Multi-omics comprehensive analyses of programmed cell death patterns to regulate the immune characteristics of head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous cancer with high morbidity and mortality. Triggering the programmed cell death (PCD) to enhance the anti-tumor therapies is being applied in multiple cancers. However, the limited understanding of genetic heterogeneity in HNSCC severely hampers the clinical efficacy. We systematically analyzed 14 types of PCD in HNSCC from The Cancer Genome Atlas (TCGA). We utilized ssGSEA to calculate the PCD scores and classify patients into two clusters. Subsequently, we displayed the genomic alteration landscape to unravel the significant differences in copy number alterations and gene mutations. Furthermore, we calculated the IC50 values of targeted drugs to predict the differences in sensitivity. To identify the immune-related prognostic types, we comprehensively estimated the relationship between immune indicators and all prognostic PCD in three datasets (TCGA, GSE65858, GSE41613). Finally, 7 regulators were filtered. Subsequently, we integrated 10 machine learning algorithms and 101 algorithm combinations to test the clinical predictive efficacy. Using WGCNA as a basis, we built a weighted co-expression network to identify modules involved in the immune landscape with different colors. Meanwhile, our results indicated that blue and red modules containing crucial regulators closely related to the CD4+, CD8+ T cells, TMB or PD-L1. FCGR2A from blue module, CSF2, INHBA, and THBS1 from the red module were determined. After verifying in vivo experiments, FCGR2A was identified as hub gene. In conclusion, our findings suggest a potential role of PCD in HNSCC, offering new insights into effective immunotherapy and anti-tumor therapies in HNSCC.

Identify and validate circadian regulators as potential prognostic markers and immune infiltrates in head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is a heterogeneity pathological malignant cancer with leading causes of morbidity and mortality. EGFR inhibitors, immune checkpoint inhibitors have become novel treatments. However, the mechanism still remained uncertain. Several studies have confirmed that the circadian rhythms induce multiple malignancies developing. We utilized multi-omics analysis to demonstrate the crosstalk between circadian clock genes and tumor microenvironment in HNSCC. Firstly, we performed the LASSO Cox regression analysis based on the 16 important clock genes. A 7-gene risk model was successfully established in TCGA and validated in GEO datasets. Next, CIBERSORT and ESTIMATE methods were performed to display the immune landscape of high risk and low risk groups, and the results showed that high abundance of mast cells activated, dendritic cells activated and neutrophils were positively correlated with poor OS. To further identify hub genes, Kaplan Meier plot was applied in all TCGA and GEO datasets and two hub genes (PER2, and PER3) were identified, especially PER3, which was found strongly associated with immune score, PDCD1, CD4 + and CD8 + T cells in HNSCCC. Moreover, to explore the innate mechanism of circadian-induced pathway, we constructed a circadian-related ceRNA regulatory network containing 34 lncRNAs, 3 miRNAs and 4 core circadian genes. In-vitro experiments also verified that Per2 or Per3 could suppressed the proliferation, migration and invasion of HNSC. This study unraveled the association between PER3 and prognosis in patients with HNSC and the innate mechanism remains to be elucidated.

Identify and validate RUNX2 and LAMA2 as novel prognostic signatures and correlate with immune infiltrates in bladder cancer.

Background: Muscle-invasive bladder cancer (MIBC) develops lymph node (LN) metastasis or distant metastasis, leading to recurrence and poor prognosis. The five-year survival rate of MIBC with LN or distant metastasis is only 8.1%; therefore, there is an urgent need to identify reliable biomarkers for prognosis and treatment regimen for patients with bladder cancer (BLCA). Methods: SEER database was used to select important clinical characteristics for MIBC. Then, weighted gene co-expression network analysis (WGCNA) was employed to identify differentially expressed genes (DEGs) to recognize significant co-expression modules by calculating the correlation between the modules and clinical data. Furthermore, Cox regression and lasso analysis were applied to screen prognostic hub genes and establish the risk predictive model. Bladder cancer cell lines (UMUC3 and 5637) were used for experimental validation in vitro. Results: Cox analysis of 122,600 MIBC patients showed that the N stage was the most important clinical factor. A total of 4,597 DEGs were calculated between N0 and N+ patients, and WGCNA with these DEGs in 368 samples revealed that expression of turquoise was positively and strongly correlated with the N stage. Eight genes were identified as important prognostic candidates using lasso regression based on Cox analysis and STRING database. Combining GEO datasets, literature, and clinical factors, we identified LAMA2 and RUNX2 as novel prognostic biomarkers. CCK8 assay showed that depletion of LAMA2 or RUNX2 significantly inhibited the proliferation of BLCA cells, and flow cytometry indicated that knockdown of LAMA2 or RUNX2 induced the apoptosis of BLCA cells. Transwell assay also showed that silencing of LAMA2 or RUNX2 weakened the migration and invasiveness of BLCA cells. Conclusions: We constructed a new eight-gene risk model to provide novel prognostic biomarkers and therapeutic targets for BLCA.

