Background
Few therapeutic options are approved as second‐line treatment after failure of platinum‐based chemotherapy for patients with extensive‐stage small‐cell lung cancer (ES‐SCLC). Topotecan ...widespread use remains challenged by the risk of severe toxicities in a pretreated population. Little is known about the efficacy and safety of epirubicin–paclitaxel doublet in second‐line and beyond and especially cerebral outcomes.
Methods
EpiTax is a retrospective multicenter observational real‐life study. We evaluated the efficacy of epirubicin 90 mg/m2 combined with paclitaxel 175 mg/m2 every 3 weeks in SCLC patients after failure of at least one line of platinum‐based chemotherapy. The primary endpoint was progression‐free survival (PFS). Secondary endpoints were overall survival (OS), objective response rate (ORR), disease control rate (DCR), intracranial control rate (ICR), and safety.
Results
A total of 29 patients were included. The median of previous systemic therapy lines was 2 (1–4). Eleven patients received the treatment in the second line. Characteristics of patients were a median age of 60 years (45–77), 65.5% of males with 72.4% of PS 0–1. Fifteen patients had a history of brain metastases. Median PFS and OS achieved 11.0 (95% CI, 8.1–16.3) and 23 (95% CI, 14.1–29.6) weeks, respectively. ORR was 34.5% and DCR was 55.2%. ICR was 3/15 (20%). Grade 3–4 adverse events were mainly hematological and concerned 7 patients. No case of febrile neutropenia or toxic death was reported.
Conclusion
Epirubicin–paclitaxel association highlighted promising efficacy with PFS and OS of 11 and 23 weeks, respectively, ORR of 34.5%, and a tolerable safety profile. This doublet could represent another valuable therapeutic option for ES‐SCLC patients treated in the second line and beyond.
In this real‐life study, we investigate the efficacy and safety of second‐line epirubicin‐paclitaxel regimen in 29 extensive‐stage small‐cell lung cancer (ES‐SCLC) patients. Our results highlight promising survival outcomes, significative systemic activity and favorable toxicity profile. This association seemed to be effective and could represent another valuable therapeutic option in a pre‐treated ES‐SCLC population.
Objective
Immune checkpoint inhibitors (ICIs) for cancer therapy frequently induce immune‐related adverse effects (IRAEs). Therefore, most patients with preexisting autoimmune diseases have been ...excluded from clinical trials of ICIs. This study was undertaken to evaluate the safety and efficacy of ICIs in patients with preexisting autoimmune disease and cancer.
Methods
A retrospective cohort study was conducted from January 2017 to January 2018 via 3 French national networks of experts in oncology and autoimmunity. Adults with preexisting autoimmune disease who were receiving ICIs were assessed for the occurrence of flare of preexisting autoimmune disease, other IRAEs, and cancer response.
Results
The study included 112 patients who were followed up for a median of 8 months. The most frequent preexisting autoimmune diseases were psoriasis (n = 31), rheumatoid arthritis (n = 20), and inflammatory bowel disease (n = 14). Twenty‐four patients (22%) were receiving immunosuppressive therapy at ICI initiation. Autoimmune disease flare and/or other IRAE(s) occurred in 79 patients (71%), including flare of preexisting autoimmune disease in 53 patients (47%) and/or other IRAE(s) in 47 patients (42%), with a need for immunosuppressive therapy in 48 patients (43%) and permanent discontinuation of ICI in 24 patients (21%). The median progression‐free survival was shorter in patients receiving immunosuppressive therapy at ICI initiation (3.8 months versus 12 months; P = 0.006), confirmed by multivariable analysis. The median progression‐free survival was shorter in patients who experienced a flare of preexisting autoimmune disease or other IRAE, with a trend toward better survival in the subgroup without immunosuppressant use or ICI discontinuation.
Conclusion
Our findings indicate that flares or IRAEs occur frequently but are mostly manageable without ICI discontinuation in patients with a preexisting autoimmune disease. Immunosuppressive therapy at baseline is associated with poorer outcomes.
