Analyse des délais de prise en charge des cancers thoraciques : étude prospective

RésuméIntroductionLe cancer broncho-pulmonaire est la première cause de décès par cancer en France. Son diagnostic est le plus souvent tardif, alors que le délai entre le début des symptômes et la prise en charge est considéré comme un facteur aggravant.Matériel et méthodesNotre étude prospective a recueilli les différentes dates de prise en charge de 139 patients consécutifs bénéficiant d’un traitement primaire pour un cancer thoracique dans notre hôpital entre novembre 2008 et mai 2009. L’objectif de cette étude était d’évaluer différents délais de prise en charge des patients porteurs d’un cancer thoracique quelle que soit sa prise en charge thérapeutique (médicale ou chirurgicale) et de déterminer la cause de ces délais.RésultatsLe délai médian entre la première imagerie pathologique et le traitement est de 9,6 semaines. Les délais étaient significativement plus courts dans les stades tardifs et les carcinomes à petites cellules (p=0,001). Il existait une tendance à des délais plus courts pour les femmes et des délais plus longs pour les classes d’âge les plus élevées.ConclusionL’évaluation des délais de prise en charge, en particulier pour les stades précoces, s’intègre dans le contrôle de la qualité de prise en charge de ces pathologies.SummaryIntroductionLung cancer is the main cause of cancer death in France. The diagnosis is often late and the delay between the onset of symptoms and management is considered an aggravating factor.Material and methodsOur prospective study collected the dates of the start of management of 139 consecutive patients receiving first line treatment for thoracic cancer in our hospital between November 2008 and May 2009. The aim of this study was to evaluate the delays in medical or surgical treatments in patients with thoracic cancer and to determine the cause of these delays.ResultsThe median delay between the first abnormal chest X-ray and treatment was 9.6 weeks. The delays were significantly shorter in the late stages and in small cell cancer (P=0.001). There was a tendency for shorter delays in women and for longer delays in older patients.ConclusionEvaluation of the delays in treatment, particularly in the early stages, is part of the quality control of management of these diseases

Near-Infrared Interferometric Measurements of Herbig Ae/Be Stars

We have observed the Herbig Ae/Be sources AB Aur, VV Ser, V1685 Cyg (BD+40 4124), AS 442, and MWC 1080 with the Palomar Testbed Interferometer, obtaining the longest baseline near-IR interferometric observations of this class of objects. All of the sources are resolved at 2.2 microns with angular size scales generally <5 mas, consistent with the only previous near-IR interferometric measurements of Herbig Ae/Be stars by Millan-Gabet and collaborators. We determine the angular size scales and orientations predicted by uniform disk, Gaussian, ring, and accretion disk models. Although it is difficult to distinguish different radial distributions, we are able to place firm constraints on the inclinations of these models, and our measurements are the first that show evidence for significantly inclined morphologies. In addition, the derived angular sizes for the early type Herbig Be stars in our sample, V1685 Cyg and MWC 1080, agree reasonably well with those predicted by the face-on accretion disk models used by Hillenbrand and collaborators to explain observed spectral energy distributions. In contrast, our data for the later-type sources AB Aur, VV Ser, and AS 442 are somewhat inconsistent with these models, and may be explained better through the puffed-up inner disk models of Dullemond and collaborators.Comment: 40 pages, 11 figures. Accepted for publication in Ap

