Predicting Outcomes From Radical Radiotherapy for Non-small Cell Lung Cancer: A Systematic Review of the Existing Literature

Radical radiotherapy (RT) is a potentially curative treatment in non-small cell lung cancer (NSCLC) and is delivered in conventional 2-Gy fractions, hypofractionated and ablative stereotactic courses. No reliable, predictive biomarkers for the clinical events of local control, appearance of distant metastases and development of toxicity have been introduced in routine clinical practice. Such a test would enable the Radiotherapist to tailor the clinical management of individual patients, considering their pre-treatment characteristics, in order reduce the risk of recurrence or toxicity e.g., dose modification, accelerated fractionation, hypofractionation, or concurrent systemic therapy. The aim of this review was to map the published literature relating to investigations of the potential predictive value of patient or treatment characteristics in radical RT for NSCLC. These investigations should remain a research focus for disease control given the upward trends in lung cancer incidence, and for the avoidance of toxicity, given the survivorship afforded to the cohort of patients that do well with radical RT, or with the increasing range of systemic agents following metastatic relapse. The conclusion of the presented analysis is that there are no published, effective and validated predictive tools for estimation of risk of local/distant recurrence or toxicity after radical RT for NSCLC. The authors have identified an important space for future research in the field of lung cancer radiotherapy

Selective Photocatalytic Reduction of CO2-to-CO in Water using a Polymeric Carbon Nitride Quantum Dot/Fe-Porphyrin Hybrid Assembly

Visible light-driven conversion of CO2 into more value-added products is a promising technology not only for diminution of CO2 emission but also for solar energy storage in the form of chemical energy. However, photocatalytic materials that can efficiently and selectively reduce CO2-to-CO in a fully aqueous solution typically involve precious metals that limit their suitability for large scale applications. Herein, a novel photocatalytic assembly is reported, consisting of polymeric carbon nitride quantum dots (CNQDs) as the visible light absorber and a Fe-porphyrin complex (Fe-p-TMA) as the catalyst for CO2-to-CO conversion. Both components were carefully selected to allow for excellent solubility in water as well as improved electronic communication through complementary electrostatic and π-π interactions. This CNQD ⋅ [Fe-p-TMA] hybrid assembly, at the optimized molar ratio, can produce CO with a turnover number (TON) exceeding 105 and selectivity ∼96 % after 10 hours of visible light irradiation (400–700 nm). It is postulated that the enhanced CO2-to-CO transformation performance is due to the convenience of a more direct charge transfer (CT) pathway between the CNQDs and [Fe-p-TMA] motif

FLIP: A Targetable Mediator of Resistance to Radiation in Non-Small Cell Lung Cancer

Resistance to radiotherapy due to insufficient cancer cell death is a significant cause of treatment failure in non-small cell lung cancer (NSCLC). The endogenous caspase-8 inhibitor, FLIP, is a critical regulator of cell death that is frequently overexpressed in NSCLC and is an established inhibitor of apoptotic cell death induced via the extrinsic death receptor pathway. Apoptosis induced by ionizing radiation (IR) has been considered to be mediated predominantly via the intrinsic apoptotic pathway; however, we found that IR-induced apoptosis was significantly attenuated in NSCLC cells when caspase-8 was depleted using RNA interference (RNAi), suggesting involvement of the extrinsic apoptosis pathway. Moreover, overexpression of wild-type FLIP, but not a mutant form that cannot bind the critical death receptor adaptor protein FADD, also attenuated IR-induced apoptosis, confirming the importance of the extrinsic apoptotic pathway as a determinant of response to IR in NSCLC. Importantly, when FLIP protein levels were down-regulated by RNAi, IRinduced cell death was significantly enhanced. The clinically relevant histone deacetylase (HDAC) inhibitors vorinostat and entinostat were subsequently found to sensitize a subset of NSCLC cell lines to IR in a manner that was dependent on their ability to suppress FLIP expression and promote activation of caspase-8. Entinostat also enhanced the anti-tumor activity of IR in vivo. Therefore, FLIP down-regulation induced by HDAC inhibitors is a potential clinical strategy to radio-sensitize NSCLC and thereby improve response to radiotherapy. Overall, this study provides the first evidence that pharmacological inhibition of FLIP may improve response of NCSLC to IR

Mutation update and genotype-phenotype correlations of novel and previously described mutations in TPM2 and TPM3 causing congenital myopathies

