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Background: Smoking cessation reduces the risk of developing smoking-related diseases. Although smoking prevalence has declined, many smokers continue smoking cigarettes. Switching to less harmful smoke-free alternatives such as the Tobacco Heating System (THS), a non-combustible tobacco-based product, is an approach to reduce the harm caused by cigarettes. Methods: We conducted a 12-month clinical study with 984 adult smokers randomized to either continue smoking or to use THS. We assessed the trajectories of biomarkers of potential harm (BoPH) known to be reversible upon smoking cessation, as one measure of different pathways involved in the pathogenesis of cardiovascular or respiratory diseases, and carcinogenicity. Beneficial impact on 8 key BoPHs was used as a proxy to evaluate harm reduction.Results: At 12 months, comparison of the 8 BoPH levels between the predominant THS use and cigarette smoking groups showed differences in favor of THS switching when contextualized to the changes reported for smoking cessation. Conclusions: Our results likely indicate a further decrease in carcinogenicity and relative risk of developing cardiovascular or respiratory diseases for smokers switching to THS compared to those who would continue smoking. These results provide additional evidence of the harm reduction potential of predominant THS use. Trial Registration clinicaltrials.gov Identifier: NCT02649556 Date of registration: 07/01/2016 (dd/mm/yyyy)(https://clinicaltrials.gov/ct2/show/NCT02649556)

Background “Heat-not-burn” tobacco products are designed to heat processed tobacco instead of combusting it, thus significantly reducing the formation of harmful and potentially harmful constituents (HPHCs) found in cigarette smoke, and ultimately reducing the risk of smoking-related diseases. The Carbon-Heated Tobacco Product (CHTP), a heat-not-burn tobacco product similar in appearance and use ritual to cigarettes, has been developed for smokers who would otherwise continue smoking as an alternative to cigarettes. To evaluate reduced risk of harm potential of CHTP, it is critical to quantify exposure to HPHCs and consequent biological pathway disturbances involved in disease onset in smokers who switch to CHTP. Methods In this 2-arm, parallel-group study, adult healthy smokers, not willing to quit, were randomized to switch to CHTP 1.2 (n = 80) or to continue using cigarettes (n = 40) for 5 days in confinement followed by 85 days in an ambulatory setting. Endpoints included biomarkers of exposure (BoExp) to HPHCs, and to nicotine, urinary excretion of mutagenic constituents (Ames assay), CYP1A2 activity, biomarkers of effect, and safety. Results In switchers to CHTP, BoExp were 40%-95% lower compared to smokers after 5 days of product use, with sustained reductions (36%-93%) observed on Day 90. Urine mutagenicity and CYP1A2 activity were also lower in the CHTP group. Exposure to nicotine was higher in the CHTP group at Day 5, but was similar between the two groups at Day 90. Favorable changes in some biomarkers of effect were observed in the CHTP group showing reductions in white blood cell count, soluble intracellular adhesion molecule-1, and 11-dehydro-thromboxane B2, respectively, indicative of reduced inflammation, endothelial dysfunction, and platelet activation. Conclusions Switching from cigarettes to CHTP resulted in significantly reduced exposure to HPHCs and was associated with observed improvements in some biomarkers of effect representative of pathomechanistic pathways underlying the development of smoking-related diseases.

Background Cigarette smoking induces cytochrome P450 1A2 (CYP1A2) expression and activity, while smoking cessation normalizes the levels of this enzyme. The aim of this publication is to summarize the data on CYP1A2 gene expression and activity in preclinical and clinical studies on the Tobacco Heating System (THS), currently marketed as IQOS® with HEETs®, and to summarize the potential effects on CYP1A2 to be expected upon switching to reduced-risk products (RRPs). Methods We summarized PMI’s preclinical and clinical data on the effects of switching from cigarette smoking to THS. Results Data from four preclinical mouse and rat studies showed that, upon either cessation of cigarette smoke exposure or switching to THS exposure, the upregulation of CYP1A2 observed with exposure to cigarette smoke reverted close to fresh-air levels. Data from four clinical studies yielded similar results on CYP1A2 activity within a time frame of five days. Furthermore, the effects of switching to THS were similar to those seen after smoking cessation. Conclusions Because smoking cessation and switching to either electronic cigarettes or THS seem to have similar effects on CYP1A2 activity, the same measures taken for patients treated with narrow therapeutic index drugs that are metabolized by CYP1A2 and who quit smoking should be recommended for those switching to RRPs.

