[How to reduce lung cancer mortality among people living with HIV?] / Comment réduire la mortalité par cancer du poumon chez les personnes vivant avec le VIH ? Du sevrage tabagique au dépistage radiologique.

Lung cancer is the leading cause of cancer related death among people living with HIV (PLHIV). Tobacco exposure is higher among PLHIV (38.5%) and mainly explains the increased risk of lung cancer. To reduce lung cancer mortality, two approaches need to be implemented: lung cancer screening with low-dose thoracic CT scan and smoking cessation. Low dose CT scan is feasible in PLHIV. The false positive rate is not higher than in the general population, except for cases with CD4 <200/mm3. The impact on survival remains to be assessed. Despite the high prevalence, smoking cessation research among PLHIV is scarce. Very low quality data from 11 studies showed that more intensive smoking cessation interventions were effective in achieving short-term abstinence. A single randomized phase 3 trial showed the superiority of varenicline compared to placebo in long-term smoking cessation. The maximum benefit of reducing lung cancer mortality should be obtained by combining smoking cessation and lung cancer screening.

Study protocol for a pragmatic randomised controlled trial evaluating efficacy of a smoking cessation e-'Tabac Info Service': ee-TIS trial.

INTRODUCTION: A French national smoking cessation service, Tabac Info Service, has been developed to provide an adapted quitline and a web and mobile application involving personalised contacts (eg, questionnaires, advice, activities, messages) to support smoking cessation. This paper presents the study protocol of the evaluation of the application (e-intervention Tabac Info Service (e-TIS)). The primary objective is to assess the efficacy of e-TIS. The secondary objectives are to (1) describe efficacy variations with regard to users' characteristics, (2) analyse mechanisms and contextual conditions of e-TIS efficacy. METHODS AND ANALYSES: The study design is a two-arm pragmatic randomised controlled trial including a process evaluation with at least 3000 participants randomised to the intervention or to the control arm (current practices). Inclusion criteria are: aged 18 years or over, current smoker, having completed the online consent forms, possessing a mobile phone with android or apple systems and using mobile applications, wanting to stop smoking sooner or later. The primary outcome is the point prevalence abstinence of 7 days at 6 months later. Data will be analysed in intention to treat (primary) and per protocol analyses. A logistic regression will be carried out to estimate an OR (95% CI) for efficacy. A multivariate multilevel analysis will explore the influence on results of patients' characteristics (sex, age, education and socioprofessional levels, dependency, motivation, quit experiences) and contextual factors, conditions of use, behaviour change techniques. ETHICS AND DISSEMINATION: The study protocol was reviewed by the ethical and deontological institutional review board of the French Institute for Public Health Surveillance on 18 April 2016. The findings of this study will allow us to characterise the efficacy of e-TIS and conditions of its efficacy. These findings will be disseminated through peer-reviewed articles. TRIAL REGISTRATION NUMBER: NCT02841683; Pre-results.

Adaptive preconditioning in neurological diseases - therapeutic insights from proteostatic perturbations.

In neurological disorders, both acute and chronic neural stress can disrupt cellular proteostasis, resulting in the generation of pathological protein. However in most cases, neurons adapt to these proteostatic perturbations by activating a range of cellular protective and repair responses, thus maintaining cell function. These interconnected adaptive mechanisms comprise a 'proteostasis network' and include the unfolded protein response, the ubiquitin proteasome system and autophagy. Interestingly, several recent studies have shown that these adaptive responses can be stimulated by preconditioning treatments, which confer resistance to a subsequent toxic challenge - the phenomenon known as hormesis. In this review we discuss the impact of adaptive stress responses stimulated in diverse human neuropathologies including Parkinson׳s disease, Wolfram syndrome, brain ischemia, and brain cancer. Further, we examine how these responses and the molecular pathways they recruit might be exploited for therapeutic gain. This article is part of a Special Issue entitled SI:ER stress.

ER stress induces NLRP3 inflammasome activation and hepatocyte death.

