Development and validation of a novel approach for evaluation of broadband UVA irradiance and total daily UVA exposures from OMI satellite data

It is important to collect and validate data from satellites in order to obtain global information about the solar UVA (320-400 nm) environment. This research reconstructed and validated the broadband UVA irradiances derived from discrete spectral irradiance data retrieved from the Ozone Monitoring Instrument (OMI) satellite from 1 January to 31 December 2009. OMI data at solar noon was compared to ground based spectral irradiance at Toowoomba (27°36’ S 151°55’ E), Australia at 310, 324 and 380 nm for both cloud free and all sky conditions. There was a strong relationship between the ground based UV spectroradiometer data and satellite based measurements with an R2 of 0.89 or better in each waveband for cloud free days. Models developed for the sub-tropical site data account for these differences and are essential for any correlation between satellite and ground based measurements. Additionally, this research has developed a model to evaluate the solar noon broadband UVA irradiance from the discrete satellite spectral irradiance at 310, 324 and 380 nm, comparing the UVA irradiance at solar noon on cloud free days to those measured over 12 months with a ground based UVA radiometer. An R2 of 0.86 was obtained confirming that for cloud free days the broadband UVA can be evaluated from the OMI satellite spectral measurements. This research also investigated the influence of cloud on the broadband UVA solar noon irradiance evaluated from the solar noon satellite based OMI spectral UV data that were compared to the ground based radiometer irradiance in a twelve year period, from 1 October 2004 to 31 December 2016. The correlation, calculated with the model, between ground based radiometer data and the evaluated OMI broadband UVA irradiance depend on whether or not the solar disc was obscured by the presence of cloud and on the total sky cloud fraction. For conditions when the sun was not obscured by cloud, the evaluated satellite and the ground-based UVA irradiance correlation was best for cloud cover between 0-2 okta (R2 = 0.78) and worst for high cloud cover of >4 and up to 8 okta (R2 between 0.30 and 0.40). The R2 value reduced with increasing cloud cover and showed significantly weaker correlation when the sun was obscured. The correlation between the evaluated satellite broadband UVA and ground-based measurements over the twelve years for total cloud cover conditions of 4 okta or less confirmed that the broadband UVA satellite evaluation model using the OMI spectral data is valid for approximately 71% of the days at the Southern Hemisphere sub-tropical study site. This research then developed a method to accurately calculate the total daily broadband UVA exposure from the satellite derived solar noon irradiance on cloud free days. The method utilises cloud free UVA irradiance data, collected daily at high temporal resolution over the period 2005 to 2016, to derive the normalised diurnal UVA exposure and determine a factor relating the solar noon irradiance to the total daily UVA exposure. To demonstrate the versatility of this approach, OMI satellite solar noon UVA irradiance data were employed in calculating the total daily UVA exposures and compared to the respective ground based site measurements. There was a strong correlation between the total daily satellite and ground based broadband UVA exposures (R2 = 0.90). The developed method enables the total daily UVA exposures to be evaluated from satellite solar noon UVA irradiances at sites that do not record short term temporal variations in terrestrial UVA. daily UVA exposure calculated from the three OMI UV spectral irradiance measures at solar noon. These evaluated satellite total daily UVA exposures were compared to the total daily UVA exposures of a ground based broadband radiometer over the period of October 2004 to December 2014 at the Toowoomba site under all cloud cover conditions including sun obscured and not obscured states. The method was employed to evaluate the influence of cloud on the total daily UVA exposure. When the sun was not obscured by cloud, there was good agreement between satellite and ground based daily UVA exposure with R2 between 0.80 and 0.84 for the cloud conditions 0 to 2, > 2 to 4, > 4 to 6 and > 6 to 8 okta. For sun obscured by cloud, the R2 was 0.71, 0.64 and 0.75 respectively for > 2 to 4, > 4 to 6 and > 6 to 8 okta. The method was validated using total daily UVA exposures from ground measurements taken in 2015 and 2016 giving a mean absolute error of 84.2 kJ/m2 (10%) and 138.8 kJ/m2 (30%) respectively for the cases of sun not obscured cloudy days and sun obscured by cloud cover. Total daily UVA exposures were able to be calculated from the OMI satellite spectral irradiance data for all cloud conditions, including cases when the sun was obscured, demonstrating the potential of the technique to be applied remotely in locations that do not record surface UVA measurements directly

Validation of ozone monitoring instrument UV satellite data using spectral and broadband surface based measurements at a Queensland site

