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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.

A metallosupramolecular polymer network is constructed by hierarchical self-assembly of a double-armed pillar[5]arene, a ditopic guest, and zinc ions, where host-guest recognition and metal-ligand coordination interactions play a crucial role.

Substituting Sr2+ for Ba2+ ions in Ba(2−x)SrxMgWO6:Er3+,Yb3+,K+ led to the formation of tetragonal phase with a fourfold increase in Sa value. The effect of the phase transition on the optical properties of the phosphors was investigated.

A series of red-emitting BaLaLiWO6:Mn4+ (BLLW:Mn4+) phosphors were successfully synthesized by a high-temperature solid-state reaction method. The SrLLW:Mn4+ phosphor is a better candidate for plants illumination LED.

Lead (Pb) and manganese (Mn) are common environmental pollutants, with high exposures potentially resulting in neurotoxicity. However, individuals are subject to co-exposures in real life, and it is therefore important to study these metals in combination. Weaning Sprague-Dawley rats (SD rats) were given ad libitum access to drinking water solutions containing Pb (100 ppm), Mn (2.5 mg/mL) or a mixture, and each treatment has its own minocycline (MC) (50 mg/Kg.d) supplement group. The results showed that in the Morris water maze (MWM) and Y maze a significant difference in the escape latency, percent time spent in target quadrant and correct response ratio were noted in all exposure groups when compared to controls. The combined exposure group exhibited the most pronounced effect when compared with each of the single metal exposure groups. The induction levels of hippocampal long-term potentiation (LTP) were significantly reduced in the single metal and combined exposure groups compared to the control group. Furthermore, the inhibitory effects of combined exposure group were significantly greter than in the single metal exposure groups. Microglia displayed activation at day 3 after exposure alone or in combination, while astrocytes showed activation at day 5 after exposure alone or in combination, accompanied by decreased expression levels of glutamate-glutamine cycle-related proteins GLAST, GLT-1, and GS. Furthermore, the levels of the excitatory neurotransmitter glutamate in the synaptic cleft increased significantly. When microglial activation and release of its activated factors were inhibited by minocycline, the activation of astrocytes, and the expression of glutamate-glutamine cycle-related proteins GLAST, GLT-1, and GS were both reversed. In addition, upon minocycline treatment the induction of hippocampal LTP and the cognitive injury were significantly alleviated in each of the exposure groups. Moreover, the effects mentioned above were more significant in the combined exposure group than in the single exposure group. These results suggest that combined exposure to lead and manganese can cause greater effects on cognition and synaptic plasticity when compared to single metal exposure groups. And the reason may involve in microglia abnormal activation leading to an excessive regulation of astrocytes, resulting in glutamate reuptake dysfunction in astrocytes and lead to perturbed cognition and synaptic plasticity.

We prove a Bernstein type theorem for ancient solutions to the mean curvature flow in higher codimension. More precisely, we show that for a complete ancient solution { M t } t ∈ ( − ∞ , 0 ) \{M_t\}_{t\in (-\infty ,0)} , if the mean curvature vector is uniformly bounded and the ω \omega -function for M t M_t satisfies ω ≥ ω 0 \omega \geq \omega _0 uniformly for some constant ω 0 > 1 2 \omega _0>\frac {1}{\sqrt {2}} , then M t M_t must be an affine subspace for each t ∈ ( − ∞ , 0 ) t\in (-\infty ,0) .

Malignant glioma, especially glioblastoma (GBM), has historically been associated with a low survival rate. The hyperactivation of STAT3 played a key role in GBM initiation and resistance to therapy; thus, there is an urgent requirement for novel STAT3 inhibitors. BP-1-102 was recently reported as a biochemical inhibitor of STAT3, but its roles and mechanism in biological behavior of glioma cells were still unclear. In this study, the effects of BP-1-102 on proliferation, apoptosis, invasion and neurosphere formation of glioma cell were investigated. Our results indicated that BP-1-102 inhibited the proliferation of U251 and A172 cells, and their IC50 values were 10.51 and 8.534 μM, respectively. Furthermore, BP-1-102 inhibited the invasion and migration abilities of U251 and A172 cells by decreasing the expression of matrix metallopeptidase 9, and induced glioma cell apoptosis by decreasing the expression of B-cell lymphoma-2. BP-1-102 also inhibited the formation of neurosphere. Mechanically, BP-1-102 reduced the phosphorylation of STAT3 and the p-STAT3's nuclear translocation in glioma cells. Thus, this study herein provided a potential drug for glioma therapy.