NBS-mediated elimination of ß-keto sulfides to access enones and dienones.

A novel transformation of ß-keto sulfides into enones has been developed. The new method facilitates an NBS-mediated elimination of sulfides to access both enones and dienones. 22 enone products were obtained in moderate to high yields. 4 different dienones were also prepared in 73%-93% yields. 7 different alkylthio motifs have been removed efficiently from ß-keto sulfides. We also found that our transformation proceeds well in gram-scale reactions showing no decrease in yield. This methodology is significant in the research and application of sulfides, giving a new pathway to transform ß-keto sulfides into enones.

Clinical value and potential mechanisms of BUB1B up-regulation in nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) has insidious onset, late clinical diagnosis and high recurrence rate, which leads to poor quality of patient life. Therefore, it is necessary to further explore the pathogenesis and therapy targets of NPC. BUB1 mitotic checkpoint serine/threonine kinase B (BUB1B) was found to be up-regulated in a variety of cancers, but only two previous study showed that BUB1B was overexpressed in NPC and the sample size was small. The clinical role of BUB1B expression and its underlying mechanism in NPC require more in-depth research. Immunohistochemical samples and public RNA-seq data indicated that BUB1B protein and mRNA expression levels were up-regulated in NPC, and summary receiver operating characteristic curve indicated that BUB1B expression level had a strong ability to distinguish NPC tissues from non-NPC tissues. Gene ontology and Kyoto Encyclopedia of genes and genomes were performed and revealed that BUB1B and its related genes were mainly involved in cell cycle and DNA replication. Protein- Protein Interaction were built to interpret the BUB1B molecular mechanism. Histone deacetylase 2 (HDAC2) could be the upstream regulation factor of BUB1B, which was verified by Chromatin Immunoprecipitation Sequencing samples. In summary, BUB1B was highly expressed in NPC, and HDAC2 may affect cell cycle by regulating BUB1B to promote cancer progression.

Potential Molecular Mechanism of Upregulated Aryl Hydrocarbon Receptor Nuclear Translocator 2 in Nasopharyngeal Carcinoma.

Background: Currently, the benefits of nasopharyngeal carcinoma (NPC) therapy are limited, and it is necessary to further explore possible therapeutic targets. Aryl hydrocarbon receptor nuclear translocator 2 (ARNT2) has been extensively studied in other cancer species, but little has been explored in NPC. The aim of this study was to verify the expression level of ARNT2 and its underlying mechanism in NPC. Methods: Datasets containing ARNT2 mRNA expression levels were retrieved and collected from various databases to explore the expression status of ARNT2 in NPC. ARNT2-related coexpressed genes, differential expressed genes, and target genes were obtained for functional enrichment analysis. The potential target gene of ARNT2 and their regulatory relationship were studied through ChIP-seq data. CIBERSORTx was used to assess the immune infiltration of NPC, and the association with ARNT2 expression was calculated through correlation analysis. Results: ARNT2 was upregulated and possessed an excellent discriminatory capability in NPC samples. ARNT2 positively correlated target genes were clustered in pathways in cancer, while negatively correlated target genes were enriched in immune-related pathway. The ChIP-seq information of ARNT2 and histone showed that prostaglandin-endoperoxide synthase 2 (PTGS2) was a potential target gene of ARNT2. CIBERSORTx revealed the immunity status in NPC, and ARNT2 expression was correlated with infiltration of five immune cells. Conclusions: ARNT2 is overexpressed in NPC and may regulate PTGS2 to participate in the cancer process. ARNT2 serves as a key oncogenic target in NPC patients.

