Cancer-associated fibroblasts secrete hypoxia-induced serglycin to promote head and neck squamous cell carcinoma tumor cell growth in vitro and in vivo by activating the Wnt/ß-catenin pathway.

BACKGROUND: The tumor microenvironment (TME) is known to play a prominent role in the pathology of head and neck squamous cell carcinoma (HNSCC). Cancer-associated fibroblasts (CAFs) have been reported to regulate tumor progression, and serglycin (SRGN), one of the paracrine cytokines of CAFs, has been reported to play an important role in various signaling pathways. Hypoxia is a distinct feature of the HNSCC TME. Here, we investigated the mechanism underlying CAF-secreted SRGN leading to HNSCC progression under hypoxia. METHODS: Immunohistochemical staining was used to detect SRGN expression in clinical HNSCC samples, after which its relation with patient survival was assessed. CAFs were isolated and SRGN expression and secretion by CAFs under normoxia and hypoxia were confirmed using qRT-PCR and ELISA assays, respectively. HNSCC sphere-forming abilities, stemness-related gene expression, and chemoresistance were assessed with or without SRGN treatment. A Wnt/ß-catenin pathway inhibitor (PNU-75,654) was used to block its activation, after which nuclear translocation of ß-catenin in the presence of SRGN with or without PNU-75,654 was evaluated. shRNAs were used to stably knock down SRGN expression in CAFs. HNSCC tumor cells with or without (SRGN silenced) CAFs were inoculated submucosally in nude mice after which tumor weights and sizes were determined to assess the effects of CAFs and SRGN on tumor growth. RESULTS: We found that SRGN was expressed in both HNSCC tumor and stroma cells, and that high SRGN expression in the stroma cells, but not in the tumor cells, was significantly related to a poor patient survival. After the extraction of CAFs and normal fibroblasts (NFs) from paired tumor samples and adjacent normal tissues, respectively, we found that the expression of CAF-specific genes, including fibroblast activation protein (FAP) and alpha-smooth muscle actin (α-SMA), was clearly upregulated compared to the expression in NFs. The hypoxia marker HIF-1α was found to be expressed in tumor stroma cells. Hypoxyprobe immunofluorescence staining confirmed stromal hypoxia in an orthotopic tongue cancer mouse model. Using qRT-PCR and ELISA we found that a hypoxic TME upregulated SRGN expression and secretion by CAFs. SRGN markedly enhanced the sphere-forming ability, stemness-related gene expression and chemoresistance of HNSCC tumor cells. SRGN activated the Wnt/ß-catenin pathway and promoted ß-catenin nuclear translocation. An in vivo study confirmed that CAFs can accelerate HNSCC tumor growth, and that this effect can be counteracted by SRGN silencing. CONCLUSIONS: Our data indicate that a hypoxic tumor stroma can lead to upregulation of SRGN expression. SRGN secreted by CAFs can promote ß-catenin nuclear translocation to activate downstream signaling pathways, leading to enhanced HNSCC cell stemness, chemoresistance and accelerated tumor growth.

Fast-timing microchannel plate photodetectors: Design, fabrication, and characterization.

We report a detailed design, fabrication, and characterization of 6 × 6 cm2 fast timing photodetectors based on next-generation microchannel plates (MCPs). The whole assembly is made of low-cost borosilicate glass materials and hermetically sealed with a bialkali photocathode in a vacuum. The flexible photodetector design provides the potential of modifying individual components as well as the entire configuration to fit for different applications. A series of prototype MCP-photodetectors were fabricated following a step-by-step process including functionalization of glass capillary array through atomic layer deposition, MCP baking and scrubbing, photocathode deposition, and hermetic thermo-compression sealing. The prototype MCP-photodetectors exhibit electron gains well beyond 107 level with good relative uniformity. An excellent rise time of 439 ps, timing distribution root-mean-square at a single photoelectron mode of 105 ps, a timing resolution of 20 ps, and magnetic field tolerance up to 1.3 T were achieved for a photodetector with 10 µm pore size MCPs, comparing to that of 536 ps, 205 ps, 63 ps, and 0.7 T for the one with 20 µm pore size MCPs.

Carrier-free nano-integrated strategy for synergetic cancer anti-angiogenic therapy and phototherapy.

Herein, a nano-integrated strategy was used to combine an anti-angiogenic agent sorafenib and a photosensitizer chlorin e6 to form carrier-free multifunctional nanoparticles (SC NPs) for synergetic anti-angiogenic therapy and phototherapy. SC NPs (diameter, ∼152 nm) presented excellent water dispersity and passive targeting ability towards tumor sites in vivo based on the enhanced permeability and retention (EPR) effect, which could be monitored by fluorescence imaging. Besides, SC NPs exhibited effective reactive oxygen species (ROS) generation and photothermal conversion abilities for both photodynamic therapy (PDT) and photothermal therapy (PTT). At a rather low dosage (200 µg kg-1) and illumination with laser (660 nm, 500 mW cm-2), SC NPs could attack tumor tissues by killing the internal tumor cells via mild phototherapy, simultaneously cutting off the external nutrient and oxygen supplements of the tumor cells via anti-angiogenesis. Besides, oxygen consumption in the PDT process may be combined with anti-angiogenic therapy to further cause cell apoptosis by tumor starvation. In addition to the highly efficient therapeutic effect in vivo, SC NPs possessed excellent biosafety and biocompatibility, making them promising for fluorescence imaging-guided synergetic anti-angiogenic therapy and phototherapy in clinic.