Acute-on-chronic liver failure (ACLF) is the abrupt exacerbation of declined hepatic function in patients with chronic liver disease.To explore the independent predictors of short-term prognosis in patients with hepatitis B virus (HBV)-related ACLF and to establish a predictive short-term prognosis model for HBV-related ACLF.From January 2016 to December 2019, 207 patients with HBV-related ACLF attending the 910th Hospital of Chinese People's Liberation Army were continuously included in this retrospective study. Patients were stratified based on their survival status 3 mo after diagnosis. Information was collected regarding gender and age; coagulation function in terms of prothrombin time and international normalized ratio (INR); hematological profile in terms of neutrophil-to-lymphocyte ratio (NLR) and platelet count (PLT); blood biochemistry in terms of alanine aminotransferase, aspartate aminotransferase, total bilirubin (Tbil), albumin, cholinesterase, blood urea nitrogen (BUN), creatinine, blood glucose, and sodium (Na); tumor markers including alpha-fetoprotein (AFP) and Golgi protein 73 (GP73); virological indicators including HBV-DNA, HBsAg, HBeAg, Anti-HBe, and Anti-HBc; and complications including hepatic encephalopathy, hepatorenal syndrome, spontaneous peritonitis, gastrointestinal bleeding, and pulmonary infection.There were 157 and 50 patients in the survival and death categories, respectively. Univariate analysis revealed significant differences in age, PLT, Tbil, BUN, NLR, HBsAg, AFP, GP73, INR, stage of liver failure, classification of liver failure, and incidence of complications (pulmonary infection, hepatic encephalopathy, spontaneous bacterial peritonitis, and upper gastrointestinal bleeding) between the two groups (The stage of liver failure, presence of GP73, pulmonary infection, hepatorenal syndrome, and HBsAg are independent predictors of short-term prognosis in patients with HBV-related ACLF, and the GP73-ACLF model has good predictive value among these patients.

Background: This study aimed to explore the efficacy and safety of drug-eluting beads bronchial arterial chemoembolization (DEB-BACE) compared with conventional bronchial arterial chemoembolization (cBACE) in lung cancer patients with hemoptysis. Materials & methods: Thirty-six lung cancer patients with hemoptysis treated by DEB-BACE or cBACE were retrospectively analyzed. Results: Technical success of BACE and clinical success of hemoptysis treatment were no different between DEB-BACE and cBACE (both p > 0.050), whereas DEB-BACE achieved increased total clinical response (p = 0.021), objective response rate (p = 0.035) and prolonged hemoptysis relapse-free survival (p = 0.013) compared with cBACE. The adverse event rates were similar between these two groups (all p > 0.05). Conclusion: DEB-BACE presents with higher tumor treatment response, prolonged hemoptysis relapse-free survival and comparable safety profiles compared with cBACE in lung cancer patients with hemoptysis.

Multifunctionalization is the development direction of personal thermal energy regulation equipment in the future. However, it is still a huge challenge to effectively integrate multiple functionalities into one material. In this study, a simple thermochemical process was used to prepare a multifunctional SiC nanofiber aerogel spring (SiC NFAS), which exhibited ultralow density (9 mg/cm3), ultralow thermal conductivity (0.029 W/(m·K) at 20 °C), excellent ablation and oxidation resistance, and a stable three-dimensional (3D) structure that composed of a large number of interlacing 3C-SiC nanofibers with diameters of 300–500 nm and lengths in tens to hundreds of microns. Furthermore, the as-prepared SiC NFAS displayed excellent mechanical properties, with a permanent deformation of only 1.3% at 20 °C after 1000 cycles. Remarkably, the SiC NFAS exhibited robust hyperelasticity and cyclic fatigue resistance at both low (∼−196 °C) and high (∼700 °C) temperatures. Due to its exceptional thermal insulation performance, the SiC NFAS can be used for personal thermal energy regulation. The results of the study conclusively show that the SiC NFAS is a multifunctional material and has potential insulation applications in both low- and high-temperature environments.