A Simple Small Molecule with Synergistic Passive and Active Dual-Targeting Effects for Imaging-Guided Photothermal Cancer Therapy.

Photothermal therapy allows spatiotemporal control of the treatment effect only at the site of the disease and provides promising opportunities for imaging-guided precision therapy. However, the development of photothermal transduction agents (PTAs) for tumor-specific accumulation and precision imaging, avoiding toxicity to the surrounding healthy tissue, is still challenging. Herein, a cyclooxygenase-2-specific small-organic-molecule-based PTA (Cy7-TCF-IMC) is developed, which can self-assemble into nanosaucers having unique photothermal and photoacoustic properties. Specifically, the self-assembling nature of Cy7-TCF-IMC affords preferential accumulation in tumors arising from synergistic passive enhanced permeability and retention effects and active targeting for precision theranostics. Antitumor therapy results show that these Cy7-TCF-IMC nanosaucers are highly photoacoustic imaging-guided PTAs for tumor ablation. These findings suggest the self-assembled Cy7-TCF-IMC nanosaucer represents a new paradigm as a single-component supramolecular medicine that can synergistically optimize passive and active targeting, thereby improving the therapeutic index of cancer and future clinical outcomes.

Genotype and phenotype distribution of 435 patients with Charcot-Marie-Tooth disease from central south China.

BACKGROUND AND PURPOSE: The purpose was to provide an overview of genotype and phenotype distribution in a cohort of patients with Charcot-Marie-Tooth disease (CMT) and related disorders from central south China. METHODS: In all, 435 patients were enrolled and detailed clinical data were collected. Multiplex ligation-dependent probe amplification for PMP22 duplication/deletion and CMT multi-gene panel sequencing were performed. Whole exome sequencing was further applied in the remaining patients who failed to achieve molecular diagnosis. RESULTS: Among the 435 patients, 216 had CMT1, 14 had hereditary neuropathy with pressure palsies (HNPP), 178 had CMT2, 24 had distal hereditary motor neuropathy (dHMN) and three had hereditary sensory and autonomic neuropathy (HSAN). The overall molecular diagnosis rate was 70%: 75.7% in CMT1, 100% in HNPP, 64.6% in CMT2, 41.7% in dHMN and 33.3% in HSAN. The most common four genotypes accounted for 68.9% of molecular diagnosed patients. Relatively frequent causes were missense changes in PMP22 (4.6%) and SH3TC2 (2.3%) in CMT1; and GDAP1 (5.1%), IGHMBP2 (4.5%) and MORC2 (3.9%) in CMT2. Twenty of 160 detected pathogenic variants and the associated phenotypes have not been previously reported. Broad phenotype spectra were observed in six genes, amongst which the pathogenic variants in BAG3 and SPTLC1 were detected in two sporadic patients presenting with the CMT2 phenotype. CONCLUSIONS: Our results provided a unique genotypic and phenotypic landscape of patients with CMT and related disorders from central south China, including a relatively high proportion of CMT2 and lower occurrence of PMP22 duplication. The broad phenotype spectra in certain genes have advanced our understanding of CMT.

Formation of α clusters in dilute neutron-rich matter.

The surface of neutron-rich heavy nuclei, with a neutron skin created by excess neutrons, provides an important terrestrial model system to study dilute neutron-rich matter. By using quasi-free α cluster-knockout reactions, we obtained direct experimental evidence for the formation of α clusters at the surface of neutron-rich tin isotopes. The observed monotonous decrease of the reaction cross sections with increasing mass number, in excellent agreement with the theoretical prediction, implies a tight interplay between α-cluster formation and the neutron skin. This result, in turn, calls for a revision of the correlation between the neutron-skin thickness and the density dependence of the symmetry energy, which is essential for understanding neutron stars. Our result also provides a natural explanation for the origin of α particles in α decay.

