p53 modeling as a route to mesothelioma patients stratification and novel therapeutic identification

Background Malignant pleural mesothelioma (MPM) is an orphan disease that is difficult to treat using traditional chemotherapy, an approach which has been effective in other types of cancer. Most chemotherapeutics cause DNA damage leading to cell death. Recent discoveries have highlighted a potential role for the p53 tumor suppressor in this disease. Given the pivotal role of p53 in the DNA damage response, here we investigated the predictive power of the p53 interactome model for MPM patients’ stratification. Methods We used bioinformatics approaches including omics type analysis of data from MPM cells and from MPM patients in order to predict which pathways are crucial for patients’ survival. Analysis of the PKT206 model of the p53 network was validated by microarrays from the Mero-14 MPM cell line and RNA-seq data from 71 MPM patients, whilst statistical analysis was used to identify the deregulated pathways and predict therapeutic schemes by linking the affected pathway with the patients’ clinical state. Results In silico simulations demonstrated successful predictions ranging from 52 to 85% depending on the drug, algorithm or sample used for validation. Clinical outcomes of individual patients stratified in three groups and simulation comparisons identified 30 genes that correlated with survival. In patients carrying wild-type p53 either treated or not treated with chemotherapy, FEN1 and MMP2 exhibited the highest inverse correlation, whereas in untreated patients bearing mutated p53, SIAH1 negatively correlated with survival. Numerous repositioned and experimental drugs targeting FEN1 and MMP2 were identified and selected drugs tested. Epinephrine and myricetin, which target FEN1, have shown cytotoxic effect on Mero-14 cells whereas marimastat and batimastat, which target MMP2 demonstrated a modest but significant inhibitory effect on MPM cell migration. Finally, 8 genes displayed correlation with disease stage, which may have diagnostic implications. Conclusions Clinical decisions related to MPM personalized therapy based on individual patients’ genetic profile and previous chemotherapeutic treatment could be reached using computational tools and the predictions reported in this study upon further testing in animal models

Topical Calendula and Betamethasone Valerate in the prevention of acute radiation dermatitis: a randomized prospective trial

Background: Acute radiation dermatitis is a very common side effect of radiation therapy for many cancers, including breast cancer. Despite the high prevalence of acute radiation dermatitis as well as wet desquamation, only a few trials studying the prophylaxis of this complication using topical treatment have been conducted. In spite of these studies, some controversy still exists about regarding treatments for acute radiation dermatitis, as does some concern about their long-term complications. For this reason, we conducted a clinical trial for a new treatment with the same effectiveness as corticosteroids, but fewer complications. Methods: This trial included 60 patients with pathologic diagnoses of breast cancer for whom radiotherapy had been planned. Patients were 30-73 years old. Patients with radical mastectomy received 5000 cGy over five weeks, and those with conservative surgery received 6000 cGy over six weeks divided in 200 cGy fractions. Patients were divided randomly into two groups: one group received a moderately-potent glucocorticoid steroid, 0.1% betamethasone ointment (30), and the other received the new treatment, 0.1% calendula ointment (30). All patients applied their respective drugs twice daily within the tangential field from the first day of radiation treatment until one month after treatment was completed. Starting one week after radiation therapy commenced, patients were monitored weekly for symptoms of dermatitis and the degree of severity as well as possible adverse drug effects, in addition to such monitoring on the days of their appointments. Four weeks after termination of therapy, patients were again examined, at which time they completed a questionnaire about dermatologic complications. Results: The mean time to develop dermatitis was 3.7 weeks for the betamethasone group and 3.87 weeks for the calendula group. Maximal dermatitis intensity during treatment in the betamethasone group was: 0, 6.7%; I, 73.3%; II, 16.7%; III, 0%; IV, 3.3%. Dermatitis intensity in the calendula group was: 0, 13.3%; I, 67%; II, 16.7%; III, 0%; IV, 3.3%. No significant differences were observed in the incidence of symptoms such as burning, pruritus and pain between the two groups (p=0.762). Conclusion: Calendula ointment is as effective as betamethasone in reducing acute radiation dermatitis