Hypochlorous acid (HClO), the core bactericidal substance of the human immune system, plays a vital role in many physiological and pathological processes in the human body. In this work, we designed and synthesized a novel deep-red fluorescent probe TCF-ClO for the determination of hypochlorous acid through theoretical analysis. The results showed that probe TCF-ClO exhibited excellent characteristics of long-wavelength emission (635 nm), fast response ( 1 min), and low detection limit (24 nM). In addition, it had been successfully used for imaging of HClO in living HeLa cells. More importantly, the TCF-ClO composited paper-based sensing material was successfully constructed. The RGB/gray value was obtained from a mobile phone and computer, which could achieve the quantitative detection of HClO, with a linear detection range of 0-50 μM and a detection limit of 1.09 μM (RGB mode)/3.38 μM (gray mode). The function of the paper-based sensor extended from qualitative to quantitative detection of HClO, and it is expected to become a portable device widely used in the environmental area.

Materials that can efficiently absorb electromagnetic waves (EMWs) are required to deal with electromagnetic pollution. Structure design appears to be an efficient way to improve the EMW-absorption performance of such materials, particularly when adjustment of the constitution or mixing ratio is limited. In this study, bowl-like and honeycomb titanium dioxide/carbon nanotube (TiO2/CNT) composites with different CNT contents were fabricated using the methods of hierarchical and mixing vacuum-assisted filtration, respectively. Compared to the honeycomb structure, the bowl-like structure simultaneously facilitated greater interfacial polarization and conduction loss in favor of dielectric polarization, and augmented multiple reflections. The high porosity of the honeycomb structure was conducive to optimizing the impedance matching characteristics. The bowl-like TiO2/CNT composite exhibited a minimum reflection loss (RLmin) of −38.6 dB (1.5 mm) with a wide effective absorption band (EAB

Background: Targeting endoplasmic reticulum (ER) stress with melatonin has been proven helpful for cerebral ischemic/reperfusion (CI/R) damage, while the mechanism remains unclear. In current study, we investigated whether melatonin could ameliorate ER stress in CI/R injury through sirtuin 2 (SIRT2). Methods: Male SD rats were underwent middle cerebral artery occlusion and reperfusion (MCAO-R) surgery. Melatonin was treated 30 min before MCAO-R. Results: Melatonin (20 mg/kg) notably improved MCAO-R-induced cerebral neurologic impairment and infarct volume. Melatonin reversed MCAO-R induced upregulation of SIRT2 and activation of ER stress (reduced phosphorylated protein kinase-like ER kinase (PERK) and phosphorylated eukaryotic initiation factor 2α). Consistently, in OGD/R-treated HT22 cells, melatonin also significantly alleviated ER stress and SIRT2 expression. Further Co-immunoprecipitation and co-immunofluorescence studies revealed that melatonin enhanced heat shock factor 1 (HSF 1)acetylation. Inhibiting of Sirt2 by siRNA also increased HSF1 acetylation in OGD/R-treated cells. Melatonin significantly inhibited PERK activator (CCT020312)-induced ER stress, while CCT020312 had no influence on SIRT2 and HSF1 acetylation. Conclusion: Our findings elucidated that SIRT2/HSF1/PERK pathway is essential for melatonin-alleviated CI/R injury, providing a novel molecular mechanism.

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

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.

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.