Introduction Tobacco Heating System (THS) 2.2, a candidate modified-risk tobacco product, aims at offering an alternative to cigarettes for smokers while substantially reducing the exposure to harmful and potentially harmful constituents found in cigarette smoke. Methods One hundred and sixty healthy adult US smokers participated in this randomized, three-arm parallel group, controlled clinical study. Subjects were randomized in a 2:1:1 ratio to menthol Tobacco Heating System 2.2 (mTHS), menthol cigarette, or smoking abstinence for 5 days in confinement and 86 subsequent ambulatory days. Endpoints included biomarkers of exposure to harmful and potentially harmful constituents (reported in our co-publication, Part 1) and biomarkers of potential harm (BOPH). Results Compliance (protocol and allocated product exposure) was 51% and 18% in the mTHS and smoking abstinence arms, respectively, on day 90. Nonetheless, favorable changes in BOPHs of lipid metabolism (total cholesterol and high- and low-density cholesterol), endothelial dysfunction (soluble intercellular adhesion molecule-1), oxidative stress (8-epi-prostaglandin F2α), and cardiovascular risk factors (eg, high-sensitivity C-reactive protein) were observed in the mTHS group. Favorable effects in other BOPHs, including ones related to platelet activation (11-dehydrothromboxane B2) and metabolic syndrome (glucose), were more pronounced in normal weight subjects. Conclusions The results suggest that the reduced exposure demonstrated when switching to mTHS is associated with overall improvements in BOPHs, which are indicative of pathomechanistic pathways underlying the development of smoking-related diseases, with some stronger effects in normal weight subjects. Implications Switching to mTHS was associated with favorable changes for some BOPHs indicative of biological pathway alterations (eg, oxidative stress and endothelial dysfunction). The results suggest that switching to mTHS has the potential to reduce the adverse health effects of smoking and ultimately the risk of smoking-related diseases. Switching to mTHS for 90 days led to reductions in a number of biomarkers of exposure in smokers, relative to those who continued smoking cigarettes, which were close to those observed when stopping smoking (reported in our co-publication, Part 1). Initial findings suggest reduced levels of 8-epi-prostaglandin F2α and intercellular adhesion molecule 1, when switching to mTHS for 90 days. These changes are comparable to what is observed upon smoking cessation. In normal weight subjects, additional favorable changes were seen in 11-dehydrothromboxane B2, fibrinogen, homocysteine, hs-CRP, percentage of predicted forced expiratory volume in 1 second, systolic blood pressure, diastolic blood pressure, glucose, high-density lipoprotein, apolipoprotein A1, and triglycerides. Trial registration NCT01989156.