The incidence of chronic liver disease is constantly increasing, owing to the obesity epidemic. However, the causes and mechanisms of inflammation-mediated liver damage remain poorly understood. Endoplasmic reticulum (ER) stress is an initiator of cell death and inflammatory mechanisms. Although obesity induces ER stress, the interplay between hepatic ER stress, NLRP3 inflammasome activation and hepatocyte death signaling has not yet been explored during the etiology of chronic liver diseases. Steatosis is a common disorder affecting obese patients; moreover, 25% of these patients develop steatohepatitis with an inherent risk for progression to hepatocarcinoma. Increased plasma LPS levels have been detected in the serum of patients with steatohepatitis. We hypothesized that, as a consequence of increased plasma LPS, ER stress could be induced and lead to NLRP3 inflammasome activation and hepatocyte death associated with steatohepatitis progression. In livers from obese mice, administration of LPS or tunicamycin results in IRE1α and PERK activation, leading to the overexpression of CHOP. This, in turn, activates the NLRP3 inflammasome, subsequently initiating hepatocyte pyroptosis (caspase-1, -11, interleukin-1ß secretion) and apoptosis (caspase-3, BH3-only proteins). In contrast, the LPS challenge is blocked by the ER stress inhibitor TUDCA, resulting in: CHOP downregulation, reduced caspase-1, caspase-11, caspase-3 activities, lowered interleukin-1ß secretion and rescue from cell death. The central role of CHOP in mediating the activation of proinflammatory caspases and cell death was characterized by performing knockdown experiments in primary mouse hepatocytes. Finally, the analysis of human steatohepatitis liver biopsies showed a correlation between the upregulation of inflammasome and ER stress markers, as well as liver injury. We demonstrate here that ER stress leads to hepatic NLRP3 inflammasome pyroptotic death, thus contributing as a novel mechanism of inflammation-mediated liver injury in chronic liver diseases. Inhibition of ER-dependent inflammasome activation and cell death pathways may represent a potential therapeutic approach in chronic liver diseases.

L-type amino-acid transporter 1 (LAT1): a therapeutic target supporting growth and survival of T-cell lymphoblastic lymphoma/T-cell acute lymphoblastic leukemia.

The altered metabolism of cancer cells is a treasure trove to discover new antitumoral strategies. The gene (SLC7A5) encoding system L amino-acid transporter 1 (LAT1) is overexpressed in murine lymphoma cells generated via T-cell deletion of the pten tumor suppressor, and also in human T-cell acute lymphoblastic leukemia (T-ALL)/lymphoma (T-LL) cells. We show here that a potent and LAT1 selective inhibitor (JPH203) decreased leukemic cell viability and proliferation, and induced transient autophagy followed by apoptosis. JPH203 could also alter the in vivo growth of luciferase-expressing-tPTEN-/- cells xenografted into nude mice. In contrast, JPH203 was nontoxic to normal murine thymocytes and human peripheral blood lymphocytes. JPH203 interfered with constitutive activation of mTORC1 and Akt, decreased expression of c-myc and triggered an unfolded protein response mediated by the C/EBP homologous protein (CHOP) transcription factor associated with cell death. A JPH203-resistant tPTEN-/-clone appeared CHOP induction deficient. We also demonstrate that targeting LAT1 may be an efficient broad spectrum adjuvant approach to treat deadly T-cell malignancies as the molecule synergized with rapamycin, dexamethasone, doxorubicin, velcade and l-asparaginase to alter leukemic cell viability.

Osteopontin deficiency aggravates hepatic injury induced by ischemia-reperfusion in mice.

Osteopontin (OPN) is a multifunctional protein involved in hepatic steatosis, inflammation, fibrosis and cancer progression. However, its role in hepatic injury induced by ischemia-reperfusion (I-R) has not yet been investigated. We show here that hepatic warm ischemia for 45 min followed by reperfusion for 4 h induced the upregulation of the hepatic and systemic level of OPN in mice. Plasma aspartate aminotransferase and alanine aminotransferase levels were strongly increased in Opn(-/-) mice compared with wild-type (Wt) mice after I-R, and histological analysis of the liver revealed a significantly higher incidence of necrosis of hepatocytes. In addition, the expression levels of inducible nitric oxide synthase (iNOS), tumor necrosis factor-α (TNFα), interleukin 6 (IL6) and interferon-γ were strongly upregulated in Opn(-/-) mice versus Wt mice after I-R. One explanation for these responses could be the vulnerability of the OPN-deficient hepatocyte. Indeed, the downregulation of OPN in primary and AML12 hepatocytes decreased cell viability in the basal state and sensitized AML12 hepatocytes to cell death induced by oxygen-glucose deprivation and TNFα. Further, the downregulation of OPN in AML12 hepatocytes caused a strong decrease in the expression of anti-apoptotic Bcl2 and in the ATP level. The hepatic expression of Bcl2 also decreased in Opn(-/-) mice versus Wt mice livers after I-R. Another explanation could be the regulation of the macrophage activity by OPN. In RAW macrophages, the downregulation of OPN enhanced iNOS expression in the basal state and sensitized macrophages to inflammatory signals, as evaluated by the upregulation of iNOS, TNFα and IL6 in response to lipopolysaccharide. In conclusion, OPN partially protects from hepatic injury and inflammation induced in this experimental model of liver I-R. This could be due to its ability to partially prevent death of hepatocytes and to limit the production of toxic iNOS-derived NO by macrophages.

