent combustion performance of HA, HNIW-HA possessed higher propulsion performances, including combustion speed (SC = 39.5 mg/s), combustion heat (QC = 8661 J/g), and specific impulse (Isp = 276.4 s), than ε-HNIW. Thus, the host-guest inclusion strategy has potential to surpass the limitations of energy density and suboptimal performances of single explosives and become a strategy for developing multipurpose intermolecular explosives.

Gene co-expression analysis identifies modules related to insufficient sleep in humans.

BACKGROUND: Insufficient sleep and circadian rhythm disruption may cause cancer, obesity, cardiovascular disease, and cognitive impairment. The underlying mechanisms need to be elucidated. METHOD: Weighted gene co-expression network analysis (WGCNA) was used to identify co-expressed modules. Connectivity Map tool was used to identify candidate drugs based on top connected genes. R ptestg package was utilized to detected module rhythmicity alteration. A hypergeometric test was used to test the enrichment of insomnia SNP signals in modules. Google Scholar was used to validate the modules and hub genes by literature. RESULTS: We identified a total of 45 co-expressed modules. These modules were stable and preserved. Eight modules were correlated with sleep restriction duration. Module rhythmicity was disrupted in sleep restriction subjects. Hub genes that involve in insufficient sleep also play important roles in sleep disorders. Insomnia GWAS signals were enriched in six modules. Finally, eight drugs associated with sleep disorders were identified. CONCLUSION: Systems biology method was used to identify sleep-related modules, hub genes, and candidate drugs. Module rhythmicity was altered in sleep insufficient subjects. Thiamphenicol, lisuride, timolol, and piretanide are novel candidates for sleep disorders.

9-Bromo-2,3-diethylbenzo[de]chromene-7,8-dione (MSN54): A novel non-intercalative topoisomerase II catalytic inhibitor.

Novel mansonone F derivative MSN54 (9-bromo-2,3-diethylbenzo[de]chromene-7,8-dione) exhibited significant cytotoxicity against twelve human tumor cell lines in vitro, with particularly strong potency against HL-60/MX2 cell line resistant to Topo II poisons. MSN54 was found to have IC50 of 0.69 and 1.43 µM against HL-60 and HL-60/MX2 cells, respectively. The resistance index is 10 times lower than that of the positive control VP-16 (etoposide). Various biological assays confirmed that MSN54 acted as a Topo IIα specific non-intercalative catalytic inhibitor. Furthermore, MSN54 exhibited good antitumor efficacy and low toxicity at a dose of 5 mg/kg in A549 tumor xenograft models. Thus, compound MSN54 is a promising candidate for the development of novel antitumor agents.

An experimental and theoretical study on the growth of plate-like ß-HMX crystals in the hydroxylated interlayer space.

Plate-like ß-HMX crystals are grown in the hydroxylated interlayer space using a crystallization technique combining the cooling crystallization and solvent-antisolvent methods. The obtained crystals have been investigated by X-ray diffraction (XRD), scanning electron microscopy (SEM), and atomic force microscopy (AFM). The experimental results indicate that the most morphologically important face of the plate-like ß-HMX crystals is the (011) face adopting a layer-by-layer growth mode. Meanwhile, molecular dynamics (MD) simulations were performed to study the crystal morphology in HMX crystal growth in the hydroxylated interlayer space based on a modified attachment energy (MAE) model. The calculated results show that the major face is the (011) face and the interaction energies between the crystal face and the hydroxylated interlayer are in the order of (011) > (110) > (020), which agree well with the experimental results above.

Assessment of tumor hypoxia and perfusion in recurrent glioblastoma following bevacizumab failure using MRI and 18F-FMISO PET.

Tumoral hypoxia correlates with worse outcomes in glioblastoma (GBM). While bevacizumab is routinely used to treat recurrent GBM, it may exacerbate hypoxia. Evofosfamide is a hypoxia-targeting prodrug being tested for recurrent GBM. To characterize resistance to bevacizumab and identify those with recurrent GBM who may benefit from evofosfamide, we ascertained MRI features and hypoxia in patients with GBM progression receiving both agents. Thirty-three patients with recurrent GBM refractory to bevacizumab were enrolled. Patients underwent MR and 18F-FMISO PET imaging at baseline and 28 days. Tumor volumes were determined, MRI and 18F-FMISO PET-derived parameters calculated, and Spearman correlations between parameters assessed. Progression-free survival decreased significantly with hypoxic volume [hazard ratio (HR) = 1.67, 95% confidence interval (CI) 1.14 to 2.46, P = 0.009] and increased significantly with time to the maximum value of the residue (Tmax) (HR = 0.54, 95% CI 0.34 to 0.88, P = 0.01). Overall survival decreased significantly with hypoxic volume (HR = 1.71, 95% CI 1.12 to 12.61, p = 0.01), standardized relative cerebral blood volume (srCBV) (HR = 1.61, 95% CI 1.09 to 2.38, p = 0.02), and increased significantly with Tmax (HR = 0.31, 95% CI 0.15 to 0.62, p < 0.001). Decreases in hypoxic volume correlated with longer overall and progression-free survival, and increases correlated with shorter overall and progression-free survival. Hypoxic volume and volume ratio were positively correlated (rs = 0.77, P < 0.0001), as were hypoxia volume and T1 enhancing tumor volume (rs = 0.75, P < 0.0001). Hypoxia is a key biomarker in patients with bevacizumab-refractory GBM. Hypoxia and srCBV were inversely correlated with patient outcomes. These radiographic features may be useful in evaluating treatment and guiding treatment considerations.

New boron nitride monolith phases from high-pressure compression of double-walled boron nitride nanotubes.

Pressure-induced phase transition of boron nitride nanotubes (BNNTs) provides an effective approach to develop new boron nitride nanostructures with more desirable functions than those of carbon nanotubes, owing to the unique polar B-N bonds. However, the synthetic BNNTs usually comprise double- or multi-walls, whose structural evolution under pressure is complicated and remains largely elusive. Here, we unveil the complete phase transition behavior of hexagonal bundles of double-walled (DW) BNNTs of different chirality and diameters under hydrostatic pressures of up to 60 GPa. A series of new monolith phases are obtained from the compressed DW-BNNT bundles, whose structures can be well retained even after releasing the pressure. The bonding characters; electronic, optical, and mechanical properties; and Raman signature of these monolith phases are elucidated, which provide essential guidance for synthesis of new boron nitride materials with unprecedented properties for technological applications.