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Radiotherapy (RT) is one of the primary treatments of head and neck squamous cell carcinoma (HNSCC), which has a high-risk of locoregional failure (LRF). Presently, there is no reliable predictive biomarker of radioresistance in HNSCC. Here, we found that mutations in NFE2L2, which encodes Nrf2, are associated with a significantly higher rate of LRF in patients with oral cavity cancer treated with surgery and adjuvant (chemo)radiotherapy but not in those treated with surgery alone. Somatic mutation of NFE2L2 led to Nrf2 activation and radioresistance in HNSCC cells. Tumors harboring mutant Nrf2E79Q were substantially more radioresistant than tumors with wild-type Nrf2 in immunocompetent mice, whereas the difference was diminished in immunocompromised mice. Nrf2E79Q enhanced radioresistance through increased recruitment of intratumoral polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) and reduction of M1-polarized macrophages. Treatment with the glutaminase inhibitor CB-839 overcame the radioresistance induced by Nrf2E79Q or Nrf2E79K. RT increased expression of PMN-MDSC–attracting chemokines, including CXCL1, CXLC3, and CSF3, in Nrf2E79Q-expressing tumors via the TLR4, which could be reversed by CB-839. This study provides insights into the impact of NFE2L2 mutations on radioresistance and suggests that CB-839 can increase radiosensitivity by switching intratumoral myeloid cells to an antitumor phenotype, supporting clinical testing of CB-839 with RT in HNSCC with NFE2L2 mutations.Significance:NFE2L2 mutations are predictive biomarkers of radioresistance in head and neck cancer and confer sensitivity to glutaminase inhibitors to overcome radioresistance.

N-doped reduced graphene oxide quantum dots (N-rGQDs) have attracted more and more attention in efficient catalytic degradation of aqueous organic pollutants. However, the synthesis of N-rGQDs is generally a complex and high energy required process for the reduction and N-doping steps. In this study, a facile and green fabrication approach of N-rGQDs is established, based on a metal-free Fenton reaction without additional energy-input. The N structures of N-rGQDs play a significant role in the promotion of their catalytic performance. The N-rGQDs with relatively high percentage of aromatic nitrogen (NAr-rGQDs) perform excellent catalytic activities, with which the degradation efficiency of pollutant is enhanced by 25 times. Density functional theory (DFT) calculation also indicates aromatic nitrogen structures with electron-rich sites are prone to transfer electron, presenting a key role in the catalytic reaction. This metal-free Fenton process provides a green and cost-effective strategy for one-step fabrication of N-rGQDs with controllable features and potential environmental catalytic applications.

The relationship between NFE2L2 mutation and radiation resistance in OC cancer. Kaplan-Meier analysis of PFS and OSin OC patients treated with surgery and postoperative (chemo)radiotherapy.

PDF file, 145K, Alda-89 does not promote cell proliferation in different HNC cell lines.

CB-839 overcomes the Nrf2E79Q-induced radiation resistance through regulating TLR4-mediated cytokine changes.

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Mutational landscape and details of NFE2L2 gene mutation in a cohort of oral cavity cancer patients treated with surgery and postoperative (chemo)radiotherapy at Stanford University.

Nrf2 mutation leads to extrinsic radiation resistance through recruitment of PMN-MDSC in tumors.

