Patients with atherosclerotic peripheral arterial disease have a high risk of lung cancer: Systematic review and meta-analysis of literature.

PURPOSE: Lung cancer and atherosclerosis share common risk factors. Literature data suggest that the prevalence of lung malignancy in patients with peripheral arterial disease (PAD) is higher than in the general population. Our goal was to determine, through a systematic literature review, the prevalence of lung cancer in patients with PAD. METHODS: We consulted available publications in the Cochrane library, MEDLINE, PUBMED, EMBASE, and ClinicalTrials.gov. We included all articles, written in English or French, published between 1990 and 2020 reporting the prevalence of lung cancer in patients with PAD (atherosclerotic aortic aneurysm or peripheral occlusive diseases). Patients with coronary artery disease, cardiac valvulopathy or carotid stenosis were not included. We did not include case reports. We performed a critical analysis of each article. Data were collected from two independent readers. A fixed effect model meta-analysis allowed to estimate a summary prevalence rate. RESULTS: We identified 303 articles, and selected 19 articles according to selection criteria. A total of 16849 patients were included (mean age 68.3 years, 75.1% of males). Aortic aneurysms were found in 29% of patients and atherosclerotic occlusive disease in 66% of patients. Lung cancer was identified in 538 patients, representing a prevalence of 3%. DISCUSSION: Lung cancer is found in 3% of patients with atherosclerotic PAD. This prevalence is higher than that found in lung cancer screening programs performed in the general population of smokers and former smokers. These patients should be screened for lung cancer. Their selection may dramatically increase the benefit of lung cancer screening.

[Targeted agents in the treatment of lung cancer]. / Place des traitements ciblés dans la prise en charge des cancers broncho-pulmonaires.

Lung cancer is in France, the leading cause of cancer death. Despite the dramatic advances that have allowed in a few years to go, for metastatic cancer, from a median survival without specific treatment of 4.5 months and now almost always more than one year, survival remains disappointing and further improvements are needed. Progress in the accumulated knowledge of the inner workings of normal and tumoral cells have paved the way for the development of targeted therapeutics called biological or simply targeted therapies. Two biological processes are already the target of marketed drugs, this is the way the receptor of epidermal growth factor (EGFR) and the path of neo-angiogenesis. It is almost assumed that, in the very near future, the inhibition of EML4-ALK will also be the subject of new drugs. In the medium term, it is conceivable that the molecular dissection of the tumors actually lead to the prescription of treatments tailored to mutations and other abnormalities that direct the growth of cancers.

Mechanics and crossbridge kinetics of tracheal smooth muscle in two inbred rat strains.

The aim of the study was to determine whether the nonspecific in vivo airway hyperresponsiveness of the inbred Fisher F-344 rat strain was associated with differences in the intrinsic contractile properties of tracheal smooth muscle (TSM) when compared with Lewis rats. Isotonic and isometric contractile properties of isolated TSM from Fisher and Lewis rats (each n=10) were investigated, and myosin crossbridge (CB) number, force and kinetics in both strains were calculated using Huxley's equations adapted to nonsarcomeric muscles. Maximum unloaded shortening velocity and maximum extent of muscle shortening were higher in Fisher than in Lewis rats (approximately 46% and approximately 42%, respectively), whereas peak isometric tension was similar. The curvature of the hyperbolic force/velocity relationship did not differ between strains. Myosin CB number and unitary force were similar in both strains. The duration of CB detachment and attachment was shorter in Fisher than in Lewis rats (approximately -46% and -34%, respectively). In Fisher rats, these results show that inherited, genetically determined factors of airway hyperresponsiveness are associated with changes in crossbridge kinetics, contributing to an increased tracheal smooth muscle shortening capacity and velocity.

Myosin cross-bridge kinetics in airway smooth muscle: a comparative study of humans, rats, and rabbits.

To analyze the kinetics and unitary force of cross bridges (CBs) in airway smooth muscle (ASM), we proposed a new formalism of Huxley's equations adapted to nonsarcomeric muscles (Huxley AF. Prog Biophys Biophys Chem 7: 255-318, 1957). These equations were applied to ASM from rabbits, rats, and humans (n = 12/group). We tested the hypothesis that species differences in whole ASM mechanics were related to differences in CB mechanics. We calculated the total CB number per square millimeter at peak isometric tension (Psi x10(9)), CB unitary force (Pi), and the rate constants for CB attachment (f(1)) and detachment (g(1) and g(2)). Total tension, Psi, and Pi were significantly higher in rabbits than in humans and rats. Values of Pi were 8.6 +/- 0.1 pN in rabbits, 7.6 +/- 0.3 pN in humans, and 7.7 +/- 0.2 pN in rats. Values of Psi were 4.0 +/- 0.5 in rabbits, 1.2 +/- 0.1 in humans, and 1.9 +/- 0.2 in rats; f(1) was lower in humans than in rabbits and rats; g(2) was higher in rabbits than in rats and in rats than in humans. In conclusion, ASM mechanical behavior of different species was characterized by specific CB kinetics and CB unitary force.

