EBV treatment in hyperinflated patients with heterogeneous emphysema without collateral ventilation resulted in clinically meaningful benefits in lung function, dyspnea, exercise tolerance, and quality of life, with an acceptable safety profile. Clinical trial registered with www.clinicaltrials.gov (NCT02022683).

1 The 5-hydroxytryptamine (5-HT) receptors mediating vasoconstriction in isolated human small muscular pulmonary arteries (SMPAs) were determined using techniques of wire myography and reverse transcription-polymerase chain reaction (RT ± PCR). 2 The agonists 5-HT, 5-carboxamidotryptamine (5-CT, unselective for 5-HT 1 receptors) and sumatriptan (selective for 5-HT 1B/D receptors) all caused contraction and were equipotent (pEC 50 s: 7.0+0.2, 7.1+0.3 and 6.7+0.1, respectively) suggesting the presence of a 5-HT 1 receptor. 3 Ketanserin (5-HT 2A -selective antagonist, 0.1 mM) inhibited 5-HT-induced contractions only at non-physiological/pathological concentrations of 5-HT (40.1 mM) whilst GR55562 (5-HT 1B/1D -selective antagonist, 1 mM) inhibited 5-HT-induced contractions at all concentrations of 5-HT (estimated pK B =7.7+0.2). SB-224289 (5-HT 1B -selective antagonist, 0.2 mM) inhibited sumatriptaninduced contractions (estimated pK B =8.4+0.1) whilst these were una ected by the 5-HT 1D -selective antagonist BRL15572 (0.5 mM) suggesting that the 5-HT 1B receptor mediates vasoconstriction in this vessel. 4 RT ± PCR con®rmed the presence of substantial amounts of mRNA for the 5-HT 2A and 5-HT 1B receptor subtypes in these arteries whilst only trace amounts of 5-HT 1D receptor message were evident. 5 These ®ndings suggest that a heterogeneous population of 5-HT 2A and 5-HT 1B receptors co-exist in human small muscular pulmonary arteries but that the 5-HT 1B receptor mediates 5-HT-induced vasoconstriction at physiological and pathophysiological concentrations of 5-HT. These results have important implications for the treatment of pulmonary hypertension in which the 5-HT 1B receptor may provide a novel and potentially important therapeutic target.

The peptide human urotensin-II (hUT-II) and its receptor have recently been cloned. The vascular function of this peptide in humans, however, has yet to be determined. Vasoconstrictor and vasodilator responses to hUT-II were investigated in human small muscular pulmonary arteries [approximately 70 microm internal diameter (ID)] and human abdominal resistance arteries (approximately 200 microm ID). Vasodilator responses were investigated in endothelin-1 (3 nM) precontracted vessels and, in the small pulmonary vessels, compared with the known vasodilators adrenomedullin, sodium nitroprusside, and acetylcholine. In human small pulmonary arteries, hUT-II did not induce vasoconstriction but was a potent vasodilator [-log M concentration causing 50% of the maximum vasodilator effect (pIC(50)) 10.4 +/- 0.5; percentage of reduction in tone (E(max)) 81 +/- 8% (vs. 23 +/- 11% in time controls), n = 5]. The order of potency for vasodilation was human urotensin-II = adrenomedullin (pIC(50) 10.1 +/- 0.4, n = 6) > sodium nitroprusside (pIC(50) 7.4 +/- 0.2, n = 6) = acetylcholine (pIC(50) 6.8 +/- 0.3, n = 6). In human abdominal arteries, hUT-II did not induce vasoconstriction but was a potent vasodilator [pIC(50) 10.3 +/- 0.7; E(max) 96 +/- 8% (vs. 43 +/- 16% in time controls), n = 4]. This is the first report that hUT-II is a potent vasodilator but not a vasoconstrictor of human small pulmonary arteries and systemic resistance arteries.