Supplemental Table S1. qRT-PCR primers used in this study Supplemental Table S2. siRNA sequence used in this study Supplemental Table S3. Primers used for shRNA plasmid construction Supplemental Table S4. Primers used for truncation variants plasmid construction Supplemental Table S5. Primers sequence used for ChIP-PCR assay Supplemental Table S6. Probe sequence of TINCR in situ hybridization (ISH) Supplemental Table S7. Clinical characteristics of nasopharyngeal carcinoma patients according to the high and low expression of TINCR Supplemental Table S8. Univariate and multivariable Cox regression analysis of TINCR expression level and survival Supplemental Table S9. The top10 proteins found by mass spectrometry analysis in the antisense-TINCR group (negative control). Supplemental Table S10. The top10 proteins found by mass spectrometry analysis in the TINCR group. The bold portion shows the proteins that overlap antisense-TINCR

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.

Frontier evidence suggests that dysregulation of long noncoding RNAs (lncRNA) is ubiquitous in all human tumors, indicating that lncRNAs might have essential roles in tumorigenesis. Therefore, an in-depth study of the roles of lncRNA in nasopharyngeal carcinoma (NPC) carcinogenesis might be helpful to provide novel therapeutic targets. Here we report that lncRNA TINCR was significantly upregulated in NPC and was associated positively with poor survival. Silencing TINCR inhibited NPC progression and cisplatin resistance. Mechanistically, TINCR bound ACLY and protected it from ubiquitin degradation to maintain total cellular acetyl-CoA levels. Accumulation of cellular acetyl-CoA promoted de novo lipid biosynthesis and histone H3K27 acetylation, which ultimately regulated the peptidyl arginine deiminase 1 (PADI1)–MAPK–MMP2/9 pathway. In addition, insulin-like growth factor 2 mRNA-binding protein 3 interacted with TINCR and slowed its decay, which partially accounted for TINCR upregulation in NPC. These findings demonstrate that TINCR acts as a crucial driver of NPC progression and chemoresistance and highlights the newly identified TINCR–ACLY–PADI1–MAPK–MMP2/9 axis as a potential therapeutic target in NPC.Significance:TINCR-mediated regulation of a PADI1–MAPK–MMP2/9 signaling pathway plays a critical role in NPC progression and chemoresistance, marking TINCR as a viable therapeutic target in this disease.

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

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.

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

Supplemental Figure S1. TINCR is upregulated in six other cancer types. Supplemental Figure S2. GSEA analyses results of TINCR silencing. Supplemental Figure S3. Overexpression of TINCR promotes NPC cell proliferation, metastasis and cisplatin resistance in vitro. Supplemental Figure S4. Overexpression of TINCR reverses the suppressive effects of TINCR knockdown on cell proliferation, cisplatin resistance and metastasis. Supplemental Figure S5. TINCR targets ACLY and impairs its ubiquitination degradation. Supplemental Figure S6. Silencing TINCR has no effects on the expressions of KAT3A and KAT3B. Supplemental Figure S7. The ACLY-binding motif CUGKR is critical for the role of TINCR in maintaining ACLY protein stability and lipid synthesis levels. Supplemental Figure S8. Acetyl-CoA is responsible for TINCR-mediated NPC progression and chemoresistance. Supplemental Figure S9. Correlation between TINCR and PADI1 expression in 16 other cancer types from the TCGA database. Supplemental Figure S10. Silencing TINCR decreases the proteolytic activities of MMP2/9, but had no effects on H3K27ac levels at MMP2/9 promoters. Supplemental Figure S11. IGFBP3 is overexpressed in NPC

NFE2L2 mutation leads to extrinsic radiation resistance.

The NFE2L2/NRF2 oncogene and transcription factor drives a gene expression program that promotes cancer progression, metabolic reprogramming, immune evasion and chemoradiation resistance. Patient stratification by NRF2 activity may guide treatment decisions to improve outcome. Here, we developed a mass spectrometry (MS)-based targeted proteomics assay based on internal standard triggered parallel reaction monitoring (IS-PRM) to quantify 69 NRF2 pathway components and targets as well as 21 proteins of broad clinical significance in head and neck squamous cell carcinoma (HNSCC). We improved the existing IS-PRM acquisition algorithm, called SureQuant™, to increase throughput, sensitivity, and precision. Testing the optimized platform on 27 lung and upper aerodigestive cancer cell models revealed 35 NRF2 responsive proteins. In formalin-fixed paraffin-embedded (FFPE) HNSCCs, NRF2 signaling intensity positively correlated with NRF2 activating mutations and with SOX2 protein expression. PD-L2/CD273 and protein markers of T-cell infiltration correlated positively with one another and with human papilloma virus (HPV) infection status. p16/CDKN2A protein expression positively correlated with the HPV oncogenic E7 protein, and confirmed the presence of translationally active virus. This work establishes a clinically actionable HNSCC protein biomarker assay capable of quantifying over 600 peptides from frozen or FFPE archived tissues in under 90 minutes.