Resolved Inner Disks around Herbig Ae/Be Stars

We have observed 14 Herbig Ae/Be sources with the long-baseline near-IR Palomar Testbed Interferometer, All except two sources are resolved at 2.2 um, with angular sizes generally <5 mas. We determine the size scales and orientations of the 2.2 um emission using various models: uniform disks, Gaussians, uniform rings, flat accretion disks with inner holes, and flared disks with puffed-up inner rims; 7 objects display significantly inclined morphologies, generally compatible with the outer disk geometries inferred from millimeter interferometric observations, implying that HAEBE disks are not significantly warped. Using the derived inner disk sizes and inclinations, we compute the spectral energy distributions for two simple physical disk models, and compare these with observed SEDs compiled from the literature and new near-IR photometry. While geometrically flat accretion disk models are consistent with the data for the earliest spectral types in our sample (MWC 297, V1685 Cyg, and MWC 1080), the later-type sources are explained better through models incorporating puffed-up inner disk walls; this may indicate different accretion mechanisms for early and late-type Herbig Ae/Be stars.Comment: 54 pages, including 16 figures. Accepted for publication in the Astrophysical Journal (October 2004 issue

Long-term optical/IR variability of the Be/X-ray binary LS V +44 17/RX J0440.9+4431

We present the first long-term study of the optical counterpart to the X-ray pulsar LS V +44 17/RX J0440.9+4431. The results of our photometric and spectroscopic analysis show that LS V +44 17/RX J0440.9+4431 contains a moderately reddened, E(B-V)=0.65+-0.05, B0.2V star located at about 3.3 kpc. The Ha line consistently shows a double-peak profile varying from symmetric shape to completely distorted on one side (V/R phases). A correlation between the equivalent width of the Ha line and the infrared magnitudes is seen: as the EW(Ha) decreases the IR magnitudes become fainter. This long-term optical/IR variability is attributed to structural changes in the Be star's circumstellar disc. The observations include a recent decline in the circumstellar disc and subsequent recovery. We have witnessed the cessation of a global oscillation due to the decline of the circumstellar disc. If the present disc growth rate continues we predict the onset of another episode of V/R variability by the end of 2006. We have investigated the typical time scales for disc variability of various Be/X-ray binaries and found a correlation with the orbital period. This correlation is hard to establish due to the difficulty in defining the exact duration of the various activity states, but it is seen both in the duration of the disc growth/dissipation phase and the value of the Ha equivalent width prior to the appearance of asymmetric profiles. These relationships provide further evidence for the interaction of the neutron star with the circumstellar disc of the Be star's companion and confirms the need of a fully developed disc for the V/R variability to be observed.Comment: 9 pages, 5 figs, accepted for publication in A&

Programmed Bending Reveals Dynamic Mechanochemical Coupling in Supported Lipid Bilayers

In living cells, mechanochemical coupling represents a dynamic means by which membrane components are spatially organized. An extra-ordinary example of such coupling involves curvature-dependent polar localization of chemically-distinct lipid domains at bacterial poles, which also undergo dramatic reequilibration upon subtle changes in their interfacial environment such as during sporulation. Here, we demonstrate that such interfacially-triggered mechanochemical coupling can be recapitulated in vitro by simultaneous, real-time introduction of mechanically-generated periodic curvatures and attendant strain-induced lateral forces in lipid bilayers supported on elastomeric substrates. In particular, we show that real-time wrinkling of the elastomeric substrate prompts a dynamic domain reorganization within the adhering bilayer, producing large, oriented liquid-ordered domains in regions of low curvature. Our results suggest a mechanism in which interfacial forces generated during surface wrinkling and the topographical deformation of the bilayer combine to facilitate dynamic reequilibration prompting the observed domain reorganization. We anticipate this curvature-generating model system will prove to be a simple and versatile tool for a broad range of studies of curvature-dependent dynamic reorganizations in membranes that are constrained by the interfacial elastic and dynamic frameworks such as the cell wall, glycocalyx, and cytoskeleton

The Non-Catalytic Carboxyl-Terminal Domain of ARFGAP1 Regulates Actin Cytoskeleton Reorganization by Antagonizing the Activation of Rac1