Background Surgery is the main modality of cure for solid cancers and was prioritised to continue during COVID-19 outbreaks. This study aimed to identify immediate areas for system strengthening by comparing the delivery of elective cancer surgery during the COVID-19 pandemic in periods of lockdown versus light restriction. Methods This international, prospective, cohort study enrolled 20 006 adult (≥18 years) patients from 466 hospitals in 61 countries with 15 cancer types, who had a decision for curative surgery during the COVID-19 pandemic and were followed up until the point of surgery or cessation of follow-up (Aug 31, 2020). Average national Oxford COVID-19 Stringency Index scores were calculated to define the government response to COVID-19 for each patient for the period they awaited surgery, and classified into light restrictions (index <20), moderate lockdowns (20–60), and full lockdowns (>60). The primary outcome was the non-operation rate (defined as the proportion of patients who did not undergo planned surgery). Cox proportional-hazards regression models were used to explore the associations between lockdowns and non-operation. Intervals from diagnosis to surgery were compared across COVID-19 government response index groups. This study was registered at ClinicalTrials.gov , NCT04384926 . Findings Of eligible patients awaiting surgery, 2003 (10·0%) of 20 006 did not receive surgery after a median follow-up of 23 weeks (IQR 16–30), all of whom had a COVID-19-related reason given for non-operation. Light restrictions were associated with a 0·6% non-operation rate (26 of 4521), moderate lockdowns with a 5·5% rate (201 of 3646; adjusted hazard ratio [HR] 0·81, 95% CI 0·77–0·84; p<0·0001), and full lockdowns with a 15·0% rate (1775 of 11 827; HR 0·51, 0·50–0·53; p<0·0001). In sensitivity analyses, including adjustment for SARS-CoV-2 case notification rates, moderate lockdowns (HR 0·84, 95% CI 0·80–0·88; p<0·001), and full lockdowns (0·57, 0·54–0·60; p<0·001), remained independently associated with non-operation. Surgery beyond 12 weeks from diagnosis in patients without neoadjuvant therapy increased during lockdowns (374 [9·1%] of 4521 in light restrictions, 317 [10·4%] of 3646 in moderate lockdowns, 2001 [23·8%] of 11 827 in full lockdowns), although there were no differences in resectability rates observed with longer delays. Interpretation Cancer surgery systems worldwide were fragile to lockdowns, with one in seven patients who were in regions with full lockdowns not undergoing planned surgery and experiencing longer preoperative delays. Although short-term oncological outcomes were not compromised in those selected for surgery, delays and non-operations might lead to long-term reductions in survival. During current and future periods of societal restriction, the resilience of elective surgery systems requires strengthening, which might include...

Environmental carcinogenic exposures are major contributors to global disease burden yet how they promote cancer is unclear. Over 70 years ago, the concept of tumour promoting agents driving latent clones to expand was rst proposed. In support of this model, recent evidence suggests that human tissue contains a patchwork of mutant clones, some of which harbour oncogenic mutations, and many environmental carcinogens lack a clear mutational signature. We hypothesised that the environmental carcinogen, <2.5μm particulate matter (PM2.5), might promote lung cancer promotion through nonmutagenic mechanisms by acting on pre-existing mutant clones within normal tissues in patients with lung cancer who have never smoked, a disease with a high frequency of EGFR activating mutations. We analysed PM2.5 levels and cancer incidence reported by UK Biobank, Public Health England, Taiwan Chang Gung Memorial Hospital (CGMH) and Korean Samsung Medical Centre (SMC) from a total of 463,679 individuals between 2006-2018. We report associations between PM2.5 levels and the incidence of several cancers, including EGFR mutant lung cancer. We nd that pollution on a background of EGFR mutant lung epithelium promotes a progenitor-like cell state and demonstrate that PM accelerates lung cancer progression in EGFR and Kras mutant mouse lung cancer models. Through parallel exposure studies in mouse and human participants, we nd evidence that in ammatory mediators, such as interleukin-1 , may act upon EGFR mutant clones to drive expansion of progenitor cells. Ultradeep mutational pro ling of histologically normal lung tissue from 247 individuals across 3 clinical cohorts revealed oncogenic EGFR and KRAS driver mutations in 18% and 33% of normal tissue samples, respectively. These results support a tumour-promoting role for PM acting on latent mutant clones in normal lung tissue and add to evidence providing an urgent mandate to address air pollution in urban areas.