Protocol for the isotoxic intensity modulated radiotherapy (IMRT) in stage III non-small cell lung cancer (NSCLC): a feasibility study

Introduction The majority of stage III patients with non-small cell lung cancer (NSCLC) are unsuitable for concurrent chemoradiotherapy, the non-surgical gold standard of care. As the alternative treatment options of sequential chemoradiotherapy and radiotherapy alone are associated with high local failure rates, various intensification strategies have been employed. There is evidence to suggest that altered fractionation using hyperfractionation, acceleration, dose escalation, and individualisation may be of benefit. The MAASTRO group have pioneered the concept of ‘isotoxic’ radiotherapy allowing for individualised dose escalation using hyperfractionated accelerated radiotherapy based on predefined normal tissue constraints. This study aims to evaluate whether delivering isotoxic radiotherapy using intensity modulated radiotherapy (IMRT) is achievable. Methods and analysis Isotoxic IMRT is a multicentre feasibility study. From June 2014, a total of 35 patients from 7 UK centres, with a proven histological or cytological diagnosis of inoperable NSCLC, unsuitable for concurrent chemoradiotherapy will be recruited. A minimum of 2 cycles of induction chemotherapy is mandated before starting isotoxic radiotherapy. The dose of radiation will be increased until one or more of the organs at risk tolerance or the maximum dose of 79.2 Gy is reached. The primary end point is feasibility, with accrual rates, local control and overall survival our secondary end points. Patients will be followed up for 5 years. Ethics and dissemination The study has received ethical approval (REC reference: 13/NW/0480) from the National Research Ethics Service (NRES) Committee North West—Greater Manchester South. The trial is conducted in accordance with the Declaration of Helsinki and Good Clinical Practice (GCP). The trial results will be published in a peer-reviewed journal and presented internationally. Trial registration number NCT01836692; Pre-result

Self-stabilised fractality of sea-coasts through damped erosion

Erosion of rocky coasts spontaneously creates irregular seashores. But the geometrical irregularity, in turn, damps the sea-waves, decreasing the average wave amplitude. There may then exist a mutual self-stabilisation of the waves amplitude together with the irregular morphology of the coast. A simple model of such stabilisation is studied. It leads, through a complex dynamics of the earth-sea interface, to the appearance of a stationary fractal seacoast with dimension close to 4/3. Fractal geometry plays here the role of a morphological attractor directly related to percolation geometry.Comment: 4 pages, 5 figure

Revealing the chemical characteristics of Arctic low-level cloud residuals – in situ observations from a mountain site

The role aerosol chemical composition plays in Arctic low-level cloud formation is still poorly understood. In this study we address this issue by combining in situ observations of the chemical characteristics of cloud residuals (dried liquid cloud droplets or ice crystals) and aerosol particles from the Zeppelin Observatory in Ny-Ålesund, Svalbard (approx. 480 m a.s.l.). These measurements were part of the 1-year-long Ny-Ålesund Aerosol and Cloud Experiment 2019–2020 (NASCENT). To obtain the chemical composition of cloud residuals at molecular level, we deployed a Filter Inlet for Gases and AEROsols coupled to a Chemical Ionization Mass Spectrometer (FIGAERO-CIMS) with iodide as the reagent ion behind a ground-based counterflow virtual impactor (GCVI). The station was enshrouded in clouds roughly 15 % of the time during NASCENT, out of which we analyzed 14 cloud events between December 2019 and December 2020. During the entire year, the composition of the cloud residuals shows contributions from oxygenated organic compounds, including organonitrates, and traces of the biomass burning tracer levoglucosan. In summer, methanesulfonic acid (MSA), an oxidation product of dimethyl sulfide (DMS), shows large contributions to the sampled mass, indicating marine natural sources of cloud condensation nuclei (CCN) and ice nucleating particle (INP) mass during the sunlit part of the year. In addition, we also find contributions of the inorganic acids nitric acid and sulfuric acid, with outstanding high absolute signals of sulfuric acid in one cloud residual sample in spring and one in late summer (21 May and 12 September 2020), probably caused by high anthropogenic sulfur emissions near the Barents Sea and Kara Sea. During one particular cloud event, on 18 May 2020, the air mass origin did not change before, during, or after the cloud. We therefore chose it as a case study to investigate cloud impact on aerosol physicochemical properties. We show that the overall chemical composition of the organic aerosol particles was similar before, during, and after the cloud, indicating that the particles had already undergone one or several cycles of cloud processing before being measured as residuals at the Zeppelin Observatory and/or that, on the timescales of the observed cloud event, cloud processing of the organic fraction can be neglected. Meanwhile, there were on average fewer particles but relatively more in the accumulation mode after the cloud. Comparing the signals of sulfur-containing compounds of cloud residuals with aerosols during cloud-free conditions, we find that sulfuric acid had a higher relative contribution to the cloud residuals than to aerosols during cloud-free conditions, but we did not observe an increase in particulate MSA due to the cloud. Overall, the chemical composition, especially of the organic fraction of the Arctic cloud residuals, reflected the overall composition of the general aerosol population well. Our results thus suggest that most aerosols can serve as seeds for low-level clouds in the Arctic.</p