Molecular characterization of hepatitis D virus genotypes circulating in Iran

Aim: To determine the molecular epidemiology and characterization of hepatitis D virus (HDV) genotypes circulating in different provinces of Iran. Patients & methods: In this study, the presence of HDV RNA was tested in sera that were positive for hepatitis B surface antigen and HDV antibody by nested-PCR. HDV genotypes were subsequently analyzed using restriction fragment length polymorphism (RFLP) assay and then confirmed by sequencing. Results: 86.5 of positive PCR patients had genotype I and 8.1 had genotype II while the genotype of 5.4 of the patients remained undetermined by RFLP. Sequencing followed by phylogenetic analysis demonstrated that all the Iranian isolates were from genotype I. Conclusion: Although analyzing the RFLP of RT-PCR is a simpler method, the gold standard of genotyping of HDV is the phylogenetic analysis based on sequencing. © 2018 Future Medicine Ltd

BAP1 status determines the sensitivity of malignant mesothelioma cells to gemcitabine treatment

Malignant mesothelioma (MMe) is a cancer with poor prognosis and resistance to standard treatments. Recent reports have highlighted the role of the BRCA1 associated protein 1 gene (BAP1) in the development of MMe. In this study, the chemosensitivity of human mesothelioma cell lines carrying BAP1 wild-type (WT), mutant and silenced was analysed. The BAP1 mutant cells were significantly less sensitive than BAP1 WT cell lines to the clinically relevant drug gemcitabine. Silencing of BAP1 significantly increased resistance of MMe cells to gemcitabine. Cell cycle analysis suggested that gemcitabine induced Sub-G1 phase accumulation of the BAP1 WT cells and increased in the S-phase in both BAP1 WT and mutant cells. Analysis of the role of BAP1 in apoptosis suggested that gemcitabine induced early apoptosis in both BAP1 WT and BAP1 mutant cells but with a much higher degree in the WT cells. Effects on the population of cells in late apoptosis, which can mark necrosis and necroptosis, could not be seen in the mutant cells, highlighting the possibility that BAP1 plays a role in several types of cell death. Significantly decreased DNA damage in the form of double-strand breaks was observed in gemcitabine-treated BAP1 mutant cells, compared to BAP1 WT cells under the same conditions. After BAP1 silencing, a significant decrease in DNA damage in the form of double-strand breaks was observed compared to cells transfected with scramble siRNA. Taken together, the results presented in this manuscript shed light on the role of BAP1 in the response of MMe cells to gemcitabine treatment and in particular in the control of the DNA damage response, therefore providing a potential route for more efficient MMe therapy

Molecular characterization of hepatitis D virus genotypes circulating in Iran

Aim: To determine the molecular epidemiology and characterization of hepatitis D virus (HDV) genotypes circulating in different provinces of Iran. Patients & methods: In this study, the presence of HDV RNA was tested in sera that were positive for hepatitis B surface antigen and HDV antibody by nested-PCR. HDV genotypes were subsequently analyzed using restriction fragment length polymorphism (RFLP) assay and then confirmed by sequencing. Results: 86.5 of positive PCR patients had genotype I and 8.1 had genotype II while the genotype of 5.4 of the patients remained undetermined by RFLP. Sequencing followed by phylogenetic analysis demonstrated that all the Iranian isolates were from genotype I. Conclusion: Although analyzing the RFLP of RT-PCR is a simpler method, the gold standard of genotyping of HDV is the phylogenetic analysis based on sequencing. © 2018 Future Medicine Ltd

Vertically-aligned silicon carbide nanowires as visible-light-driven photocatalysts