Purpose: To assess aldehyde dehydrogenase (ALDH) expression in adult human and murine submandibular gland (SMG) stem cells and to determine the effect of ALDH3 activation in SMG stem cell enrichment.Experimental Design: Adult human and murine SMG stem cells were selected by cell surface markers (CD34 for human and c-Kit for mouse) and characterized for various other stem cell surface markers by flow cytometry and ALDH isozymes expression by quantitative reverse transcriptase PCR. Sphere formation and bromodeoxyuridine (BrdUrd) incorporation assays were used on selected cells to confirm their renewal capacity and three-dimensional (3D) collagen matrix culture was applied to observe differentiation. To determine whether ALDH3 activation would increase stem cell yield, adult mice were infused with a novel ALDH3 activator (Alda-89) or with vehicle followed by quantification of c-Kit+/CD90+ SMG stem cells and BrdUrd+ salispheres.Results: More than 99% of CD34+ huSMG stem cells stained positive for c-Kit, CD90 and 70% colocalized with CD44, Nestin. Similarly, 73.8% c-Kit+ mSMG stem cells colocalized with Sca-1, whereas 80.7% with CD90. Functionally, these cells formed BrdUrd+ salispheres, which differentiated into acinar- and ductal-like structures when cultured in 3D collagen. Both adult human and murine SMG stem cells showed higher expression of ALDH3 than in their non–stem cells and 84% of these cells have measurable ALDH1 activity. Alda-89 infusion in adult mice significantly increased c-Kit+/CD90+ SMG population and BrdUrd+ sphere formation compared with control.Conclusion: This is the first study to characterize expression of different ALDH isozymes in SMG stem cells. In vivo activation of ALDH3 can increase SMG stem cell yield, thus providing a novel means for SMG stem cell enrichment for future stem cell therapy. Clin Cancer Res; 17(23); 7265–72. ©2011 AACR.

Purpose: To determine the effect of Alda-89 (an ALDH3 activitor) on (i) the function of irradiated (radiotherapy) submandibular gland (SMG) in mice, (ii) its toxicity profile, and (iii) its effect on the growth of head and neck cancer (HNC) in vitro and in vivo.Experimental Design: Adult mice were infused with Alda-89 or vehicle before, during, and after radiotherapy. Saliva secretion was monitored weekly. Hematology, metabolic profile, and postmortem evaluation for toxicity were examined at the time of sacrifice. Alda-89 or vehicle was applied to HNC cell lines in vitro, and severe combined immunodeficient (SCID) mice transplanted with HNC in vivo with or without radiation; HNC growth was monitored. The ALDH3A1 and ALDH3A2 protein expression was evaluated in 89 patients with HNC and correlated to freedom from relapse (FFR) and overall survival (OS).Results: Alda-89 infusion significantly resulted in more whole saliva production and a higher percentage of preserved acini after radiotherapy compared with vehicle control. There was no difference in the complete blood count, metabolic profile, and major organ morphology between the Alda-89 and vehicle groups. Compared with vehicle control, Alda-89 treatment neither accelerated HNC cell proliferation in vitro, nor did it affect tumor growth in vivo with or without radiotherapy. Higher expression of ALDH3A1 or ALDH3A2 was not significantly associated with worse FFR or OS in either human papillomavirus (HPV)-positive or HPV-negative group.Conclusion: Alda-89 preserves salivary function after radiotherapy without affecting HNC growth or causing measurable toxicity in mice. It is a promising candidate to mitigate radiotherapy-related xerostomia. Clin Cancer Res; 19(16); 4455–64. ©2013 AACR.

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Supplemental Table 1 shows patients distribution in OC cohorts from Stanford University. Supplemental Table 2 shows primers for mutagenesis. Supplemental Table 3 shows primers for real-time PCR. Supplemental Table 4 shows gene mutations identified by targeted next generation sequencing in a cohort of oral cavity cancer patients treated with surgery and postoperative (chemo)radiotherapy at Stanford University. Supplemental Table 5 shows tumor growth delay of indicated MOC1 xenografts using 1000mm3 tumor size as a proxy.

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PDF file, 89K, Low dose of Alda-89 does not protect SMG Function after RT.