Arctic observations of hydroperoxymethyl thioformate (HPMTF) – seasonal behavior and relationship to other oxidation products of dimethyl sulfide at the Zeppelin Observatory, Svalbard

Dimethyl sulfide (DMS), a gas produced by phytoplankton, is the largest source of atmospheric sulfur over marine areas. DMS undergoes oxidation in the atmosphere to form a range of oxidation products, out of which sulfuric acid (SA) is well known for participating in the formation and growth of atmospheric aerosol particles, and the same is also presumed for methanesulfonic acid (MSA). Recently, a new oxidation product of DMS, hydroperoxymethyl thioformate (HPMTF), was discovered and later also measured in the atmosphere. Little is still known about the fate of this compound and its potential to partition into the particle phase. In this study, we present a full year (2020) of concurrent gas- and particle-phase observations of HPMTF, MSA, SA and other DMS oxidation products at the Zeppelin Observatory (Ny-Ålesund, Svalbard) located in the Arctic. This is the first time HPMTF has been measured in Svalbard and attempted to be observed in atmospheric particles. The results show that gas-phase HPMTF concentrations largely follow the same pattern as MSA during the sunlit months (April–September), indicating production of HPMTF around Svalbard. However, HPMTF was not observed in significant amounts in the particle phase, despite high gas-phase levels. Particulate MSA and SA were observed during the sunlit months, although the highest median levels of particulate SA were measured in February, coinciding with the highest gaseous SA levels with assumed anthropogenic origin. We further show that gas- and particle-phase MSA and SA are coupled in May–July, whereas HPMTF lies outside of this correlation due to the low particulate concentrations. These results provide more information about the relationship between HPMTF and other DMS oxidation products, in a part of the world where these have not been explored yet, and about HPMTF's ability to contribute to particle growth and cloud formation.</p

Pituitary apoplexy following shoulder arthroplasty: a case report

<p>Abstract</p> <p>Introduction</p> <p>Pituitary apoplexy following a major surgical procedure is a catastrophic event and the diagnosis can be delayed in a previously asymptomatic patient. The decision on thromboprophylaxis in shoulder replacements in the absence of definite guidelines, rests on a careful clinical judgment.</p> <p>Case presentation</p> <p>A previously healthy 62-year-old Caucasian male patient who underwent shoulder arthroplasty developed hyponatremia resistant to correction with saline replacement. The patient had a positive family history of deep vein thrombosis and pulmonary embolism and heparin thromboprophylaxis was considered on clinical grounds. The patient developed hyponatremia resistant to conventional treatment and later developed ocular localizing signs with oculomotor nerve palsy. The diagnosis was delayed due to other confounding factors in the immediate post-operative period. Subsequent workup confirmed a pituitary adenoma with features of pituitary insufficiency. The patient was managed successfully on conservative lines with a multidisciplinary approach.</p> <p>Conclusions</p> <p>A high index of suspicion is required in the presence of isolated post-operative hyponatremia resistant to medical correction. A central cause, in particular pituitary adenoma, should be suspected early. Thromboprophylaxis in shoulder replacements needs careful consideration as it may be a contributory factor in precipitating this life-threatening condition.</p