HOTTIP Functions as a Key Candidate Biomarker in Head and Neck Squamous Cell Carcinoma by Integrated Bioinformatic Analysis.

BACKGROUND: Accumulating evidence has demonstrated the pivotal role of long noncoding RNAs (lncRNAs) in competing endogenous RNA (ceRNA) networks for predicting survival and evaluating prognosis in cancer patients. However, the pathogenesis of head and neck squamous cell carcinoma (HNSCC) remains unclear, and prognostic biomarkers for HNSCC are still lacking. METHODS: A total of 546 RNA sequencing profiles of HNSCC patients with clinical outcome data were obtained from the Cancer Genome Atlas (TCGA) database, providing a large sample of RNA sequencing data. From these, 71 Long noncoding RNAs lncRNAs, 8 microRNAs (miRNAs), and 16 messenger RNAs (mRNAs) were identified to construct a HNSCC-specific ceRNA network (fold change >2, P < 0.05). Univariate and multivariate Cox proportional regression models were used to assess independent indicators of prognosis. Then the expression of lncRNAs harboring prognostic value was validated in human HNSCC cell lines and tumor samples from our cohort and another two datasets from GEO (Gene Expression Omnibus) databases. RESULTS: As a result, a 3-mRNA signature and 6-lncRNA signature were identified. The six-lncRNA signature exhibited the highest prognostic value. Notably, in the six lncRNAs, HOTTIP showed the greatest prognostic value and was significantly correlated with clinical stage and histological grade of HNSCC patients. Furthermore, it was proved that HOTTIP was upregulated in HNSCC cell lines and cancerous tissues compared with corresponding normal cell lines and normal tissues. Functional assessment analysis revealed that HOTTIP might play a key role in the oncogenesis and progression of HNSCC. CONCLUSION: The present study deepened our understanding of the ceRNA-related regulatory mechanism in the pathogenesis of HNSCC and identified candidate prognostic biomarkers for clinical outcome prediction in HNSCC. HOTTIP may function as a key candidate biomarker in HNSCC and serve as a prognostic marker for HNSCC patients.

Metformin sensitizes hypoxia-induced gefitinib treatment resistance of HNSCC via cell cycle regulation and EMT reversal.

OBJECTIVES: The objectives of this study were to explore the mechanisms of metformin sensitization to hypoxia-induced gefitinib treatment in resistant head and neck squamous cell carcinoma (HNSCC) and evaluate the effects of this combined treatment strategy. METHODS: The effects of gefitinib treatment on HNSCC were measured under normoxic and hypoxic conditions. The relationship between hypoxia and cell cycle and epithelial-mesenchymal transition (EMT) in tumor cells were analyzed. Palbociclib and LY294002 were used in combination with gefitinib to evaluate the effects on HNSCC cell cytotoxicity during hypoxia. Finally, metformin was used to evaluate the sensitizing effects of gefitinib treatment on HNSCC in vivo and in vitro. RESULTS: Cell viability and apoptosis assays demonstrated a significant difference in HNSCC cells treated with gefitinib between the normoxia and hypoxia groups. Hypoxia induced the expression of cyclin D1, decreased the percentage of cells in G1, and promoted the EMT of tumor cells. Both palbociclib and LY294002 enhanced gefitinib-induced cytotoxicity of HNSCC cells under hypoxic conditions. Encouragingly, metformin sensitized HNSCC to gefitinib treatment in vivo and in vitro. CONCLUSION: Hypoxia promotes G1-S cell cycle progression and EMT in HNSCC, resulting in gefitinib treatment resistance. Metformin sensitizes HNSCC to gefitinib treatment, which might serve as a novel combined treatment strategy.

Wavelength-shifting properties of luminescence nanoparticles for high energy particle detection and specific physics process observation.

Ultraviolet (UV) photon detection is becoming increasingly important in the quest to understand the fundamental building blocks of our universe. Basic properties of neutrinos and Dark Matter are currently being explored through interactions with noble elements. In response to interactions with fundamental particles, these elements emit scintillation photons in the UV range. However, most available detectors have poor response in the UV so it is typically necessary to shift UV to a wavelength, matching the sensitivity of the viable detectors. We report on development of UV-enhanced photosensors using wavelength-shifting properties of nanoparticles. Several nanoparticle coatings were tested for absorption of UV light with subsequent emission in the visible wavelength for high energy particle detection. ZnS:Mn,Eu, ZnS:Mn, CuCy (Copper Cysteamine) and CdTe nanoparticles all exhibited enhanced detection for wavelengths in the range 200-320 nm in several different tests, while ZnS:Ag and CdS nanoparticle showed little or no enhancement in that range. In addition, various LaF3:Ce nanoparticle concentrations in approximately constant thickness of 2,5-diphenyloxazole (PPO)/polystyrene bases were also tested to optimize the nanoparticle concentration for the best outcome. Our studies indicated that ZnS:Mn,Eu, ZnS:Mn, Cu-Cy, CdTe and LaF3:Ce nanoparticles show potential for light detection from fundamental particle interactions.

