Studies on human papillomaviruses in head and neck cancer

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. The traditional risk factors for HNSCC are smoking and alcohol. However, recently IARC has also recognized human papillomaviruses (HPV) as an etiological factor for oropharyngeal cancer, a subset of head and neck cancers. Among oropharyngeal cancer, tonsillar and tongue base cancer dominate, both often associated with HPV. The aim of the present study was to examine the involvement of human papillomavirus (HPV) in two subtypes of HNSCC, tonsillar and hypopharyngeal cancer. For tonsillar cancer the purpose was to evaluate the prevalence of HPV over time and in relation to clinical outcome. In addition we wanted to evaluate if EGFR or phosphorylated EGFR were useful as markers, together with HPV, to predict response to treatment. For hypopharyngeal cancer, the aim was to analyze the prevalence of HPV and if HPV was a risk factor for this tumor type. In the first paper, we found a 7‐fold increase in the incidence of HPV positive tonsillar cancer, between 1970 and 2006, in the County of Stockholm, highlighting HPV as the causative factor for the increased incidence of this tumor type. In addition we found a decline in the incidence of HPV negative tonsillar cancer. In the second paper, we found a high 5‐year disease specific survival for HPV positive tonsillar cancer (81%), as compared to 36% for patients with HPV negative tonsillar cancer. HPV E6 and/or HPV E7 RNA were present in 94% of the samples analyzed, demonstrating the involvement of HPV in carcinogenesis. In the third paper, we analyzed the presence of HPV in HNSCC from Greece and found that HPV is common in tonsillar carcinoma also from this country. In the fourth paper, the presence of HPV and overexpression of p16 in hypopharyngeal cancer from patients in Stockholm, was evaluated. Only 6% were HPV positive, indicating that HPV is not an important risk factor for this disease.   In the fifth paper, overexpression of EGFR and presence of phoshorylated EGFR in tonsillar cancer, were evaluated in relation to tumor HPV status and clinical outcome. We found a correlation between the presence of phosphorylated EGFR and HPV, but not between phosphorylated EGFR and clinical outcome, when HPV positive and negative tumors were evaluated separately. Our studies revealed HPV as a major factor behind the increased incidence of tonsillar cancer in the Stockholm area and an important prognostic factor for this disease, while HPV was not an important risk factor for hypopharyngeal cancer in this area. 

Very large phase shift of microwave signals in a 6 nm Hf x Zr 1− x O 2 ferroelectric at ±3 V

In this letter, we report for the first time very large phase shifts of microwaves in the 1–10 GHz range, in a 1 mm long gold coplanar interdigitated structure deposited over a 6 nm Hf x Zr1−x O2 ferroelectric grown directly on a high resistivity silicon substrate. The phase shift is larger than 60° at 1 GHz and 13° at 10 GHz at maximum applied DC voltages of ±3 V, which can be supplied by a simple commercial battery. In this way, we demonstrate experimentally that the new ferroelectrics based on HfO2 could play an important role in the future development of wireless communication systems for very low power applications

Tumor Infiltrating CD8+ and Foxp3+ Lymphocytes Correlate to Clinical Outcome and Human Papillomavirus (HPV) Status in Tonsillar Cancer

BACKGROUND: Human papillomavirus (HPV) is a causative factor for tonsillar squamous cell carcinoma (TSCC) and patients with HPV positive (HPV(+)) TSCC have a better clinical outcome than those with HPV negative (HPV(-)) TSCC. However, since not all patients with HPV(+) TSCC respond to treatment, additional biomarkers are needed together with HPV status to better predict response to therapy and to individualize treatment. For this purpose, we examined whether the number of tumor infiltrating cytotoxic and regulatory T-cells in TSCC correlated to HPV status and to clinical outcome. METHODS: Formalin fixed paraffin embedded TSCC, previously analysed for HPV DNA, derived from 83 patients, were divided into four groups depending on the HPV status of the tumor and clinical outcome. Tumors were stained by immunohistochemistry and evaluated for the number of infiltrating cytotoxic (CD8(+)) and regulatory (Foxp3(+)) T-cells. RESULTS: A high CD8(+) T-cell infiltration was significantly positively correlated to a good clinical outcome in both patients with HPV(+) and HPV(-) TSCC patients. Similarly, a high CD8(+)/Foxp3(+) TIL ratio was correlated to a 3-year disease free survival. Furthermore, HPV(+) TSCC had in comparison to HPV(-) TSCC, higher numbers of infiltrating CD8(+) and Foxp3(+) T-cells. CONCLUSIONS: In conclusion, a positive correlation between a high number of infiltrating CD8(+) cells and clinical outcome indicates that CD8(+) cells may contribute to a beneficial clinical outcome in TSCC patients, and may potentially serve as a biomarker. Likewise, the CD8(+)/Foxp3(+)cell ratio can potentially be used for the same purpose