Introduction The Tobacco Heating System (THS) is a “heat-not-burn” tobacco product designed to generate significantly lower levels of harmful and potentially harmful constituents (HPHCs) and present lower risk of harm than cigarettes. This study assessed the exposure reduction to selected HPHCs in smokers switching to menthol Tobacco Heating System (mTHS) 2.2 compared with smokers continuing smoking menthol cigarettes (mCCs) and smoking abstinence (SA) for 5 days in a confined setting, followed by an 86-day ambulatory period. Methods A total of 160 healthy adult US smokers participated in this randomized, three-arm parallel group, controlled clinical study. Biomarkers of exposure to 16 HPHCs were measured in blood and 24-hour urine. Safety was monitored throughout the study. Information was also gathered on product evaluation, product use, subjective effects, and clinical risk markers (co-publication Part 2). Results Nicotine uptake was comparable in both exposure groups (mTHS:mCC ratio of 96% on day 90). On day 5, biomarker of exposure levels to other HPHCs were reduced by 51%–96% in the mTHS group compared with the mCC group, and these reductions were sustained for most biomarkers of exposure over ambulatory period. After 90 days of use, the level of satisfaction with mTHS and suppression of urge to smoke were comparable to mCC. Conclusion Switching from mCCs to mTHS significantly reduced the exposure to HPHCs to levels approaching those observed in subjects who abstained from smoking for the duration of the study. Implications This study compared the impact of switching to mTHS on biomarkers of exposure, relative to continued smoking or SA. Clinical Significance Trial Registration NCT01989156 (ClinicalTrials.gov).

Highlights • Cigarette smoking is an important modifiable risk factor for cardiovascular disease. • Cigarette smoking affects oxidative stress markers such as 8-iso prostaglandin F2α. • The effect of smoking on urinary 8-iso prostaglandin F2α levels was meta-analyzed. • Urinary 8-iso prostaglandin F2α levels were increased in smokers., Background To evaluate the reduced-risk potential of alternative tobacco products, biomarkers that are involved in the biological pathways affected by cigarette smoking and smoking cessation are needed. Isoprostanes, a measure of oxidative stress, appear to be influenced by smoking and reversible upon smoking cessation and therefore could be a good biomarker. This review aims at quantifying the effect of smoking and smoking cessation on levels of urinary 8-iso prostaglandin F2α (8-epi-PGF2α), an isoprostane. Methods PubMed and Scopus databases were searched for publications that reported 8-epi-PGF2α levels in smokers and nonsmokers as well as articles reporting the effect of smoking cessation on 8-epi-PGF2α levels. Results Eighteen studies assessing 8-epi-PGF2α levels by smoking status were identified. Five of the papers reported the results as quantity excreted in 24-hour urine (μg/24 h), and 15 reported creatinine adjusted values. The meta-analyses show increased levels of 8-epi-PGF2α in current smokers compared with nonsmokers (mean difference = 0.16, 95% confidence interval [95%CI]: 0.14–0.19 μg/24 h with inconsistency statistic [I2] = 98%; mean difference = 172.38, 95%CI: 152.75–192.01 pg/mg creatinine with I2 = 89%, respectively). There were too few publications to perform a meta-analysis assessing the effects of smoking cessation on 8-epi-PGF2α levels. Conclusions Due to the high heterogeneity among the studies included in these meta-analyses, it is difficult to generalize the results; however, our study indicates increased levels of 8-epi-PGF2α and therefore increased oxidative stress in smokers compared with nonsmokers. More studies are still needed to assess if 8-epi-PGF2α levels are reversible after cessation.

In addition to smoking cessation, for those who would otherwise continue to smoke, replacing cigarettes with less harmful alternatives can reduce the harms of smoking. Heating instead of burning tobacco reduces, or eliminates, the formation of harmful and potentially harmful constituents (HPHC) that are found in cigarette smoke. The Carbon-Heated Tobacco Product (CHTP), a heat-not-burn tobacco product, mimics the cigarette smoking ritual. This randomized, open-label, two-arm, parallel-group, short-term confinement study tested the hypothesis that the geometric means of the BoExp levels for subjects switching to CHTP 1.0 for 5 days are lower relative to those continuing to smoke cigarettes. Biomarkers of exposure (BoExp), including nicotine, urinary excretion of mutagenic constituents (Ames test), and cytochrome P450 (CYP) 1A2 activity, were measured in blood and/or 24-h urine samples during ad libitum product use. Nicotine exposure remained at similar levels in individuals using CHTP as in those continuing to smoke cigarettes. Switching to CHTP resulted in marked decreases in all other urinary BoExp (56–97%), carboxyhemoglobin (59%), urinary mutagenic constituents, and CYP1A2 activity compared with continued cigarette smoking. Our results provide evidence of decreased exposure to 15 selected HPHCs in smokers switching from cigarettes to exclusive CHTP use.Trial registration ClinicalTrials.gov: NCT02503254; Date of first registration: 20/07/2015 https://www.clinicaltrials.gov/ct2/show/NCT02503254.Study protocol Study protocol published at: https://www.clinicaltrials.gov/ProvidedDocs/54/NCT02503254/Prot_000.pdf.