This research reconstructed and validated the broadband UVA irradiances derived from discrete spectral irradiance data retrieved from the Ozone Monitoring Instrument (OMI) satellite from 1 January to 31 December 2009. OMI data at solar noon was compared to ground based spectral irradiances at Toowoomba (27°36’ S 151°55’ E), Australia at 310, 324 and 380 nm for both cloud free and all sky conditions. There was a strong relationship between the ground based UV spectroradiometer data and satellite based measurements with an R2 of 0.89 or better in each waveband for cloud free days. The data show an over-estimate of the satellite derived spectral irradiances compared to the ground based data. The models developed for the sub-tropical site data account for this over-estimation and are essential for any data correlation between satellite and ground based measurements. Additionally, this research has compared solar noon broadband UVA irradiances evaluated with a model and the discrete satellite spectral irradiances for the solar noon values of cloud free days to those measured with a ground based UVA radiometer. An R2 of 0.86 was obtained confirming that for cloud free days the broadband UVA can be evaluated from the OMI satellite spectral irradiances

Satellite monitoring of environmental solar ultraviolet A (UVA) exposure and irradiance: a review of OMI and GOME-2

Excessive exposure to solar ultraviolet (UV) radiation has damaging effects on life on Earth. High-energy short-wavelength ultraviolet B (UVB) is biologically effective, influencing a range of dermal processes, including the potentially beneficial production of vitamin D. In addition to the damaging effects of UVB, the longer wavelength and more abundant ultraviolet A (UVA) has been shown to be linked to an increased risk of skin cancer. To evaluate this risk requires the monitoring of the solar UVA globally on a time repetitive basis in order to provide an understanding of the environmental solar UVA irradiance and resulting exposures that humans may receive during their normal daily activities. Satellite-based platforms, with the appropriate validation against ground-based instrumentation, can provide global monitoring of the solar UVA environment. Two satellite platforms that currently provide data on the terrestrial UVA environment are the ozone monitoring instrument (OMI) and the global ozone monitoring experiment (GOME-2). The objectives of this review are to provide a summary of the OMI and GOME-2 satellite-based platforms for monitoring the terrestrial UVA environment and to compare the remotely sensed UVA data from these platforms to that from ground-based instrumentation

Oncolytic reovirus as a combined antiviral and anti-tumour agent for the treatment of liver cancer

Objective: Oncolytic viruses (OVs) represent promising, proinflammatory cancer treatments. Here, we explored whether OV-induced innate immune responses could simultaneously inhibit HCV while suppressing hepatocellular carcinoma (HCC). Furthermore, we extended this exemplar to other models of virus-associated cancer. Design and results: Clinical grade oncolytic orthoreovirus (Reo) elicited innate immune activation within primary human liver tissue in the absence of cytotoxicity and independently of viral genome replication. As well as achieving therapy in preclinical models of HCC through the activation of innate degranulating immune cells, Reo-induced cytokine responses efficiently suppressed HCV replication both in vitro and in vivo. Furthermore, Reo-induced innate responses were also effective against models of HBV-associated HCC, as well as an alternative endogenous model of Epstein–Barr virus-associated lymphoma. Interestingly, Reo appeared superior to the majority of OVs in its ability to elicit innate inflammatory responses from primary liver tissue. Conclusions: We propose that Reo and other select proinflammatory OV may be used in the treatment of multiple cancers associated with oncogenic virus infections, simultaneously reducing both virus-associated oncogenic drive and tumour burden. In the case of HCV-associated HCC (HCV-HCC), Reo should be considered as an alternative agent to supplement and support current HCV-HCC therapies, particularly in those countries where access to new HCV antiviral treatments may be limited

BRAF- and MEK-targeted small molecule inhibitors exert enhanced antimelanoma effects in combination with oncolytic reovirus through ER stress

Reovirus type 3 (Dearing) (RT3D) infection is selective for cells harboring a mutated/activated RAS pathway. Therefore, in a panel of melanoma cell lines (including RAS mutant, BRAF mutant and RAS/BRAF wild-type), we assessed therapeutic combinations that enhance/suppress ERK1/2 signaling through use of BRAF/MEK inhibitors. In RAS mutant cells, the combination of RT3D with the BRAF inhibitor PLX4720 (paradoxically increasing ERK1/2 signaling in this context) did not enhance reoviral cytotoxicity. Instead, and somewhat surprisingly, RT3D and BRAF inhibition led to enhanced cell kill in BRAF mutated cell lines. Likewise, ERK1/2 inhibition, using the MEK inhibitor PD184352, in combination with RT3D resulted in enhanced cell kill in the entire panel. Interestingly, TCID 50 assays showed that BRAF and MEK inhibitors did not affect viral replication. Instead, enhanced efficacy was mediated through ER stress-induced apoptosis, induced by the combination of ERK1/2 inhibition and reovirus infection. In vivo, combined treatments of RT3D and PLX4720 showed significantly increased activity in BRAF mutant tumors in both immune-deficient and immune-competent models. These data provide a strong rationale for clinical translation of strategies in which RT3D is combined with BRAF inhibitors (in BRAF mutant melanoma) and/or MEK inhibitors (in BRAF and RAS mutant melanoma)

