Cigarette smoke exposure facilitates allergic sensitization in mice

BACKGROUND: Active and passive smoking are considered as risk factors for asthma development. The mechanisms involved are currently unexplained. OBJECTIVE: The aim of this study was to determine if cigarette smoke exposure could facilitate primary allergic sensitization. METHODS: BALB/c mice were exposed to aerosolized ovalbumin (OVA) combined with air or tobacco smoke (4 exposures/day) daily for three weeks. Serology, lung cytopathology, cytokine profiles in bronchoalveolar lavage fluid (BALF) and on mediastinal lymph node cultures as well as lung function tests were performed after the last exposure. The natural history and the immune memory of allergic sensitization were studied with in vivo recall experiments. RESULTS: Exposure to OVA induced a small increase in OVA-specific serum IgE as compared with exposure to PBS (P < 0.05), while no inflammatory reaction was observed in the airways. Exposure to cigarette smoke did not induce IgE, but was characterized by a small but significant neutrophilic inflammatory reaction. Combining OVA with cigarette smoke not only induced a significant increase in OVA-specific IgE but also a distinct eosinophil and goblet cell enriched airway inflammation albeit that airway hyperresponsiveness was not evidenced. FACS analysis showed in these mice increases in dendritic cells (DC) and CD4(+ )T-lymphocytes along with a marked increase in IL-5 measured in the supernatant of lymph node cell cultures. Immune memory experiments evidenced the transient nature of these phenomena. CONCLUSION: In this study we show that mainstream cigarette smoke temporary disrupts the normal lung homeostatic tolerance to innocuous inhaled allergens, thereby inducing primary allergic sensitization. This is characterized not only by the development of persistent IgE, but also by the emergence of an eosinophil rich pulmonary inflammatory reaction

HER2 overexpression and amplification as a potential therapeutic target in colorectal cancer: Analysis of 3256 patients enrolled in the QUASAR, FOCUS and PICCOLO colorectal cancer trials.

HER2-overexpression/amplification is linked to trastuzumab response in breast/gastric cancers. One suggested anti-EGFR resistance mechanism in colorectal cancer (CRC) is aberrant MEK/AKT-pathway activation through HER2 up-regulation. We assessed HER2-amplification/overexpression in stage II-III and IV CRC patients, assessing relationships to KRAS/BRAF and outcome. Pathological material was obtained from 1,914 patients in the QUASAR stage II-III trial and 1,342 patients in stage IV trials (FOCUS and PICCOLO). Tissue microarrays were created for HER2 immunohistochemistry. HER2-amplification was assessed using FISH and copy number variation. KRAS/BRAF mutation status was assessed by pyrosequencing. Progression-free survival (PFS) and overall survival (OS) data was obtained for FOCUS/PICCOLO and recurrence and mortality for QUASAR. 29/1,342 (2.2%) stage IV and 25/1,914 (1.3%) stage II-III tumours showed HER2 protein overexpression. Of the HER2-overexpressing cases, 27/28 (96.4%) stage IV tumours and 20/24 (83.3%) stage II-III tumours demonstrated HER2-amplification by FISH. 41/47 (87.2%) also showed copy number gains. HER2-overexpression was associated with KRAS/BRAF-wildtype (WT) status in all stages: in 5.2% WT versus 1.0% mutated tumours (p<0.0001) in stage IV and 2.1% versus 0.2% in stage II-III tumours (p=0.01) respectively. HER2 was not associated with OS or PFS. In stage II-III, there was no significant correlation between HER2-overexpression and 5FU/FA response. A higher proportion of HER2-overexpressing cases experienced recurrence, but the difference was not significant. HER2-amplification/overexpression is identifiable by immunohistochemistry, occurring infrequently in stage II-III CRC, rising in stage IV and further in KRAS/BRAF-WT tumours. The value of HER2-targeted therapy in patients with HER2-amplified CRC must be tested in a clinical trial

Lipophilic aroylhydrazone chelator HNTMB and its multiple effects on ovarian cancer cells