The automotive electric supercharger provides high torque at low engine speeds. During accelerations, it fills the power gap due to the turbocharger’s inertia and avoids turbo lag. Its operation is of short duration because once this deficit has been juggled, it must be stopped in order not to generate unnecessary electricity consumption and to avoid overheating of the electric motor which would compromise its lifetime. Usually the power of automotive turbocharger is calculated assuming an adiabatic air compression and the adiabatic efficiency is assessed. At low speed or for low compression ratio, which is the case of electric supercharger, this hypothesis is no more valid and special experiments have to be done. On our test bench the compressor is driven by a turbine supplied with cold compressed air. Between the compressor and the turbine, a torque meter is inserted to measure the power given to the compressor shaft. The tests were conducted with a non-insulated compressor and an insulated compressor for eight iso-speeds. Additional tests were carried out to assess the actual power supplied to the fluid including bearing losses measurements and to assess the influence of different preload springs used to counter the axial thrust of the compressor. This article presents and analyses the results of this work.

Background: Thromboxane is a key clinical risk endpoint of smoking-induced inflammation which has been associated in the pathogenesis of cardiovascular disease. The goal of this review is to quantify the effect of smoking and smoking cessation on one of its urinary metabolites, 11-dehydrothromboxaneB2. Methods: PubMed and SCOPUS were searched to identify publications which report urinary 11-dehydrothromboxaneB2 levels in smokers and non-smokers, as well as articles reporting the effect of smoking cessation on urinary 11-dehydrothromboxaneB2 excretion. Results: We found ten studies assessing urinary 11-dehydrothroboxaneB2 levels in smokers and non-smokers. Four papers reported the amount of urinary 11-dehydrothromboxaneB2 excreted in 24 h while six reported the amount excreted adjusted for creatinine. The meta-analyses comparing the excretion of urinary 11-dehydrothromboxane in current smokers to non-smokers report increased levels in current smokers (mean difference = 0.31 μg/24-h [95%CI: 0.27–0.34] and 166.45 pg/mg creatinine [95%CI: 120.51–212.40]). There were not enough publications to perform meta-analyses on the effects of smoking cessation on urinary 11-dehydrothromboxaneB2 excretion. Conclusions: Urinary 11-dehydrothromboxaneB2 levels are increased in cigarette smokers, however, more data are needed to elucidate the effects of smoking cessation on urinary 11-dehydrothromboxaneB2 excretion. Keywords: Smoking, Inflammation, Thromboxane, Meta-analysis

Summary The smoking questionnaire (SQ), a multidimensional questionnaire covering the major dimensions of cigarette smoking, was developed to address the heterogeneity in the assessment of smoking exposure. It consists of eight questions and can be completed within a few minutes. Test-retest reliability of the SQ and concurrent validity with the Behavior Risk Factor Surveillance System (BRFSS) 2011 questionnaire were examined in a clinical study conducted in adult US current menthol cigarette smokers. The SQ and the BRFSS were self-administrated twice before and after randomization with a 6-day interval. The inter-temporal analyses included current smokers aged 22 to 66 years who completed the SQ at both timepoints. The percent agreement of items and 95% confidence intervals were calculated for the comparisons between the two timepoints and between the SQ and the BRFSS questionnaire. To evaluate the feasibility of the SQ and to capture subjects’ opinions about the SQ, a meta-questionnaire was administrated. High test-retest reliability levels (percent agreement of > 70 to 100% between the two timepoints) were found for SQ smoking behavior items, in particular for items related to current smoking status, 100-cigarettes lifetime, regular smoking, age of initiation and preferred brand. Moderate (55% agreement) to high test-retest reliability (84% agreement) was found for daily consumption of manufactured cigarettes. The comparison between the SQ and the BRFSS 2011 showed a high concurrent validity (98 to 100% agreement). The SQ was completed on average in 3 to 4 min and was assessed as easy to use. The findings demonstrate that the SQ is reliable in smokers and a practical tool to assess smoking exposure in clinical studies.