In recent years, therapeutic strategies based on macrophages have been inspiringly developed, but due to the high intricacy and immunosuppression of the tumor microenvironment, the widespread use of these strategies still faces significant challenges. Herein, an artificial assembled macrophage concept (AB@LM) was presented to imitate the main antitumor abilities of macrophages of tumor targeting, promoting the antitumor immunity, and direct tumor-killing effects. The artificial assembled macrophage (AB@LM) was prepared through an extrusion method, which is to fuse the macrophage membrane with abemaciclib and black phosphorus quantum dot (BPQD)-loaded liposomes. AB@LM showed good stability and tumor targeting ability with the help of macrophage membrane. Furthermore, AB@LM reversed the immunosuppressive tumor microenvironment by inhibiting regulatory T cells (Tregs) and stimulating the maturation of antigen-presenting cells to activate the antitumor immune response through triggering an immunogenic cell death effect. More importantly, in the colorectal tumor model in vivo, a strong cooperative therapeutic effect of photo/chemo/immunotherapy was observed with high tumor inhibition rate (95.3 ± 2.05%). In conclusion, AB@LM exhibits excellent antitumor efficacy by intelligently mimicking the abilities of macrophages. A promising therapeutic strategy for tumor treatment based on imitating macrophages was provided in this study.

Extracellular vesicles (EVs) contain thousands of proteins and nucleic acids, playing an important role in cell-cell communications. Sertoli cells have been essential in the testis as a "nurse cell". However, EVs derived from human Sertoli cells (HSerCs) have not been well investigated.EVs were isolated from HSerCs via ultracentrifugation and characterized by transmission electron microscopy, tunable resistive pulse sensing, and Western blotting. The cargo carried by HSerCs-EVs was measured via liquid chromatography-mass spectrometry and GeneChip miRNA Arrays. Bioinformatic analysis was performed to reveal potential functions of HSerCs-EVs.A total of 860 proteins with no less than 2 unique peptides and 88 microRNAs with high signal values were identified in HSerCs-EVs. Biological processes related to molecular binding, enzyme activity, and regulation of cell cycle were significantly enriched. Specifically, many proteins in HSerCs-EVs were associated with spermatogenesis and regulation of immune system, including Septins, Large proline-rich protein BAG6, Clusterin, and Galectin-1. Moreover, abundant microRNAs within HSerCs-EVs (miR-638, miR-149-3p, miR-1246, etc.) had a possible impact on male reproductive disorders such as asthenozoospermia and oligozoospermia.Our study has shown that HSerCs-EVs contain diverse components such as proteins and microRNAs. Further research is required to evaluate HSerCs-EVs in spermatogenesis, which are underutilized but highly potent resources with particular promise for male infertility.

Spindle cell hemangioma is a rare benign hemangioma. It is mainly found as small soft tissue nodules in the distal extremities, especially in the hands. The manifestation in bone is extremely rare. We present a case of spindle cell hemangioma of bone in the frontal bone. We also reviewed the literature to find the common imaging findings of intraosseous hamangiomas. The main manifestations of X-ray and CT were osteolytic lesions with soap bubble-like changes, and soft tissue mass formation. Magnetic resonance imaging mainly showed a lobulated mass with clear boundary, uneven hyperintense on T2WI, and obvious enhancement on contrast-enhanced scan. Surgical excision is curative. While this lesion is rare, it can be considered in the differential diagnosis if the characteristic imaging features are present.