Validation of OMI erythemal doses with multi-sensor ground-based measurements in Thessaloniki, Greece

The aim of this study is to validate the Ozone Monitoring Instrument (OMI) erythemal dose rates using ground-based measurements in Thessaloniki, Greece. In the Laboratory of Atmospheric Physics of the Aristotle University of Thessaloniki, a Yankee Environmental System UVB-1 radiometer measures the erythemal dose rates every minute, and a Norsk Institutt for Luftforskning (NILU) multi-filter radiometer provides multi-filter based irradiances that were used to derive erythemal dose rates for the period 2005–2014. Both these datasets were independently validated against collocated UV irradiance spectra from a Brewer MkIII spectrophotometer. Cloud detection was performed based on measurements of the global horizontal radiation from a Kipp & Zonen pyranometer and from NILU measurements in the visible range. The satellite versus ground observation validation was performed taking into account the effect of temporal averaging, limitations related to OMI quality control criteria, cloud conditions, the solar zenith angle and atmospheric aerosol loading. Aerosol optical depth was also retrieved using a collocated CIMEL sunphotometer in order to assess its impact on the comparisons. The effect of total ozone columns satellite versus ground-based differences on the erythemal dose comparisons was also investigated. Since most of the public awareness alerts are based on UV Index (UVI) classifications, an analysis and assessment of OMI capability for retrieving UVIs was also performed. An overestimation of the OMI erythemal product by 3–6% and 4–8% with respect to ground measurements is observed when examining overpass and noontime estimates respectively. The comparisons revealed a relatively small solar zenith angle dependence, with the OMI data showing a slight dependence on aerosol load, especially at high aerosol optical depth values. A mean underestimation of 2% in OMI total ozone columns under cloud-free conditions was found to lead to an overestimation in OMI erythemal doses of 1–5%.While OMI overestimated the erythemal dose rates over the range of cloudiness conditions examined, its UVIs were found to be reliable for the purpose of characterising the ambient UV radiation impact

Small molecule FGF receptor inhibitors block FGFR-dependent urothelial carcinoma growth in vitro and in vivo

BACKGROUND: Activating mutations of FGFR3 are frequently identified in superficial urothelial carcinoma (UC) and increased expression of FGFR1 and FGFR3 are common in both superficial and invasive UC. METHODS: The effects of inhibition of receptor activity by three small molecule inhibitors (PD173074, TKI-258 and SU5402) were investigated in a panel of bladder tumour cell lines with known FGFR expression levels and FGFR3 mutation status. RESULTS: All inhibitors prevented activation of FGFR3, and inhibited downstream MAPK pathway signalling. Response was related to FGFR3 and/or FGFR1 expression levels. Cell lines with the highest levels of FGFR expression showed the greatest response and little or no effect was measured in normal human urothelial cells or in UC cell lines with activating RAS gene mutations. In sensitive cell lines, the drugs induced cell cycle arrest and/or apoptosis. IC(50) values for PD173074 and TKI-258 were in the nanomolar concentration range compared with micromolar concentrations for SU5402. PD173074 showed the greatest effects in vitro and in vivo significantly delayed the growth of subcutaneous bladder tumour xenografts. CONCLUSION: These results indicate that inhibition of FGFR1 and wild-type or mutant FGFR3 may represent a useful therapeutic approach in patients with both non-muscle invasive and muscle invasive UC

Reovirus exerts potent oncolytic effects in head and neck cancer cell lines that are independent of signalling in the EGFR pathway