Smoking conventional cigarettes (CCs) exposes smokers to harmful and potentially harmful constituents (HPHCs). The Tobacco Heating System 2.2 (THS 2.2), a candidate modified risk tobacco product, was developed to reduce or eliminate the formation of HPHCs, while preserving as much as possible the taste, sensory experience, nicotine delivery profile and ritual characteristics of CC. This randomized, controlled, open-label study in confinement for 5 day exposure aimed to demonstrate the reduction in exposure to selected HPHCs, to assess nicotine uptake and subjective effects, in participants switching to THS 2.2 (n = 80) compared to participants continuing smoking CCs (n = 40) and abstaining from smoking (n = 40). The subjects were randomized according to sex and daily CC consumption. The levels of biomarkers of exposure to HPHCs were significantly reduced in participants switching to THS 2.2, compared to CC use. More importantly, the magnitude of exposure reduction observed was close to that which was seen in participants who abstained from smoking for 5 days, while nicotine uptake was maintained. Reduction in urge-to-smoke was comparable between THS and CC groups, however THS 2.2 was slightly less satisfactory than CCs. The new, alternative tobacco product THS 2.2 was well tolerated.

The Tobacco Heating System (THS) 2.2, a candidate Modified Risk Tobacco Product (MRTP), is designed to heat tobacco without burning it. Tobacco is heated in order to reduce the formation of harmful and potentially harmful constituents (HPHC), and reduce the consequent exposure, compared with combustible cigarettes (CC). In this 5-day exposure, controlled, parallel-group, open-label clinical study, 160 smoking, healthy subjects were randomized to three groups and asked to: (1) switch from CCs to THS 2.2 (THS group; 80 participants); (2) continue to use their own non-menthol CC brand (CC group; 41 participants); or (3) to refrain from smoking (smoking abstinence (SA) group; 39 participants). Biomarkers of exposure, except those associated with nicotine exposure, were significantly reduced in the THS group compared with the CC group, and approached the levels observed in the SA group. Increased product consumption and total puff volume were reported in the THS group. However, exposure to nicotine was similar to CC at the end of the confinement period. Reduction in urge-to-smoke was comparable between the THS and CC groups and THS 2.2 product was well tolerated.

International audience; On vehicles equipped with a turbocharged engine, there is a risk of compressor surge. This surge generates instabilities that lead to driving inconvenience, or even mechanical failure of the supercharging system. In general, the surge appears rather in transient operation: sudden closing of the throttle valve on gasoline engine, regulation of the EGR on diesel engine linked also to turbine regulation (VNT device or Waste Gate). On a turbocharger test stand, we set up the surge line in a “conventional way”: stationary experiments. Then we set up this line in transient conditions for different positions of an electric throttle placed upstream the compressor. It appears that: the surge limit is pushing back to lower flow rates when it is determined in transient; the surge limit is pushing back to lower flow rates when closing the throttle valve. The tests were carried on by the transient analysis of the surge during a quick closing-opening of the electric throttle valve.