Purpose: Hepatocyte growth factor (HGF) is a hypoxia-induced secreted protein that binds to cMet and regulates interleukin (IL)-8 expression. We evaluated the role of circulating HGF and IL-8 as prognostic and predictive factors for efficacy of tirapazamine (TPZ), a hypoxic cell cytotoxin.Experimental Design: Patients with stages III to IV head and neck cancer were randomized to receive radiotherapy with cisplatin (CIS) or CIS plus TPZ (TPZ/CIS). Eligibility for the substudy included plasma sample availability for HGF and IL-8 assay by ELISA and no major radiation deviations (N = 498). Analyses included adjustment for major prognostic factors. p16INK4A staining (human papillomavirus surrogate) was carried out on available tumors. Thirty-nine patients had hypoxia imaging with 18F-fluoroazomycin arabinoside (18FAZA)–positron emission tomography.Results: Elevated IL-8 level was associated with worse overall survival (OS) irrespective of treatment. There was an interaction between HGF and treatment arm (P = 0.053); elevated HGF was associated with worse OS in the control but not in the TPZ/CIS arm. Similar trends were observed in analyses restricted to p16INK4A-negative patients. Four subgroups defined by high and low HGF/IL-8 levels were examined for TPZ effect; the test for interaction with arm was P = 0.099. TPZ/CIS seemed to be beneficial for patients with high HGF and IL-8 but adverse for low HGF and high IL-8. Only HGF correlated with 18FAZA tumor standard uptake value.Conclusions: IL-8 is an independent prognostic factor irrespective of treatment. There is an interaction between HGF and treatment arm. Certain subgroups based on IL-8/HGF levels seemed to do better with TPZ/CIS while others did worse, highlighting the complexity of hypoxia targeting in unselected patients. Clin Cancer Res; 18(6); 1798–807. ©2012 AACR.

Radiotherapy (RT) is one of the primary treatments of head and neck squamous cell carcinoma (HNSCC), which has a high-risk of locoregional failure (LRF). Presently, there is no reliable predictive biomarker of radioresistance in HNSCC. Here, we found that mutations in NFE2L2, which encodes Nrf2, are associated with a significantly higher rate of LRF in patients with oral cavity cancer treated with surgery and adjuvant (chemo)radiotherapy but not in those treated with surgery alone. Somatic mutation of NFE2L2 led to Nrf2 activation and radioresistance in HNSCC cells. Tumors harboring mutant Nrf2E79Q were substantially more radioresistant than tumors with wild-type Nrf2 in immunocompetent mice, whereas the difference was diminished in immunocompromised mice. Nrf2E79Q enhanced radioresistance through increased recruitment of intratumoral polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) and reduction of M1-polarized macrophages. Treatment with the glutaminase inhibitor CB-839 overcame the radioresistance induced by Nrf2E79Q or Nrf2E79K. RT increased expression of PMN-MDSC–attracting chemokines, including CXCL1, CXLC3, and CSF3, in Nrf2E79Q-expressing tumors via the TLR4, which could be reversed by CB-839. This study provides insights into the impact of NFE2L2 mutations on radioresistance and suggests that CB-839 can increase radiosensitivity by switching intratumoral myeloid cells to an antitumor phenotype, supporting clinical testing of CB-839 with RT in HNSCC with NFE2L2 mutations.Significance:NFE2L2 mutations are predictive biomarkers of radioresistance in head and neck cancer and confer sensitivity to glutaminase inhibitors to overcome radioresistance.

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CB-839 overcomes RT resistance in Nrf2E79Q MOC1 cells through regulating the tumor microenvironment.

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Somatic mutation of NFE2L2 leads to Nrf2 activation and promotes intrinsic radiation resistance in human head and neck squamous cell carcinoma (HNSCC).

NFE2L2 mutation leads to extrinsic radiation resistance.

Supplementary Legends for Figures 1-5 from Tumor Galectin-1 Mediates Tumor Growth and Metastasis through Regulation of T-Cell Apoptosis

Supplementary Figure 3 from Tumor Galectin-1 Mediates Tumor Growth and Metastasis through Regulation of T-Cell Apoptosis

Supplementary Figure 1 from Tumor Galectin-1 Mediates Tumor Growth and Metastasis through Regulation of T-Cell Apoptosis

Supplementary Figure 5 from Tumor Galectin-1 Mediates Tumor Growth and Metastasis through Regulation of T-Cell Apoptosis