Comparative Transcriptomic Analysis in Paddy Rice under Storage and Identification of Differentially Regulated Genes in Response to High Temperature and Humidity.

The transcriptomes of paddy rice in response to high temperature and humidity were studied using a high-throughput RNA sequencing approach. Effects of high temperature and humidity on the sucrose and starch contents and α/ß-amylase activity were also investigated. Results showed that 6876 differentially expressed genes (DEGs) were identified in paddy rice under high temperature and humidity storage. Importantly, 12 DEGs that were downregulated fell into the "starch and sucrose pathway". The quantitative real-time polymerase chain reaction assays indicated that expression of these 12 DEGs was significantly decreased, which was in parallel with the reduced level of enzyme activities and the contents of sucrose and starch in paddy rice stored at high temperature and humidity conditions compared to the control group. Taken together, high temperature and humidity influence the quality of paddy rice at least partially by downregulating the expression of genes encoding sucrose transferases and hydrolases, which might result in the decrease of starch and sucrose contents.

Prognostic factors of palatal mucoepidermoid carcinoma: a retrospective analysis based on a double-center study.

Mucoepidermoid carcinoma (MEC) of the palate is a common malignancy of minor salivary glands. This study was designed to identify the prognostic factors for MEC of the palate. The medical records of patients diagnosed with MEC of the palate who visited the Department of Oral and Maxillofacial Surgery at Nanjing Stomatological Hospital and the Department of Stomatology at Central Hospital of Xuzhou were retrospectively studied. The prognostic factors were determined using a Cox proportional hazards model. Furthermore, the expression of cancer stem cell (CSC) markers CD44, CD133, Nanog and Sox2 were detected in neoplastic samples of these patients by immunohistochemistry. As a result, both univariate analysis and multivariate analysis proved a high histological grade and an advanced tumor stage as negative prognostic factors for overall survival. By immunohistochemistry staining and survival analysis, a combination of CD44/CD133/SOX2 was found to have the strongest prognostic value for palatal MEC patients. In conclusion, the proposed nomogram which include histological grade and tumor stage along with cancer stem cell markers provides a more accurate long-term prediction for palatal MEC patients.

Metformin sensitizes the response of oral squamous cell carcinoma to cisplatin treatment through inhibition of NF-κB/HIF-1α signal axis.

Resistance towards chemotherapy is a common complication in treatment of oral cancers, which leads to treatment failure and poor outcome. In recent years, a growing body of evidence has shown that tumour hypoxia significantly contributes to chemoresistance. Metformin, a widely used oral hypoglycaemic drug, can reportedly potentiate the efficacy of chemotherapeutic drugs in various cancers; however, the underlying mechanisms are intricate and have not been fully understood. In this study, we explored the role of metformin in chemosensitivity of oral squamous cell carcinoma cells (OSCC) to cisplatin both in vitro and in vivo, and attempted to elucidate its possible underlying mechanisms. Encouragingly, we found that metformin synergistically enhanced cisplatin cytotoxicity and reversed the chemoresistance to certain extent. This mechanism could likely be related with inhibition of the NF-κB/HIF-1α signal axis and lead to the downregulation of hypoxia-regulated genes products. Therefore, metformin could serve as a chemosensitiser for cisplatin-based regimens for OSCC, thereby providing a theoretical basis for future use in the treatment of oral cancers.

Molecular-based synthetic approach to new group IV materials for high-efficiency, low-cost solar cells and Si-based optoelectronics.

Ge(1-x-y)Si(x)Sn(y) alloys have emerged as a new class of highly versatile IR semiconductors offering the potential for independent variation of band structure and lattice dimension, making them the first practical group IV ternary system fully compatible with Si CMOS processing. In this paper we develop and apply new synthetic protocols based on designer molecular hydrides of Si, Ge, and Sn to demonstrate this concept from a synthesis perspective. Variation of the Si/Sn ratio in the ternary leads to an entirely new family of semiconductors exhibiting tunable direct band gaps (E(o)) ranging from 0.8 to 1.2 eV at a fixed lattice constant identical to that of Ge, as required for the design of high-efficiency multijunction solar cells based on group IV/III-V hybrids. As a proof-of-concept demonstration, we fabricated lattice-matched Si(100)/Ge/SiGeSn/InGaAs architectures on low-cost Si(100) substrates for the first time. These exhibit the required optical, structural, and thermal properties, thus representing a viable starting point en route to a complete four-junction photovoltaic device. In the context of Si-Ge-Sn optoelectronic applications, we show that Ge(1-x-y)Si(x)Sn(y) alloys serve as higher-gap barrier layers for the formation of light emitting structures based on Ge(1-y)Sn(y) quantum wells grown on Si.