The immune modulatory oligonucleotide IMO-2055 (EMD 1201081) is a phosphorothioate oligodeoxynucleotide agonist of Toll-like receptor 9. In preclinical studies, IMO-2055 was shown to activate natural killer cells and to support the antitumor activity of monoclonal antibodies. This phase 1b, open-label, 3 + 3 dose-escalation trial was performed to determine the recommended phase 2 dose of IMO-2055 combined with FOLFIRI/cetuximab in patients with previously treated, advanced/metastatic colorectal cancer (NCT00719199).Patients received 14-day cycles of cetuximab (days 1/8; 400 mg/m(2) day 1 cycle 1, 250 mg/m(2) for subsequent days/cycles), irinotecan (day 1; 180 mg/m(2)), folinic acid (day 1; 400 mg/m(2) racemic or 200 mg/m(2) L-form), 5-fluorouracil (day 1; 400 mg/m(2) intravenous bolus, followed by 2,400 mg/m(2) as 46-h infusion), and escalating IMO-2055 doses (days 1/8; 0.16, 0.32, 0.48 mg/kg). Fifteen patients received IMO-2055, including six, three, and six patients who were treated at the dose levels 0.16, 0.32, and 0.48 mg/kg, respectively.One dose-limiting toxicity was observed (grade 3 fatigue; at dose level 0.16 mg/kg). The most common adverse events were injection site reactions, diarrhea, fatigue, hypomagnesemia, and stomatitis. One patient achieved a confirmed partial response; 12 had stable disease, including five with stable disease ≥4.0 months.IMO-2055 combined with FOLFIRI/cetuximab was well tolerated at all dose levels tested. IMO-2055 0.48 mg/kg was considered as the recommended phase 2 dose.

5516^ Background: Prognosis for patients with recurrent and/or metastatic squamous cell cancer of the head and neck (R/M-SCCHN) is very poor. αvβ5 integrin is overexpressed in SCCHN and selective integrin blockade is being investigated as a treatment strategy. Methods: ADVANTAGE was a phase I/II study evaluating cilengitide with cetuximab and platinum-based chemotherapy. Eligible patients were ≥18 years with ≥1 measurable lesion, Karnofski performance status ≥70%, and confirmed R/M-SCCHN. The phase II part reported herein was an open-label, randomized, controlled trial investigating progression-free survival (PFS) in patients treated with 2 cilengitide 2000 mg regimens: once weekly (CIL1W) and twice weekly (CIL2W) administration combined with cisplatin, 5-FU, and cetuximab (PFE) as compared with PFE alone (control). Secondary objectives included overall survival (OS) and objective response (OR). Treatment-emergent adverse events (TEAEs) were monitored. Results: 184 eligible patients were enrolled. Overall, patient characteristics were similar across arms. Median duration of treatments was shorter in the CIL2W arm compared with the CIL1W arm (cilengitide: 16.1 vs 23.4 wk, cetuximab: 16.0 vs 22.6 wk, platinum: 16.0 vs 18.0 wk, and 5-FU: 14.6 vs 18.0 wk). Median PFS was 6.4 months in the CIL1W group, 5.6 months in the CIL2W group and 5.7 months in the control group, with CIL1W and CIL2W having HRs of 1.03 (95% CI: 0.67–1.59) and 1.55 (95% CI: 0.99–2.43) vs control. The latter HR was possibly due to less compliance in the CIL2W arm. Median OS was 12.4, 10.6, and 11.6 months in the CIL1W, CIL2W, and control groups, respectively. ORs were observed in 46.8%, 26.7%, and 35.5% of patients in the CIL1W, CIL2W, and control arms, respectively. Most common (≥15%) grade 3/4 TEAEs were neutropenia, hypokalemia, leukopenia, stomatitis, and fatigue. No safety differences were noted between treatment arms. Overall, there were 7 drug-related TEAEs (2 in CIL1W, 2 in CIL2W, and 3 in control) leading to death. Conclusions: In this population, neither of the cilengitide-containing regimens was able to demonstrate a PFS benefit over PFE alone.