Hydroxyl radical-dominated oxidation in catalytic ozonation is, in particular, important in water treatment scenarios for removing organic contaminants, but the mechanism about ozone-based radical oxidation processes is still unclear. Here, we prepared a series of transitional metal (Co, Mn, Ni) single-atom catalysts (SACs) anchored on graphitic carbon nitride to accelerate ozone decomposition and produce highly reactive ·OH for oxidative destruction of a water pollutant, oxalic acid (OA). We experimentally observed that, depending on the metal type, OA oxidation occurred dominantly either in the bulk phase, which was the case for the Mn catalyst, or via a combination of the bulk phase and surface reaction, which was the case for the Co catalyst. We further performed density functional theory simulations and in situ X-ray absorption spectroscopy to propose that the ozone activation pathway differs depending on the oxygen binding energy of metal, primarily due to differential adsorption of O

Photoinduced interfacial release of volatile organic compounds (VOCs) from surfactants receives emerging concerns. Here, we investigate the photoreaction of 1-nonanol (NOL) as a model surfactant at the air-water interface, especially for the important role of 1O2 in the formation of VOCs. The production of VOCs is real-time quantitated. The results indicate that the oxygen content apparently affects the total yields of VOCs during the photoreaction of interfacial NOL. The photoactivity of NOL is about 8 times higher under air than that under nitrogen, which is mainly attributed to the generation of 1O2. Additionally, the production of VOCs increased by about 4 times with the existence of the air-water interface. Quenching experiments of 1O2 also illustrate the contribution of 1O2 to VOC formation, which could reach more than 95% during photoirradiation of NOL. Furthermore, density functional theory calculations show that 1O2 generated via energy transfer of photosensitizers can abstract two hydrogen atoms from a fatty alcohol molecule. The energy barrier of this reaction is 72.3 kJ/mol, and its reaction rate coefficient is about 2.742 s-1 M-1. 1O2 significantly promotes photoinduced oxidation of fatty alcohols and VOC formation through hydrogen abstraction, which provides a new insight into the interfacial photoreaction.

Spent lithium-ion battery recycling has attracted significant attention because of its importance in regard to the environment and resource importance. Traditional hydrometallurgical methods usually leach all valuable metals and subsequently extract target meals to prepare corresponding materials. However, Li recovery in these processes requires lengthy operational procedures, and the recovery efficiency is low. In this research, we demonstrate a method to selectively recover lithium before the leaching of other elements by introducing a hydrothermal treatment. Approximately 90% of Li is leached from high-Ni layered oxide cathode powders, while consuming a nearly stoichiometric amount of hydrogen ions. With this selective recovery of Li, the transition metals remain as solid residue hydroxides or oxides. Furthermore, the extraction of Li is found to be highly dependent on the content of transition metals in the cathode materials. A high leaching selectivity of Li (> 98%) and nearly 95% leaching efficiency of Li can be reached with LiNi0.8Co0.1Mn0.1O2. In this case, both the energy and material consumption during the proposed Li recovery is significantly decreased compared to traditional methods; furthermore, the proposed method makes full use of H+ to leach Li+. This research is expected to provide new understanding for selectively recovering metal from secondary resources.

The use of zero-valent iron (ZVI) to enhance anaerobic digestion (AD) systems is widely advocated as it improves methane production and system stability. Accurate modeling of ZVI-based AD reactor is conducive to predicting methane production potential, optimizing operational strategy, and gathering reference information for industrial design in place of time-consuming and laborious tests. In this study, three machine learning (ML) algorithms, namely random forest (RF), extreme gradient boosting (XGBoost), and deep learning (DL), were evaluated for their feasibility of predicting the performance of ZVI-based AD reactors based on the operating parameters collected in 9 published articles. XGBoost demonstrated the highest accuracy in predicting total methane production, with a root mean squared error (RMSE) of 21.09, compared to 26.03 and 27.35 of RF and DL, respectively. The accuracy represented by mean absolute percentage error also showed the same trend, with 14.26%, 15.14% and 17.82% for XGBoost, RF and DL, respectively. Through the feature importance generated by XGBoost, the parameters of total solid of feedstock (TSf), sCOD, ZVI dosage and particle size were identified as the dominant parameters that affect the methane production, with feature importance weights of 0.339, 0.238, 0.158, and 0.116, respectively. The digestion time was further introduced into the above-established model to predict the cumulative methane production. With the expansion of training dataset, DL outperformed XGBoost and RF to show the lowest RMSEs of 11.83 and 5.82 in the control and ZVI-added reactors, respectively. This study demonstrates the potential of using ML algorithms to model ZVI-based AD reactors.