Wild bees are declining, mainly due to the expansion of urban habitats that have led to land-use changes. Effects of urbanization on wild bee communities are still unclear, as shown by contrasting ...reports on their species and functional diversities in urban habitats. To address this current controversy, we built a large dataset, merging 16 surveys carried out in 3 countries of Western Europe during the past decades, and tested whether urbanization influences local wild bee taxonomic and functional community composition. These surveys encompassed a range of urbanization levels, that were quantified using two complementary metrics: the proportion of impervious surfaces and the human population density. Urban expansion, when measured as a proportion of impervious surfaces, but not as human population density, was significantly and negatively correlated with wild bee community species richness. Taxonomic dissimilarity of the bee community was independent of both urbanization metrics. However, occurrence rates of functional traits revealed significant differences between lightly and highly urbanized communities, for both urbanization metrics. With higher human population density, probabilities of occurrence of above-ground nesters, generalist and small species increased. With higher soil sealing, probabilities of occurrence of above-ground nesters, generalists and social bees increased as well. Overall, these results, based on a large European dataset, suggest that urbanization can have negative impacts on wild bee diversity. They further identify some traits favored in urban environments, showing that several wild bee species can thrive in cities.
Summary
The formation of biofilm results in a major lifestyle switch that is thought to affect the expression of multiple genes and operons. We used DNA arrays to study the global effect of biofilm ...formation on gene expression in mature Escherichia coli K‐12 biofilm. We show that, when biofilm is compared with the exponential growth phase, 1.9% of the genes showed a consistent up‐ or downregulation by a factor greater than two, and that 10% of the E. coli genome is significantly differentially expressed. The functions of the genes induced in these conditions correspond to stress response as well as energy production, envelope biogenesis and unknown functions. We provide evidence that the expression of stress envelope response genes, such as the psp operon or elements of the cpx and rpoE pathways, is a general feature of E. coli mature biofilms. We also compared biofilm with the stationary growth phase and showed that the biofilm lifestyle, although sharing similarities with the stationary growth phase, triggers the expression of specific sets of genes. Using gene disruption of 54 of the most biofilm‐induced genes followed by a detailed phenotypic study, we validated the biological relevance of our analysis and showed that 20 of these genes are required for the formation of mature biofilm. This group includes 11 genes of previously unknown function. These results constitute a comprehensive analysis of the global transcriptional response triggered in mature E. coli biofilms and provide insights into its physiological signature.
In the context of worldwide biodiversity and wild bee decline, it is increasingly important to better understand the effect of land-use changes on wild bee communities at a global scale. To do so, we ...studied the effect of city area and urban green spaces layout on wild bee species richness and community composition, as well as on wild bee species with an unfavorable UICN conservation status. This study was based on a large European dataset encompassing 20 cities from France, Belgium and Switzerland. We found a mean wild bee species richness in cities of 96 ± 48 (SD), showing that this species richness was highly variable among cities. The main factor positively influencing wild bee species richness in cities was the area of the city. Conversely, species richness was not significantly related to the total area of urban green spaces in a given city, measured as the spatial extent of urban parks, wastelands and other semi-natural habitats, excluding urban private gardens. Species with conservation status were quite scarce in urban environments, especially when compared to the European Red List of Bees, and we could not link their presence to either city or urban green space area. Dissimilarities in wild bee species community compositions were not associated with any of the studied characteristics of cities. We found that the dissimilarity of wild bee community composition among cities was mainly driven by the rarest species, as the most common ones were found in a majority of the cities sampled. Overall, these results emphasize that larger cities host more wild bee species, but are no refuge for the ones with concerning conservation status. Thus, stakeholders are encouraged to design their cities in favor of biodiversity to better support wild bee communities, and perhaps mitigate the established effect of the urban ecological filter.