Flavones induce neutrophil apoptosis by down-regulation of Mcl-1 via a proteasomal-dependent pathway

Neutrophil apoptosis and subsequent nonphlogistic clearance by surrounding phagocytes are key to the successful resolution of neutrophilic inflammation, with dysregulated apoptosis reported in multiple human inflammatory diseases. Enhancing neutrophil apoptosis has proresolution and anti-inflammatory effects in preclinical models of inflammation. Here we investigate the ability of the flavones apigenin, luteolin, and wogonin to induce neutrophil apoptosis in vitro and resolve neutrophilic inflammation in vivo. Human neutrophil apoptosis was assessed morphologically and by flow cytometry following incubation with apigenin, luteolin, and wogonin. All three flavones induced time- and concentration-dependent neutrophil apoptosis (apigenin, EC(50)=12.2 μM; luteolin, EC(50)=14.6 μM; and wogonin, EC(50)=28.9 μM). Induction of apoptosis was caspase dependent, as it was blocked by the broad-spectrum caspase inhibitor Q-VD-OPh and was associated with both caspase-3 and caspase-9 activation. Flavone-induced apoptosis was preceded by down-regulation of the prosurvival protein Mcl-1, with proteasomal inhibition preventing flavone-induced Mcl-1 down-regulation and apoptosis. The flavones abrogated the survival effects of mediators that prolong neutrophil life span, including lipoteichoic acid, peptidoglycan, dexamethasone, and granulocyte-macrophage colony stimulating factor, by driving apoptosis. Furthermore, wogonin enhanced resolution of established neutrophilic inflammation in a zebrafish model of sterile tissue injury. Wogonin-induced resolution was dependent on apoptosis in vivo as it was blocked by caspase inhibition. Our data show that the flavones induce neutrophil apoptosis and have potential as neutrophil apoptosis-inducing anti-inflammatory, proresolution agents.—Lucas, C. D., Allen, K. C., Dorward, D. A., Hoodless, L. J., Melrose, L. A., Marwick, J. A., Tucker, C. S., Haslett, C., Duffin, R., Rossi, A. G. Flavones induce neutrophil apoptosis by down-regulation of Mcl-1 via a proteasomal-dependent pathway

Downregulation of Mcl-1 has anti-inflammatory pro-resolution effects and enhances bacterial clearance from the lung

Phagocytes not only coordinate acute inflammation and host defense at mucosal sites, but also contribute to tissue damage. Respiratory infection causes a globally significant disease burden and frequently progresses to acute respiratory distress syndrome, a devastating inflammatory condition characterized by neutrophil recruitment and accumulation of protein-rich edema fluid causing impaired lung function. We hypothesized that targeting the intracellular protein myeloid cell leukemia 1 (Mcl-1) by a cyclin-dependent kinase inhibitor (AT7519) or a flavone (wogonin) would accelerate neutrophil apoptosis and resolution of established inflammation, but without detriment to bacterial clearance. Mcl-1 loss induced human neutrophil apoptosis, but did not induce macrophage apoptosis nor impair phagocytosis of apoptotic neutrophils. Neutrophil-dominant inflammation was modelled in mice by either endotoxin or bacteria (Escherichia coli). Downregulating inflammatory cell Mcl-1 had anti-inflammatory, pro-resolution effects, shortening the resolution interval (R(i)) from 19 to 7 h and improved organ dysfunction with enhanced alveolar–capillary barrier integrity. Conversely, attenuating drug-induced Mcl-1 downregulation inhibited neutrophil apoptosis and delayed resolution of endotoxin-mediated lung inflammation. Importantly, manipulating lung inflammatory cell Mcl-1 also accelerated resolution of bacterial infection (R(i); 50 to 16 h) concurrent with enhanced bacterial clearance. Therefore, manipulating inflammatory cell Mcl-1 accelerates inflammation resolution without detriment to host defense against bacteria, and represents a target for treating infection-associated inflammation

Transcriptome-scale similarities between mouse and human skeletal muscles with normal and myopathic phenotypes