In membrane distillation (MD), complicated feed water with amphiphilic contaminants induces fouling/wetting of the MD membrane and can even lead to process failure. This study reports a facile approach to fabricate robust and self-healing hybrid amphiphobic membranes for anti-surfactant-wetting MD based on the ultra-low surface energy of fluorinated polyhedral oligomeric silsesquioxanes (F-POSS) and its thermal induced motivation and rotation. The thermal treatment makes the membranes achieving amphiphobicity at a very low cost of F-POSS (13.04 wt.%), which is about 1/3 of without thermal treatment. The prepared membrane exhibits excellent amphiphobicity, i.e. ethanol contact angle of 120.3°, without using environmentally toxic fluorinated nanoparticles. Robust MD performance was observed for the amphiphobic membrane in concentrated sodium dodecyl sulfate (SDS) feed solutions. Furthermore, the fabricated membrane exhibited stable amphiphobicity even in extreme environments, including strong acid or alkaline solutions. In the event of a damaged or abraded membrane surface where the F-POSS can be removed, the amphiphobic membrane exhibits self-healing ability with additional thermal treatment. This simple approach without the use of nanoparticles provides an environmentally friendly way for fabrication of amphiphobic membranes for anti-surfactant-wetting membrane distillation.

A major limitation of vanadium oxides in aqueous Zn/V2O5 ion battery applications is that they suffer from strong coulombic ion–lattice interactions with divalent Zn2+. Correspondingly, vanadium oxides show the poor utilization of their electrochemically active surface areas and unsatisfactory structural stability. The Gibbs free energy of Zn2+ adsorption in the vicinity of oxygen vacancies can be reduced to a thermoneutral value, which suggests that the Zn2+ adsorption/desorption process on the oxygen-deficient oxide lattice is more reversible as compared to a less defective vanadium oxide. In this work, it is demonstrated that these problems can be significantly ameliorated via creating oxygen vacancies in vanadium oxide host materials. Specifically, for the first time, vanadium oxides with abundant oxygen defects (labeled Vo-V2O5) are fabricated via a new water-steam activation strategy. Such water-steam activation forms abundant oxygen defects, and the as-prepared materials show a 3.5-fold increase in the carrier density, together with larger electrochemically active surface areas compared to a less defective vanadium oxide. When used as a cathode material for aqueous zinc ion batteries, Vo-V2O5 exhibits a high specific capacity (335 mA h g−1 at 0.2 A g−1) and excellent cell stability (∼87.2% capacity retention after 3500 continuous charge/discharge cycles at 5.0 A g−1). Thus, this water-steam activation approach for disordered metal oxides yields highly competitive cathode materials, which may also aid in the future development of advanced materials in related energy fields.

Recycling of spent lithium-ion batteries (LIBs) is of great importance for both critical metal supply and environmental protection. Although the physical chemistry is still focused on pyrometallurgy, hydrometallurgy and electrometallurgy, state-of-the-art recycling technologies are a trend that is turning towards being more material/energy efficient in line with the principles of green chemistry. For instance, selective recycling of specified metals and direct regeneration of battery materials are being trialled to develop short-cut processes that prevent secondary pollution generation and improve the atomic economy during the whole recycling process. In this review, a number of technologies for recycling spent LIBs are overviewed, especially at different recycling stages to stepwise recover battery materials. It is clearly understood that extraction of critical metals and subsequent regeneration of materials are only part of the recycling process, while pretreatment to obtain black mass powder from battery cells and pollution control, in view of the recycling process to minimise environmental impact, are also extremely important. Furthermore, green design of batteries, as well as process design in view of the whole life cycle of LIBs, are topping the list of the research which requires profound and elaborate efforts. It is expected that this review could provide a guideline for implementing green chemistry principles into spent LIB recycling and stimulate further discussions on improving the green degree of the process.