[Pleuropneumonia due to Mycobacterium chelonae]. / Pleuropneumonie à Mycobacterium chelonae.

Mycobacterium chelonae (M. chelonae) is rarely responsible for respiratory infection. This report concerns the case of an 81-year-old man with previously asymptomatic bronchiectasis, colonised by M. chelonae for 3 years. He was hospitalised for acute dyspnoea and fever due to a right hydro-pneumothorax with cavitated alveolar opacities of the right lung. Pleural fluid and bronchial aspiration were positive for M. chelonae and no other microorganisms were detected. The effusion was drained and the patient treated with clarythromycin and amikacin. The radiological abnormalities improved but the patient's general condition remained poor. Treatment was continued for 11 months. Because of the absence of any other bacteria, clinical deterioration following broad-spectrum antibiotics and stabilisation of the lesions after anti-mycobacterial treatment, our diagnosis was severe M. chelonae pleuro-pneumonia in an immunocompetent patient.

[Thoracic involvement in Hodgkin's lymphoma]. / Atteintes thoraciques au cours des lymphomes hodgkiniens.

INTRODUCTION: Hodgkin's lymphoma is defined by a malignant prolifération of Reed-Sternberg or Hodgkin cells that are clonally related B-cell-derived malignant cells. This disease is characterized by a good outcome (cure rate more than 80%). Initial thoracic involvement is usual and the more frequent localization is the mediastinum, following by the lung parenchyma and the pleura. In the last two cases, histological diagnosis is warranted since this involvement modified the staging and the prognosis of the disease. STATE OF THE ART: Early one, infectious diseases were the most frequent complications. Functional deficiency following mediastinal radiotherapy and chemotherapy (including bleomycin) is often detected, whatever this is associated with symptom or CT scan abnormalities. Granulomatous disease can be associated at any time during the disease and differential diagnosis from relapse is often difficult. Finally, these patients have an increased risk of developing solid cancers and particularly lung cancers. PERSPECTIVES AND CONCLUSIONS: Hodgkin lymphoma patients are more likely to die from acute and late treatment-related toxicities and the major task is to reduce treatment associated toxicity while maintaining cure rate.

[Early pneumonia after allogenic stem cell transplantation]. / Complications pulmonaires précoces des allogreffes de cellules souches hématopoïétiques.

INTRODUCTION: Pneumonia is one of the main causes of mortality following allogenic stem cell transplantation, especially in the first months after the transplant has been performed. STATE OF THE ART: Pneumonia is the most common infection occurring after transplant and the infection with the highest mortality. Following the classical, myeloablative approach to transplant, two thirds of the pneumonias that occur are of infectious origin. Their causes roughly follow the timing of the immune reconstitution, and may depend on the type of transplant, the match between donor and recipient, and, overall, the occurrence of graft-versus-host disease. Most bacterial pneumonias occur during the initial neutropenic phase. The 2nd and 3rd month post transplant are mainly complicated by viral pneumonia, especially respiratory virus and adenovirus pneumonia in deeply immunosuppressed patients. Preemptive and prophylactic strategies have considerably reduced the incidence of cytomegalovirus pneumonia. Pneumonia due to encapsulated bacteria, such as Haemophilus influenzae and Streptococcus pneumoniae, usually considered to be late infections, may actually be observed from the second month post-transplant. PERSPECTIVES: The increasing use of reduced-intensity conditioning regimens has modified the time course of the main adverse events following transplantation, including the timing of the infectious pneumonias. The pneumonias that are specifically related to allogenic transplant are idiopathic interstitial pneumonia, bronchiolitis obliterans, and bronchiolitis obliterans organizing pneumonia, which are all considered to be pulmonary manifestations of graft-versus-host disease, and treated as such. Prophylaxis for many of these infectious pneumonias (i.e., P jiroveci, S pneumoniae, toxoplasmosis) are well standardized. CONCLUSIONS: Much remains to be done to decrease the incidence of pneumonia in these patients and to understand their mechanisms.