Graphene nanoribbons (GNRs) have attracted strong interest from researchers worldwide, as they constitute an emerging class of quantum-designed materials. The major challenges toward their ...exploitation in electronic applications include reliable contacting, complicated by their small size (<50 nm), and the preservation of their physical properties upon device integration. In this combined experimental and theoretical study, we report on the quantum dot behavior of atomically precise GNRs integrated in a device geometry. The devices consist of a film of aligned five-atom-wide GNRs (5-AGNRs) transferred onto graphene electrodes with a sub 5 nm nanogap. We demonstrate that these narrow-bandgap 5-AGNRs exhibit metal-like behavior at room temperature and single-electron transistor behavior for temperatures below 150 K. By performing spectroscopy of the molecular levels at 13 K, we obtain addition energies in the range of 200–300 meV. DFT calculations predict comparable addition energies and reveal the presence of two electronic states within the bandgap of infinite ribbons when the finite length of the 5-AGNR is accounted for. By demonstrating the preservation of the 5-AGNRs’ molecular levels upon device integration, as demonstrated by transport spectroscopy, our study provides a critical step forward in the realization of more exotic GNR-based nanoelectronic devices.
Cytotoxic T lymphocytes (CTLs) and natural killer cells help control infections and tumors via a killing activity that is mediated by the release of cytotoxic granules. Granule secretion at the ...synapse formed between the CTL and the target cell leads to apoptosis of the latter. This process involves polarization of the CTL's secretory machinery and cytotoxic granules. The small GTPase Rab27a and the hMunc13-4 protein have been shown to be required for both granule maturation and granule docking and priming at the immunologic synapse. Using a tandem affinity purification technique, we identified a previously unknown hematopoietic form of Slp2a (Slp2a-hem) and determined that it is a specific effector of the active form of Rab27a. This interaction occurs in vivo in primary CTLs. We have shown that (1) Rab27a recruits Slp2a-hem on vesicular structures in peripheral CTLs and (2) following CTL-target cell conjugate formation, the Slp2a-hem/Rab27a complex colocalizes with perforin-containing granules at the immunologic synapse, where it binds to the plasma membrane through its C2 domains. The overexpression of a dominant-negative form of Slp2a-hem markedly impaired exocytosis of cytotoxic granules—indicating that Slp2a is required for cytotoxic granule docking at the immunologic synapse.
BACKGROUNDAfter lung transplantation (LT), early prediction of grade 3 pulmonary graft dysfunction (PGD) remains a research gap for clinicians. We hypothesized that it could be improved using ...extravascular lung water (EVLWi) and plasma biomarkers of acute lung injury.
METHODSAfter institutional review board approval and informed consent, consecutive LT recipients were included. Transpulmonary thermodilution-based EVLWi, plasma concentrations of epithelial (soluble receptor for advanced glycation endproducts sRAGE) and endothelial biomarkers (soluble intercellular adhesion molecule-1 and endocan full-length and cleaved p14 fragment) were obtained before and after LT (0 H0, 6, 12, 24, 48 and 72 hours after pulmonary artery unclamping). Grade 3 PGD was defined according to the International Society for Lung and Heart Transplantation definition, combining arterial oxygen partial pressure (PaO2)/inspired fraction of oxygen (FiO2) ratio and chest X-rays. Association of clinical risk factors, EVLWi and biomarkers with grade 3 PGD was analyzed under the Bayesian paradigm, using logistic model and areas under the receiver operating characteristic curves (AUCs).
RESULTSIn 47 LT recipients, 10 developed grade 3 PGD, which was obvious at H6 in 8 cases. Clinical risk factors, soluble intercellular adhesion molecule-1 and endocan (both forms) were not associated with grade 3 PGD. Significant predictors of grade 3 PGD included (1) EVLWi (optimal cutoff, 13.7 mL/kg; AUC, 0.74; 95% confidence interval CI, 0.48-0.99), (2) PaO2/FiO2 ratio (optimal cutoff, 236; AUC, 0.68; 95% CI, 0.52-0.84), and (3) sRAGE (optimal cutoff, 11 760 pg/mL; AUC, 0.66; 95% CI, 0.41-0.91) measured at H0.
CONCLUSIONSImmediate postreperfusion increases in EVLWi and sRAGE along with impaired PaO2/FiO2 ratios were early predictors of grade 3 PGD at or beyond 6 hours and may trigger early therapeutic interventions.