Mortality And Morbidity of Severe Traumatic Brain Injuries; A Pediatric Intensive Care Unit Experience Over 15 Years.

OBJECTIVE: To determine the mortality, morbidity, types of intracranial hemorrhages, and factors associated with length of stay (LOS) associated with accidental traumatic brain injury (TBI) at a pediatric intensive care unit (PICU) of a regional trauma center in an Asian city. METHODS: This study is a retrospective review of types of head injury, mortality and morbidity demographics of patients admitted to a PICU with TBI. All patients with accidental TBI were included, namely road traffic injury (RTI) and fall, and their demographics compared. Non-accidental injuries (NAI) were excluded. RESULTS: 95 children (78% males) were admitted to a PICU with RTI or falls from 2002 to 2017. They accounted for 3.7% of PICU admissions. Comparing with falls, victims of RTI were older (p<0.001) and more likely to suffer from skull fracture (p=0.017). There were 4 deaths with falls (6.8%) but none with RTI. Subarachnoid hemorrhages, extradural hemorrhages, the use of mechanical ventilation, inotropes and neurological supports were associated with longer LOS in PICU in these injuries (p<0.001). CONCLUSION: A longer PICU LOS is associated with extradural and subarachnoid hemorrhages, usage of inotropes, mechanical ventilation and neurological supports in falls and RTI. Three-quarters of victims are males. Preventive health education should be especially directed to boys to reduce severe TBI in this Asian city.

Grafting polycaprolactone diol onto cellulose nanocrystals via click chemistry: Enhancing thermal stability and hydrophobic property.

Hydrophobic and thermally-stable cellulose nanocrystals (CNCs) were synthesized by polycarpolactone diol (PCL diol) grafting via click chemistry strategy. The synthesis was designed as a three-step procedure containing azide-modification of CNCs, alkyne-modification of PCL diol and sequent copper(I)-catalyzed azide-alkyne cycloaddition reaction. The structure of azide-modified CNCs and alkyne-modified PCL diol, the structure, hydrophobic ability and thermal stability of click products CNC-PCL were characterized. FTIR, XPS and H1 NMR results indicated a successful grafting of the N3 groups onto the CNCs, synthesis of PCL diol-CCH, and formation of the CNC-PCL material. CNC-PCL had enhanced dispersion in the non-polar solvent chloroform owing to the well-maintained microscale size and PCL-induced hydrophobic surface. The thermal stability of CNC-PCL was largely increased due to the grafting of thermally-stable PCL. This work demonstrates that click chemistry is an attractive modification strategy to graft CNCs with polyester chains for further potential application in polymer composites.

Synthesis of Cs3PMo12O40/Bi2O3 composite with highly enhanced photocatalytic activity under visible-light irradiation.

A novel visible-light-active Cs3PMo12O40/Bi2O3 (CsPMo/Bi2O3) composite was prepared by a simple dissolution-precipitation method. The as-prepared samples were characterized by XRD, XPS, FT-IR, SEM, UV-Vis DRS, N2 adsorption-desorption isotherms and electrochemical analysis. The results revealed that Bi2O3 was successfully modified by trace CsPMo. After the addition of H3PMo12O40 acid (HPMo), the surface of Bi2O3 can be roughed. Subsequently, the presence of Cs2CO3 can neutralize the protons of HPMo forming CsPMo precipitate on Bi2O3. Comparing to naked Bi2O3 and CsPMo, the binary composite exhibited many beneficial characteristics in charge generation and separation, such as formation of p-n heterojunction, decreased band gap, enhanced photocurrent response and greatly reduced charge transfer resistance. The photocatalytic activities of the as-prepared samples were evaluated by the degradation of phenol under visible light. The calculated pseudo-first-order rate constants for phenol degradation were 2.7 and 14.8 times relative to that on Bi2O3 and CsPMo, respectively. Dramatically enhanced photocatalytic performance can be observed when the optimal CsPMo/Bi2O3 composite (2.5% CsPMo) was applied. The major active species involved in the degradation process are in the following order: superoxide radical (O2-) > hydroxyl radical (OH) ≈ hole (h+). Besides, the CsPMo/Bi2O3 composite also displayed good stability in cyclic experiments.