Asthma severity and adequacy of management in accident and emergency departments in France: a prospective study.

BACKGROUND: Recent guidelines have enabled doctors to establish accident and emergency department management strategies for acute asthma on the basis of severity of exacerbations at presentation. However, there is no available information on acute asthma patients classified according to severity of disease. Our aim was to describe the severity of such exacerbations at presentation, and the adequacy of treatment and management. METHODS: We did a 12-month multicentre cross-sectional observational cohort study in adult patients with acute asthma who attended one of 37 accident and emergency departments in France. The doctors who examined the patients obtained information using a formatted chart. We classified exacerbations according to severity (life-threatening, severe, or mild to moderate), on the basis of clinical findings and peak expiratory flow value, as defined by currently used guidelines. FINDINGS: Of 3772 patients with acute asthma, 975 (26%) had life-threatening attacks, 1834 (49%) had severe exacerbations without life-threatening features, and 963 (26%) had mild to moderate exacerbations. Initial treatment included nebulised b2 agonists, anticholinergics, and systemic corticosteroids in 3492 (93%), 1841 (49%), and 2252 (60%), respectively. According to severity classification, anticholinergics were used in 494 (51%), 913 (50%), and 434 (45%) of patients in life-threatening, severe, and mild to moderate exacerbations groups, respectively; corticosteroids were given in 666 (68%), 1117 (61%), and 468 (49%), respectively. The overall admission rate was 54.2%, and mean stay was 6.1 (SD 6.0) days. Patients were admitted in 747 (77%), 1018 (55%), and 278 (29%) of cases in life-threatening, severe, and mild to moderate groups, respectively. Three patients died in hospital. INTERPRETATION: Acute asthma exacerbations are often life-threatening in patients who attend accident and emergency departments, and management of patients is not ideal, mainly because of underuse of corticosteroids and inappropriate admission rates according to severity.

[Biomechanics and bio-energetics of smooth muscle contraction. Relation to bronchial hyperreactivity]. / Biomécanique et bioénergétique de la contraction musculaire lisse--Liens avec l'hyperréactivité bronchique.

Mechanical studies of isolated muscle and analysis of molecular actomyosin interactions have improved our understanding of the pathophysiology of airway smooth muscle. Mechanical properties of airway smooth muscle are similar to those of other smooth muscles. Airway smooth muscle exhibits spontaneous intrinsic tone and its maximum shortening velocity (Vmax) is 10-30 fold lower than in striated muscle. Smooth muscle myosin generates step size and elementary force per crossbridge interaction approximately similar to those of skeletal muscle myosin. Special slow cycling crossbridges, termed latch-bridges, have been attributed to myosin light chain dephosphorylation. From a mechanical point of view, it has been shown that airway hyperresponsiveness is characterized by an increased Vmax and an increased shortening capacity, with no significant change in the force-generating capacity.

Impaired load dependence of diaphragm relaxation during congestive heart failure in the rabbit.

The load dependence (LD) of relaxation was studied in the diaphragm of rabbits with congestive heart failure (CHF). CHF (n = 15) was induced by combined chronic volume and pressure overload. Aortic insufficiency was induced by forcing a catheter through the aortic sigmoid valves, followed 3 wk later by abdominal aortic stenosis. Six weeks after the first intervention, animals developed CHF. Sham-operated animals served as controls (C; n = 12). Diaphragm mechanics were studied in vitro on isolated strips, at 22 degrees C, in isotonic and isometric loading conditions. Contractility was lower in the CHF group, as reflected by lower total tension: 1.11 +/- 0.10 in CHF vs. 2.38 +/- 0.15 N/cm(2) in C in twitch (P < 0.001) and 2.46 +/- 0.22 in CHF vs. 4.90 +/- 0.25 N. cm(-2) in C in tetanus (P < 0.001). The index LD was used to quantify the load dependence of relaxation: LD is <1 in load-dependent muscles and tends toward 1 in load-independent muscles. LD was significantly higher in CHF than in C rabbits, in both twitch (0.99 +/- 0.01 vs. 0.75 +/- 0.03; P < 0. 001) and tetanus (0.95 +/- 0.02 vs. 0.84 +/- 0.02; P < 0.001). In the CHF rabbits' diaphragm, the fall in total tension was linearly related to the fall in load dependence of relaxation. The decrease in load dependence of relaxation in CHF animals suggests sarcoplasmic reticulum abnormalities. Impairment of the sarcoplasmic reticulum may also partly account for the decrease in contractile performance of diaphragm in CHF animals.