Background: reovirus exploits aberrant signalling downstream of Ras to mediate tumor-specific oncolysis. Since ~90% squamous cell carcinomas of the head and neck (SCCHN) over-express EGFR and SCCHN cell lines are sensitive to oncolytic reovirus, we conducted a detailed analysis of the effects of reovirus in 15 head and neck cancer cell lines. Both pre- and post-entry events were studied in an attempt to define biomarkers predictive of sensitivity/resistance to reovirus. In particular, we analysed the role of EGFR/Ras signalling in determining virus-mediated cytotoxicity in SCCHN. Methods: to test whether EGFR pathway activity was predictive of increased sensitivity to reovirus, correlative analyses between reoviral IC50 by MTT assay and EGFR levels by western blot and FACS were conducted. Inhibition or stimulation of EGFR signalling were analysed for their effect on reoviral oncolysis by MTT assay, and viral growth by TCID50 assay. We next analysed the effects of inhibiting signalling downstream of Ras, by specific inhibitors of p38MAPK, PI3-K or MEK, on reoviral killing examined by MTT assay. The role of PKR in reoviral killing was also determined by blockade of PKR using 2-aminopurine and assaying for cell survival by MTT assay. The apoptotic response of SCCHN to reovirus was examined by western blot analysis of caspase 3 cleavage. Results: correlative analyses between reoviral sensitivity and EGFR levels revealed no association. Intermediate sub-viral and core particles showed the same infectivity/cytotoxicity as intact reovirus. Therefore, sensitivity was not determined by cell entry. In 4 cell lines, oncolysis and viral growth were both unaffected by inhibition or stimulation of EGFR signalling. Inhibition of signalling downstream of Ras did not abrogate reoviral oncolysis and, in addition, modulation of PKR using 2-aminopurine did not alter reovirus sensitivity in resistant cell lines. Caspase 3 cleavage was not detected in infected cells and oncolysis was observed in pan-caspase inhibited cells. Conclusions: in summary, reovirus is potently oncolytic in a broad panel of SCCHN cell lines. Attempts to define sensitivity/resistance by analysis of the EGFR/Ras/MAPK pathway have failed to provide a clear predictive biomarker of response. Further analysis of material from in vitro and clinical studies is ongoing in an attempt to shed further light on this issue

A Systematic Study of Gene Mutations in Urothelial Carcinoma; Inactivating Mutations in TSC2 and PIK3R1

Abstract BACKGROUND: Urothelial carcinoma (UC) is characterized by frequent gene mutations of which activating mutations in FGFR3 are the most frequent. Several downstream targets of FGFR3 are also mutated in UC, e.g., PIK3CA, AKT1, and RAS. Most mutation studies of UCs have been focused on single or a few genes at the time or been performed on small sample series. This has limited the possibility to investigate co-occurrence of mutations. METHODOLOGY/PRINCIPAL FINDINGS: We performed mutation analyses of 16 genes, FGFR3, PIK3CA, PIK3R1 PTEN, AKT1, KRAS, HRAS, NRAS, BRAF, ARAF, RAF1, TSC1, TSC2, APC, CTNNB1, and TP53, in 145 cases of UC. We show that FGFR3 and PIK3CA mutations are positively associated. In addition, we identified PIK3R1 as a target for mutations. We demonstrate a negative association at borderline significance between FGFR3 and RAS mutations, and show that these mutations are not strictly mutually exclusive. We show that mutations in BRAF, ARAF, RAF1 rarely occurs in UC. Our data emphasize the possible importance of APC signaling as 6% of the investigated tumors either showed inactivating APC or activating CTNNB1 mutations. TSC1, as well as TSC2, that constitute the mTOR regulatory tuberous sclerosis complex were found to be mutated at a combined frequency of 15%. CONCLUSIONS/SIGNIFICANCE: Our data demonstrate a significant association between FGFR3 and PIK3CA mutations in UC. Moreover, the identification of mutations in PIK3R1 further emphasizes the importance of the PI3-kinase pathway in UC. The presence of TSC2 mutations, in addition to TSC1 mutations, underlines the involvement of mTOR signaling in UC

Biology of urothelial tumorigenesis: insights from genetically engineered mice

Urothelium, one of the slowest cycling epithelia in the body, embodies a unique biological context for cellular transformation. Introduction of oncogenes into or removing tumor suppressor genes from the urothelial cells or a combination of both using the transgenic and/or knockout mouse approaches has provided useful insights into the molecular mechanisms of urothelial transformation and tumorigenesis. It is becoming increasingly clear that over-activation of the receptor tyrosine kinase (RTK) pathway, as exemplified by the constitutively activated Ha-ras oncogene, is both necessary and sufficient to initiate the low-grade, non-invasive urothelial carcinomas. Dosage of the mutated Ha-ras, but not concurrent inactivation of pro-senescence molecules p16Ink4a and p19Arf, dictates whether and when the low-grade urothelial carcinomas arise. Inactivation of both p53 and pRb, a prevailing paradigm previously proposed for muscle-invasive urothelial tumorigenesis, is found to be necessary but insufficient to initiate this urothelial carcinoma variant. Instead, downregulation in p53/pRb co-deficient urothelial cells of p107, a pRb family member, is associated with the genesis of the muscle-invasive bladder cancers. p53 deficiency also seems to be capable of cooperating with that of PTEN in eliciting invasive urothelial carcinomas. The genetically engineered mice have improved the molecular definition of the divergent pathways of urothelial tumorigenesis and progression, helped delineate the intricate crosstalk among different genetic alterations within a urothelium-specific context, identified new prognostic markers and novel therapeutic targets potentially applicable for clinical intervention, and provided in vivo platforms for testing preventive strategies of bladder cancer