Cellulose Nanocrystals (CNCs) from Corn Stalk: Activation Energy Analysis.

Cellulose nanocrystals (CNCs) were isolated from corn stalk using sulfuric acid hydrolysis, and their morphology, chemical structure, and thermal stability properties were characterized. The CNCs had an average length of 120.2 ± 61.3 nm and diameter of 6.4 ± 3.1 nm (L/D = 18.7). The degree of crystallinity of the CNCs increased to 69.20% from the 33.20% crystallinity of raw corn stalk fiber, while the chemical structure was well kept after sulfuric acid hydrolysis. Thermal stability analysis showed that the degradation temperature of the CNCs reached 239.5 °C, which was higher than that of the raw fiber but lower than that of the extracted cellulose. The average activation energy values for the CNCs, evaluated using the Friedman, Flynn-Wall-Ozawa (F-W-O) and Coats-Redfern methods, were 312.6, 302.8, and 309 kJ·mol-1 in the conversion range of 0.1 to 0.8. The isolated CNCs had higher values of activation energy than did the purified cellulose, which was attributed to the stronger hydrogen bonds present in the crystalline domains of CNCs than in those of cellulose. These findings can help better understand the thermal properties of polymer/CNC composites.

Preparation and Properties of Electrospun Poly (Vinyl Pyrrolidone)/Cellulose Nanocrystal/Silver Nanoparticle Composite Fibers.

Poly (vinyl pyrrolidone) (PVP)/cellulose nanocrystal (CNC)/silver nanoparticle composite fibers were prepared via electrospinning using N,N'-dimethylformamide (DMF) as a solvent. Rheology, morphology, thermal properties, mechanical properties, and antimicrobial activity of nanocomposites were characterized as a function of material composition. The PVP/CNC/Ag electrospun suspensions exhibited higher conductivity and better rheological properties compared with those of the pure PVP solution. The average diameter of the PVP electrospun fibers decreased with the increase in the amount of CNCs and Ag nanoparticles. Thermal stability of electrospun composite fibers was decreased with the addition of CNCs. The CNCs help increase the composite tensile strength, while the elongation at break decreased. The composite fibers included Ag nanoparticles showed improved antimicrobial activity against both the Gram-negative bacterium Escherichia coli (E. coli) and the Gram-positive bacterium Staphylococcus aureus (S. aureus). The enhanced strength and antimicrobial performances of PVP/CNC/Ag electrospun composite fibers make the mat material an attractive candidate for application in the biomedical field.

Room temperature polariton lasing vs. photon lasing in a ZnO-based hybrid microcavity.

We report on the room temperature polariton lasing and photon lasing in a ZnO-based hybrid microcavity under optical pumping. A series of experimental studies of the polariton lasing (exciton-photon detunings of δ = -119 meV) in the strong-coupling regime are discussed and compared to a photon lasing (δ = -45 meV) in the weak-coupling regime obtained in the same structure. The measured threshold power density (31.8 kW/cm2) of polariton lasing is one order of magnitude lower than that of the photon lasing (318.2 kW/cm2). In addition, the comparison between polariton lasing and photon lasing is done in terms of the linewidth broadening, blue-shift of the emission peak, and polarization.

Room temperature current injection polariton light emitting diode with a hybrid microcavity.

The strong light-matter interaction within a semiconductor high-Q microcavity has been used to produce half-matter/half-light quasiparticles, exciton-polaritons. The exciton-polaritons have very small effective mass and controllable energy-momentum dispersion relation. These unique properties of polaritons provide the possibility to investigate the fundamental physics including solid-state cavity quantum electrodynamics, and dynamical Bose-Einstein condensates (BECs). Thus far the polariton BEC has been demonstrated using optical excitation. However, from a practical viewpoint, the current injection polariton devices operating at room temperature would be most desirable. Here we report the first realization of a current injection microcavity GaN exciton-polariton light emitting diode (LED) operating under room temperature. The exciton-polariton emission from the LED at photon energy 3.02 eV under strong coupling condition is confirmed through temperature-dependent and angle-resolved electroluminescence spectra.