Vertically-aligned crystalline silicon carbide nanowires (VASiCs) (1 mm long and 50–90 nm in diameter) were synthesised in gram scale using SiO2-infiltrated vertically-aligned multi-wall carbon nanotubes (VACNTs) and Si powder. In situ residual gas analysis was employed to study their formation and revealed CO to be the main by-product during synthesis. The in situ studies also showed that the formation of VASiCs begins at 1150 °C with the growth rate reaching a maximum at 1350 °C. A possible growth mechanism was established based on both, in situ and ex situ characterisation. The VASiCs have an estimated band gap of 2.15 eV, are photocatalytically active, and show strong light absorbance of up to 577 nm. Under UV-visible light (260–800 nm) as grown VASiCs could remove 90% Rhodamine B (RhB) within 30 min. Over period of 4 hours under visible light (400–800 nm) more than 95% RhB was removed demonstrating their potential as visible-light-driven photocatalysts

Vertically-aligned silicon carbide nanowires as visible-light-driven photocatalysts

Vertically-aligned crystalline silicon carbide nanowires (VASiCs) (1 mm long and 50–90 nm in diameter) were synthesised in gram scale using SiO2-infiltrated vertically-aligned multi-wall carbon nanotubes (VACNTs) and Si powder. In situ residual gas analysis was employed to study their formation and revealed CO to be the main by-product during synthesis. The in situ studies also showed that the formation of VASiCs begins at 1150 °C with the growth rate reaching a maximum at 1350 °C. A possible growth mechanism was established based on both, in situ and ex situ characterisation. The VASiCs have an estimated band gap of 2.15 eV, are photocatalytically active, and show strong light absorbance of up to 577 nm. Under UV–vis light (260–800 nm) as grown VASiCs could remove 90% Rhodamine B (RhB) within 30 min. Over period of 4 h under visible light (400–800 nm) more than 95% RhB was removed demonstrating their potential as visible-light-driven photocatalysts

Correlating Local Structure and Sodium Storage in Hard Carbon Anodes: Insights from Pair Distribution Function Analysis and Solid-State NMR.

Hard carbons are the leading candidate anode materials for sodium-ion batteries. However, the sodium-insertion mechanisms remain under debate. Here, employing a novel analysis of operando and ex situ pair distribution function (PDF) analysis of total scattering data, supplemented by information on the local electronic structure provided by operando 23Na solid-state NMR, we identify the local atomic environments of sodium stored within hard carbon and provide a revised mechanism for sodium storage. The local structure of carbons is well-described by bilayers of curved graphene fragments, with fragment size increasing, and curvature decreasing with increasing pyrolysis temperature. A correlation is observed between the higher-voltage (slope) capacity and the defect concentration inferred from the size and curvature of the fragments. Meanwhile, a larger lower-voltage (plateau) capacity is observed in samples modeled by larger fragment sizes. Operando PDF data on two commercially relevant hard carbons reveal changes at higher-voltages consistent with sodium ions stored close to defective areas of the carbon, with electrons localized in the antibonding π*-orbitals of the carbon. Metallic sodium clusters approximately 13-15 Å in diameter are formed in both carbons at lower voltages, implying that, for these carbons, the lower-voltage capacity is determined by the number of regions suitable for sodium cluster formation, rather than by having microstructures that allow larger clusters to form. Our results reveal that local atomic structure has a definitive role in determining storage capacity, and therefore the effect of synthetic conditions on both the local atomic structure and the microstructure should be considered when engineering hard carbons.ACKNOWLEDGMENTS We acknowledge Diamond Light Source for time on I15 and I15-1 under proposals EE17785-1 and EE13681-1. J.M.S was supported by the US DoE under Prime Contract no. DE-AC02-05CH11231 (Sub-contract no. 7368738 via Lawrence Berkeley National La-boratory). C.P.G acknowledges support from the Faraday Institu-tion (grant FIRG018). P.K.A acknowledges a Birmingham Fellow-ship from the University of Birmingham. M.T would like to acknowledge EPSRC grants EP/R021554/2 and EP/S018204/2. S.S.M, J.B and C.W.R acknowledge Dr Steven Huband from the University of Warwick for SAXS data acquisition and modelling