Decreased VEGF concentration in lung tissue and vascular injury during ARDS.

Endothelial injury is an important prognostic factor in acute respiratory distress syndrome (ARDS). Decreased production of vascular endothelial growth factor (VEGF) in ARDS may favour vascular lesions, since VEGF promotes endothelial survival by inhibiting apoptosis. This study sought to document low VEGF levels in lung tissue from ARDS patients, to determine whether the cause was injury to alveolar type II cells (the main pulmonary source of VEGF) and to evaluate the vascular consequences. Lung specimens were obtained by open biopsy or autopsy from 29 patients with severe ARDS (two survivors) and five controls. As compared with controls, homogenates of lung tissue from ARDS patients contained less VEGF (median (interquartile range) ARDS 8.2 (4.7-12.2) versus controls 28.4 (9.9-47.1) ng x g(-1) protein). Increased immunostaining with surfactant protein B was seen in ARDS lungs. Extensive cellular apoptosis (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labelling staining), including endothelial and alveolar type II cells, was demonstrated, and vascular bed density (CD31 immunostaining) decreased in ARDS lungs as compared with controls. VEGF levels were negatively correlated to apoptotic endothelial cell counts. In conclusion, decreased vascular endothelial growth factor levels in lung tissue may participate in the decrease in lung perfusion in acute respiratory distress syndrome.

[Impact of prior biological assessment of coagulation on the hemorrhagic risk of fiberoptic bronchoscopy]. / Bilan de coagulation et risque hémorragique de la fibroscopie bronchique.

INTRODUCTION: The goals of the study were to test the value of coagulation tests to predict bleeding events during fiberoptic bronchoscopy (FOB) and to identify risk factors. METHODS: A monocentric prospective study of 426 procedures performed by one physician was realized. A standardized questionnaire and coagulation tests including prothrombine time, activated cephaline time and platelets counts were performed before the procedure. Bleeding events, defined by a loss of more than 50 ml of blood, were recorded for all patients. RESULTS: 44 patients (10.3%) had bleeding events, modifying the procedure in 19 cases. No death occurred following FOB during the study. Among the 17 patients with abnormalities on coagulation test before FOB, only one had significant bleeding. Two risk factors were found as predictors of bleeding events: nose or gum bleeding (OR=4.99, CI (95%) [2.6-9.5]; p<0.001) and left cardiac failure (OR=4.53, CI (95%) [1.7-12.1]; p<0.01). CONCLUSION: This study shows that abnormalities on coagulation tests are not predictive for bleeding events. Nose or gum bleeding and left cardiac failure may be risk factors for bleeding events during FOB.

Spontaneous apoptosis in primary cultures of human and rat hepatocytes: molecular mechanisms and regulation by dexamethasone.

To elucidate the biochemical pathways leading to spontaneous apoptosis in primary cultures of human and rat hepatocytes, we examined the activation of the caspase cascade, the expression of Bcl-2-related-proteins and heat shock proteins. Comparisons were made before and after dexamethasone (DEX) treatment. We show that DEX inhibited spontaneous apoptosis in a dose-dependent manner. DEX increases the expression of anti-apoptotic Bcl-2 and Bcl-x(L) proteins, decreases the expression of pro-apoptotic Bax and inhibits Bad translocation thereby preventing the release of cytochrome c, the activation of caspases, and cell death. Although, the expression of Hsp27 and Hsp70 proteins remained unchanged, the oncogenic protein c-Myc is upregulated upon DEX-treatment. These results indicate that DEX mediates its survival effect against spontaneous apoptosis by acting upstream of the mitochondrial changes. Thus, the mitochondrial apoptotic pathway plays a major role in regulating spontaneous apoptosis in these cells. Blocking this pathway therefore may assist with organ preservation for transplant, drug screening, and other purposes.

[Update in pneumology]. / Actualités en pneumologie.