Mutations affecting skeletal muscle isoforms of the tropomyosin genes may cause nemaline myopathy, cap myopathy, core-rod myopathy, congenital fiber-type disproportion, distal arthrogryposes, and Escobar syndrome. We correlate the clinical picture of these diseases with novel (19) and previously reported (31) mutations of the TPM2 and TPM3 genes. Included are altogether 93 families: 53 with TPM2 mutations and 40 with TPM3 mutations. Thirty distinct pathogenic variants of TPM2 and 20 of TPM3 have been published or listed in the Leiden Open Variant Database (http://www.dmd.nl/). Most are heterozygous changes associated with autosomal-dominant disease. Patients with TPM2 mutations tended to present with milder symptoms than those with TPM3 mutations, DA being present only in the TPM2 group. Previous studies have shown that five of the mutations in TPM2 and one in TPM3 cause increased Ca2+ sensitivity resulting in a hypercontractile molecular phenotype. Patients with hypercontractile phenotype more often had contractures of the limb joints (18/19) and jaw (6/19) than those with nonhypercontractile ones (2/22 and 1/22), whereas patients with the non-hypercontractile molecular phenotype more often (19/22) had axial contractures than the hypercontractile group (7/19). Our in silico predictions show that most mutations affect tropomyosin–actin association or tropomyosin head-to-tail binding

Shaking Dutch Grounds Won't Shatter the European Gas Market

The Netherlands have been a pivotal supplier in Western European natural gas markets in the last decades. Recent analyses show that the Netherlands would play an important role in replacing Russian supplies in Germany and France in case of Russian export disruption (Richter & Holz, 2015). However, the Netherlands have suffered from regular earthquakes in recent years that are related to the natural gas production in the major Groningen field. Natural gas production rates- that are politically mandated in the Netherlands - have consequently been substantially reduced, with an estimated annual production 30% below the 2013 level. We implement a realistically low production path for the next decades in the Global Gas Model and analyze the geopolitical impacts. We find that the diversification of the European natural gas imports allows spreading the replacement of Dutch gas over many alternative sources, with diverse pipeline and LNG supplies.There will be hardly any price or demand reduction effect. Even if Russia fails to supply Europe, the additional impact of the lower Dutch production is moderate. Again, alternative suppliers from various sources are able to replace the Dutch volumes. Hence, the European consumers need not to worry about the declining Dutch natural gas production and their security of supplies

CONFIRM: a double-blind, placebo controlled phase III clinical trial investigating the effect of nivolumab in patients with relapsed mesothelioma: study protocol for a randomised controlled trial

Background: Mesothelioma is an incurable, apoptosis-resistant cancer caused in most cases by previous exposure to asbestos and is increasing in incidence. It represents a growing health burden but remains under-researched, with limited treatment options. Early promising signals of activity relating to both PD-L1- and PD-1-targeted treatment in mesothelioma implicate a dependency of mesothelioma on this immune checkpoint. There is a need to evaluate checkpoint inhibitors in patients with relapsed mesothelioma where treatment options are limited. Methods: The addition of 12 months of nivolumab (anti-PD1 antibody) to standard practice will be conducted in the UK using a randomised, placebo-controlled phase III trial (the Cancer Research UK CONFIRM trial). A total of 336 patients with pleural or peritoneal mesothelioma who have received at least two prior lines of therapy will be recruited from UK secondary care sites. Patients will be randomised 2:1 (nivolumab:placebo), stratified according to epithelioid/non-epithelioid, to receive either 240 mg nivolumab monotherapy or saline placebo as a 30-min intravenous infusion. Treatment will be for up to 12 months. We will determine whether the use of nivolumab increases overall survival (the primary efficacy endpoint). Secondary endpoints will include progression-free survival, objective response rate, toxicity, quality of life and cost-effectiveness. Analysis will be performed according to the intention-to-treat principle using a Cox regression analysis for the primary endpoint (and for other time-to-event endpoints). Discussion: The outcome of this trial will provide evidence of the potential benefit of the use of nivolumab in the treatment of relapsed mesothelioma. If found to be clinically effective, safe and cost-effective it is likely to become the new standard of care in the UK

The state of the Martian climate

60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes

Long Term Observations of B2 1215+30 with Veritas

We report on VERITAS observations of the BL Lac object B2 1215+30 between 2008 and 2012. During this period, the source was detected at very high energies (VHEs; E \u3e 100 GeV) by VERITAS with a significance of 8.9σ and showed clear variability on timescales larger than months. In 2011, the source was found to be in a relatively bright state and a power-law fit to the differential photon spectrum yields a spectral index of 3.6 ± 0.4stat ± 0.3syst with an integral flux above 200 GeV of (8.0 ± 0.9stat ± 3.2syst) × 10−12 cm−2 s−1. No short term variability could be detected during the bright state in 2011. Multi-wavelength data were obtained contemporaneously with the VERITAS observations in 2011 and cover optical (Super-LOTIS, MDM, Swift/UVOT), X-ray (Swift/XRT), and gamma-ray (Fermi-LAT) frequencies. These were used to construct the spectral energy distribution (SED) of B2 1215+30. A one-zone leptonic model is used to model the blazar emission and the results are compared to those of MAGIC from early 2011 and other VERITAS-detected blazars. The SED can be reproduced well with model parameters typical for VHE-detected BL Lac objects. Key words: BL Lacertae objects: general – BL Lacertae objects: individual (B2 1215+30, VER J1217+301