Effects of load and tone on the mechanics of isolated human bronchial smooth muscle.

Isotonic and isometric properties of nine human bronchial smooth muscles were studied under various loading and tone conditions. Freshly dissected bronchial strips were electrically stimulated successively at baseline, after precontraction with 10(-7) M methacholine (MCh), and after relaxation with 10(-5) M albuterol (Alb). Resting tension, i.e., preload determining optimal initial length (Lo) at baseline, was held constant. Compared with baseline, MCh decreased muscle length to 93 +/- 1% Lo (P < 0.001) before any electrical stimulation, whereas Alb increased it to 111 +/- 3% Lo (P < 0.01). MCh significantly decreased maximum unloaded shortening velocity (0.045 +/- 0.007 vs. 0.059 +/- 0.007 Lo/s), maximal extent of muscle shortening (8.4 +/- 1.2 vs. 13.9 +/- 2.4% Lo), and peak isometric tension (6.1 +/- 0.8 vs. 7.2 +/- 1.0 mN/mm2). Alb restored all these contractile indexes to baseline values. These findings suggest that MCh reversibly increased the number of active actomyosin cross bridges under resting conditions, limiting further muscle shortening and active tension development. After the electrically induced contraction, muscles showed a transient phase of decrease in tension below preload. This decrease in tension was unaffected by afterload levels but was significantly increased by MCh and reduced by Alb. These findings suggest that the cross bridges activated before, but not during, the electrically elicited contraction may modulate the phase of decrease in tension below preload, reflecting the active part of resting tension.

Effects of initial length on intrinsic tone in guinea pig tracheal smooth muscle.

In the guinea pig, tracheal smooth muscle (TSM) exhibits intrinsic tone (IT). The active nature of IT suggests that it could be influenced by muscle length and load. In the guinea pig, IT is entirely suppressed by the cyclooxygenase inhibitor indomethacin. IT could be measured as the difference between resting tone before and after indomethacin addition. We examined, in electrically stimulated TSM strips (n = 9), the influence of initial muscle length (Li) on IT, the relationship between IT and the maximum extent of relaxation (DeltaF1), and the influence of indomethacin on active isometric force. When Li decreased from 100 to 75% of optimal Li, there was a significant decrease in IT (from 12.0 +/- 0.2 to 5.3 +/- 0.1 mN; P < 0.001). Over the range of Li studied, DeltaF1 underestimated the amount of IT, but there was a close linear relationship between DeltaF1 and IT (r = 0.9). Compared with the basal state, indomethacin increased active isometric force (from 9.5 +/- 1.0 to 19.7 +/- 2.0 mN at optimal Li; P < 0.001) and induced its length dependency. In guinea pig TSM, Li was an important determinant of IT.

A new yeast artificial chromosome vector designed for gene transfer into mammalian cells.

This report describes the construction of a new yeast artificial chromosome (YAC) vector designed for gene transfer into mammalian cells. For ease of use, the two arms of the vector were cloned separately. The vector harbours the Neo and Hyg genes for dominant selection in mammalian cells, a putative human origin of replication, a synthetic matrix attachment region and two loxP sites (one on each arm). The cloning ability of the vector was demonstrated by successful propagation of the cDNA of the cystic fibrosis gene, CFTR, as a YAC in Saccharomyces cerevisiae. A YAC containing the entire CFTR gene was also constructed by retrofitting the two arms of a pre-existing clone (37AB12) with the two arms of the novel vector. Both the cDNA and entire gene containing YACs were circularized in yeast by inducible expression of the Cre recombinase. Recombination occurred very specifically at the loxP sequences present on the two arms of the YAC. Applications of the vector to gene transfer are discussed.

Identification of several genes differentially expressed during progression of chronic myelogenous leukemia.

The Bcr-Abl fusion protein plays a crucial role in the initiation and maintenance of chronic myelogenous leukemia (CML). However, additional events are necessary for the transition from the chronic phase to the terminal phase of the disease. To identify genes involved in the disease progression, we constructed a subtractive library from enriched K562 cell mRNA. We obtained 1084 cDNA clones. After a specific hybridization of these clones with a cDNA probe from either chronic phase or K562 cells, 43 clones which present a differential hybridization level have been selected. Among them, several clones corresponded to ribosomal protein genes showing an increased transcription level during the blast crisis. We observed variations in the expression of a cellular adhesion molecule, a laminin-binding protein. An increased transcription level of the MAZ gene has been shown in the terminal phase of the disease. This gene encodes a protein that regulates the transcription of myc.