The end of the century has not brought any great modification in pneumology therapy. Prospective studies in asthma using combined therapeutic approaches, systemic or local steroid treatment in mild or moderate chronic obstructive pulmonary disease or itraconazole in allergic bronchopulmonary aspergillosis are summarized in this review. Innovation is coming from radiology, with confirmation of the interest of positive-emission tomography for the preoperative stage of lung cancer.

Vascular endothelial growth factor synthesis in the acute phase of experimental and clinical lung injury.

Vascular endothelial growth factor (VEGF) is a potent angiogenic and endothelial survival factor, which is abundantly expressed in the normal lung. Conceivably, VEGF may be released by numerous cell types found around the airspaces, including alveolar type 2 cells, alveolar macrophages, and polymorphonuclear neutrophils. Using a bacteria-induced lung injury model in rats, VEGF expression in lung was investigated. Both VEGF protein and VEGF messenger ribonucleic acid (mRNA), 4 and 24 h after bacterial challenge (Pseudomonas aeruginosa), were decreased compared with sham rats. VEGF protein was also investigated in bronchoalveolar lavage (BAL) from patients studied within 7 days of acute respiratory distress syndrome (ARDS) onset and in patients without ARDS. VEGF protein levels in BAL were decreased in patients with ARDS versus those without (14.3 +/- 11.1 pg x mL(-1) versus 76.8 +/- 51.1 pg x mL(-1), p = 0.03). In aggregate, these findings show that the initial phase of acute lung injury is associated with a decrease in vascular endothelial growth factor in the lung. This downregulation may represent a protective mechanism aimed at limiting endothelial permeability, and may participate in the decrease in capillary number that is observed during early acute respiratory distress syndrome.

Dexamethasone inhibits spontaneous apoptosis in primary cultures of human and rat hepatocytes via Bcl-2 and Bcl-xL induction.

We examined the effects of dexamethasone (DEX) on the apoptotic process in primary cultures of human and rat hepatocytes. DEX prolonged cell viability, inhibited the development of an apoptotic morphology, and stabilised the expression of procaspase-3 in both human and rat hepatocytes. In addition, the inhibition of apoptosis by DEX was strongly correlated with a decrease of caspase-3-like protease activity. Moreover, DEX treatment increased the expression of anti-apoptotic Bcl-2 and Bcl-xL proteins in human and rat hepatocytes, respectively, whereas the expression of pro-apoptotic proteins Bcl-xS or Bad was not detected or remained unchanged. The bcl-xL transcript is regulated at the transcriptional level and its expression paralleled that of Bcl-xL protein in DEX-treated rat hepatocytes. Taken together, these results indicate that this glucocorticoid exerts a protective role on cell survival and it delays apoptosis of human and rat hepatocytes by modulating caspase-3-like protease activity and bcl-2 and bcl-x gene expression.

[Evaluation of occupational exposures in lung cancer]. / Evaluation des expositions professionnelles et cancer bronchopulmonaire.

Occupational lung cancers are underestimated by the number of cases compensated in the French National Insurance System. Rules of compensation of occupational diseases were recently modified in France. Therefore a study was conducted on incident cases of lung cancer in a general hospital in the Paris area. The aim was to evaluate the exposure to carcinogens using data of a detailed specific occupational questionnaire, and to determine the number of cases who could receive compensation. Two hundred and seven subjects (171 males, 36 females, mean age = 64.5 years) were eligible in 1996, and 122 had an occupational questionnaire. Definite exposure to one or more occupational carcinogens in at least one job was identified in 50 subjects, the most frequent agent was asbestos (42 subjects). Claim for compensation was done in 32 subjects, mainly for asbestos (30 subjects). This study emphasizes the frequency of occupational exposure to carcinogens, and the usefulness of systematic occupational questionnaire in subjects having lung cancer. Social and financial consequences are important for these subjects. Further studies are needed, with recruitement of control subjects to allow calculation of the attributable risk to occupational factors in lung cancer.

Traumatic coronary-pulmonary artery fistula, 23 years after a stab wound.

We describe a 50-year-old man with onset of severe hemoptysis and anemia. Twenty-three years earlier, he had undergone a surgical procedure for a left thoracic wound as a result of a knife injury. Current diagnosis of aneurysm of the left ventricle and coronary-pulmonary artery fistula was made after coronary arteriography. The patient underwent resection of the aneurysm and repair of the fistula.