Accidental dural puncture is an uncommon complication of epidural analgesia and can cause postdural puncture headache (PDPH). We aimed to describe management practices and outcomes after PDPH treated ...by epidural blood patch (EBP) or no EBP.
Following ethics committee approval, patients who developed PDPH after accidental dural puncture were recruited from participating countries and divided into two groups, those receiving EBP or no EBP. Data registered included patient and procedure characteristics, headache symptoms and intensity, management practices, and complications. Follow-up was at 3 months.
A total of 1001 patients from 24 countries were included, of which 647 (64.6%) received an EBP and 354 (35.4%) did not receive an EBP (no-EBP). Higher initial headache intensity was associated with greater use of EBP, odds ratio 1.29 (95% confidence interval 1.19–1.41) per pain intensity unit increase. Headache intensity declined sharply at 4 h after EBP and 127 (19.3%) patients received a second EBP. On average, no or mild headache (numeric rating score≤3) was observed 7 days after diagnosis. Intracranial bleeding was diagnosed in three patients (0.46%), and backache, headache, and analgesic use were more common at 3 months in the EBP group.
Management practices vary between countries, but EBP was more often used in patients with greater initial headache intensity. EBP reduced headache intensity quickly, but about 20% of patients needed a second EBP. After 7 days, most patients had no or mild headache. Backache, headache, and analgesic use were more common at 3 months in patients receiving an EBP.
By means of the SAETTA 3D lightning mapping array, the total lightning activity has been detected in a 240 km × 240 km square domain centred on the island of Corsica located in the West Mediterranean ...basin, and characterized by a maritime and mountainous environment, with a complex and relatively high relief. The study period covers the months from April to December of the 6 years from 2014 to 2019. Observations are reported with a horizontal resolution of 1 km and a vertical resolution of 0.1 km in terms of density of VHF sources emitted by lightning, and of number of lightning day, in plane- and vertical- projections. Vertical distributions of VHF sources are also provided monthly for the whole period and over the full domain. These 3D long term observations show that the number of lightning days is more important on the main relief of the island. The density of VHF sources exhibits a sharp maximum over the confluence area of the 3 main valleys in the center of the northern part of the island, characterized by a recurrent and vertically well developed lightning activity. The period from 11:00 UTC to 14:00 UTC in July, and in a lesser extent in June and August, is at the origin of this density maximum. This behavior is thus due to a diurnal convection. The whole lightning activity is characterized by 2 maxima in June and September. The first one is linked with the diurnal convection in phase with the maximum elevation of the Sun. The second one must be due to usual large-scale organized thunderstorm events of the fall season. The vertical distribution of VHF sources exhibits an increase in the number of VHF sources from April to August at all altitudes, as well as an increase in the altitude of the main upper peak (from 5.8 km to 10 km) and of the secondary lower peak (from 4.2 km to 6.7 km) of this distribution. From August to December, the opposite evolution appears, except that October is characterized by a strong anomaly with a single intense lower peak at 5.5 km, apparently due to 2 strong events corresponding to anomalously electrified thunderstorms. Several of these anomalously electrified thunderstorms (negative dipoles) are reported. They are all characterized by the movement of cloud cells spatially small and relatively undeveloped vertically propagating from southwest to northeast and associated with a strong transport of desert dust from the African continent. The analysis of the meteorological environment of some of the studied events allows concluding that in each of the studied cases elevated convection was triggered, above the relatively dry atmospheric boundary layer characterized by a strong convective inhibition. The low cloud liquid water content which is a key parameter of the non-inductive charging process is probably a good candidate to explain the anomalous electrification of these events.
•First 3D lightning climatology in a maritime and mountainous region.•Maximum of lightning activity mainly due to spring diurnal convection between 11:00 and 14:00 UTC.•The most intense lightning activity is located at the crossroads of the 3 main valleys.•Occurrences of anomalously electrified thunderstorms correspond to southern flows with strong transport of African dust•Convection of anomalously electrified thunderstorms triggered above the boundary layer with strong convective inhibition
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