The regulation of the actin cytoskeleton and membrane trafficking is coordinated in mammalian cells. One of the regulators of membrane traffic, the small GTP-binding protein ARF1, also activates phosphatidylinositol kinases that in turn affect actin polymerization. ARFGAP1 is a GTPase activating protein (GAP) for ARF1 that is found on Golgi membranes. We present evidence that ARFGAP1 not only serves as a GAP for ARF1, but also can affect the actin cytoskeleton.As cells attach to a culture dish foci of actin appear prior to the cells flattening and spreading. We have observed that overexpression of a truncated ARFGAP1 that lacks catalytic activity for ARF, called GAP273, caused these foci to persist for much longer periods than non-transfected cells. This phenomenon was dependent on the level of GAP273 expression. Furthermore, cell spreading after re-plating or cell migration into a previously scraped area was inhibited in cells transfected with GAP273. Live cell imaging of such cells revealed that actin-rich membrane blebs formed that seldom made protrusions of actin spikes or membrane ruffles, suggesting that GAP273 interfered with the regulation of actin dynamics during cell spreading. The over-expression of constitutively active alleles of ARF6 and Rac1 suppressed the effect of GAP273 on actin. In addition, the activation of Rac1 by serum, but not that of RhoA or ARF6, was inhibited in cells over-expressing GAP273, suggesting that Rac1 is a likely downstream effector of ARFGAP1. The carboxyl terminal 65 residues of ARFGAP1 were sufficient to produce the effects on actin and cell spreading in transfected cells and co-localized with cortical actin foci.ARFGAP1 functions as an inhibitor upstream of Rac1 in regulating actin cytoskeleton. In addition to its GAP catalytic domain and Golgi binding domain, it also has an actin regulation domain in the carboxyl-terminal portion of the protein

TRAF4 is a novel phosphoinositide-binding protein modulating tight junctions and favoring cell migration

Tumor necrosis factor (TNF) receptor-associated factor 4 (TRAF4) is frequently overexpressed in carcinomas, suggesting a specific role in cancer. Although TRAF4 protein is predominantly found at tight junctions (TJs) in normal mammary epithelial cells (MECs), it accumulates in the cytoplasm of malignant MECs. How TRAF4 is recruited and functions at TJs is unclear. Here we show that TRAF4 possesses a novel phosphoinositide (PIP)-binding domain crucial for its recruitment to TJs. Of interest, this property is shared by the other members of the TRAF protein family. Indeed, the TRAF domain of all TRAF proteins (TRAF1 to TRAF6) is a bona fide PIP-binding domain. Molecular and structural analyses revealed that the TRAF domain of TRAF4 exists as a trimer that binds up to three lipids using basic residues exposed at its surface. Cellular studies indicated that TRAF4 acts as a negative regulator of TJ and increases cell migration. These functions are dependent from its ability to interact with PIPs. Our results suggest that TRAF4 overexpression might contribute to breast cancer progression by destabilizing TJs and favoring cell migration

The N-Terminal Amphipathic Helix of the Topological Specificity Factor MinE Is Associated with Shaping Membrane Curvature

Pole-to-pole oscillations of the Min proteins in Escherichia coli are required for the proper placement of the division septum. Direct interaction of MinE with the cell membrane is critical for the dynamic behavior of the Min system. In vitro, this MinE-membrane interaction led to membrane deformation; however, the underlying mechanism remained unclear. Here we report that MinE-induced membrane deformation involves the formation of an amphipathic helix of MinE2–9, which, together with the adjacent basic residues, function as membrane anchors. Biochemical evidence suggested that the membrane association induces formation of the helix, with the helical face, consisting of A2, L3, and F6, inserted into the membrane. Insertion of this helix into the cell membrane can influence local membrane curvature and lead to drastic changes in membrane topology. Accordingly, MinE showed characteristic features of protein-induced membrane tubulation and lipid clustering in in vitro reconstituted systems. In conclusion, MinE shares common protein signatures with a group of membrane trafficking proteins in eukaryotic cells. These MinE signatures appear to affect membrane curvature

Genetic Determinants of Cardiovascular Events among Women with Migraine: A Genome-Wide Association Study