A series of Ni/HZSM-5 and Ni/HIM-5 bi-functional catalysts were synthesized and applied to the aqueous-phase hydrodeoxygenation (HDO) of phenol. The Ni dispersibility and particle sizes were shown to be directly related to the porosity and crystal sizes of the parent zeolites, which further influenced the catalytic performances. The large pores and small crystal sizes of the parent zeolites were beneficial for dispersing Ni and forming small Ni particles, and the corresponding Ni/zeolite catalyst exhibited a higher phenol conversion and selectivity towards hydrocarbons. Importantly, the Ni/HIM-5 bi-functional catalyst exhibited a high activity (98.3%) and high selectivity for hydrocarbons (98.8%) when heated at 220°C for 1 h and is thus a new potential catalyst for the HDO of phenolics to form hydrocarbons in the aqueous phase.

Cadmium-containing wastewater draws worldwide attention due to its toxicity. In this work, a high-efficiency and eco-friendly MnO2-coated amorphous carbon (AG@MnO2) adsorbent for cadmium (Cd (II)) ...

OBJECTIVEThe authors sought to compare the dosimetric quality of hypofractionated stereotactic radiosurgery in treating sizeable brain tumors across the following treatment platforms: GammaKnife (GK) Icon, CyberKnife (CK) G4, volumetric modulated arc therapy (VMAT) on the Varian TrueBeam STx, double scattering proton therapy (DSPT) on the Mevion S250, and intensity modulated proton therapy (IMPT) on the Varian ProBeam.METHODSIn this retrospective study, stereotactic radiotherapy treatment plans were generated for 10 patients with sizeable brain tumors (> 3 cm in longest diameter) who had been treated with VMAT. Six treatment plans, 20–30 Gy in 5 fractions, were generated for each patient using the same constraints for each of the following radiosurgical methods: 1) GK, 2) CK, 3) coplanar arc VMAT (VMAT-C), 4) noncoplanar arc VMAT (VMAT-NC), 5) DSPT, and 6) IMPT. The coverage; conformity index; gradient index (GI); homogeneity index; mean and maximum point dose of organs at risk; total dose volume (V) in Gy to the normal brain for 2 Gy (V2), 5 Gy (V5), and 12 Gy (V12); and integral dose were compared across all platforms.RESULTSAmong the 6 techniques, GK consistently produced a sharper dose falloff despite a greater central target dose. GK gave the lowest GI, with a mean of 2.7 ± 0.1, followed by CK (2.9 ± 0.1), VMAT-NC (3.1 ± 0.3), and VMAT-C (3.5 ± 0.3). The highest mean GIs for the proton beam treatments were 3.8 ± 0.4 for DSPT and 3.9 ± 0.4 for IMPT. The GK consistently targeted the lowest normal brain volume, delivering 5 to 12 Gy when treating relatively smaller- to intermediate-sized lesions (less than 15–20 cm3). Yet, the differences across the 6 modalities relative to GK decreased with the increase of target volume. In particular, the proton treatments delivered the lowest V5 to the normal brain when the target size was over 15–20 cm3 and also produced the lowest integral dose to the normal brain regardless of the target size.CONCLUSIONSThis study provides an insightful understanding of dosimetric quality from both photon and proton treatment across the most advanced stereotactic radiotherapy platforms.

N-doped defective nanocarbon (N-DNC) catalysts have been widely studied due to their exceptional catalytic activity in many applications, but the O