<p>Abstract</p> <p>Background</p> <p>Metal chelators have gained much attention as potential anti-cancer agents. However, the effects of chelators are often linked solely to their capacity to bind iron while the potential complexation of other trace metals has not been fully investigated. In present study, we evaluated the effects of various lipophilic aroylhydrazone chelators (AHC), including novel compound HNTMB, on various ovarian cancer cell lines (SKOV-3, OVCAR-3, NUTU-19).</p> <p>Methods</p> <p>Cell viability was analyzed via MTS cytotoxicity assays and NCI60 cancer cell growth screens. Apoptotic events were monitored via Western Blot analysis, fluorescence microscopy and TUNEL assay. FACS analysis was carried out to study Cell Cycle regulation and detection of intracellular Reactive Oxygen Species (ROS)</p> <p>Results</p> <p>HNTMB displayed high cytotoxicity (IC50 200-400 nM) compared to previously developed AHC (oVtBBH, HNtBBH, StBBH/206, HNTh2H/315, HNI/311; IC50 0.8-6 μM) or cancer drug Deferoxamine, a hexadentate iron-chelator (IC50 12-25 μM). In a NCI60 cancer cell line screen HNTMB exhibited growth inhibitory effects with remarkable differences in specificity depending on the cell line studied (GI50 10 nM-2.4 μM). In SKOV-3 ovarian cancer cells HNTMB treatment led to chromatin fragmentation and activation of the extrinsic and intrinsic pathways of apoptosis with specific down-regulation of Bcl-2. HNTMB caused delayed cell cycle progression of SKOV-3 through G2/M phase arrest. HNTMB can chelate iron and copper of different oxidation states. Complexation with copper lead to high cytotoxicity via generation of reactive oxygen species (ROS) while treatment with iron complexes of the drug caused neither cytotoxicity nor increased ROS levels.</p> <p>Conclusions</p> <p>The present report suggests that both, non-complexed HNTMB as a chelator of intracellular trace-metals as well as a cytotoxic HNTMB/copper complex may be developed as potential therapeutic drugs in the treatment of ovarian and other solid tumors.</p

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Feasibility of preoperative chemotherapy for locally advanced, operable colon cancer: The pilot phase of a randomised controlled trial

Summary: Background Preoperative (neoadjuvant) chemotherapy and radiotherapy are more eff ective than similar postoperative treatment for oesophageal, gastric, and rectal cancers, perhaps because of more eff ective micrometastasis eradication and reduced risk of incomplete excision and tumour cell shedding during surgery. The FOxTROT trial aims to investigate the feasibility, safety, and effi cacy of preoperative chemotherapy for colon cancer. Methods In the pilot stage of this randomised controlled trial, 150 patients with radiologically staged locally advanced (T3 with ≥5 mm invasion beyond the muscularis propria or T4) tumours from 35 UK centres were randomly assigned (2:1) to preoperative (three cycles of OxMdG [oxaliplatin 85 mg/m², l-folinic acid 175 mg, fl uorouracil 400 mg/m² bolus, then 2400 mg/m² by 46 h infusion] repeated at 2-weekly intervals followed by surgery and a further nine cycles of OxMdG) or standard postoperative chemotherapy (12 cycles of OxMdG). Patients with KRAS wild-type tumours were randomly assigned (1:1) to receive panitumumab (6 mg/kg; every 2 weeks with the fi rst 6 weeks of chemotherapy) or not. Treatment allocation was through a central randomisation service using a minimised randomisation procedure including age, radiological T and N stage, site of tumour, and presence of defunctioning colostomy as stratifi cation variables. Primary outcome measures of the pilot phase were feasibility, safety, and tolerance of preoperative therapy, and accuracy of radiological staging. Analysis was by intention to treat. This trial is registered, number ISRCTN 87163246. Findings 96% (95 of 99) of patients started and 89% (85 of 95) completed preoperative chemotherapy with grade 3–4 gastrointestinal toxicity in 7% (seven of 94) of patients. All 99 tumours in the preoperative group were resected, with no signifi cant diff erences in postoperative morbidity between the preoperative and control groups: 14% (14 of 99) versus 12% (six of 51) had complications prolonging hospital stay (p=0·81). 98% (50 of 51) of postoperative chemotherapy patients had T3 or more advanced tumours confi rmed at post-resection pathology compared with 91% (90 of 99) of patients following preoperative chemotherapy (p=0·10). Preoperative therapy resulted in signifi cant downstaging of TNM5 compared with the postoperative group (p=0·04), including two pathological complete responses, apical node involvement (1% [one of 98] vs 20% [ten of 50], p<0·0001), resection margin involvement (4% [ four of 99] vs 20% [ten of 50], p=0·002), and blinded centrally scored tumour regression grading: 31% (29 of 94) vs 2% (one of 46) moderate or greater regression (p=0·0001). Interpretation Preoperative chemotherapy for radiologically staged, locally advanced operable primary colon cancer is feasible with acceptable toxicity and perioperative morbidity. Proceeding to the phase 3 trial, to establish whether the encouraging pathological responses seen with preoperative therapy translates into improved long-term oncological outcome, is appropriate