Migraine is associated with an increased risk for cardiovascular disease (CVD). Both migraine and CVD are highly heritable. However, the genetic liability for CVD among migraineurs is unclear.We performed a genome-wide association study for incident CVD events during 12 years of follow-up among 5,122 migraineurs participating in the population-based Women's Genome Health Study. Migraine was self-reported and CVD events were confirmed after medical records review. We calculated odds ratios (OR) and 95% confidence intervals (CI) and considered a genome-wide p-value <5×10(-8) as significant.Among the 5,122 women with migraine 164 incident CVD events occurred during follow-up. No SNP was associated with major CVD, ischemic stroke, myocardial infarction, or CVD death at the genome-wide level; however, five SNPs showed association with p<5×10(-6). Among migraineurs with aura rs7698623 in MEPE (OR = 6.37; 95% CI 3.15-12.90; p = 2.7×10(-7)) and rs4975709 in IRX4 (OR = 5.06; 95% CI 2.66-9.62; p = 7.7×10(-7)) appeared to be associated with ischemic stroke, rs2143678 located close to MDF1 with major CVD (OR = 3.05; 95% CI 1.98-4.69; p = 4.3×10(-7)), and the intergenic rs1406961 with CVD death (OR = 12.33; 95% CI 4.62-32.87; p = 5.2×10(-7)). Further, rs1047964 in BACE1 appeared to be associated with CVD death among women with any migraine (OR = 4.67; 95% CI 2.53-8.62; p = 8.0×10(-7)).Our results provide some suggestion for an association of five SNPs with CVD events among women with migraine; none of the results was genome-wide significant. Four associations appeared among migraineurs with aura, two of those with ischemic stroke. Although our population is among the largest with migraine and incident CVD information, these results must be treated with caution, given the limited number of CVD events among women with migraine and the low minor allele frequencies for three of the SNPs. Our results await independent replication and should be considered hypothesis generating for future research

Elective Cancer Surgery in COVID-19-Free Surgical Pathways During the SARS-CoV-2 Pandemic: An International, Multicenter, Comparative Cohort Study.

PURPOSE: As cancer surgery restarts after the first COVID-19 wave, health care providers urgently require data to determine where elective surgery is best performed. This study aimed to determine whether COVID-19-free surgical pathways were associated with lower postoperative pulmonary complication rates compared with hospitals with no defined pathway. PATIENTS AND METHODS: This international, multicenter cohort study included patients who underwent elective surgery for 10 solid cancer types without preoperative suspicion of SARS-CoV-2. Participating hospitals included patients from local emergence of SARS-CoV-2 until April 19, 2020. At the time of surgery, hospitals were defined as having a COVID-19-free surgical pathway (complete segregation of the operating theater, critical care, and inpatient ward areas) or no defined pathway (incomplete or no segregation, areas shared with patients with COVID-19). The primary outcome was 30-day postoperative pulmonary complications (pneumonia, acute respiratory distress syndrome, unexpected ventilation). RESULTS: Of 9,171 patients from 447 hospitals in 55 countries, 2,481 were operated on in COVID-19-free surgical pathways. Patients who underwent surgery within COVID-19-free surgical pathways were younger with fewer comorbidities than those in hospitals with no defined pathway but with similar proportions of major surgery. After adjustment, pulmonary complication rates were lower with COVID-19-free surgical pathways (2.2% v 4.9%; adjusted odds ratio [aOR], 0.62; 95% CI, 0.44 to 0.86). This was consistent in sensitivity analyses for low-risk patients (American Society of Anesthesiologists grade 1/2), propensity score-matched models, and patients with negative SARS-CoV-2 preoperative tests. The postoperative SARS-CoV-2 infection rate was also lower in COVID-19-free surgical pathways (2.1% v 3.6%; aOR, 0.53; 95% CI, 0.36 to 0.76). CONCLUSION: Within available resources, dedicated COVID-19-free surgical pathways should be established to provide safe elective cancer surgery during current and before future SARS-CoV-2 outbreaks