Anti-staphylococcal activity and mode of action of thioridazine photoproducts

Antibiotic resistance became an increasing risk for population health threatening our ability to fight infectious diseases. The objective of this study was to evaluate the activity of laser irradiated thioridazine (TZ) against clinically-relevant bacteria in view to fight antibiotic resistance. TZ in ultrapure water solutions was irradiated (1–240 min) with 266 nm pulsed laser radiation. Irradiated solutions were characterized by UV–Vis and FTIR absorption spectroscopy, thin layer chromatography, laser-induced fluorescence, and dynamic surface tension measurements. Molecular docking studies were made to evaluate the molecular mechanisms of photoproducts action against Staphylococcus aureus and MRSA. More general, solutions were evaluated for their antimicrobial and efflux inhibitory activity against a panel of bacteria of clinical relevance. We observed an enhanced antimicrobial activity of TZ photoproducts against Gram-positive bacteria. This was higher than ciprofloxacin effects for methicillin- and ciprofloxacin-resistant Staphylococcus aureus. Molecular docking showed the Penicillin-binding proteins PBP3 and PBP2a inhibition by sulforidazine as a possible mechanism of action against Staphylococcus aureus and MRSA strains, respectively. Irradiated TZ reveals possible advantages in the treatment of infectious diseases produced by antibiotic-resistant Gram-positive bacteria. TZ repurposing and its photoproducts, obtained by laser irradiation, show accelerated and low-costs of development if compared to chemical synthesis.publishersversionpublishe

Oxygen-vacancy induced ferroelectricity in nitrogen-doped nickel oxide

This paper reports the onset of ferroelectricity in NiO by breaking the crystallographic symmetry with oxygen vacancies created by N doping. Nitrogen-doped NiO was grown at room temperature by RF sputtering of Ni target in Ar–O2–N2 plasma on silicon and fused silica substrates. The impact of the nitrogen doping of NiO on microstructural, optical, and electrical properties has been investigated. According to x-ray diffraction investigations, by increasing the N doping level in NiO, a transition from (002) to a (111) preferential orientation for the cubic NiO phase was observed, as well as a lattice strain relaxation, that is usually ascribed to structural defect formation in crystal. The x-ray diffraction pole figures the presence of a distorted cubic structure in NiO and supports the Rietveld refinement findings related to the strain, which pointed out that nitrogen doping fosters lattice imperfections formation. These findings were found to be in agreement with our far-infrared measurements that revealed that upon nitrogen doping a structural distortion of the NiO cubic phase appears. X-ray photo-emission spectroscopy measurements reveal the presence of oxygen vacancies in the NiO film following nitrogen doping. Evidence of ferro-electricity in nitrogen-doped NiO thin films has been provided by using the well-established Sawyer–Tower method. The results reported here provide the first insights on oxygen-vacancy induced ferroelectricity in nitrogen-doped nickel oxide thin films

Transparent all-oxide hybrid NiON/TiO2 heterostructure for optoelectronic applications

Nickel oxide (NiO) is a p-type oxide and nitrogen is one of the dopants used for modifying its properties. Until now, nitrogen-doped NiO has shown inferior optical and electrical properties than those of pure NiO. In this work, we present nitrogen-doped NiO (NiO:N) thin films with enhanced properties compared to those of the undoped NiO thin film. The NiO:N films were grown at room temperature by sputtering using a plasma containing 50% Ar and 50% (O2 + N2) gases. The undoped NiO film was oxygen-rich, single-phase cubic NiO, having a transmittance of less than 20%. Upon doping with nitrogen, the films became more transparent (around 65%), had a wide direct band gap (up to 3.67 eV) and showed clear evidence of indirect band gap, 2.50–2.72 eV, depending on %(O2-N2) in plasma. The changes in the properties of the films such as structural disorder, energy band gap, Urbach states and resistivity were correlated with the incorporation of nitrogen in their structure. The optimum NiO:N film was used to form a diode with spin-coated, mesoporous on top of a compact, TiO2 film. The hybrid NiO:N/TiO2 heterojunction was transparent showing good output characteristics, as deduced using both I-V and Cheung’s methods, which were further improved upon thermal treatment. Transparent NiO:N films can be realized for all-oxide flexible optoelectronic devices

Proteomic and cellular localisation studies suggest non-tight junction cytoplasmic and nuclear roles for occludin in astrocytes

Occludin is a component of tight junctions, which are essential structural components of the blood brain barrier. However, occludin is expressed in cells without tight junctions, implying additional functions. We determined the expression and localisation of occludin in astrocytes in cell culture and in human brain tissue, and sought novel binding partners using a proteomic approach. Expression was investigated by immunocytochemistry and immunoblotting in the 1321N1 astrocytoma cell line and ScienCell human primary astrocytes, and by immunohistochemistry in human autopsy brain tissue. Recombinant N- and C-terminal occludin was used to pull down proteins from 1321N1 cell lysates and protein binding partners identified by mass spectrometry analysis. Occludin was expressed in both the cytoplasm and nucleus of astrocytes in vitro and in vivo. Mass spectrometry identified binding to nuclear and cytoplasmic proteins, particularly those related to RNA metabolism and nuclear function. Occludin is expressed in several subcellular compartments of brain cell-types that do not form tight junctions and the expression patterns in cell culture reflect those in human brain tissue, indicating they are suitable model systems. Proteomic analysis suggests that occludin has novel functions in neuroepithelial cells that are unrelated to tight junction formation. Further research will establish the roles of these functions in both cellular physiology and in disease states. This article is protected by copyright. All rights reserved