BACKGROUND: Mouse and human skeletal muscle transcriptome profiles vary by muscle type, raising the question of which mouse muscle groups have the greatest molecular similarities to human skeletal muscle. METHODS: Orthologous (whole, sub-) transcriptome profiles were compared among four mouse-human transcriptome datasets: (M) six muscle groups obtained from three mouse strains (wildtype, mdx, mdx(5cv)); (H1) biopsied human quadriceps from controls and Duchenne muscular dystrophy patients; (H2) four different control human muscle types obtained at autopsy; and (H3) 12 different control human tissues (ten non-muscle). RESULTS: Of the six mouse muscles examined, mouse soleus bore the greatest molecular similarities to human skeletal muscles, independent of the latters' anatomic location/muscle type, disease state, age and sampling method (autopsy versus biopsy). Significant similarity to any one mouse muscle group was not observed for non-muscle human tissues (dataset H3), indicating this finding to be muscle specific. CONCLUSION: This observation may be partly explained by the higher type I fiber content of soleus relative to the other mouse muscles sampled

Neutrophil cannibalism – a back up when the macrophage clearance system is insufficient

BACKGROUND: During a lipopolysaccharide-induced lung inflammation, a massive accumulation of neutrophils occurs, which is normally cleared by macrophage phagocytosis following neutrophil apoptosis. However, in cases of extensive apoptosis the normal clearance system may fail, resulting in extensive neutrophil secondary necrosis. The aim of this study was to explore the hypothesis that neutrophils, in areas of the lung with extensive cellular infiltration, contribute to clearance by phagocytosing apoptotic cells and/or cell debris derived from secondary necrosis. METHODS: Intranasal lipopolysaccharide administration was used to induce lung inflammation in mice. The animals were sacrificed at seven time points following administration, bronchoalveolar lavage was performed and tissue samples obtained. Electron microscopy and histochemistry was used to assess neutrophil phagocytosis. RESULTS: Electron microscopic studies revealed that phagocytosing neutrophils was common, at 24 h after LPS administration almost 50% of the total number of neutrophils contained phagosomes, and the engulfed material was mainly derived from other neutrophils. Histochemistry on bronchoalvolar lavage cells further showed phagocytosing neutrophils to be frequently occurring. CONCLUSION: Neutrophils are previously known to phagocytose invading pathogens and harmful particles. However, this study demonstrates that neutrophils are also able to engulf apoptotic neutrophils or cell debris resulting from secondary necrosis of neutrophils. Neutrophils may thereby contribute to clearance and resolution of inflammation, thus acting as a back up system in situations when the macrophage clearance system is insufficient and/or overwhelmed

Regulation of neutrophil senescence by microRNAs

Neutrophils are rapidly recruited to sites of tissue injury or infection, where they protect against invading pathogens. Neutrophil functions are limited by a process of neutrophil senescence, which renders the cells unable to respond to chemoattractants, carry out respiratory burst, or degranulate. In parallel, aged neutrophils also undergo spontaneous apoptosis, which can be delayed by factors such as GMCSF. This is then followed by their subsequent removal by phagocytic cells such as macrophages, thereby preventing unwanted inflammation and tissue damage. Neutrophils translate mRNA to make new proteins that are important in maintaining functional longevity. We therefore hypothesised that neutrophil functions and lifespan might be regulated by microRNAs expressed within human neutrophils. Total RNA from highly purified neutrophils was prepared and subjected to microarray analysis using the Agilent human miRNA microarray V3. We found human neutrophils expressed a selected repertoire of 148 microRNAs and that 6 of these were significantly upregulated after a period of 4 hours in culture, at a time when the contribution of apoptosis is negligible. A list of predicted targets for these 6 microRNAs was generated from http://mirecords.biolead.org and compared to mRNA species downregulated over time, revealing 83 genes targeted by at least 2 out of the 6 regulated microRNAs. Pathway analysis of genes containing binding sites for these microRNAs identified the following pathways: chemokine and cytokine signalling, Ras pathway, and regulation of the actin cytoskeleton. Our data suggest that microRNAs may play a role in the regulation of neutrophil senescence and further suggest that manipulation of microRNAs might represent an area of future therapeutic interest for the treatment of inflammatory disease